Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease

The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am in 100% agreement with the CMS decision that Medicare NOT pay for Aduhelm and other similar drugs except in good clinical trials that use actual measures of effectiveness. As a retired physician as well as caretaker of a [PHI Redacted] who lived with dementia for 12 years, I was appalled at the FDA decision to approve this drug in the face of a lack of evidence for its clinical effectiveness. There is essentially no good evidence that this drug helps. In fact the FDA advisory panel recommended against it and a number of the members even felt compelled to resign over the FDA final approval despite their recommendation. I remind you that there is not even good evidence that decreasing amyloid (on which this approval was based) actually is associated with clinical improvement, and there are significant side effects. There are many better ways for Medicare to spend this inordinate amount of money on helping patients and families with dementia, especially home health care and support, as well as other medical issues in senior patients, than on a drug for which there is no good evidence that it works.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Regarding: National Coverage Analysis (NCA) Proposed Decision Memo: Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease CAG-00460N

I compliment CMS on the thoughtful analysis in the proposed National Coverage Analysis (NCA), “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease [CAG-00460N],” but I hope it will take into consideration the following comments for the final coverage determination.

My background, qualifications, and conflict-of-interest statement

I am a board-certified neurologist with subspecialty training (United Council for Neurologic Subspecialties-accredited fellowship) in geriatric neurology. I am an assistant professor of neurology at the Albert Einstein College of Medicine and have a full-time clinical practice at Montefiore Medical Center. I work at our multidisciplinary Memory Disorders Center and at our Center for the Aging Brain, where I am the Site Director for Education. We exclusively care for older adults with cognitive impairment & dementia and their families. The below represents my personal opinions and in no way represents the views of my academic institution, medical center, department, center, or colleagues.

My [PHI Redacted] had Alzheimer disease dementia, and my work hopefully honors his memory.

I have no financial conflicts of interest. Neither I nor my immediate family members own or have owned stock in Biogen, Eisai, or competing pharmaceutical companies. Neither I nor my immediate family members have accepted money (including speaker fees) or gifts from Biogen, Eisai, or competing pharmaceutical companies. I have not done research supported by Biogen or Eisai. Given recent reports of potential financial conflicts of interest by the Alzheimer’s Association [https://www.alz.org/media/Documents/PharmaCompaniesOver10k-FY21.pdf ; https://www.medscape.com/viewarticle/947047], and potential inappropriate contact between Biogen and regulators at FDA [https://www.washingtonpost.com/health/2021/07/09/aduhelm-new-alzheimers-drug-hhs-inspector-general/], I urge CMS to consider the incentives of those lobbying for or against certain actions.

General comments on the NCA

Aducanumab was approved by the US Food and Drug Administration under an Accelerated Approval Pathway based on a surrogate endpoint, specifically improvement in brain amyloid as measured by amyloid PET, and not based on clinical efficacy [https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/aducanumab-marketed-aduhelm-information]. The merits and demerits of this action may be debated, but FDA approval alone does not entitle the approved item to Medicare coverage; CMS operates under a different regulatory standard. CMS approval must be based on whether it is “reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member for the affected Medicare beneficiary population…” There is no clear evidence that aducanumab is reasonable or necessary for the treatment of Alzheimer disease. While a decision by CMS to not cover the medication at all may adhere closest to CMS’s mandate, approval only as part of a study demonstrating efficacy is prudent given the small but present clinical uncertainty regarding aducanumab’s risks and benefits.

Aducanumab data

There have been no published, peer-reviewed articles on the efficacy of aducanumab beyond preliminary, phase-1 trial data. There have been no phase-2 trials of aducanumab, published or unpublished. Most of the available data on aducanumab comes from post-hoc analyses of two identically-designed phase-3 clinical trials, whose results are known only from industry release and from FDA documentation. Both phase-3 trials were terminated early by the sponsor due to lack of efficacy. Data collection continued, and after re-evaluation one of the studies was determined to be positive and one determined to be negative.

The “positive” trial showed statistically significant improvement in cognition among those who received the highest dose of the medication compared to placebo. Protocol changes had been made resulting in dosage changes during the study for many participants, and the outcomes for a large proportion of study participants, who received lower doses, were disregarded altogether. The statistically significant benefits are well below the established minimal clinically important differences (MCID) for these outcomes. That is, the differences in outcomes between the high-dose and placebo groups are so small that patients, their caregivers, and their doctors would not be expected to notice any change. My patients care about being able to go to the bathroom by themselves, not p values.

For the primary outcome, the Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB), the difference in decline between the two groups was 0.39 points. The MCID for the CDR-SB is 1-2 points [Andrews JS, Desai U, Kirson NY, Zichlin ML, Ball DE, Matthews BR. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials. Alzheimers Dement (NY). 2019;5:354-363. Published 2019 Aug 2. doi:10.1016/j.trci.2019.06.005]. That is, even if the medication were twice as effective, it would still be a clinically meaningless change. Patients’ daily function got worse, whether or not they got the medication or placebo.

A secondary outcome, the Mini-Mental State Exam (MMSE), is a measure of cognition. Participants who got the highest dose of aducanumab declined 0.6 points less than those who got placebo. While statistically significant, the medication would need to be more than twice as effective to have a noticeable and meaningful change in this population given a MCID of 1.3-2.3 points [Andrews JS, Desai U, Kirson NY, Zichlin ML, Ball DE, Matthews BR. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials. Alzheimers Dement (NY). 2019;5:354-363. Published 2019 Aug 2. doi:10.1016/j.trci.2019.06.005 ; Burback D., Molnar F.J., St John P., Man-Son-Hing M. Key methodological features of randomized controlled trials of Alzheimer's disease therapy. Minimal clinically important difference, sample size and trial duration. Dement Geriatr Cogn Disord. 1999;10:534–540]. Another secondary outcome, the ADAS-Cog 13, also showed a statistically significant but clinically meaningless benefit, 0.7-point difference compared to an MCID of 3 points [Schrag A, Schott JM; Alzheimer's Disease Neuroimaging Initiative. What is the clinically relevant change on the ADAS-Cog? J Neurol Neurosurg Psychiatry. 2012 Feb;83(2):171-3. doi: 10.1136/jnnp-2011-300881. Epub 2011 Oct 21. PMID: 22019547]. The final secondary outcome, the ADCS-ADL-MCI, does not have a clearly established MCID but the statistically significant difference between aducanumab and placebo was small. Will this medication keep my patients from getting worse? No, unless one has very skewed beliefs on the meanings of “keep” and “worse.”

Where is the amyloid PET data, which formed the basis for approval? It was not a primary or secondary endpoint. A subset of participants received the PET scans. There was a time- and dose-dependent reduction in amyloid as measured by PET in those who received aducanumab. However, there was no significant relationship between change in amyloid PET and cognition.

This was the positive study. What about the negative study? This identically-designed study, with similar participants and protocol changes, showed no statistically or clinically significant improvement on any primary or secondary outcome in those who received aducanumab. The medication did improve participants’ amyloid PET scans, but again there was no correlation with cognitive or functional improvement. Pictures got better but people did not. I take care of people and their families. I do not take care of pictures.

Though there is no evidence of clinical benefit, we have considerable evidence of harm from this medication. 41% of those participants who received high-dose aducanumab developed amyloid-related imaging abnormalities (ARIA), which is swelling of or bleeding in the brain. 21% of participants receiving aducanumab developed headache, 15% had falls, 9% diarrhea, and 8% had confusion or change in mental status even in the absence of ARIA. One participant was reported to have died from medication side effects [https://www.nytimes.com/2021/11/22/health/aduhelm-death-safety.html]. Other anti-amyloid antibodies have different side effect profiles, but there must be clearly established benefit that outweighs the risk for any medication to be reasonable and necessary.

Specific commentary on the NCA

Decision to treat anti-amyloid monoclonal antibodies as a class: While aducanumab is the only anti-amyloid antibody currently approved, several other pharmaceutical companies are trying to get FDA approval for their medications based on the same accelerated approval pathway, without clinical evidence of improvement in cognition or function. CMS Evidence Table 1 [“Individual Phase-3 RCTs of monoclonal antibodies versus placebo in Alzheimer’s Disease: Summary-level information”] clearly shows the lack of clinical benefit among this class of medications, and they fare no better in meta-analysis [Ackley SF, Zimmerman SC, Brenowitz WD, Tchetgen Tchetgen EJ, Gold AL, Manly JJ, Mayeda ER, Filshtein TJ, Power MC, Elahi FM, Brickman AM, Glymour MM. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021 Feb 25;372:n156. doi: 10.1136/bmj.n156. PMID: 33632704; PMCID: PMC7905687]. It is not reasonable and necessary to use aducanumab or other anti-amyloid antibodies to treat Alzheimer disease based on current data, regardless of subtle difference in mechanism or biomarker. Treating these medications as a class allows for a proper determination of “reasonable and necessary” if they are to be approved without this evidence. This protects patients and provides clarity to their families.

Coverage with Evidence Development only in randomized controlled trials: I interpret the phase-3 trials as demonstrating evidence of lack of benefit. One might interpret them as showing lack of evidence of benefit. Even though the pharmaceutical company itself decided on the participants to enroll, the outcomes, the changes in study protocols, and the premature termination of the trials, it is possible that were the studies conducted properly, they might have shown a different outcome. Unlikely, but possible. Given the devastating impact of Alzheimer disease on patients in this country and around the world, the generous approach to facilitate more trials by CMS is reasonable.

Inclusion of amyloid PET coverage in such trials: This is an important feature of the NCA as it increases the probability that participants in Alzheimer disease treatment trials actually have Alzheimer disease pathology. Clinical diagnosis of Alzheimer disease without biomarker support is insufficiently sensitive and specific [Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol. 2012 Apr;71(4):266-73. doi: 10.1097/NEN.0b013e31824b211b. PMID: 22437338; PMCID: PMC3331862], and may obscure the effects of a medication. Improving access to amyloid PET may allow participation of those who would otherwise be hesitant to participate were a lumbar puncture be required to confirm amyloid status. Not covering repeat PET is reasonable, but perhaps consider exceptions for those whose prior PET had an indeterminate result based on SUVR. Amyloid PET results dichotomize a continuous variable, and those close to the cutoff may later have a clearly positive test.

Allowing randomized controlled trials to be extended to prospective longitudinal studies: Alzheimer disease is chronic and progressive, with most patients living more than seven years after diagnosis [Armstrong RA. Factors determining disease duration in Alzheimer's disease: a postmortem study of 103 cases using the Kaplan-Meier estimator and Cox regression. Biomed Res Int. 2014;2014:623487. doi:10.1155/2014/623487]. Long-term extensions answer many important questions that shorter randomized controlled trials cannot, while balancing the need for faster answers for patients and their families.

Clinically meaningful benefit in cognition and function: This is the key stipulation of the trials. Statistically significant but clinically meaningless outcomes do not help patients or families. The trials should specify ahead of time the MCID for each outcome of interest and should specify ahead of time how these outcomes will be analyzed.

Patients must not have any neurological or other medical condition (other than Alzheimer disease) that may significantly contribute to cognitive decline: Comorbid brain diseases (e.g., vascular dementia or Lewy Body dementia) are common, as mentioned in the NCA. “Autopsy studies support that less than 20 percent of persons with AD have “pure” AD (no mixed pathology)…” Would CMS want to exclude 80% of those with Alzheimer disease from these trials? Heart disease and many other ailments that can affect cognition are also common among Medicare recipients who have Alzheimer disease. While inclusion criteria are necessary to identify the effectiveness of a study medication, overly restrictive inclusion/exclusion criteria reduce the applicability of study results to real-world patients and also hamper participant recruitment. 92% of Medicare beneficiaries would not have been eligible for the initial phase-3 trials of aducanumab, and 77% of beneficiaries met >=2 exclusion criteria [Anderson TS, Ayanian JZ, Souza J, Landon BE. Representativeness of Participants Eligible to Be Enrolled in Clinical Trials of Aducanumab for Alzheimer Disease Compared With Medicare Beneficiaries With Alzheimer Disease and Mild Cognitive Impairment. JAMA. 2021 Sep 9. doi: 10.1001/jama.2021.15286. Epub ahead of print. PMID: 34499725]. Separately, Alzheimer disease is very common among those with Down Syndrome [Bayen E, Possin KL, Chen Y, Cleret de Langavant L, Yaffe K. Prevalence of aging, dementia, and multimorbidity in older adults with down syndrome. JAMA Neurol. 2018;75(11):1399-1406]. As written, the NCA would preclude CMS coverage of aducanumab for studies involving people with Down Syndrome. CMS should consider easing this restriction.

Public release of all prespecified outcomes, even if the study is negative or terminated early: Results must be made public in order for clinicians, scientists, administrators, regulators, and others to understand these medications and future related medications.

The study must discuss subpopulations, including traditionally underrepresented groups in clinical studies, and plan for the retention and reporting of said populations in the trial: The phase-3 trials were not representative of the Medicare population. In the “positive” trial, only four African American participants (0.4%) received high-dose study medication. Only 4% were Hispanic. Most of the Asian participants were recruited at trial sites in Asia and were not Asian American. For reference, most of my patients are from the Bronx, NY. Our county is 44% African American and 56% identify as Hispanic [US Census]. Race is a social construct, not a biological one, but social determinants of health disproportionately affect certain groups so may change risks and benefits associated with various medications. I applaud the inclusion of this stipulation

Other comments on the NCA and reactions to it

As a taxpayer, the idea that CMS will subsidize studies to see if medications work after they are approved without sufficient evidence is odious. If the medication is ultimately approved, do taxpayers get our money back from the pharmaceutical company that makes hundreds of millions of dollars in profit? I understand the unique and unfortunate position CMS is in for this class of medication, but it is not something that should establish precedent.

If the Alzheimer’s Association and other groups are concerned about disproportionate harms of the CMS decision on underrepresented and disadvantaged groups , they should have been equally concerned about the lack of representation in the original trials. Limiting access to a medication that may have more harms than benefits does not exaggerate health inequities. The draft decision specifically requires that a representative population be studied.

No one “deserves” access to medications that cause more harm than benefit. When evaluating a patient with a papercut, I should not discuss amputation as a possible alternative to soap, water, and an elastic bandage. CMS has a mandate to determine what is reasonable and necessary. If there is insufficient evidence, CMS should not cover the medication. Barring this, we should get the best evidence possible. The draft decision, with minor modification, will help get the best evidence possible.

I appreciate the careful consideration of this issue and my comments by CMS.

Sincerely, Jason Cohen, MD

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I strongly support the proposed CMS decision when it come to Medicare covering Aduhlem only in clinical trial settiings. Please follow their recommendation and not the lobbying points of the pharmaceutical industry.

Alzheimer's patients need services that support their ability to carry out daily activities of life. They deserve to be protected from drugs that have harmful side effects. The evidence is missing that this monoclonal antibody is benefitting patients which means you should heed the recommendation from CMS at this time. Don't fund a drug that doesn't work.

Thanks for your consideration.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefited Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

Less

The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I strongly urge reconsideration of the proposed National Coverage for aducanumab for the following reasons:

1) There is reasonable evidence suggesting a clinical benefit in slowing symptomatic and functional decline which is supported by biomarker findings and initial results of similar drugs in it's class that are currently in clinical trials
2) The published data indicate that the potential adverse effects of the drug ( ARIA) can be safely managed with proper surveillance
3) The current proposed policy promotes inequality of access — only those who can afford the medication out of pocket or who participate in a clinical trial as proposed ( which are historically not representative of the national population diagnosed with Alzheimer's disease)

The CMS proposal seems based on a biased and inaccurate representation of basic science and clinical presentation of Alzheimer's disease, the role of amyloid in pathophysiology of the disease, and recent findings related to current anti-amyloid agents. Moreover, the proposal to require participation in a randomized clinical trial is fraught with difficulties and does not help accelerate the availability of a possible disease modifying medication to those who could benefit from it.

As a clinician who treats Alzheimer's disease on a daily basis, I have great respect for the autonomy of these patients and their ability to assess information we provide them about the risks and potential benefits of aducanumab and make a decision which is best for them. My MCI patients with Alzheimer's disease ( 10-15% of whom will progress to dementia in a year) and who understand that there is disagreement in the field about the degree of effectiveness of aducanumab, should have the opportunity to take the drug. My suggestion would be to create a CED program more like a national registry where appropriate patients based on the prior clinical trials will have access to aducanumab and data can be collected in an organized manner to gain the further knowledge about safety and efficacy in a more representative population.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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By way of background, I am a neurologist who specializes in dementia. I have been involved in many clinical treatment trials for Alzheimer’s disease (AD) over the last 30+ years. I have also been involved in many studies of the mechanisms underlying AD. I direct a large group of investigators.

In my opinion, the anti-amyloid antibodies, as a class, are useful for slowing the progression of AD. Six were positive in Phase II trials. And one, aducanumab, was positive, in two Phase III trials. It slowed progression by 20-40% cognitively, 40% in terms of activities of daily living, and 87% in terms of neuropsychiatry symptoms. Phase III trials of 3 other antibodies should be completed later this year.

For people with AD, and their loved ones, this class of medication is a great cause for hope until a cure is found. In the meantime, withholding these medications from the million Americans with MCI is, in my opinion, a great cause for consternation and for loss of the hope that keeps them going.

Requiring that these medications undergo a CMS approved, placebo-controlled, clinical trial mean that probably 1% of currently eligible patients will get these medications. 99% will be left to pray for something to be positive before it is too late for them.

In summary, I beseech you to please reconsider your draft opinion and open this class of medications to many more patients who are experiencing the very real and very frightening prospect of losing their minds over the next few years while they await an approved treatment.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

Less

The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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As a former caregiver for my [PHI Redacted] who had AD, I FULLY support and applaud CMS’s decision regarding the approval of Aducanumab only in clinical trials. I have been following discussions amongst hundreds of doctors and researchers regarding this medication and I am appalled that the FDA approved it when the efficacy is VERY questionable, the costs are outrageous, and dangers to patients exist. I am outraged by Biogen’s efforts to ram this through and their recent threats to sue. HOW DARE THEY!!!!

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.
While I encourage the FDA to pursue treatments for Alshaimer's disease, I do not approve circumventing standard and necessary safety procedures long established by the CDC. Recently there has been almost a war on the integrity and scientific accuracy of the drug approval process. The CMS is not allowed to do this. We have to follow protocol until clear scientific evidence support the approval of any drug.

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Friends,
The FDA's ill-advised decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged. These perilous days, we can't afford this.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program. We seniors deserve better.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am writing to applaud the Centers for Medicare and Medicaid Services (CMS) for their proposed national coverage decision regarding “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease” issued on January 11, 2022. I am a practicing physician and, like many other clinicians, I was deeply disturbed by the Food and Drug Administration’s (FDA) recent decision to approve the Alzheimer’s disease drug, aducanumab, despite the significant lack of evidence regarding its efficacy as well as concerns about the drug’s safety. While the FDA has defended this decision by noting that they granted accelerated approval to aducanumab, which only requires the drug to demonstrate an effect on a surrogate marker thought to be predictive of clinical benefit, the agency has failed to note that the particularly surrogate marker underpinning aducanumab’s approval – that of beta-amyloid seen on MRI scans of the brain – has failed in over two dozen clinical trials to show any association with clinically meaningful changes in Alzheimer’s disease patients. Expensive treatments should not be promoted on the basis of surrogate markers that have unproven clinical effects.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021.

Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program. Medicare recipients should not be forced to pay for this potentially useless drug. You are charged with helping to protect Medicare for all Americans; please do your job and halt this approval. This is an urgent request! Thank you.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a disregard for science and ignored the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been gravely damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Hello,
My name is Shia Harger and I live in Wisconsin. My [PHI Redacted] was born last year and surprised us with an extra chromosome (Down syndrome). As I have learned more about his disability and how best to prepare for his future, it's so important to me that he has access to any treatments that will be developed in the future. I strongly believe that CMS should not move forward with any coverage process that excludes people with Down syndrome and other disabilities. If people on Medicare or Medicaid without disabilities can access new treatments, people with disabilities who are covered should have the same access. Please reconsider your current proposal to not exclude individuals with intellectual and developmental disabilities now and into the future.
Thank you,
Shia Harger

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I was bothered by the Food and Drug Administration’s highly questionable decision to approve Aduhelm for treatment of Alzheimer’s disease. It showed a disregard for science and violated the agency’s standards for approving new drugs. Because of this action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefited Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility. Aduhelm should not be approved

CMS should not act to compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Because of the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. In 2022, Medicare Part B premiums are increasing by $21.60 per person per month. That price increase is due almost entirely to the ridiculously higjh price of a single drug: Aduhelm and amounts to a tremendous burden on all people paying for Medicare

I urge that CMS issues a determination that excludes Aduhelm from coverage under the Medicare program.

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I am responding to the upcoming decision of the use of Monoclonal Antibodies for Alzheimer’s. I would like to make the following suggestions to modify the report decision:

The drug be covered for all patients that fit the criteria listed in the research study and follows the protocol that was done in the study.
The drug should only be administered by clinics that are accredited~ not just hospital based~ it should be enough that they were either part of the study or adhere to the same guidelines.
The drug should be stopped it it shows any sign of brain injury (ARIA) just like in the study.
Unlike the study, the clinicians evaluate the patients every year for outcome measures and if the patient is declining that the drug be stopped, or at a minimum the drug coverage by Medicare / CMS no longer be covered.
I believe these compromises will effectively support care and research in the area of Alzheimer’s.

Regards,

Judy Lundgren
1033 Liberty Drive
Clarkston WA 99403
208-791-9315

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Global Alzheimer’s Platform Foundation Comment

CMS Draft National Coverage Determination
Monoclonal Antibodies Directed Against Amyloid for the
Treatment of Alzheimer’s Disease
February 10, 2022

Mr. Secretary and Madame Administrator:

Thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services’ (CMS’s) proposed National Coverage Determination (NCD). The Global Alzheimer’s Platform Foundation (GAP) is a patient centered organization dedicated to accelerating clinical trials to discover cures or treatments for Alzheimer’s. In furtherance of our mission, GAP has undertaken12 advanced Alzheimer’s disease (AD) clinical trials since 2019. GAP intends to comment on the life threatening and unprecedented NCD proposed by CMS on January 11, 2022.

GAP will summarize its position as follows:

1. The Food and Drug Administration’s (FDA) use of the accelerated approval pathway (AAP) to approve Aduhelm for the treatment of AD was an informed and appropriate exercise of the authority vested in the FDA by Congress.
2. The NCD proposed by CMS is an unprecedented and capricious effort to regulate drugs in a manner that invades the FDA’s jurisdiction, violates CMS’s own regulations and long-standing practices, and denies more than a million potential patients’ coverage to label for the first approved therapy for AD in 20 years.
3. The Coverage with Evidence Development (CED) which proposes limiting coverage to a randomized clinical trial (RCT) for approximately1,500 patients will delay access to Aduhelm or any other mAbs for millions of patients up to 12 years allowing more than 3 million AD patients to progress in this fatal disease to a point where Aduhelm (or any other mAbs) will be unavailable to provide clinical benefit.
4. The NCD’s fatal impairments are outrageously amplified by requiring all monoclonal antibodies (mAbs) directed against amyloid for the treatment of Alzheimer’s disease to run the same arbitrary RCT gauntlet
5. Any other form of CED purportedly designed to collect evidence of safety or efficacy, such as a registry, will essentially be a pretext for restricting access to mAbs to a few thousand patients and take several years to stand up based on CMS’ documented chronic underperformance in these endeavors.
6. Therefore, GAP calls on Secretary Becerra and Administrator Brooks-LaSure to rescind the NCD and revert to CMS’s long-standing practice of coverage to label for a drug which was approved by the FDA pursuant to the AAP— thereby giving AD patients, in consultation with their families and physicians, the option to avail themselves of disease modifying therapies that can slow the progression of this heinous and always fatal disease.

Our concerns regarding the NCD and our rationale for urging CMS to provide coverage to label for the class of drugs in question is below.

The FDA decision to approve Aduhelm pursuant to the accelerated approval pathway was appropriate under the law and good for AD patients.

On June 7, 2021, the FDA gave accelerated approval to Aduhelm, a Biogen drug for reducing beta-amyloid plaque in the brain to slow the progression of Alzheimer's disease. This disease modifying drug is the first FDA approved drug for Alzheimer’s patients in over 20 years—giving newfound hope to people living with Alzheimer’s and their families. They did this pursuant to their authority to accelerate approvals for treatments that address life threatening conditions that otherwise do not have approved treatments. Under FDA’s accelerated approval pathway, the FDA may approve a drug that affects changes in a surrogate endpoint adequate to convince the FDA that it is “reasonably likely…to predict clinical benefit.”¹

Since 1992, the FDA has used the AAP to approve over 270 drugs attacking cancers, HIV and a number of other indications devoid of therapies with patient populations facing certain death as a result². The reasonable likely standard is intended to convey a lower standard of proof of efficacy; thus, a confirmatory trial is required. From a patient’s perspective, Congress has decided that when the data is a close question in life threatening cases, the tie goes to patients.

There is no doubt the approval of Aduhelm was controversial³ and not support by the Advisory Committee that reviewed Biogen’s application. Commentators point out that accelerated approval was not presented to the Committee, and new evidence from Lilly and Eisai from their drugs in this class augmented Biogen’s data supporting beta-amyloid as a surrogate endpoint. Ultimately, the sole authority to approve Aduhelm based on the degree to which it reduced beta amyloid plaque in AD patients was the FDA’s. GAP firmly believes that this decision was well grounded, reasonable, and overwhelming good for patients.

The proposed NCD is a discriminatory, unprecedented breach of CMS’ regulations and past practices with respect to FDA approved drugs. Consequently, it threatens to deprive AD patients of Aduhelm as well as similar therapies in the future and allow millions of AD patients’ conditions to progress unabated.

If this NCD is finalized as drafted, then Alzheimer's patients will receive the most restrictive NCD for a drug in the history of the agency, as compared to a traditional coverage to label. This is one of many discriminatory and unwelcome firsts:

• This is the first time CMS has tried to overrule FDA on an accelerated approval.
• This is the first time CMS will breach its own regulations prohibiting the duplication of FDA clinical trial efforts or interfering with the FDA’s processes.
• This is the first time that CMS has opined on the cause of Alzheimer's disease, in conflict with the FDA and the research community generally.
• This is the first time CMS has issued an NCD-CED for an entire class of drugs.
• And this is the first time that CMS has prescribed an NCD requiring randomized clinical trials for drugs that will take over a decade to conduct as written.⁴ Moreover, to shed some light on some of the draft NCD’s hypocritical hyperbole regarding Aduhelm’s safety (and that of the unseen class), GAP reviewed drugs that were covered by CMS after receiving an accelerated approval from the FDA in the last 10 years. The results of the review show⁵:
• 75 drugs were approved through AAP from 2012-2022;
• All of them received CMS coverage;
• 24% or 18 of the 75 had a Black Box warning. (Aduhelm does not have a Black Box.)
• 9% or 7 of the 75 had a REMS. (Aduhelm does not have a REMS.)
• Currently, the annual prices of the 75 drugs range from a high of $2.57 million to a low of $336 (a vaccine.) The average annual price is $313,000.
• Aduhelm, at $28,200 is in the bottom quartile of the list of prices; 9th lowest of 75 drug prices.
• The vast majority of the patient populations for which the drugs in question could be prescribed were less than 20,00 (orphan indications.)
• Aduhelm was one of two indications with potential patients of more than 1 million.

In short, CMS issued a punitive, restrictive, and unprecedented NCD on a drug and its whole class. GAP’s research shows that Aduhelm (and by extension the class) is not an outlier on safety, in fact nearly 25% of the other drugs had far more serious safety profiles. And while not within CMS’ legal remit, Congress can rest easy that the price of this drug is in the bottom quartile of drugs covered in the last 10 years. So, if it’s not an issue of safety, and consistent biomarker evidence of clinical benefit was present among all 75 other drugs (all AAP approved), what is it that triggers CMS’ asymmetrical response to this drug class?

GAP thinks the facts show that CMS is refusing to do what is required of it because of the size of the patient population that could qualify for the drug. It is discriminating against AD patients because there are so many of them. For the first time in the history of the agency, the fact that more than a million patients could benefit from a drug has triggered a never-seen-before RCT based CED that would limit paid drug access to a few thousand patients. CMS is rationing AD patients’ care. It is an unconscionable policy that cannot stand.

The proposed NCD proposes a RCT structure that is designed to fail. It is fair to characterize it as an ornate duplication of FDA Phase 3 pivotal trials or Phase 4 confirmatory trials that will only succeed in blocking patients from obtaining access to mAbs that will slow the progression of their disease.

The NCD proposes a RCT that has been faulted as poorly conceived by groups that are both for and against the FDA approval of Aduhelm. Among the “consensus” elements that are most ill-advised about the RCT concept, are:

• The RCT duplicates protocol development and designs to measure clinical meaningfulness.
• The RCT will be executed by parties unaccustomed to conducting these kinds of clinical studies.
• Restricting the RCT to “outpatient hospital settings” will limit the network to roughly 50 tertiary locations.⁶
• Such locations historically are slow at activating and enrolling volunteers in RCTs, especially during Covid.
• Such locations historically underperform in recruiting diverse populations of participants in volume.
• The suggested exclusion and inclusion criteria were uninformed as well as inconsistent with emerging best practices for recruiting diverse populations.
• The RCT structure largely shuts out deployment to rural communities.
• The number of volunteers needed to populate the RCT would probably not exceed 1,500 and take over 10 years to conduct; resulting in about 1% of the patients that could benefit from Aduhelm receiving the drug during this time.⁷

In summary, the overwhelming majority of the AD community thinks the RCT concept is fatally flawed as proposed and unsalvageable given the time such an effort would require in redesign and execution. CMS should allow the FDA mandated Phase 4 confirmatory trial Biogen will start next month to play out, provide coverage to label while it does, and allow patients and their doctors an opportunity to avail themselves of this drug and the class below.

The NCD’s fatal impairments are outrageously amplified by requiring all monoclonal antibodies (mAbs) directed against amyloid for the treatment of Alzheimer’s disease to run the same arbitrary RCT gauntlet set out for Aduhelm.

It is hard to imagine that CMS, one of the crown jewel agencies of Health and Human Services (HHS), could conceive of such a bad idea as taking a whole class of drugs that offer 1,000,000 patients potential life extending therapies and place them in the same regulatory “tiger cage” that they built for Aduhelm, a structure that will constrict their availability for patients for more than 10 years.

The FDA has and will evaluate each drug application on its individual merits for safety and efficacy and determine whether it merits approval. It will derive a label for each drug to guide patients and physicians on the safe and appropriate use of the therapy.

In contrast, without reviewing the data or FDA decision, CMS intends to offer these approved drugs the same flawed RCT that is being roundly criticized by the AD community. This process will generate different standards and hurdles to coverage than the drug development field has ever seen before. It is inconsistent with CMS statutory authority, its regulations, and its mission to serve Medicare beneficiaries. It is, however a very effective way to ration care to AD patients, and patients with other diseases such as cancer, and it cannot stand.

Moreover, in conversations with CMS, the stakeholder community reports that CMS leadership has advanced a narrative that it will provide accommodations for FDA approved therapies, whether AAP approved or traditionally approved it is unclear, that will avoid the RCT quagmire. These musings talk about “expedited reconsiderations” for example without specificity, accountability, or enforceability. These are empty promises from an agency that prides itself on rigor. Especially when access to life prolonging therapies hangs in the balance.

If CMS, has serious alternative formulations for the class, they should have floated them in the NCD. GAP’s healthy skepticism is based on CMS’ past track record in reconsiderations. The field has waited nearly a year to learn if CMS’ NCD for coverage of BA PET images will be reconsidered. Then, we will wait a minimum of nine months until we learn whether CMS decides to consider the PET decision. Our data shows that on average a CMS reconsideration takes 678 days from the time it is taken up until the time it is decided.

A group of AD experts recently said:
“Every day, an estimated 1,000 people progress from mild AD to moderate AD. Because individuals with early-stage disease are most likely to benefit from therapeutic intervention with mAbs – and progression may make patients ineligible for treatment in the future – it is important to address these concerns quickly.”⁸

CMS needs to understand that 687 days means at least 687,000 AD patients could progress to a point where future therapies will not benefit them. Give AD patients coverage to label for the entire class. CMS cannot and will not guarantee patients a clear process that can possibly warrant this level of human devastation.

Any other form of CED purportedly designed to collect evidence of safety or efficacy, such as a registry, will only succeed in restricting access to mAbs to a few thousand patients and take several years to stand up based on CMS’ past performance in these endeavors.

It is axiomatic that science and clinical practice are improved with the accumulation and sharing of reliable clinical data. In stakeholder meetings with CMS, concepts were discussed regarding other means, such as a CED in the form of a registry, by which the agency might be able to meet its need for evidence of safety or efficacy outside the FDA mandated trials described above. GAP strongly discourages CMS from considering a registry or similar evidence gathering endeavor in the form of a CED that would substitute for the current RCT concept.

In GAP’s experience, there are several elements to a registry that affect their performance, including:

• Clear protocols defining how safety and benefit will be measured for the drugs being administered.
• Protocols need to be informed and consistent with the extensive benefit/risk discussions the drug sponsor(s) have had with drug approving agencies around the world.
• Keeping required data appropriately balanced for the clinical and financial burden on patients and practicing physicians so as not to create a deterrent to patients participating in the registry.
• Funding that will allow for creation and scaling of a “state-of-the-art” digital environment—in our estimation an AD registry will ultimately require $50-$100 million dollars.
• Interoperability with most of the leading electronic medical records (EMR), clinical trial data collection tools, and other registries.
• A registry design with flexibility to amend the protocol as needed to take advantage of new emerging technologies that will inform the field and CMS on how to more precisely detect AD and treat AD patients; and
• Generating an adequate pool of patients on a drug to recruit into a registry; GAP believes the field should target 100,000 patients.

GAP full throatedly supports the use of technology like that described above after a mAbs drug receives FDA approval and is covered to label. There are several important initiatives underway in the private and public sectors that represent a fertile opportunity for CMS to meet its evidentiary needs. We call on CMS to work collaboratively with these initiatives outside of a CED to catalyze the process and contribute to their deployment.

GAP does not support any registry or similar information gathering initiative that is undertaken under the guise of a CED. The AD field’s experience in the IDEAS studies demonstrates that CMS is not well organized to deploy these kinds of programs quickly or with the requisite adaptability to stay abreast of the science and technologies underpinning AD research. CMS should provide coverage to label for the whole mAbs class of drugs giving AD patients unfettered access to this class of drugs. CMS should access the robust pool of patients it will have catalyzed to collaborate with the private and public sector entities striving to achieve the same goal that CMS has articulated.

Conclusion:

For all the foregoing reasons, GAP calls on Secretary Becerra and Administrator Brooks-LaSure to rescind the NCD and revert to CMS’s long-standing practice of coverage to label for a drug which was approved by the FDA pursuant to the AAP— thereby giving AD patients, in consultation with their families and physicians, the choice of availing themselves of disease modifying therapies that can slow the progression of this heinous and always fatal disease.

1 U.S. Food and Drug Administration. CDER drug and biologic accelerated approval based on a surrogate endpoint. Updated December 31, 2021. Accessed February 7, 2022. https://www.fda.gov/media/151146/download.
2 Ibid..
3 FDA grants accelerated approval for Alzheimer’s drug. U.S. Food and Drug Administration. June 7, 2021. Accessed February 7, 2022. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug
4 Global Alzheimer’s Platform Foundation. Projected Timeline NCD/CED. February 2022.
5 Global Alzheimer’s Platform Foundation. Review of 75 Drugs Covered by CMS.
6 Based on the number of sites in national networks for clinical trials, including the National Institute on Aging-supported Alzheimer’s Clinical Trials Consortium and the Global Alzheimer’s Platform Foundations’ GAP-Net sites.
7 Based on an enrollment of approximately 1,500 in most commercial therapeutic and NIH-sponsored trials for AD and assuming some trial enrollees are on a placebo or in another non-mAb control arm.
8 Davis M, et al doi: 10.2174/1567205015666180119092427. PMID: 29357799; PMCID: PMC6156780.

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I applaud the CMS’ proposed decision to provide Coverage with Evidence Development (CED) for monoclonal antibody anti-amyloid treatments for Alzheimer’s Disease (AD), restricting coverage to individuals participating in a CMS-approved or NIH-funded randomized trial and requiring diverse study participants. This decision will provide access to safe and effective medications for CMS’ beneficiaries and advance us more quickly towards effective therapies for people with AD. The evidence for benefit of medications in this class is at best murky and discouraging. Evidence to date rules out the possibility that amyloid removal has substantial short-term benefits for a large fraction of people affected by AD. Due to the design of prior trials, we have not ruled out the possibility that either amyloid removal helps a small subgroup of individuals or amyloid removal has benefits that emerge only years after treatment initiation. Although speculative, neither of these possibilities are strictly ruled out by the evidence to date, and both are consistent with leading biological hypotheses about amyloid removal.

Given this, I hope CMS will preserve their preliminary decision with the following slight changes to their CED determination:

Although large studies entail extra expense, they are in the best interest of CMS beneficiaries. Without large studies, we would not be able to identify subgroups who might benefit while preserving fair type 1 error rates (i.e., we would be vulnerable to fluke findings of subgroup benefit). The potential value if even a small fraction of people with MCI or AD can benefit would far outweigh the short-term cost of a large trial.

The proposed alternatives to CED with a randomization requirement, such patient registries, clinical data research networks, observational claims analyses, are entirely inadequate to evaluate safety and efficacy of these medications. If these ‘real-world’ strategies are widely adopted, many patients will potentially be harmed and we will likely never learn about the efficacy of amyloid reduction strategies. If there is any promise in this therapeutic approach, we must learn exactly for whom that promise holds in order to build on it. The methods euphemistically entitle “real world evidence” will never be able to uncover the truth regarding who, if anyone, benefits. The CED with randomization requirement would foster innovation and progress towards effective treatments by providing solid evidence on which to build.

Thank you again for putting beneficiaries first. I hope this decision sparks the development of meaningful evidence about efficacy and safety.

Maria Glymour, ScD
Professor
Department of Epidemiology and Biostatistics, UCSF

Citations
1. Glymour MM, Mor V. A Large Pragmatic Trial is the Right Solution for Testing Anti-Amyloid Therapies for Alzheimer's Disease. J Am Geriatr Soc. 2022 Feb 6. doi: 10.1111/jgs.17695. Epub ahead of print. PMID: 35128639.
2. Ackley SF, Zimmerman SC, Brenowitz WD, Tchetgen EJ, Gold AL, Manly JJ, Mayeda ER, Filshtein TJ, Power MC, Elahi FM, Brickman AM. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021 Feb 25;372.
3. Manly JJ, Glymour MM. What the aducanumab approval reveals about Alzheimer disease research. JAMA neurology. 2021 Nov 1;78(11):1305-6.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am writing in support of the CMS proposal to restrict coverage of aducanumab or other anti-amyloid monoclonal antibodies for the treatment of Alzheimer’s disease to the setting of randomized controlled clinical trials under Coverage for Evidence Development. I am an epidemiologist who has worked on the safety of drugs used to treat neuropsychiatric conditions and am concerned that aducanumab poses unacceptable safety risks to vulnerable patients that are not counterbalanced by clinically meaningful benefits in delaying progression to severe dementia. The safety risks posed by this drug (Aduhelm) are not trivial and include brain inflammation. I urge CMS to adopt this proposal as their final national coverage determination to ensure that patients have access to truly effective medications where the benefits outweigh the safety risks.

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February 9, 2022

Tamara Syrek Jensen
Director, Coverage and Analysis Group Center for Clinical Standards and Quality Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Chiquita Brooks-LaSure Administrator
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N)

Dear Director Jensen and Administrator Brooks-LaSure,

The Balm In Gilead, on behalf of the College of Bishops of the Christian Methodist Episcopal Church (CME), the Board of Bishops of the African Methodist Episcopal Church (AME), the Bishops of The Church & Chief Officers of the African Methodist Episcopal Zion (AMEZ) Church & The Women’s Home and Overseas Missionary Society of the AME Zion Church, wish to express our appreciation for the opportunity to provide comment and feedback regarding the Centers for Medicare & Medicaid Services (“CMS” or the “Agency”) proposed National Coverage Determination (“NCD”) requiring Coverage with Evidence Development (“CED”) for monoclonal antibodies (“mABs”) targeting amyloid for the treatment of Alzheimer’s disease (“AD”).

For more than 33 years, The Balm In Gilead, Inc. has worked to build and strengthen the capacity of faith communities in the United States and in the United Republic of Tanzania (East Africa) to deliver programs and services that contribute to the elimination of health disparities, through the development and implementation of culturally tailored awareness and educational programs specifically designed to establish sustainable, integrated systems of public health and faith, which helps to improve health outcomes of individuals living in urban, rural, and remote communities. The Balm has developed an international reputation for providing insightful understanding of religious cultures, values and extraordinary abilities to build strong, trusted partnerships with faith communities throughout the world. In partnership with its African American Denominational Health Leadership Initiative (AADHLI) which represents more than 10 million members serving over 7000 congregations, The Balm launched its National Brain Health Center for African Americans (NBHCAA) to combat the growing challenges and disparities related to Alzheimer’s Disease and other related Dementias (ADRDs) among African Americans. The NBHCAA works with the faith community, public health, and other stakeholders to provide holistic and culturally sensitive awareness, education, advocacy, and support for persons living with ADRDs, their caregivers, and the community at large. Our firsthand, grassroots reach and connection to these congregations and communities cannot allow us to support the CMS NCD as it has been proposed.

As international organizations serving predominantly African and African American communities across the diaspora, we strongly encourage CMS to abandon its current proposal based on the following implications that would be harmful to African Americans and other minoritized communities:

1. Impacts on mAB Class of Drug Therapies:
The proposed NCD applies to the entire class of mAB drugs, which would impact both the currently FDA- approved mAB drug, aducanumab, as well as future drug therapies in this class. Given the regulatory governance granted to the FDA by Congressional order, this element of the NCD is over-reaching and creates a divisive relationship between two of the most critical federal agencies in the country. This decision would also require mAB drugs already in development, which may have different demographic and efficacy profiles, to be subjected to a CED process that lacks its own data and findings with regards to diversity, inclusion, and efficacy. Furthermore, it is slightly hypocritical of CMS to justify the implementation of its CED process on the basis of a lack of diversity in aducanumab trial data when it cannot show evidence that its own sponsored trials are significantly better at recruiting minorities. The precedent set by this CMS decision would have significant generational impacts on minoritized communities that would only magnify the existing disparities & inequities experienced by these populations. This should be alarming to CMS given that African Americans are twice as likely and Latinos/Hispanics are 1.5 times as likely to develop Alzheimer’s when compared to non-Hispanic White Americans.(i) In addition to the increased risks for ADRDs which are exacerbated by a disproportionate burden of chronic diseases, socioeconomic barriers, and systemic racism and mistreatment in today’s health system, these communities also face major gaps in access to Alzheimer’s diagnostics, treatments, and research. In fact, Black Americans are 35% less likely than Whites to be diagnosed during an initial visit with a physician. (ii) Further, patients of color frequently go without treatment until the later, more severe stages of the disease. (iii)

2. Exclusion of Persons Living with Chronic Conditions:
While we applaud and share CMS’ calls for increased equity and inclusion in clinical trials and research, we believe this decision would result in the exact opposite. The CED would exclude individuals “with medical conditions, other than Alzheimer’s, [that are] likely to increase significant adverse events.” These medical conditions such as diabetes, cardiovascular diseases and other co-morbidities effectively eliminate millions of African Americans and Hispanics that are disproportionately impacted by these conditions. This should be alarming given that these two populations represent 10.4% and 9% of Medicare beneficiaries, nationally respectively. (iv) This requirement is also a major setback to the decades long fight of researchers, patient advocacy organizations, and even the FDA and NIH to remove these restriction and exclusive practices from clinical research and trials.

3. Required Enrollment to Randomized Controlled Trials
The struggles to recruit and enroll African Americans and other minority communities in clinical trials is well documented. Randomized controlled trials (RCTs) are no exception and there is little to no evidence that suggests those sponsored by CMS and NIH will yield the desired study results outlined in the NCD related to diversity, efficacy, and drug safety. What the decision to restrict coverage of all mAB treatments for Alzheimer's to participants enrolled in qualifying randomized controlled trials (RCT) will achieve is limiting coverage to individuals with access to traditional clinical trial sites. (v) This poses major challenges given the severe underrepresentation of people of color in traditional RCTs. Historically, just 1.2% of clinical trial participants for new Alzheimer's drugs have been African American, 5.6% Hispanic, 4.4% Asian, and just 0.9% other or multiracial. (vi) Furthermore, communities of color and persons living in rural areas will incur additional barriers and cost to participate in these trials as evidenced by the concern shared with a congregational member living in rural South Carolina:

This family’s burden and experience is shared by many African American families who like other minorities were hardest hit by the COVID-19 pandemic that further widened the gap in health and other socioeconomic disparities. These harsh realities of a failed and flawed clinical trial and research system also hold true for NIH- conducted trials, which are a central component of the proposed CED. Despite the fact that NIH for decades has had explicit policies and mandates regarding the inclusion of minority populations in NIH-sponsored clinical trials, it has proven nearly impossible for NIH to meet these objectives in its own trials. Notably, NIH’s Alzheimer’s disease clinical trials have consistently been glaringly unsuccessful at engaging let along enrolling minorities at the contemplated rates because of institutional and systemic barriers that also include the lack of minority researchers and community partners. NIH’s most recent published data indicates that its Alzheimer’s disease clinical trial participants include only 6% blacks or African Americans, and that its Alzheimer’s Disease Related Dementia trials include only 3% of blacks or African Americans. This is unacceptable.

Rather than using its authority to challenge the drug approval processes of the FDA and putting forth this unprecedented NCD that comes across more as a political PR campaign, we strongly and emphatically request that CMS change course and consider a more collaborative and truly equitable path forward with not only the FDA, but drug manufacturers, consumer and patient advocacy groups and most importantly the persons and families being impacted by this progressive and debilitating disease that currently has no cure. Possible strategies to consider may include but should not be limited to:

Increase and improve the integration of practice-based research networks (PBRNs) based on their proven track record of integrating community-based stakeholders and health providers into the research process and their reach into communities traditionally underrepresented into research. As of August 2020, there are 185 PBRNs registered with the Agency for Healthcare Research and Quality PBRN Resource Center.(vii)

As previously stated, the mistrust and continued existence of systemic and unethical treatment of minorities by the healthcare system as a whole is a primary reason African Americans refuse to participate in clinical trials and research. CMS has a unique opportunity with this decision to review the current systems and practices of all clinical trials in partnership with the FDA and NIH to identify these barriers and others in both quantifiable and qualitative ways. To begin earning and rebuilding this trust, The Balm suggests that CMS, the FDA and other stakeholders leverage the trusted relationships, influence, and cultural understanding of minoritized communities that exist in non-academic, non-governmental organizations to create an equitable and sustainable infrastructure that not only looks to improve engagement and enrollment in clinical trials but also addresses the socioeconomic issues these communities face to show a genuine commitment to health equity.

In conclusion, CMS is fully aware that Alzheimer’s disease is a devastating and often fatal disease that affects more than six million Americans, 80% of who are Medicare beneficiaries. Similar to the fight to end other stigmatized and costly diseases like HIV and cancer, both of which have higher mortality rates among African Americans, ADRDs have and will continue to be a priority of The Balm In Gilead and its faith partners. Now more than ever communities that for generations have felt left behind and treated as pawns on this country’s political chess board, need sensible and ethical minds and powers to prevail. We remain committed through our Brain Health Center and other programs to lift up the voices of the voiceless by serving as a bridge between public health and faith. We invite CMS and other stakeholders to join us so that decisions like this are no longer a part of our ethos and practices. We thank you for your time and consideration.

Abiding in Faith,

Pernessa Seele, PhD
CEO/Founder
The Balm In Gilead, Inc.

References:
i https://www.alz.org/aaic/downloads2020/2020_Race_and_Ethnicity_Fact_Sheet.pdf
ii https://www.nia.nih.gov/news/data-shows-racial-disparities-alzheimers-disease-diagnosis-between-black-and-white-research
iii https://www.alz.org/aaic/downloads2020/2020_Race_and_Ethnicity_Fact_Sheet.pdf
iv https://www.kff.org/medicare/state-indicator/medicare-beneficiaries-by- raceethnicity/?dataView=0¤tTimeframe=0&sortModel=%7B%22colId%22:%22Location%22,%22sort%22:%22asc%22%7D#note-1
v https://www.cms.gov/newsroom/press-releases/cms-proposes-medicare-coverage-policy-monoclonal-antibodies-directed-against-amyloid-treatment
vi https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.12433
vii https://pbrn.ahrq.gov/

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I do not want my tax dollars given to drug companies that offer questionable results for Alzheimer's Disease treatment at inflated prices. My [PHI Redacted] was treated for years with Aricept, which may or may not have slowed the progression of her dementia, but did seem to keep her behavior more cooperative . When drug companies are given outrageous profits for drugs which may not help the suffering of families, it is wrong! It is and has been wrong for drug companies to gain great profits from medications which are essential and effective, let alone for those medications which have still not been proven to help.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

We need a drug that has been thoroughly tested and proven to work. We don’t need to waste our resources on drugs that don’t work. If three committed scientists distrust the testing enough to resign, something is wrong.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

Furthermore, as a medicare beneficiary and a medicare counselor, I am outraged that CMS has made a decision to raise medicare premium rates to pay for this drug that is simply not effective and was approved as a result of clearly corrupt collusion between the FDA and manufacturer. The financial stability of medicare cannot be jeopardized by this prospective plan to pay for this drug; nor should I and my fellow Medicare beneficiaries be forced to pay for this bogus drug.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I want to take this opportunity to write about Aduhelm which is a promising miracle drug for Alzheimers Disease. This is exciting not only for the patients who are suffering or at risk of developing this devastating disease but also for the Physicians who were treating these patients with frustration and no hope for possible cure.

In my opinion it will be unfair to limit access of Aduhelm for patients who have very little other treatment options. Aduhelm should be available for treatment for everone who wants it.

Physicians like myself are ready to facilitate Aduhelm treatment at our facilities. I am planning to screen, workup and treat patients at my office in underserved rural area in Pennsylvania.

I am looking forward for achieving this goal.

Danish Saeed, MD

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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ELECTRONIC SUBMISSION

February 10, 2022

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Centers for Medicare & Medicaid Services

RE: Proposed National Coverage Determination with Evidence Development for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N)

Dear Ms. Syrek Jensen:

The National Minority Quality Forum (NMQF) is submitting this public comment in opposition to the Coverage with Evidence Development component of the CMS Proposed National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N). NMQF recommends that CMS modify their proposed determination to cover all FDA-approved monoclonal antibody therapies directed against amyloid for the treatment of Alzheimer’s disease.

The National Minority Quality Forum (NMQF) is a 501(c)(3) not-for-profit research and advocacy organization based in Washington, DC. The mission of NMQF is to reduce patient risk by assuring optimal care for all. NMQF’s vision is an American health services research, delivery and financing system whose operating principle is to reduce patient risk for amenable morbidity and mortality while improving quality of life. NMQF has established the Institute for Equity in Health Policy and Practice to enable critical stakeholders to respond to these challenges in the context of centering structural and systemic health equity in every aspect of the American health services research, delivery and financing system.

Alzheimer’s Disease (AD) is a fatal, degenerative brain disease that affects roughly 6.2 million individuals and is currently the 6th leading cause of death in the United States. Alzheimer’s Disease is devasting to individuals diagnosed with the disease, as well as their families, caregivers and significant others. African Americans are two to three times more likely than non-Hispanic Whites to develop AD; and, Latinos are 1.5 times as likely. These disparities exist throughout all phases of AD. It is estimated that by 2030, nearly 40 percent of all Americans living with AD will be Black or Latinx. Alzheimer’s Disease is the only one of the top 10 leading causes of death in the United States for which there is not yet a proven means of prevention, disease modification or cure.

NMQF was heartened, therefore, by the June 2021 decision by FDA to approve through the Accelerated Approval pathway a monoclonal antibody that targets amyloid in individuals diagnosed with Alzheimer’s Disease. The FDA Accelerated Approval Program allows for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint, which is a marker that is thought to predict clinical benefit, but is not itself a measure of clinical benefit (e.g., a laboratory measurement, a radiographic image, physical sign or another measure).

Our positive view of the FDA decision is reinforced by the FDA requirement that drug companies who receive an Accelerated Approval are required to conduct Phase 4 confirmatory trials to demonstrate the anticipated clinical benefit. If the confirmatory trial shows that the drug actually provides a clinical benefit, then FDA grants traditional approval for the drug. If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place to remove the drug from the market.

NMQF is concerned that CMS may have proposed a coverage determination that over-steps its legal authority and is inconsistent with prior CMS decision-making. It is our understanding that FDA is the entity that administers the Food, Drug, and Cosmetic Act and renders determinations about safety and effectiveness. As such, the apparent contradiction by CMS of FDA’s conclusive determination that an approved therapy is safe and effective causes us great concern as American citizens, as health care consumers, and as health policy advocates.

Further, CMS has not evinced a clear basis for their conjecture that anti-amyloid therapies that FDA has determined to be safe and effective are clinically inappropriate when used in Medicare populations. A case can more readily be made that FDA has already conclusively evaluated issues of clinical appropriateness in Medicare populations because the studies that FDA evaluated during the approval process included a large proportion of Medicare beneficiaries.

Perhaps most importantly, the proposed NCED betrays the commitment articulated by President Biden in his Executive Order on Advancing Racial Equity and Support for Underserved Communities Through the Federal Government:

The National Minority Quality Forum believes that the proposed CMS NCED for monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease fails to live up to the letter and the intent of President Biden’s Executive Order.

In closing, the proposed NCED effectively contravenes the validity of the FDA approval of aducanumab and all monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease that may subsequently be approved by FDA, and challenges the validity of the valuable Accelerated Approval Pathway. It is particularly egregious that the proposed CMS NCED unnecessarily, and perhaps callously, heightens the clinical and financial risk for patient and families who are contending with a life-threatening, progressively and horrifically disabling disease for which there is yet no cure. The needs of patients and families must be moderated to the extent possible. The science must be able to advance. And the integrity of our federal government must be respected and enforced.

The National Minority Quality Forum recommends that CMS modify their proposed determination to cover all FDA-approved monoclonal antibody therapies directed against amyloid for the treatment of Alzheimer’s disease and allow patients and physicians the ability to make the medical decisions in the best interests of those suffering from Alzheimer’s Disease.

Sincerely,

Gretchen C. Wartman
Vice President for Policy and Program
Director, Institute for Equity in Health Policy and Practice
National Minority Quality Forum

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I support the CMS proposal to limit the coverage of a new Alzheimer’s drug aducanumab, (marketed by Biogen under the name Aduhelm) to experimental settings.

The scientific evidence on the benefits of this drug is limited. The cost of providing this drug, which would be borne by Medicare, and US taxpayers, is unreasonable and excessive, especially relative to the limited benefits the drug apparently provides.

Thank you for your consideration of this comment. Sincerely,

Miriam Laugesen, PhD
Associate Professor
Columbia University

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I strongly support the Medicare administrators decision not to pay for aducanumab.

As a physician I was deeply disturbed by the Food and Drug Administration’s (FDA) recent decision to approve the Alzheimer’s disease drug, aducanumab, despite the significant lack of evidence regarding its efficacy as well as concerns about the drug’s safety. While the FDA has defended this decision by noting that they granted accelerated approval to aducanumab, which only requires the drug to demonstrate an effect on a surrogate marker thought to be predictive of clinical benefit, the agency has failed to note that the particularly surrogate marker underpinning aducanumab’s approval – that of beta-amyloid seen on MRI scans of the brain – has failed in over two dozen clinical trials to show any association with clinically meaningful changes in Alzheimer’s disease patients

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Kaiser Permanente[1] appreciates the opportunity to provide comments in response to the proposed National Coverage Determination (NCD) for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. Given the controversy surrounding the approval of the first-in-class Aduhelm™ (aducanumab), Kaiser Permanente appreciates the thoughtfulness and objectivity with which CMS has approached the NCD process to determine whether and to what extent Aduhelm™ and future drugs directed against amyloid should be covered for the Medicare population. We believe CMS has reached a reasonable and clinically appropriate decision that will both permit coverage and facilitate collection of consistent, robust clinical evidence that can potentially lead to future advancement in Alzheimer’s Disease research.

As the largest private integrated health care delivery system in the United States, Kaiser Permanente delivers health care to more than 12.5 million members in eight states and the District of Columbia. Kaiser Foundation Health Plan, Inc., one of the nation’s largest not-for-profit health plans, and all our health plan subsidiaries are Medicare Advantage Organizations (MAOs), serving a total of more than 1.7 million Medicare beneficiaries. Within our footprint, we maintain a primarily internalized pharmacy system, including over 550 outpatient, hospital, infusion, specialty and mail order pharmacy sites staffed by over 14,000 pharmacy personnel. Kaiser Permanente spends approximately $10 billion annually on pharmaceuticals. Our Permanente Medical Group (PMG) physicians and other authorized practitioners prescribe, and our pharmacies dispense, over 90 million prescriptions annually. Kaiser Permanente’s mission is to provide high-quality, affordable health care services and to improve the health of our members and the communities we serve.

Given our large Medicare Advantage (MA) population and our primarily internalized drug purchasing and pharmacy operations, Kaiser Permanente and our members will be directly affected by the outcome of the NCD for Aduhelm™ and this new class of therapies. We endorse the comments being submitted by America’s Health Insurance Plans (AHIP) and wish to emphasize several points in these comments.

Kaiser Permanente continues to have significant concerns regarding the accelerated approval by the Food and Drug Administration (FDA) of Aduhelm™ over the strong opposition of the advisory committee. The drug was not shown in clinical trials to improve memory or function, and while the drug was shown to reduce beta-amyloid in the brain, the link between reduction of beta-amyloid and a clinical benefit has yet to be established even though it has been widely studied. Equally importantly, Aduhelm™ has been shown to have significant safety risks: 30 to 40 percent of patients developed brain swelling and bleeding after only 12 to 18 months of treatment.

Kaiser Permanente clinicians know and witness daily that Alzheimer’s Disease and related dementia syndromes take a devastating toll on patients and their families and caregivers. We are committed to working to improve the diagnosis, treatment and support of patients and families suffering from these conditions. The impact on the Medicare population is outsized, with over 11 percent of Medicare beneficiaries diagnosed with Alzheimer’s Disease or a related dementia. Kaiser Permanente therefore acknowledges and supports the need for effective treatments. However, we continue to have serious concerns regarding Aduhelm™ given the lack of clinical effectiveness and the significant safety concerns. Our clinical specialists believe that, in general, the risks to our patients exceed the benefit of reducing amyloid burden, without clinically meaningful improvement.

As the existing evidence does not support the routine use of Aduhelm™ for the treatment of Alzheimer’s Disease, our specialists believe the drug should only be administered in the context of a randomized clinical trial. We therefore support CMS’ proposed approach using the coverage with evidence development (CED) process as well as CMS’ proposal to apply this NCD to the entire class of anti-amyloid monoclonal antibodies, since there are at least three other such drugs nearing Phase 3 trials. The trials that qualify for Medicare coverage should be rigorous double-blinded, randomized, case-controlled studies that can demonstrate whether there is clinically meaningful improvement as a result of treatment with the drug. We also support CMS’ proposal to require that the setting for approved trials be hospital-based outpatient facilities to ensure consistent, high-quality care. Finally, we strongly agree with CMS’ stipulation that the randomized controlled trials must include a nationally representative population; as a health plan and provider with a diverse membership, it is very difficult to generalize the manufacturers’ trial results from a more homogenous population to our membership in order to feel confident about its safety and efficacy.

While we support CMS’ proposed NCD, there are some issues that need additional clarification in order to ensure appropriate implementation by Medicare Advantage plans. In particular, MA plans will need clear guidance regarding what they are expected to cover and provide payment for related to a member’s participation in an approved clinical trial. In addition to the cost of the drug and/or the placebo, there are likely to be imaging tests (e.g. MRIs), laboratory tests, and other treatments and services that are related to the trial and separate from the member’s usual benefit coverage. We expect there will also be a clinical workup for a patient who is a possible candidate for an approved trial – it is important that responsibility for the tests and appointments related to eligibility determination be made clear in advance so that MA plans can communicate clear and accurate information to members who express interest in participating in a trial. Finally, we request that CMS develop informational and educational materials that plans can use with members explaining CMS’ approach to Medicare coverage under CED, plans’ role in coverage of clinical trials, and the processes enrollees/caregivers should follow to participate in qualifying trials.

***

Kaiser Permanente appreciates CMS’ consideration of these comments and would be pleased to provide additional information as the agency develops the final NCD.

***

[1] Kaiser Permanente comprises Kaiser Foundation Health Plan, Inc. and its health plan subsidiaries outside California and Hawaii; the not-for-profit Kaiser Foundation Hospitals, which operates 39 hospitals and over 700 other clinical facilities; and the Permanente Medical Groups, self-governed physician group practices that exclusively contract with Kaiser Foundation Health Plan and its health plan subsidiaries to meet the health needs of Kaiser Permanente’s members.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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If CMS adopts general coverage for aducanumab, they will be complicit in providing families and patients false hope, given the marginal results and significant side effects documented in the studies concerning the Biogen distribution of aducanumab, branded as Aduhelm. In addition to this, Doctor GC Alexander (2021) discusses that general coverage of aducanumab will force clinicians into some unusual disclosure with patients about the uncertainty of whether or not there are actual benefits to this extremely expensive medication. According to bioethicist Marleen Eikholt (2020) the "False Hope Harms (FHH) Argument" corroborates the notion that allowing general coverage for the distribution of this drug will be an unkind and unethical burden upon those seeking aid. Of the high-dosage patients that receive aducanumab, 40 percent will be at risk of lethal side effects, such as brain swelling and bleeding, as reported by medical ethicist, Leonard Fleck (2021). So, why would CMS cover this drug that yields such a high danger for patients and results of minimal treatment effectiveness? The FDA’s results, despite the accelerated approval, reveal these great risks of Aduhelm, but Biogen skips over such concerns in pursuit of profits. Profits over people is a cruel mindset that this company is inflicting on families in immeasurable pain caused by Alzheimer’s Disease. In regards to Biogen, their posthoc analysis was a devious attempt to exploit the desperation of these people. As per scientific experts Alexander, Emerson, and Kesselheim’s regulatory review of Aduhelm (2021), the EMERGE study was a “prespecified analytic plan” which undermined the credibility of the results. Additionally, in an article by Adam Feuerstein (2021), the campaign Project Onyx made a push to put aducanumab on the market and is quoted by Doctor Alexander as not being FDA policy and “a highly atypical relationship between a drug manufacturer and a regulator.”

References
Alexander, G. C., Emerson, S., & Kesselheim, A. (2021, May 04). Evaluation of Aducanumab for Alzheimer Disease. Retrieved January 30, 2022, from https://jamanetwork.com/journals/jama/fullarticle/2778191
Alexander, G. C., Karlawish, J., & Janiaud, P. (2021 September). The Problem of Aducanumab for the Treatment of Alzheimer Disease. Annals of Internal Medicine. Retrieved January 30, 2022, from https://www.acpjournals.org/doi/10.7326/M21-2603
Eijkholt, Marleen. (2020). Medicine’s collision with false hope: The False Hope Harms (FHH) argument. Bioethics 34, 703–711. https://doi.org/10.1111/bioe.12731
Feuerstein, A., Herper, M., & Garde, D. (2022, January 12). Inside 'Project Onyx': How Biogen used an FDA back channel to win approval of its polarizing Alzheimer's drug. Retrieved February 6, 2022, from https://www.statnews.com/2021/06/29/biogen-fda-alzheimers-drug-approval-aduhelm-project-onyx/
Fleck, L. M. (2021, June 22). Alzheimer's and Aducanumab: Unjust Profits and False Hopes. Retrieved January 30, 2022, from https://onlinelibrary.wiley.com/doi/full/10.1002/hast.1264

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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he Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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PLEASE reconsider the approval of this drug.
The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urgently ask CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.
Thank you for your time.

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Dear Sir or Madam:

The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

Sincerely,
Theresa Stewart

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As a neurologist with specific focus on degenerative disorders including Alzheimer's I would like to point out that we finally an option that provides a fighting chance against this devastating disease to both the patient and their loved ones. The current available widely used drugs such as Aricept and Namenda are not anywhere close to providing the same opportunity to our patients as they are not medications that could help in delaying progression of disease. I believe that ultimately the cost of aduhelm is ultimately more cost effective solution than the overall disease burden cost to our society which is estimated at 100 billion dollars a year when one considers all factors. Thus I would urge CMS to include aduhelm as a covered option to correct patient population (MCI and early AD only).

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The Food and Drug Administration’s (FDA’s) decision to approve Aduhelm for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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It’s imperative that we continue to put time, effort, and funds behind any drug or treatment that can stop or slow the progression of Alzheimer’s. This disease is taking lives slowly and painfully, and not just for the person who receives the diagnosis. Family members are often forced to make major life changes in order to become caregivers. We need to do all that we can to support the researchers, doctors, and all treatments available. We cannot afford to lose any hope or momentum in the search for a cure. We owe it to all of those suffering from Alzheimer’s.

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Mr. Secretary:

While I appreciate the well-reasoned counterarguments to this opinion and given the FDA "accelerated" approval, I think Medicare should cover this drug with carefully constructed guidelines crafted through collaboration with the FDA and reflecting the role of CMS to equitably protect beneficiary health and well-being and ensure safety.

Of all the illnesses and conditions that afflict humans, Alzheimer's disease is among the most tragic. For its victims, this slowly progressive illness day by day eliminates all things we hold dear as independently functioning and social people. Family members are left to witness the decline and, in many cases, become the direct hands-on caregiver.

For the past 25 years, I have been a specialist geriatrician practicing in community-based health systems and specializing in caring for patients with Alzheimer's disease and related disorders (ADRD) and supporting their family caregivers. Two FDA-approved symptomatic medications were available during this time, but the benefits were modest and short-lived. I can describe thousands of versions of the sad "long goodbye." Just today, a family caregiver texted to notify me of the recent passing of both her mother, who had been the caregiver and her father, who had Alzheimer's disease. The scourge of this incurable illness is tremendous and will continue to be so until we understand the complete pathophysiology and identify strategies to modify it. In mid 2021 I joined a private clinical trials company to aid in this work.

As this critical debate continues, I respectfully offer several points for additional consideration:

To begin, I question the need for separate CMS qualified studies and continued evidence development when the FDA requirement of a Phase 4 study is in place and represents a recognition of the need for additional real-world (and appropriately diverse) evidence to ensure or further refine the safety of this approved drug. Designed and executed properly, THIS is precisely the next study and data set needed to advance the knowledge on this medication's safety, acceptance to a diverse and carefully identified cadre of patients and caregivers, and ability of care delivery across various healthcare settings. It could also be used to evaluate key essential healthcare delivery and economic outcomes. (The economic questions posed by this are well outside my expertise. The “value” of aducanumab, its reasonable cost, and strategies to manage the financial impact will need detailed discussion with appropriate experts.) 

The requirement of this determination as a class-based one is puzzling. There are numerous examples of differential efficacy and side effects within many drug classes. I routinely choose a medication for a particular attribute be it better performance, cost, formulation, or impact on co-morbidities. It seems premature and inconsistent with published evidence across the class in this situation. I fear this will prematurely slow the progression of research and discovery at the exact time we are poised to have significant progress in this disease state. In addition to the key outcomes, there is essential knowledge about disease pathophysiology uncovered by studies involving individual agents within the class.

I further encourage Medicare to review the requirement for hospital-based locations and physicians of a specific specialty, limiting access. Indeed, for safety, I favor licensed locations. Providers who are experienced in the care of ADRD would be ideal, but requirements should reflect known resource limitations and allow for locally-determined strategies to meet the need without undue discrimination. With the proliferation of tele-health applications, the expertise needed could be more widely available.

Since June 2021, I have had numerous conversations with patients and family caregivers about this drug. As with anything, the range of opinions is broad. However, it is notable how many of the patients with Alzheimer's disease - who can still fully participate in shared-decision making - find the decision relatively straightforward. For many, if the FDA has approved a medication and their provider recommends it, they feel confident taking it and would expect it to be covered by their insurance. The potential for brain swelling or hemorrhage is of little concern for most "relative to what is going to happen from the Alzheimer's." Certainly, even this argument of patient need and desire has to be tempered by individual and global cost/benefit analysis when resources are limited. Inter-agency discussion that includes patients, family caregivers, and other key stakeholders and experts could form a key advisory group focused on balancing all factors, maintaining scientific progress, and promoting safe and equitable access amid high clinical need and limited resources. Given the demographics this issue is not going away with this decision.

Iappreciate your consideration of this complex matter. I will continue to do what I can and work towards helping patients and family caregivers consider the best treatment and care options available to them.

These opinions are mine alone.

Thank you

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I am writing to express my concern regarding the status of aducanumab. I applaud Medicare administrators' restriction of coverage of aducanumab, and encourage you to continue or further tighten this restriction.
The American public's faith and trust in our nation's health care administration is in crisis, with extremely high numbers of citizens having lost that faith an trust in the public health administration doing the right thing for the public health. The FDA approval of aducanumab struck a further severe blow to this faith and trust by approving the drug despite evidence of harm exceeding evidence of benefit. The decision appears to have been based upon corporate and personal lobbying rather than sound science. Medicare's refusal to provide broad coverage for aducanumab took a necessary first step toward restoring that trust in science.
As a licensed physician, I urge you to NOT allow Medicare coverage of aducanumab except in the context of randomized-controlled trials under Coverage for Evidence Development (CED) as such a coverage decision prioritizes and protects patients above all else.

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I am a senior citizen on Medicare [PHI Redacted]. I am writing to support your decision to require proof - from an experimental study - that this drug works before asking all of the American taxpayers to pay for it. There is no evidence is a cure for Alzheimer's disease and Biogen's study failed to show removing plaque slowed cognitive decline at all - let alone in a clinically meaningful way. There is also no evidence that removing plaque and the amount removed correlates with any slowing of cognitive decline. The FDA's statistician's report plotted out the substudy results showing no relationship between amount of plaque removed and the degree of change on the primary endpoint in the study. I am very concerned about reports of an inappropriate relationship between the FDA people shepharding this through approval and Biogen that includes reports of meetings outside of public view or only open to people who supported approval. Shame on them! Lastly, where is the data from the study? Where is the peer-reviewed paper where they make their case???? I see many people worried about whether loved ones with Down's syndrome who develop Alzheimers will have access to this drug. Biogen excluded people with Down syndrome from their study — why? As a result, there is no data on the safety or efficacy of this drug for this population. The side effects of brain bleeding and brain swelling are not trivial. We all want to ensure our loved ones receive a treatment that works but this isn't it. There are so many support services people with disabilities need to be able to fulfill their potential insurers don't pay for because not medical. So many services people with dementia - whatever the cause - need today to live with dignity and to spare their families emotional and financial burn-out. Medicare does not pay for what we need. Where is our outrage? That all said, God bless the staff at Medicare for standing up to what Dr. Kesselheim rightfully called one of the "worst" FDA decisions in "recent history." (I'd say all history myself.) People with Alzheimer's aren't marks for Big Pharma. They are people who deserve to be treated with respect and dignity. That requires regulators to do their duty like you have here. You are going to be bombarded by Big Pharma and their handmaidens. Remember your humanity and your ethics and your moral compass and do what is right. Requiring evidence before making such a huge investment is what is right.

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I am 63 years old and I am a grandma to eight healthy grandchildren! However, I have friends who have children or grandchildren that have down syndrome. I truly feel that everyone including down syndrome individuals should have access to testing to help prevent or cure that horrible disease – Alzheimer’s. After all, about 30% of the individuals with down syndrome will present some symptoms of Alzheimer’s in their 50s or even earlier.! With one out of 700 babies carrying and presenting DS characteristics that’s a high percentage of people you are discriminating against when and that is absolutely ridiculous! SHAME ON YOU FOR THINKING YOU HAVE THE POWER TO DECIDE WHAT IS BEST FOR ALL PEOPJE!!!

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As an American citizen, I am against the FDA decision to approve Aduhelm. The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Like most citizens, my family has been touched by the disease of Alzheimers. I have worked as a therapist with those suffering from Alzheimers. I know there are services that help people with dementia - dementia-friendly communities, intensive day services, family support groups, home health aides (to help with dressing, bathing, cooking). I am an expert in the benefits of music therapy. Music brings awareness and memory to the forefront even as other faculties diminish. It brings joy. None of these things are covered by Medicare even though we know today it would matter to hundreds of thousands of people. To think Biogen wants Medicare to now pay for Aduhelm - a drug that its own trial demonstrated did not have clinical efficacy and where 40% of the people who received the drug had evidence of brain swelling and bleeding — absolutely floors me. Thank you for saying, "Biogen - you need to prove your monthly infusions actually make a positive difference in the lives of people with Alzheimer's lives before you will agree to cover it. And thank you for requiring real evidence - not some observational study that Biogen could game. Medicare cannot afford to pay $25,000 a year for false hope. Pay for what matters. Please stand strong as I am sure the Big Pharma lobbyists and those who take money from them are going to be on DefCon 1 asking you to pay for this treatment despite the flimsiness of the "evidence" (not to mention the numerous investigations into what appears to have been an overly close relationship between the FDA and Biogen). Stay strong. Stay true to the science. Thank you.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I congratulate CMS on making the decision to carefully restrict the use of aducanumab. As a family physician and family member of a person with dementia my understanding of the desperation of patients for effective therapy is broad and deep. What our patients depend upon us for as professionals is ensuring their safety and carefully elucidating and guiding them through known risks. I trust the agency will continue to uphold this standard and not endorse this medication for payment except as articulated in the context of well designed clinical trials. Given the power of direct to consumer advertising, physicians depend in large part on CMS' coverage decisions to guide patients. I strongly encourage the agency to stand strong in holding to its decision regarding aducanumab. Thank you.

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I request that CMS not approve the drug Aduhelm excluding it for Medicare recipients. While the object of the drug is laudable, it did not prove to be effective in one clinical study that was stopped because of this reason. The second study did not improve thinking, memory or the ability to function. FDA's own advisory panel recommended that FDA not approve the drug but it as approved anyway. The studies were faulty. In addition the cost is tremendous and will adversely impact the Medicare Fund.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The decision of the Food and Drug Administration to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Dear Sirs:

The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

Sincerely,
Mike Seyfried

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Im Robin, live in indiana, I have [PHI Redacted] who has Down syndrome, and I need to plan now for her future. I know that she is more likely than other people to develop Alzheimer’s disease, not only due to her DS but also because I've had [PHI Redacted] decline from Alzheimers disease. So even though there’s no cure now, it’s very important to me that she has access to any treatments that will be developed in the future. I’ve become aware that the Centers for Medicare & Medicaid Services might exclude her from clinical trials related to new Alzheimer’s treatments. I strongly believe that CMS should not move forward with any coverage process that excludes people with Down syndrome and other disabilities- thats discrimination! If people on Medicare or Medicaid without disabilities can access new treatments, people with disabilities who are covered should 100% have the same access.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The treatment is something that families and patients should have the right to deside if they would like to use. All I hear about is the cost. Really with contracts that facilities and physicians negotiate the cost of this drug is not as costly as the media has made it out to be. Reality is that the cost of this drug is not even close to some drugs that are used but the link that keeps coming up is to Medicare costs. That is a big deterant to patients because of what they read. Do they really know what thier other medications costs are? I think they would be surprised. Many patients and families would see this as hope for a loved one and should be given the opprotunity to explore this drug.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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My [PHI Redacted] has mild, 1st stage AD. He has had 9 Aduhelm infusions with no side effects and hopes to have 3 more. Our hope is that it will take several years for the amyloid to build back up and [PHI Redacted]. When he was diagnosed, we were looking at a depressing future of his loss of self, incontinence, and death. Because of this treatment, he has remained able to drive, volunteer at a community garden and participate in an active family, church, and social life with no perceptible deterioration. He is still himself. Please enable insurance coverage for this treatment to a wider group of people. Lives are hanging in the balance for people who could experience the reprieve which Aduhelm has enabled for us. I know the cost is dear and everyone won't be able to afford it, as with many medicines. but helping some is better than the limited, exclusive path you've proposed. Time is critical. Alzheimer's patients don't have time to wait for clinical trials when this medicine is working as we can testify.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am a citizen who has family members touched by Alzheimer's disease. People with Alzheimers deserve more than false hope. I commend your standing up to the FDA's ill-advised approval that seems to be based on a too cozy relationship with Biogen. Please don't change your mind about requiring an experimental study showing Aduhelm works before approving payment under Medicare. From what I read, Biogen conducted two identical studies. One showed a nominal benefit versus placebo (not clinically meaningful and which could be the result of the placebo group deterioration versus treatment effect) and the other identical study did not show any treatment effect. There is no justification to approve or to pretend the trial did not happen and approved on the accelerated approval pathway. That is not the back-up if a trial fails. And surrogate There is no expert consensus that that plaque reduction coincides with some slowing of cognitive decline. In fact, the evidence to date is to the contrary. See, for example. Ackley, S., Zimmerman, S., Brenowitz, W., Tchetgen, E., Gold, A. et al. (2021). Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. The BMJ. 2021 Feb 25;372:n156. PubMed. see Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics. https://www.fda.gov/media/86377/download (Accessed November 19, 2021.)

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Hi Folks,

The former guy did all he could to make money during his time in office. It sounds like that included pushing along the approval of a drug that is not ready for prime time. Because he destroyed so many records, we don't know who greased his palm, but "grift" would be the easiest explanation for this.

Our democracy depends upon trust in our government. The Food and Drug Administration’s (FDA’s) decision to approve Aduhelm for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been badly damaged.

Like so many governmental decisions during the previous presidential term, this one needs to also be reversed.

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MHPA
1575 Eye Street, NW Suite 300 Washington, D.C. 20005
TEL (202) 857-5720 FAX (202) 857-5731 www.medicaidplans.org

February 10, 2022
The Honorable Chiquita Brooks-LaSure
Administrator
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease

Dear Administrator Brooks-LaSure:

The Medicaid Health Plans of America (MHPA) appreciates the opportunity to comment on the proposed National Coverage Determination (NCD) decision memorandum released by the Centers for Medicare & Medicaid Services (CMS) related to the coverage of Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) that target amyloid for the treatment of Alzheimer’s disease through coverage with evidence development. The proposed NCD would provide Medicare coverage only for beneficiaries enrolled in qualifying clinical trials. Specifically, we are seeking clarity from CMS related to Medicaid coverage for this class of therapies, including the FDA-approved Aduhelm. Alzheimer’s disease is the sixth-leading cause of death in the United States with an estimated 6.2 million Americans aged 65 and older living with Alzheimer’s dementia in 2021.¹ Alzheimer’s disease can also place a heavy emotional, physical, and financial toll on caregivers and family members.

MHPA is the only national trade association with a sole focus on Medicaid, representing more than 130 managed care organizations (MCOs) serving more than 43 million Medicaid beneficiaries in 40 states, the District of Columbia and Puerto Rico. MHPA’s members include both for-profit and non-profit, national and regional, as well as single-state health plans that compete in the Medicaid market. Nearly three-quarters of all Medicaid beneficiaries receive health care through MCOs, and the association provides research and advocacy services that support policy solutions to enhance the delivery and coordination of comprehensive, cost-effective, and quality health care for Medicaid beneficiaries.

In the proposed NCD, CMS states that, based on its review of the totality of the evidence, “due to the lack of clear clinical benefit and the frequency of adverse events like ARIA², the evidence does not support that the benefits outweigh the harms for mAbs directed against amyloid for the treatment of AD.” CMS adds that more rigorous clinical trials continue to be necessary to determine the clinical benefit. While the NCD is an important step for establishing Medicare-focused coverage for drugs such as Aduhelm, we would like to underscore that the NCD also has ramifications for coverage in Medicaid and particularly for people dually eligible for Medicare and Medicaid. Medicaid covers some services that Medicare either does not cover or only partially covers, such as nursing home care and home- and community-based care. When an individual is dually eligible for coverage under both the Medicare and Medicaid programs and receives health care services that could be covered by either Medicare or Medicaid, Medicare is the primary payer.

However, current policies can also position Medicaid as the primary payor in certain circumstances. For example, created by the Omnibus Budget Reconciliation Act of 1990, the Medicaid Drug Rebate Program (MDRP)³ requires that participating pharmaceutical manufacturers provide specific discounts to state Medicaid programs in exchange for coverage of the manufacturer’s FDA-approved products. As a result, should a dually eligible individual be prescribed a drug that is not covered by Medicare, but that drug meets the definition of “covered outpatient drug” under the terms of the Medicaid Drug Rebate Program, then the state Medicaid Program becomes the primary source of coverage for that drug. With the combination of the proposed policy under the NCD and the established policy under the MDRP, we believe a shift of coverage of monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease, like Aduhelm, from Medicare to Medicaid is likely, raising questions about the allowance for state flexibilities to address the clinical and patient safety issues noted in the NCD and causing concern about the potential financial implications for Medicaid due to the cost-shifting construct.⁴

Given the “lack of a clear clinical benefit and the frequency of adverse events” that CMS found in its assessment of this class, in support of financial sustainability of the Medicaid program, and in furtherance of the efficiencies of a consistent application of coverage guidance across government programs, we respectfully request that CMS address and clarify in guidance the following for state Medicaid programs:

• Whether and how states are allowed to implement utilization management criteria for monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease, including Aduhelm, that mirror the Medicare NCD, in the Medicaid program.
• Specify the types of medical necessity criteria and other flexibilities that may be available to state Medicaid programs.
• Provide risk mitigation options to minimize the impact of cost-shifting from Medicare that would safeguard state Medicaid programs from significant budgetary impacts and that would allow the Medicaid program to continue as a viable and sustainable approach for meeting public health needs.

Thank you for the opportunity to provide feedback on this important coverage decision. Should you have any questions, please do not hesitate to contact me at sattanasio@mhpa.org.

Sincerely,

Shannon Attanasio
Vice President, Government Relations and Advocacy

1 https://www.alz.org/media/documents/alzheimers-facts-and-figures.pdf
2 Note: ARIA references amyloid-related imaging abnormalities
3 https://www.ssa.gov/OP_Home/ssact/title19/1927.htm
4 For 2021, the total national cost of caring for people living with Alzheimer’s and other dementias was projected to reach $355 billion, not including the estimated $257 billion price of unpaid caregiving. Coverage under Medicare and Medicaid was estimated at $239 billion, or 67%, of the total health care and long-term care payments for people with Alzheimer’s or other dementias. See https://www.alz.org/media/documents/alzheimers-facts-and-figures.pdf.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I urge the CMS to modify their decision on Aduhelm and not create the harsh limitations on anti-amyloid monoclonal antibody drug trials currently in Phase 3 as well as any further similar drug trials. Alzheimer’s and dementia make up the #6 cause of death among Americans and is the ONLY killer without any cure, control, or prevention.

I am utterly appalled that the CMS is now rejecting FDA approval for aducanumab (Aduhelm). This will make Medicare support for Aduhelm only available through hospital-based drug trials where the patients who has benefited from this drug is not assured of receiving this medication but forced to participate in duplicative double-blind studies where they may get only a placebo! How CRUEL!!

In addition, requiring approved hospital-based administration further restricts how many of the two million Americans currently with Mild Cognitive Impairment and Mild Alzheimer’s live near what likely would be high population dense metropolitan hospitals which become Aduhelm trial distributors. Further, such restrictions for Aduhelm and current/future research and clinical trials that target monoclonal antibodies against amyloids will greatly reduce the participation levels among the Black and Hispanic and women who have a much higher rate of Alzheimer’s.

Again, I urge the CMS to modify their decision on Aduhelm and not create the harsh limitations on anti-amyloid monoclonal antibody drug trials currently in Phase 3 as well as any further similar drug trials. Alzheimer’s and dementia make up the #6 cause of death among Americans and is the ONLY killer without any cure, control, or prevention.

- Establish recommendations that Medicare coverage for Aduhelm only be permitted on a limited basis for patients who can most benefit – Mild Cognitive Impairment and Mild Alzheimer’s.
- Eliminate the highly restrictive approved hospital-based administration through clinical trials for Aduhelm and coverage for future FDA approved monoclonal antibodies targeting amyloids.
- Base future decisions on FDA approved medication for Alzheimer’s and dementia on the merits of the documented Phase 3 drug trials without placing extraordinary hardships on researchers and drug companies limiting them to approved hospital-based locations where wide representative participants need to be increased.

CMS must give the families and patients with Alzheimer’s needed HOPE that through science, research, and participation in clinical trials we can identify ways to suppress, control and cure Alzheimer’s and numerous types of dementia.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s (FDA’s) decision to approve Aduhelm for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am a retired rheumatologist immunologist. While I was initially hopeful that the monoclonal technology that created aducanumab would provide an effective agent for Alzheimers. Unfortunately the data suggests it is not particularly helpful in improving cognitive function in early disease although it apparently removes amyloid plaques. Over 40 years ago I worked at Harvard alongside people who were working on the hypothesis that amyloid causes Alzheimer's. Their data was marginal at that time and has since never truly panned out so it is no surprise to me that this medication does not work. Plus it requires MRIs for brain bleeds and is hideously expensive. Spend the money on real Alzheimer's research. Think outside the bod as to cause. Here is a review of the amyloid Alzheimer's unproven relationship. Do not spend taxpayer money on aducanumab. https://www.psychiatrictimes.com/view/aducanumab-a-tentative-position

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Comment concerning the Centers for Medicare and Medicaid Services’ (CMS) proposed National Coverage Determination (NCD) to restrict coverage for drugs used to treat patients suffering from Alzheimer’s.

There are many levels of controversy concerning CMS’s proposed determination concerning the Alzheimer’s approved drug amyloid. I wish to comment on, what I feel should be, the highest level of concern.

The FDA approved the use of amyloid for the treatment of Alzheimer’s under their accelerated pathway process, using the same strict guidelines used for the approval of many cancer treatments and drugs for the treatment of HIV. We often use the term “gold standard” to describe the work of the FDA. We rely on that agency to only approve treatments that are safe and effective. They have established a reputation that warrants the worldwide “gold standard” moniker.

My concern with this coverage determination is the usurpation of power by the CMS. The CMS has no legal or moral right to determine that the FDA has not done its due diligence concerning the approval of amyloid. By only allowing its use in the confines of a government-mandated randomized clinical trial the CMS has decided to assume the mantel of a drug approval agency by requiring more clinical trials before allowing broad access to this FDA approved drug. The CMS has neither the staff nor the expertise to make such decisions. It’s not right and should be abhorrent to every branch of our government. There should have been and immediate uproar concerning this misuse of power.

If the trust in the FDA has eroded, if we suspect that they are not maintaining their high standards or being influenced, not by science but by outside pressures, then we need to fix that problem. Allowing another ill-equipped agency to assume their duties is not the answer.

If we, a nation guided by the separation of power and duties, allow this proposed coverage determination to stand we have opened the gates for further power grabs and misuse of power. I testified at a CMS hearing over a decade ago that dealt with a similar coverage decision concerning an approved prostrate drug. I used the term rationing then and I’m compelled to use the term again in this case. If this proposed coverage determination is allowed to stand, they are choosing who can and cannot have access to this FDA approved drug, they are effectively rationing access to this drug.

I ask that CMS withdraw this proposed coverage determination and let the oft proven drug approval and implementation process work. It is the right thing to do.

Thair Phillips
Former President and CEO, RetireSafe

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I strongly support the proposed coverage decision for aducanamab. In the proposed decision, CMS has recognized the need for further investigation to protect older and disabled adults. Importantly, CMS has suggested requiring that the drug be tested through well-designed, randomized controlled trials within patients representative of populations most impacted by Alzheimer’s disease, including racial and ethnic minorities. Patients and their families need this information in order to make decisions about a novel therapy that carries significant risks and for which we do not yet know the degree of benefit in the diversity of patients living with Alzheimer’s disease.

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February 10, 2022

VIA ELECTRONIC FILING —- https://www.cms.gov/medicare-coverage-database/reports/national-coverage-ncacal-status-report.aspx?ncacaldoctype=NCA&status=Open%20for%20Public%20Comment

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
Department of Health and Human Services
ATTN: CAG – 004460N
7500 Security Blvd.
Baltimore, MD 21244-1850

RE: NATIONAL COVERAGE DETERMINATION FOR MONOCLONAL ANTIBODIES DIRECTED AGAINST AMYLOID FOR THE TREATMENT OF ALZHEIMER’S DISEASE

Dear Ms. Syrek Jensen:

Alnylam Pharmaceuticals, Inc. (Alnylam) appreciates the opportunity to comment on the Proposed National Coverage Determination (NCD) for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (AD). Alnylam has led the translation of RNA interference (RNAi) from a Nobel Prize winning discovery into a new class of innovative medicines with the potential to transform the lives of patients who have limited or inadequate treatment options. We are advancing a deep pipeline of innovative RNAi medicines in four strategic therapeutic areas: genetic medicines, cardio-metabolic diseases, infectious diseases, and central nervous system (CNS) and ocular diseases.

Alnylam recently announced that we submitted a Clinical Trial Authorization application to The Medicines and Healthcare Products Regulatory Agency in the United Kingdom to initiate a Phase 1 study of ALN-APP.[1] ALN-APP is an investigational RNAi therapeutic targeting amyloid precursor protein for the treatment of Alzheimer’s Disease and cerebral amyloid angiopathy. Additionally, ALN-APP represents the first-ever RNAi therapeutic targeting CNS diseases.

Alnylam is writing to express our concerns with the proposed decision memo from the Centers for Medicare & Medicaid Services (CMS or Agency) on the National Coverage Analysis for Monoclonal Antibodies Directed Against Amyloid for the Treatment of AD. We are specifically concerned about the implications this NCD could have for patient access to innovative treatments for AD, and for continued investment in innovation in this area of high unmet medical need, if finalized. Moreover, we are concerned that CMS could act in a way that undermines FDA authority to determine whether drugs are safe and effective for the treatment of a condition. We provide further detail on our perspectives below.

In addition, we support the comments provided by our trade association, the Biotechnology Innovation Organization (BIO), on the Proposed NCD. We underscore the concerns BIO raises regarding the use of Randomized Controlled Trials (RCTs) as part of coverage with evidence development, and believe it could set a dangerous precedent for future treatments of AD – and other disease areas with high unmet need. We also echo the importance of preserving the accelerated approval pathway as a means to advance therapies that treat patients with serious, life-threatening conditions.

CMS’s Proposal Would Impose Inordinate Barriers to Patient Access to Innovative Medicines in an Area of Serious Unmet Medical Need

Alnylam is concerned that the Proposed NCD would set a restrictive precedent on Medicare beneficiary access to innovative therapies, if finalized as proposed. The Proposed NCD would require coverage with evidence development (CED) in CMS-approved RCTs, and trials controlled by National Institutes of Health (NIH). This proposal to limit coverage only to patients enrolled in CMS-approved RCTs will cause a significant percentage of those suffering from AD to have no meaningful access to an FDA-approved medicine simply because of where they live and where they go for care.

As AD is a degenerative medical condition, there is an increased potential for permanent loss of cognitive ability each year that an Alzheimer’s patient goes without treatment. Forcing Medicare beneficiaries with AD to participate in a clinical trial where they may receive a placebo, assuming that is how the RCTs would be structured – which they might be required to pay for under this NCD with CED proposal – seems not only unethical, but potentially cruel if participation in the CMS-approved trial could bar them from participating in an FDA-approved trial where they might have a better chance of receiving active study drug.

CMS’s Proposal Would Have Damaging Repercussions for Investment in Innovation for an Area of Serious Unmet Medical Need

As an innovator of RNAi medicines, Alnylam is deeply concerned that CMS’s proposed NCD with CED could drive investment decisions away from innovative therapies for this area of high unmet medical need. The investment required to bring therapies to market for difficult-to-treat conditions like AD is exceptionally high. Indeed, the total private research and development funding invested into Alzheimer’s Disease since 1995 totals $42.5 billion, with the greatest costs incurred during late-stage drug development.[2]

Alzheimer’s is an area desperately in need of therapeutic innovation – the low hanging fruit on the tree of therapeutic options has been picked and proven unsuccessful in treating this devastating disease. An access environment that encourages, rather than discourages, innovation is paramount to maintain the private capital needed to fund the research and development engine for AD and other devastating CNS diseases and disorders.

Furthermore, the proposed NCD with CED, if finalized, would be binding for all monoclonal antibodies directed against amyloid for the treatment of AD, regardless of potential differences in benefit / risk profiles or FDA-labeled indications. In effect, CMS is imposing undue coverage restrictions on an entire class of medicines at a time when only one therapy in the class has been approved and is on market. It is unlikely that any manufacturers would be willing to invest further dollars on anti-amyloid monoclonal antibodies with this decision. Surely, that was not the intent of the Agency.

Alnylam urges CMS to exercise judicious use of NCDs as it has done previously, and apply them, when warranted, on a drug-by-drug approach, based on the "reasonable and necessary” evidence presented for a particular therapy. Otherwise, a class-based approach to coverage will disincentivize research and development in the class if it’s already been decided that products will not be adequately covered by Medicare, even if they were determined to be safe and effective by the FDA.

CMS Should Not Undermine FDA Authority in Determining Whether Drugs and Biologicals Are Safe and Effective for the Treatment of a Condition

As the NCD is proposed, CMS appears to have deemed itself as the ultimate arbiter of clinical trial outcomes despite the fact that FDA is authorized to approve drugs and biologicals based on a benefit-risk assessment that determines whether a product demonstrates substantial evidence of effectiveness. CMS provides coverage for drugs and biologicals that are “reasonable and necessary for the […] treatment of illness or injury or to improve the functioning of a malformed body member.”[3] CMS has neither the resources, nor authority, nor expertise to judge the appropriateness of surrogate endpoints accepted by the FDA.

That CMS believes it is able to “evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest” veers into FDA authority, with implications about the Agency’s effectiveness – not to mention patients’ ability to access to an FDA-approved treatment for this neurodegenerative disease.

In order to continue to stimulate investment in research and development into AD and other CNS conditions, it is important for clinical trial sponsors to be able to rely on FDA’s determination of which biomarkers are appropriate for use as a surrogate marker for clinical benefit. The uncertainty that is created by the potential for a CMS reassessment of a biomarker, undermining FDA’s determination and potentially creating restrictions to a product for the population for which it is indicated, would act as a significant disincentive to research. For these reasons, we underscore our considerable concern with the proposed RCT as part of CED.

Finally, while CMS does not explicitly call into question the use of the Accelerated Approval pathway, we note the importance for manufacturers and FDA to identify surrogate biomarkers that are appropriate to speed development of new therapies and access for patients with high-unmet need diseases.

Conclusion

Alnylam appreciates the opportunity to comment on the Proposed NCD. We would be glad to answer any questions or provide any additional information that may be of interest to the Agency. Please feel free to contact me at aeisenberg@alnylam.com.

Sincerely,

Alan F. Eisenberg
Vice President
Global Public Policy & Government Relations
Alnylam Pharmaceuticals, Inc.

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[1] “Alnylam Submits CTA Application for ALN-APP, an Investigational RNAi Therapeutic for the Treatment of Alzheimer’s Disease and Cerebral Amyloid Angiopathy.” Business Wire, 22 Dec. 2021, https://www.businesswire.com/news/home/20211220005959/en/Alnylam-Submits-CTA-Application-for-ALN-APP-an-Investigational-RNAi-Therapeutic-for-the-Treatment-of-Alzheimer%E2%80%99s-Disease-and-Cerebral-Amyloid-Angiopathy. Press release.
[2] Cummings JL, et al. The costs of developing treatments for Alzheimer’s disease: A retrospective exploration. Alzheimer’s Dement. 2021; 1-9. https://doi.org/10.1002/alz.12450
[3] Social Security Act §1862(a)(1)(A).

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Would you commit to paying $20 per month ($240 per year) on a drug for your child that doesn't work? Of course not. So why would every Medicare subscriber be forced to spend this amount on an Alzheimer's drug that is of no benefit to Alzheimer's patients?

The FDA's decision to approve Aduhelm showed a disregard for science and for process and standards for approving new drugs. The FDA has not been a shining light throughout the Covid pandemic and this has added to its credibility issues. Two identical phase 3 trials were stopped early because reviewed data found that the trials, if completed, were unlikely to show the drug benefitted Alzheimer's patients. In addition, Biogen and the FDA were 'snuggling very close' during the analysis of data from the key clinical trials after the termination of phase 3 because further testing would prove futile.

I am urging you not to compound the FDA's 'error.' Aduhelm has shown no scientific evidence that there is any clinically meaningful benefit in terms of cognitive function. It's an expensive failure. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under Medicare. That way, we Medicare clients could see our monthly premium reduced by $20 (I hope!).

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am a member of the Right Care Alliance and I hope to one day become a geriatrician. I am invested in making sure that all drugs approved by the FDA, and specially those mainly for older adults, work and that their benefits outweigh their risks. Thank you for requiring Biogen to show just that, and thank you for requiring that their trial is experimental, not observational. With the stakes as high as they are given the population of people with Alzheimer's, it does not make sense to require anything less - particularly when, as here, the safety profile was very troubling. (40% brain swelling and bleeding seen on MRIs). I am very distressed Biogen has still not published the data on 301 and 302; it strongly suggests their presentation of the data is biased. I want there to be effective treatment for Alzheimer's disease - I don't want false hope to be packaged up as an effective treatment. Please stay strong."

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Please do not continue with the FDA's decision to approve "Aduhelm" for treatment of Alzheimer’s disease at this time. The process by which the approval was done was flawed, and the drug may not be of any benefit at all.

The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefited Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s approval of Aduhelm for treatment of Alzheimer’s disease showed a disturbing disregard for scientific evidence and eviscerated the agency’s own standards for approving new drugs. As a result, the agency’s credibility has been damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a data review found that the trials, if continued to completion, were highly unlikely to show the drug benefited Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s serious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful cognitive benefit for Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable or necessary for treatment of such patients. I strongly urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Thank you for the opportunity to comment on the national coverage analysis (NCA) for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (AD) (CAG-00460N) proposed decision published on January 11, 2022. My name is Tanyaluck Thientunyakit and I am a member of The Society of Nuclear Medicine and Molecular Imaging (SNMMI) and current board member of the Brain Imaging Council.

We appreciate efforts by the Centers for Medicare & Medicaid Services (CMS) to engage with interested stakeholders on this important topic. We have met with the Coverage and Analysis Group (CAG) concerning this NCA twice, and we are now submitting written comments to provide CMS with our recommendations regarding Medicare coverage for amyloid PET for patients who may be candidates for anti-amyloid monoclonal antibody therapy as well as for its use in patients who receive the therapy.

In the SNMMI’s first comment letter regarding this NCA, we emphasized the importance of a national coverage policy for amyloid PET tracers to improve health equity and access to monoclonal antibodies for the treatment class for AD. Beta amyloid PET is essential for identifying patients who have beta amyloid in their brains who may, therefore, benefit from antibody products that target beta amyloid. Further, it is useful for quickly identifying patients who won’t benefit from this therapy and could suffer from toxic side effects without therapeutic benefit. The trials that led to Food and Drug Administration (FDA) approval of aducanumab, the only monoclonal antibody targeted at amyloid for the treatment of AD that is approved by the FDA, required PET confirmation of the presence of beta amyloid in the brain. Currently, there are three FDA-approved radiopharmaceuticals for the identification of amyloid plaque in the brain: 18F florbetapir, 18F flutemetamol, and 18F florbetaben.

Under existing national coverage determination (NCD) 220.6.20, Medicare only covers amyloid PET in the context of an approved clinical study under the Coverage with Evidence Development (CED) policy. In the draft national coverage determination (NCD) on monoclonal antibodies, CMS proposes to provide the following coverage for amyloid PET:

For any CMS approved trials, or trials supported by the NIH, that include a beta amyloid positron emission tomography (PET) scan as part of the protocol, it has been determined that these trials also meet the CED requirements included in the Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease NCD (220.6.20), and one beta amyloid PET scan will be covered per patient, if the patient did not previously receive a beta amyloid PET scan.

This proposal inappropriately limits access to the critical diagnostic information provided by amyloid PET scans, creates inefficiencies for study sponsors, and may increase the emotional burden on patients with mild cognitive impairment who must enroll in a clinical trial before getting a PET scan only to find out after enrollment that they are not eligible to receive monoclonal antibodies because there is no beta amyloid present in their brain. We describe these concerns in greater detail below and provide recommendations for improvements CMS should make in the final NCD.

CMS should cover an amyloid PET scan before a patient is considered eligible for a CMS-approved study

Under the draft NCD, amyloid PET will only be covered as part of the protocol for a study that meets the CED requirements for coverage of monoclonal antibodies. In other words, patients must be enrolled in a clinical trial for the PET scan to be covered. However, the information provided by the PET scan helps to determine whether the patient meets one of the two criteria required for inclusion in the study—specifically whether the patient has amyloid pathology consistent with AD. In order for study sponsors to obtain the information about whether the patient is a candidate for the therapy and therefore is a candidate for the clinical trial, the patient must first be enrolled in the trial.

This requirement is illogical, highly inefficient, and will create significant burdens for both trial sponsors and patients. Enrolling patients in a clinical trial, including obtaining the necessary informed consent agreement, requires substantial time and resources. It also requires educating the patient about the trial, the potential benefits of the study therapy, and the associated risks. Going through those steps for patients who should not receive the therapy and cannot continue in the trial wastes sponsor resources and may cause unnecessary emotional harm to patients, who will be educated about a treatment option that is not available to them at a time when other therapeutic options are extremely limited. It may also increase out-of-pocket costs for patients in underserved areas who need to travel to distant locations to participate in clinical studies. Such patients could spend time and money to reach trial sites only to learn that they are not in fact eligible to participate in the study.

Amyloid PET can identify patients who will not benefit from aducanumab ahead of time and simplify the enrollment process for patients and trial sponsors. It will also improve care for patients without beta amyloid as the treating professionals and caregivers can focus on treatment modalities that are appropriate for those patients. CMS should not limit coverage to trial participants but should provide coverage of amyloid PET to determine whether a patient should be enrolled in the trial. This will require that CMS finalize coverage for one PET scan to all patients considered candidates for aducanumab. CMS could accomplish this by retiring the beta amyloid CED NCD or by establishing additional, non-CED coverage of beta amyloid PET as part of the monoclonal antibody NCD. For additional reasons discussed below, we recommend that CMS retire NCD 220.6.20.

CMS should not finalize a limit of one beta amyloid PET scan per lifetime

Patients who are potential candidates for monoclonal antibodies should have an amyloid PET scan immediately before determining whether they are a candidate for monoclonal antibody therapy and before entering a covered trial. Amyloid status observed in earlier scans may no longer reflect a patient’s current beta amyloid status. Studies evaluating use of blood biomarkers to determine amyloid status have noted the progression of some patients from positive blood/negative PET to positive PET. There is no evidence to suggest that a single amyloid PET scan per patient is appropriate or that an outdated scan can provide the diagnostic information needed to determine whether a patient is currently a candidate for therapy. Furthermore, SNMMI does not understand the scientific basis for limiting beta amyloid PET to one scan per lifetime. Not only can CNS beta-amyloid status change over time, as discussed below, ongoing clinical trials for monoclonal antibody therapies for AD have used the results of post-treatment beta amyloid PET to inform a decision to discontinue monoclonal antibody therapy.

CMS should require post-treatment beta amyloid PET to be performed as needed to document the removal of beta amyloid PET from the brain

In addition to scans to determine a patient’s eligibility for therapy, CMS should require and cover post treatment PET scans to determine whether beta amyloid has been removed. The Phase 2 Lilly trial for a monoclonal antibody under development (donanemab) required multiple post-treatment PET scans and participants were switched to the placebo if amyloid plaque levels fell below certain parameters.

CMS should require trial sites to use beta amyloid PET pre- and post-treatment to assure accurate measurement of beta amyloid. CMS should allow as many PET scans as are needed to ensure that the trial design is optimal and reliable and provides physicians the information needed to make informed decisions about initiating and continuing therapy. Notably, one or more scans during therapy to verify removal of amyloid must be covered.

CMS should retire the current PET CED in conjunction with finalizing the monoclonal antibody NCD

We reiterate our previous requests that CMS retire NCD 220.6.20 as soon as possible. Continuation of limitations on amyloid PET while other uses of PET for AD, such as tau PET, are covered at the discretion of the Medicare Administrative Contractors (MAC) creates an illogical and confusing situation for physicians, patients, and clinical trial designers. Under the current disjointed coverage, patients can, in principle, have an unlimited number of tau PET scans, but can have only one amyloid PET scan - and that single PET scan is limited to CED. Under current coverage, there is an incentive to preferentially use tau PET to identify patients for clinical trials and for diagnosing AD even though this is not the current standard of care. Coverage of tau and beta-amyloid PET should be equivalent, i.e. at the level of care currently allowed for tau PET, to allow full access to appropriate diagnostic tools.

We understand that CMS may be awaiting results from the New IDEAS trial that is approved under the CED requirements for NCD 220.6.20 before acting on our request. The completed IDEAS trial found beta-amyloid PET was associated with changes in management in more than 60% of patients with mild cognitive impairment or dementia of uncertain etiology and a change in diagnosis in 36% of patients. However, the data that will come from New IDEAS is not relevant to the proposed decision for monoclonal antibodies. The design and endpoints of New IDEAS are completely different than the proposed CED requirements in the draft NCD.

Furthermore, New IDEAS is currently undergoing a 6-month pause due to problems in enrolling underrepresented populations. The accrual phase for the study was originally projected to close in Q3 of September 2023. However, closure of accrual is based on the enrollment of 7,000 participants and closure is now expected in 2024. Therefore, while preliminary data from New IDEAS are very promising, we do not believe CMS should wait for additional evidence to retire the amyloid PET NCD. If anything, CAG should be more concerned with results of aim 2 of IDEAS, which are due imminently.

CMS should resolve inconsistencies in coverage for diagnostic tools that may be used in CED trials for monoclonal antibodies by retiring NCD 220.6.20 and providing coverage of amyloid PET at MAC discretion.

CMS Should Not Limit Sites of Service for Approved Clinical Trials to Hospitals

In its proposed decision CAG stated, “We also propose that the setting for CMS-approved clinical trials remain in hospital-based outpatient facilities as this ensures integrated and coordinated care, availability of advanced imaging or other diagnostic tests, and rapidly-available advanced care if needed.” There are many clinics and multispecialty groups who regularly participate in clinical trials and have the expertise to enroll patients and implement complex clinical trials. Additionally, many academic faculty practice plans where patients with mild cognitive impairment are seen and treated are associated with hospitals but are not hospitals themselves are actually enrolled in Medicare as physician offices. Furthermore, requiring that patients who are potentially eligible for a CMS approved clinical trials travel to hospitals to get a PET scan is burdensome, especially for patients in underserved areas and may inhibit enrollment in those trials. We would like to note that in IDEAS about 69% of participants were referred to non-hospital-based PET facilities. Limiting the trials to only hospitals would greatly impede patient access due to geographical and payment considerations and contribute to health care disparities.

Appropriate reimbursement of amyloid PET is necessary
Currently, the three amyloid PET tracers are reimbursed an average of nine percent of their pass-through payment rate due to being bundled in with the scan in the hospital outpatient prospective payment system (OPPS). Under the Medicare Physician Fee Schedule (MPFS), which includes non-hospital facilities, amyloid PET tracers are paid separately. The current bundling policy will make it impracticable for hospitals to participate in the therapy CED trial (for those patients that do not already have a PET scan).

New IDEAS illustrates the chilling effect that the lack of appropriate reimbursement of amyloid PET scans has on the enrollment of hospitals in this study: Only approximately 16 hospitals out of the 125 hospitals who participated in the IDEAS trial are participating in the New IDEAS trial. In fact, the 2020 Government Accountability Office (GAO) Report notes the impact of the current OPPS policy. In their report, the GAO acknowledged that hospitals’ use of diagnostic radiopharmaceuticals was higher when drugs were eligible for the initial pass-through payments than when they were bundled with the scan. Additionally, at the CMS Advisory Panel on Hospital Outpatient Payment (HOP) meeting on August 31, 2020, the panel recommended that “CMS pay separately for all diagnostic radiopharmaceuticals.”

* * * * *

In conclusion, in conjunction with the final NCD on monoclonal antibodies directed against amyloid for the treatment of AD, we strongly recommend that CMS remove the coverage limitations on amyloid PET by:

Retiring NCD 220.6.20;

Establishing that amyloid PET will be covered pre-clinical trial to identify patients who are candidates to receive monoclonal antibody therapy and as necessary after therapy initiation to inform treatment decisions; and

Clarifying that there is no lifetime limit on the number of medically necessary amyloid PET scans that a patient can receive.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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In their proposed decision for coverage of aducanumab and other such monoclonal antibodies, CMS has recognized the need for further investigation to protect older and disabled adults. Importantly, CMS has suggested requiring that the drug be tested through well-designed, randomized controlled trials within patients representative of populations most impacted by Alzheimer’s disease, including racial and ethnic minorities. We see this as correcting the precedent set forth by the FDA in awarding accelerated approval for aducanumab. Through this coverage decision, manufacturers will instead have to meet a higher standard when conducting clinical trials for such Alzheimer’s disease drugs by making evident that the treatments show a clear change in patients’ cognition and function and are safe, not just a change in the level of a surrogate marker seen on MRI imaging.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a serious disregard for science and a complete disregard for the agency’s standards for approving new drugs, thus damaging the agency’s credibility.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s profound error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Thank you for the opportunity to share comments on the proposed National Coverage Determination requiring Coverage with Evidence Development (NCD with CED) for monoclonal antibodies (mABs) targeting amyloid for the treatment of Alzheimer’s disease. We have several serious concerns about the proposed NCD with CED and urge you to reconsider, remove CED requirements in this NCD, and allow coverage for FDA-approved uses of these Alzheimer’s disease therapies for Medicare beneficiaries nationally. People living with Alzheimer’s disease in consultation with their care partners and treating physicians should have the option to use FDA-approved therapies and CMS should not take those treatment options away.

The NCD with CED would exacerbate known health disparities.

Eliminating health disparities to advance health equity has never nor will ever be achieved by erecting barriers to access. The restrictions that the proposed NCD with CED erects significant barriers that disproportionately will affect people living in rural areas, people of color already underrepresented in clinical research, and people living with Downs syndrome. All are excluded from participation either by explicit exclusion in the proposed CED trials or by the realities of the barriers this CED erects. Simply mandating diversity and then compounding the existing systemic barriers to achieving greater participation is not opening a door to greater representation, but instead closes the door and bolts it.

The NCD with CED would set a dangerous precedent that should not stand.

The proposed draft NCD with CED would establish a dangerous precedent that threatens access for all Alzheimer’s treatments within the class identified as well as any new therapies for which Medicare deems FDA approval and associated clinical data provides insufficient evidence of “clinical benefit” to Medicare beneficiaries. CMS has never applied an NCD with CED to any drug approved by the FDA nor extended those restrictions to an entire therapeutic class. This issue is made even more troubling as it proposes to cover an entire class of potential therapies for which clinical trials are not yet complete nor final clinical trial data are available. The proposed NCD with CED if finalized as drafted sets an unprecedented new standard for coverage of FDA-approved therapies and significantly undermines FDA’s authority to evaluate the safety and effectiveness of therapeutics.

This precedent, if it proceeds, would have a devastating effect not only on people living with or at risk of developing Alzheimer’s disease, but also on people living with other life-threatening conditions for which treatment options are limited to non-existent but have hope for new therapies in clinical trials. To the extent that FDA-approval via the accelerated approval pathway is a factor of this proposal, the NCD with CED subverts the purpose behind the Accelerated Approval pathway and further impedes the development of and access to promising Alzheimer’s disease therapies in currently development. The potential precedent also threatens the design and intent of the Accelerated Approval pathway as established by the FDA, codified by Congress, and operational for more than 20 years.

Public comments by individuals with lived experiences with therapies in question universally are opposed to the proposed NCD with CED.

CMS has received several thousands of comments on the proposed NCD with CED. By our count, fewer than 15 (as of Thursday, February 10th) were comments from individuals with direct, personal, lived experiences with one or more of the therapies subject to the proposed NCD with CED. Those individuals include care partners of patients receiving treatments, prescribers, and clinical investigators. Universally, those individuals oppose the proposed NCD with CED. As you evaluate the many comments you receive, we hope that you will pay closest attention to those individuals with these experiences and follow their advice.

Alzheimer’s disease is a cruel, fatal illness that emotionally and financially devastates individuals affected and their families. It is not a “normal” part of aging and should receive the same compassion and attention as fatal cancers, genetic diseases, and other serious, life-threatening illnesses. We urge you to reverse course and issue an NCD providing coverage based on the FDA-approved labeling and leave the evaluation of risks and benefits to the individuals affected, their families, and their trusted physicians.

Sincerely,

Candace DeMatteis
Policy Director
Partnership to Fight Chronic Disease

List of Individuals Providing Comments and Noting Lived Experiences with Therapies in Question:

Robert Mannel, 1/12/2022
David Weisman, 1/17/2022
Laura Graves, 1/17/2022
Sanglin Oh, 1/17/2022
Vithal Dhaduk, 1/18/2022
Claudia Vierra, 1/18/2022
Cynthia Murphy, 1/20/2022
Kate Turner, 1/21/2022
Joseph Masdeu, 2/5/2022
Teresa Masi, 2/7/22
Linda Neel, 2/8/2022
Diane Michalczuk, 2/8/2022
Concetta Forchetti, 2/8/2022

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Hello, my name is Kathy Horn, and I’m from Lyons, Ne. I have a [PHI Redacted] with Down syndrome. I believe that people with Down syndrome and other disabilities should have the same right to health care as everyone else. I have recently become aware of a new Alzheimer’s drug called aducanumab and that CMS has proposed coverage that excludes people with Down syndrome and other intellectual and developmental disabilities. I understand the need to make sure treatments are safe, but this is the wrong path forward. CMS must abandon the proposed CED process because it?discriminates against people with intellectual and developmental disabilities now and into the future. Having Down syndrome should not prevent a patient from accessing Alzheimer’s treatments. If one patient covered by Medicare or Medicaid can access an Alzheimer’s treatment, every patient covered by Medicare or Medicaid should be able to if their doctor believes it’s right for them.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and ignored the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefited Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am writing to you regarding the Proposed National Coverage Determination (NCD) for monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease. This proposed decision most immediately affects five anti-amyloid treatments, including the Food and Drug Administration (FDA) approved Alduhelm.

Under the proposed NCD, the Centers for Medicare and Medicaid Services (CMS) would only cover this class of treatments for people enrolled in randomized placebo-controlled clinical trials. I am concerned about the overly restrictive and unprecedented CMS draft decision: It would restrict accessibility and place a major burden on those seeking treatment, many of whom would only receive a placebo. In order to participate, many people such as myself would need to travel long distances to research institutions. Also, the proposed NCD would restrict the availability and coverage for other anti-amyloid medications that are still undergoing clinical trials and whose results we do not yet know. This unscientific and clinically unsound policy will effectively ration care by delaying access to many patients who will then probably not be able to benefit or receive treatment because of the progression of their disease.

Aduhelm is only a first and imperfect step in developing treatments that slow or halt the progression of Alzheimer’s disease, but much more can be learned if the proposed NCD is less restrictive. The NCD can still require specialized teams to manage its use and collect data regarding its effectiveness and side effects without the necessity of additional expensive placebo-controlled clinical trials that will take many years to complete. This can still contribute to the development of clinical care guidelines for the prudent use of anti-amyloid drugs.

CMS should not make policies that will stifle the development and use of other anti-amyloid drugs before current clinical trials are complete and have been reviewed by the FDA. Please give individuals, families and caregivers facing a devastating fatal disease more life. I urge you to reconsider the proposed NCD in order to ensure better access for all who could benefit from FDA approved treatments. Feel free to contact me if you have further questions. Thank you for your consideration.

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As a nurse & former caregiver I am truly concerned regarding the direction this is taking in limiting care to those in need. I serve our American Heros in a rural community. Many of them are being diagnosed with Alzheimer's and other related Diseases. The limitation on approval and lack of payment would keep many if not all of them from getting the care they need and deserve. Many of them do not have access to participate in a clinical trial, for various reasons.

As a former caregiver I would have done whatever I could to prolong time with my [PHI Redacted] who passed away with Alzheimer's Disease a few years ago. The thought that people would be denied this medication based on their ability to participate in a clinical is heart breaking and needs to change immediately.

Please reconsider and share this gift of life with EVERYONE in need.

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I am in support of the current CMS standing concerning limiting further use of aducanumab to only RCT study.

The Amyloid Cascade Hypothesis surfaced in 1992. Since that time much has been learned about Alzheimer's disease at the cellular and molecular level. Hundreds of different monoclonal antibodies have been developed through the years to try to halt cognitive decline and all have failed for various reasons.

Recently a new monoclonal antibody was submitted for approval to the FDA by Biogen. In the FDA approval process the drug was judged ineffective for arresting cognitive decline in Alzheimer's disease by the FDA Advisory Board based upon Biogen's two randomized controlled trials (RCT). Ten members of the board deemed it ineffective and one abstained. The FDA statatician also submitted a detailed report stating the drug showed no benefit for arresting cognitive decline.

The FDA administration however overruled the advisory board and gave broad approval. Three members of the board resigned out of frustration and disgust stating that this was the worst decision ever made by the FDA in granting drug approval. Behind the scene meetings had been held between Biogen and the FDA administration before its approval of the drug. This is highly suspect and now is the subject of a congressional investigation.

Currently a publicity campaign is being waged to have the CMS allow broad funding of this drug. In the campaign there is appeal made to emotion as well as mention of the support of many Alzheimer Associations (although there is failure to mention than many of these are supported by the pharmaceutical industry.)

Complications of using monoclonal antibodies to reduce amyloid plaque have been known for many years. However this also results in removing the amyloid buildup in arteriole walls that comes with advancing age and moreso with Alzheimer's disease leaving them prone to leakage of blood and plasma causing the microbleeds (or larger) and edema.

The argument that aducanumab's ability to remove extracellular amyloid plaque is an adequate surrogate of its ability to halt cognition decline is wrong. This is equivalent to thinking that umbrellas are present when it is raining thus to remove the umbrellas will stop the rain. What more needs to be said.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

You probably should read this article https://www.nytimes.com/2021/07/19/health/alzheimers-drug-aduhelm-fda.html Please don't let Biogen get away with fleecing the American public and lining their own pockets with undeserved money. I've worked in big pharma companies and know and understand how they work to manipulate data to their advantage. This is another example!

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I applaud CMS’s proposal to restrict coverage of anti-amyloid monoclonal antibodies such as aducanumab for the treatment of Alzheimer’s disease only in the setting of randomized-controlled trials under Coverage for Evidence Development (CED) as such a coverage decision prioritizes and protects patients above all else. As a practicing physician, we urge CMS to adopt this proposal as their final national coverage determination to ensure that our patients have access to truly effective and safe medications.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s (FDA’s) decision to approve Aduhelm for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program. It’s imperative to put patients and consumers before Big Pharma profits.

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Dear Secretary Becerra and Administrator Brooks-LaSure,

I am a neurologist at the Mayo Clinic in Rochester, MN,, Director of the Mayo Clinic Alzheimer’s Disease Research Center and former Chair of the Advisory Council on Research, Care and Services for the US Plan to Address Alzheimer’s Disease.

The CMS proposal for Coverage with Evidence Determination (CED) for monoclonal antibodies represents a reasonable decision given the circumstances surrounding the accelerated approval of aducanumab by the FDA. Clearly, CMS was faced with a difficult task regarding either full coverage, denial or a CED type of approach, and they chose the CED. However, some of the specifics of the proposed CED are very problematical.

The requirement that coverage be determined on the basis of the beneficiaries being involved in a randomized controlled trial (RCT) is absolutely unique to Alzheimer’s disease. This is highly unusual and will put a significant restriction on the availability of the treatment to patients. In particular, the proposal states that the RCTs should be performed in a hospital-based environment. This will, in fact, further restrict the patient populations that may be eligible for participation. While CMS appropriately comments on the necessity for the participation of diverse populations in these RCTs, this requirement will be counterproductive toward that goal.

The proposal appears to usurp some of the role of the FDA in approving drugs for accessibility to the population. The FDA is charged with the approval process for drugs, based on efficacy and safety, and consequently, they have given accelerated approval for the use of aducanumab for Alzheimer’s disease. The FDA has determined that aducanumab lowers amyloid plaque levels in the brain but is uncertain of its clinical utility. Consequently, to determine if this drug is clinically beneficial, one needs to evaluate its efficacy in a broad range of patients in the country in the real-world environment rather than those who have access to hospital based RCT’s. Several efforts are underway to maximize the safety of patients through appropriate use recommendations. Furthermore, if the RCT’s are contingent upon NIH funding, the delays that will be encountered are unacceptable.

The decision to include all monoclonal antibodies in this class is also problematical. Each of these compounds has a different mechanism of action and, consequently, should be viewed as an individual therapeutic option depending on its performance in RCTs.

It is unclear how ongoing clinical trials that are sponsored either by industry or by public-private partnerships will be evaluated. Does the CED suggest that ongoing trials that may seek full approval from the FDA will have to abide by this NCD to receive coverage?

The US National Plan to Address Alzheimer’s Disease has as its primary goal the development of effective treatments for Alzheimer’s disease. The target date of that goal is 2025, and the CED, as currently proposed, will make it extremely unlikely that definitive data will be forthcoming before that deadline is reached.

In summary, CMS has made a responsible decision to propose a CED to assist them in making decisions on coverage; however, the manner in which the CED is constructed is particularly convoluted and will, in fact, result in lack of access for persons with Alzheimer’s disease from receiving adequate therapies. We ask that CMS reconsider the restrictions placed on the CED.

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As a board-certified geriatrician and a former health services researcher, I am strongly in favor of CMS's plan to only pay for Aduhelm in the setting of a clinical trial, and I urge CMS administrators to finalize this plan.

I work with patients and families affected by Alzheimer's. I understand how desperately they are seeking for cures, treatments, or ways to delay the progression of the disease. But so far there is very little evidence that Aduhelm provides meaningful benefit, while there is clear evidence that it is risky. Medicare should not cover this treatment until further research clarifies just who — if anyone — is likely to benefit. We do need to invest more in Alzheimer's treatment, but we need to focus that investment on clinically proven approaches...which include non-pharmacological approaches such as social support and teaching families and patients dementia management strategies (those could be covered at a fraction of the cost of Aduhelm).

Thank you CMS!

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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February 10, 2022

The Honorable Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
Hubert H. Humphrey Building
200 Independence Avenue, SW
Washington, DC 20201

RE: Proposed National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N)

Dear Administrator Brooks-LaSure:

The Federation of American Hospitals (FAH) is the national representative of more than 1,000 leading tax-paying hospitals and health systems throughout the United States. FAH members provide patients and communities with access to high-quality, affordable care in both urban and rural areas across 46 states, plus Washington, D.C and Puerto Rico. Our members include teaching, acute, inpatient rehabilitation, behavioral health, and long-term care hospitals and provide a wide range of inpatient, ambulatory, post-acute, emergency, children’s, and cancer services.

The Federation supports CMS’ recognition of the importance of providing Medicare coverage for new and potentially innovative treatment of Alzheimer’s disease. With nearly 6 million Americans suffering from Alzheimer’s disease, there is a well-recognized unmet need for treatment. Alzheimer’s disease is the primary cause of dementia in older Americans and the disease also is prevalent in Black and Hispanic populations. CMS’ proposed coverage will advance efforts to treat America’s seniors suffering from Alzheimer’s disease, as well as contribute to reduced health disparities, an important goal for this Administration and the Federation.

CMS proposes to cover FDA-approved monoclonal antibodies against amyloid for the treatment of Alzheimer’s disease under Coverage with Evidence Development (CED) in CMS-approved randomized controlled trials and in trials supported by the National Institutes of Health. For trials covered by CMS, CMS proposes that these trials also meet the CED requirements in the Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease NCD (220.6.20). Although there is currently one monoclonal antibody against amyloid approved by the FDA, the proposed CED would cover the entire class of similar drugs if, and when, they are approved by the FDA.

The Federation supports the proposed CED but does not think that it should be inclusive of all drugs that are FDA-approved monoclonal antibodies against amyloid. The FAH believes that CMS should determine the appropriate coverage for each drug based on the specific clinical benefits and risks associated with each drug in this class. We do not believe it is appropriate to propose a broad class CED based on the evidence from Aduhelm™, the first drug approved by the FDA. We agree with CMS’ conclusions that the evidence for Aduhelm does not support a clear clinical benefit and it is difficult to assess if the benefits from treatment outweigh the risks of adverse events such as ARIA. For Aduhelm, we support CMS’ proposal to conduct clinical trials to evaluate whether the treatment results in a significant and clinical meaningful difference in decline in cognition and function and to quantify the adverse events associated with this treatment. We are concerned, however, that CMS is assuming that all other FDA-approved drugs in this class will have the same limitations in the evidence (provided for both clinical benefits and risks).

We appreciate that CMS generally provides broad national coverage for a medical procedure that involves a device, and coverage is not specific to each device manufactured by different companies. Although monoclonal antibodies directed against amyloid can be considered a drug class, there can be important differences in the monoclonal antibodies that can produce significant differences in clinical outcomes and associated risks. We believe CMS is premature in proposing CED coverage for this entire class. Instead, in order to facilitate treatment with innovative therapies, CMS should evaluate each drug and expand the CED only if appropriate.

The Federation also believes it is important for CMS to closely monitor the data accumulated from CEDs and make public determinations, potentially annually, as to whether or not additional data are needed for CMS to conclude that a treatment is reasonable and necessary for treatment of Medicare beneficiaries. We appreciate the Administration’s actions to increase the diversity of patients enrolled in clinical trials, but the most equitable way to reduce health disparities is to provide treatment in all clinical settings and not restrict access to clinical trials. We recommend that CMS evaluate the duration of CEDs to ensure they are completed in a timely fashion.

**************

The FAH appreciates the opportunity to provide these comments on the proposed NCD. If you have any questions or would like to discuss further, please do not hesitate to contact me or a member of my staff at (202) 624-1534.

Sincerely,
Charles N. Kahn III
President and CEO
Federation of American Hospitals

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Hello
It is time to stop supporting Big Pharma insatiable greed. There is no way to justify Aduhelm's outrageous cost ($56k a year). No way at all.

I seem to remember that the process to certify Aduhelm was flawed and that the process was accelerated to accommodate the pharmaceutical giant. The FDA's advisory committee DID NOT recommend approval so why did the FDA overruled its own advisory committee and approve a drug with NO therapeutic benefit.

It's time to stop the greed and corruption in our country on all levels and Medicare patient abuse is a good place to start.

Thank you.

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The FDA’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease shows a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged. The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion , were unlikely to show the drug benefitted Alzheimer’s disease patients. The integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analysis of data from the key clinical trials of the phrase 3 clinical trials because of futility,
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2022. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s diseased patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients.
I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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FDA’s accelerated approval to aducanumab is a HORRIFYING, UNACCEPTABLE BLOW to millions impacted by Alzheimer’s disease. Aducanumab has NO DATA showing effectiveness compared to placebo. Worse, it caused life threatening side effects (brain swelling & bleeding) in 40% receiving an FDA approved dose. First, DO NO HARM!!! Life threatening injuries (brain swelling & bleeding) caused by a drug no better than placebo? If anyone collected data on suffering, it would include: pain, suffering, death, increased hospitalizations (with accompanying horrible effects) as well as raising false hopes, causing financial suffering, (this list could be pages long)…this is UNACCEPTABLE. The FDA’s inappropriate, terrible precedent has led to other manufacturers of monoclonal antibodies with uncertain mechanisms of action to pivot towards (inappropriate) accelerated approval. These also lack clinical efficacy within pivotal trials. Should these other therapies also receive such approval, manufacturers would only need to confirm clinical benefits in post-marketing trials. Stunningly, the FDA awarded the manufacturer of aducanumab an extraordinary NINE years (far longer than the median deadline granted to other accelerated approval drugs). Exposing patients to a drug without proven effectiveness and the very high risk of serious life threatening side effects including brain swelling and bleeding? STOP THE MADNESS…PLEASE…

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The Food and Drug Administration’s (FDA’s) decision to approve Aduhelm for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Dear Administrator Brooks-LaSure:

On behalf of GE Healthcare, thank you for the opportunity to comment on the Centers for Medicare and Medicaid Services (CMS) National Coverage Analysis (NCA) Proposed Decision for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease. As a leading global medical technology, pharmaceutical diagnostics, and digital solutions innovator, GE Healthcare enables clinicians to make faster, more informed decisions through intelligent devices, data analytics, applications, and services. GE Healthcare Pharmaceutical Diagnostics is the global leader in the production and supply of contrast media and molecular imaging agents used to enhance medical imaging exams for major disease area diagnostic and treatment pathways. Our Pharmaceutical Diagnostics products are used in over 100 million procedures globally every year.

GE Healthcare appreciates CMS’ thorough review of coverage for monoclonal antibodies for treatment of Alzheimer’s Disease; however, we believe that there are opportunities to modify CMS’ coverage with evidence development (CED) proposal. We believe this could result in more rapid access for a greater number of beneficiaries with mild cognitive impairment (MCI) and mild Alzheimer’s disease who are in dire need of improved diagnosis and treatments, while facilitating a greater understanding of the impact on patient outcomes.

GE Healthcare acknowledges that the proposed decision memo includes coverage of a beta amyloid Positron Emission Tomography (PET) imaging scan if it is included in the authorized study protocol. Coverage of amyloid PET will ensure improved diagnostic accuracy. Clinical studies have shown that beta amyloid PET imaging results in changes of the etiologic diagnosis in a significant number of patients with suspected Alzheimer’s Disease and leads to changes in patient management—thus ensuring that the right patients will receive therapy.

However, we are concerned that the following three policy proposals will harm beneficiary access to amyloid PET:

1. Covering only one amyloid PET scan under the CED
The proposed decision memo restricts the number of scans to one per patient lifetime. CMS should not interfere with clinical decision-making in this manner. Arbitrarily limiting coverage to a single scan is problematic if a clinical need for additional scans, for example to confirm treatment response and possibly adjust treatment, is identified. The one scan limitation could also preclude enrollment if a beneficiary had a negative scan in the past, prior to the availability of therapy. At minimum, coverage should include a follow-up scan to determine the extent of amyloid removal.

2. Limiting trials to the hospital outpatient setting
The requirement that “[a]ll trials must be conducted in a hospital-based outpatient setting” is highly problematic from an access perspective. Hospital-based Randomized Clinical Trials are feasible primarily in academic medical centers, meaning that CED-eligible trial sites will be concentrated at such centers under the proposed decision memo’s coverage criteria. Accordingly, the agency’s proposal risks concentrating access to anti-amyloid mABs, for the foreseeable future, among people who live in major metropolitan areas or who have the resources to frequently travel to those areas.

Additionally, CMS’ policy of packaging payment for beta amyloid PET in the hospital outpatient setting continues to create a disincentive for hospitals to use beta amyloid PET or participate in clinical trials, which could further exacerbate access disparities. CMS should instead outline the clinical qualifications of clinical trial sites, rather than specify whether the care is provided in a hospital or free-standing outpatient setting.

3. Proposed CED continues the current NCD limitations on beneficiaries’ access
The evidence shows that beta amyloid PET imaging provides an accurate etiologic diagnosis for patients with suspected Alzheimer’s Disease. To date, the largest prospective study in Alzheimer’s Disease, the Imaging Dementia—Evidence for Amyloid Scanning Study (IDEAS), a CMS approved CED study, has shown beta amyloid PET scans result in a change in diagnosis for 35.6% of patients with MCI and dementia, and 36.1% of patients who were considered to have Alzheimer’s Disease following clinical assessment alone. The amyloid PET scan also led physicians to change patient management in more than 60% of patients . CMS should therefore resolve the persistent access issue coming from the current CED (Decision Memorandum CAG-00431N) under NCD 220.6.20 and remove the CED requirement for beta amyloid PET. This can be accomplished by fast tracking full national coverage of beta amyloid PET at the same time as the Decision Memorandum for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease is finalized.

We share the agency’s interest in providing access to high quality care for beneficiaries with Alzheimer’s Disease and welcome this opportunity to comment and to collaborate in the future.

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I have been following the story of this drug in the news, and have spoke to a number of physician friends, including geriatric doctors. Unwarranted approval of drugs like these do nothing but line the pockets of big Pharma and give false hope to patients and their families. It is simply wrong to approve drugs that have not faced rigorous and comprehensive scrutiny and trials.
In their proposed decision for coverage of aducanumab and other such monoclonal antibodies, CMS has recognized the need for further investigation to protect older and disabled adults. Importantly, CMS has suggested requiring that the drug be tested through well-designed, randomized controlled trials within patients representative of populations most impacted by Alzheimer’s disease, including racial and ethnic minorities. We see this as correcting the appalling precedent set by the FDA in awarding accelerated approval for aducanumab. Through this coverage decision, manufacturers will instead have to meet a higher standard when conducting clinical trials for such Alzheimer’s disease drugs by making evident that the treatments show a clear change in patients’ cognition and function and are safe, not just a change in the level of a surrogate marker seen on MRI imaging.

Thank you, Kathleen M. Casey

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Nearly a decade ago, CMS consigned amyloid PET to "coverage with evidence development." Despite the fact that three FDA ligands had already been approved even before the decision was rendered, in 2022 I still cannot order an amyloid PET for patients who might benefit greatly from the increased diagnostic precision afforded by such imaging.

In the case of aducanumab, I remain agnostic in the great risk/benefit controversy, perhaps leaning slightly toward perceiving risk in excess of benefit. But that applies only to aducanumab.

The decision to consign all monoclonal antibodies that might finish clinical trials in the future to coverage with evidence development on the basis of the aducanumab molecule is narrow-minded and short-sighted. This action will knock AD therapeutic trials backward to an unconscionable degree.

If your hope was to hamstring and disincentivize pharmacotherapy development for the millions of patients and families suffering from AD, congratulations. You have achieved your misbegotten aim.

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I am writing to applaud the Centers for Medicare and Medicaid Services (CMS) for their proposed national coverage decision regarding “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease” issued on January 11, 2022. I am a practicing geriatrician and, like many other clinicians, patients, and experts, I was deeply disturbed by the Food and Drug Administration’s (FDA) recent decision to approve the Alzheimer’s disease drug, aducanumab, despite the significant lack of evidence regarding its efficacy as well as concerns about the drug’s safety. While the FDA has defended this decision by noting that they granted accelerated approval to aducanumab, which only requires the drug to demonstrate an effect on a surrogate marker thought to be predictive of clinical benefit, the agency has failed to note that the particularly surrogate marker underpinning aducanumab’s approval – that of beta-amyloid seen on MRI scans of the brain – has failed in over two dozen clinical trials to show any association with clinically meaningful changes in Alzheimer’s disease patients.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this action, the agency’s credibility has been damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was inappropriately and adversely affected by the close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.am.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was, in my opinion, based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug provided benefit for Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and certain members of the FDA during the analyses of data from the key clinical trials of the drug following termination of the phase 3 clinical trials due to lack of evidence for benefit.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit to cognitive function in Alzheimer’s disease patients, the drug must not be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The FDA's decision to approve Aduhelm for treatment of Alzheimer’s disease showed a complete disregard for science and contradicted the agency’s standards for approving new drugs. Because of this action, the agency’s credibility has been seriously damaged.
The approval of Aduhelm was based on flawed analyses of trials that were stopped early after a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefited patients with Alzheimer’s disease.
CMS must not compound the FDA’s error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm improves cognitive function in Alzheimer’s patients, the drug cannot be deemed necessary for treating such patients. I urge CMS to exclude Aduhelm from Medicare coverage.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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When I read "Dopesick" and "Empire of Pain" I thought it wouldn't be possible for the FDA to again engage in corrupt practices benefiting a pharmaceutical company like Purdue. Surely any unlikely drug approvals or sweetheart deals would be glaringly obvious and prevent nefarious actions. Unfortunately, the FDA approval of Aduhelm shows that not to be true. Another fabulously expensive drug has been approved based upon junk science following an inappropriate collaboration between the manufacturer, Biogen, and the FDA.

Who stands to profit from this unholy alliance? How much will it cost us all when an unproven medication that is unlikely to be effective but will be prescribed must be paid for through Medicare? Medicare doesn't have the ability to negotiate a lower price so we will all pay for Aduhelm's use.

I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The responsibility of the FDA, as described by its mission statement, is: "The Food and Drug Administration is responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs." Why then are they prioritizing the approval of this drug on an accelerated track through backdoor deals and discussions? The FDA approval rating has taken a drastic downturn during the pandemic: "37% of doctors, 27% of nurses, and 41% of WebMD readers said they trust the FDA in general."(2) In the current landscape in which the public trust in the FDA and medicine has been on a steep decline, it has become more difficult for the public to accept the FDA-approval as a sign of quality. We cannot further endanger the nation's trust by supporting broad coverage for an unproven drug whose effectiveness and legitimacy has been called into question, especially at such a dramatically high price. Nobody wants to see the disaster that is going on regarding the acceptance of vaccines spread to other fields of medicine. With the rise in Medicare premiums for the public that would be required to pay for broad CMS coverage of this drug, the nation's already thinning trust will further decrease while also taxing the general public. The complete radio silence from the CDER Patrizia Cavazzoni regarding inquiries regarding Aduhelm and its suspect approval. The double standards regarding the approval of Aduhelm and things such as Vaccine implementation can lead to the public questioning the safety legitimacy of other more proven and tested pharmaceuticals. If Aduhelm was approved on an accelerated track with little evidence of its effectiveness and 23 different tests saying it doesn’t work, how can people be sure of anything else approved by the FDA. As a governmental body, having standards apply consistently and fairly is one of the most important parts of making these decisions. For an organization that has the health and safety of millions upon millions of people in its hands, this lack of transparency cannot be acceptable. There is no doubt that Alzheimer's is a devastating illness, but we cannot allow ourselves to be clouded by desperation for a cure, and instead properly find an effective treatment. Aducanumab is not the answer that we need, therefore I do not support it’s coverage unless new evidence of its effectiveness is provided.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I support the decision to NOT cover Aduhelm. The FDA's own expert committee noted that it has not been shown to be effective and that it causes dangerous adverse effects. The cost for a drug that has no convincing evidence of effectiveness (and that does have evidence of harm) is absurd. The fact that the drug company halved the price when uptake was poor shows how egregiously overpriced it was initially, and given the likelihood that it doesn't have a meaningful clinical effect means it would be a wasted cost (and more wasted medical resources to administer it and watch for/treat adverse effects) at its current inflated price of $28,000.

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I am an Assistant Professor and a cognitive neurologist at the UCSF Memory and Aging Center in the Department of Neurology. I work within our clinical trials division, where we conduct trials for patients with neurodegenerative diseases such as Alzheimer’s and frontotemporal dementia. I was a Sub-Investigator on both the ENGAGE and the EMBARK clinical trials, but I have no financial relationship with Biogen or any other company involved with anti-amyloid antibodies. I believe I am familiar with the clinical trial data relevant to this issue, so I am writing here to share my opinion on the CMS decision, prompted in part by my desire to amplify the voices of my patients and clinical trial participants. However, this opinion is mine alone and does not reflect my institution’s or my colleagues’ opinions.

While CED initially made sense to me given a controversial FDA approval from incomplete Phase 3 trials, careful consideration has led me to disagree with this decision, primarily because the path forward to gain additional trial data for aducanumab and related drugs is not clear. Who will fund and conduct these CMS-sponsored trials? Will they compete with required Phase 4 trials and planned registry efforts, not to mention other pharma-sponsored trials of drugs in this class? If CMS approval is now needed for CED trials, will CMS become the de facto arbiters of “clinically meaningful” trial design for all future AD drugs? If these trials do occur, is CMS taking on what was previously the role of the FDA?

I understand the rationale for this decision, but I think the CED decision provides too narrow of a window for additional data gathering and sets an unusual and possibly troubling precedent. Realistically, I don’t believe RCTs will take place within a meaningful timeframe, so I support the use of registries for a very select patient population with interpretation of data guided by experts in our field. Based on my own analyses of the patient population seen here at UCSF, fewer than 5% of patients would qualify for such efforts using clinical trial criteria.

I also do not understand the rationale for applying this decision to the entire drug class, especially as several other anti-amyloid antibodies are set to read out Phase 3 trial data within the next two years. Will CMS revise the coverage analysis if these results are positive? If negative, will they halt CED efforts? Will it require a case-by-case revision if there are divergent results? Again, more questions than answers, but I think the approach should be case-by-case as we find our way forward with these new therapies.

Finally, I will say that I am not insensitive to the issue of cost, and I have issues with the cost of this therapy. However, our health care system has chronically underfunded neurodegenerative diseases at every level, from caregiver to patient to provider, with the lack of coverage for our most useful diagnostic tool (PET) being only one example. My concerns about efficacy and safety regarding this specific therapeutic aside, I worry that this sets a precedent to deny coverage for our first generation of potentially disease-modifying therapies before we are able to explore their potential.

I thank you very much for the opportunity to comment on this important issue.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s (FDA’s) June 7, 2021 decision to approve Aduhelm for "treatment" of Alzheimer’s disease showed a stunning disregard for science and the agency’s own standards for approving new drugs. FDA relied on an accelerated approval pathway for a medication of unproven therapeutic benefit, and overruled an FDA advisory committee's nearly unanimous vote against approval. Because of FDA's reckless actions in approving Aduhelm, its credibility as an impartial arbiter of therapeutically beneficial medication is seriously tarnished.

The approval of Aduhelm was based on seriously flawed post-hoc analyses of two nearly identical, incomplete phase 3 trials. The trials were shut down prematurely in March 2019 because a preliminary review of the data found that those trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. On the other hand, trial participants were at real risk of cerebral swelling or bleeding, significant morbidities for already vulnerable patients.

Perhaps even more disturbing than the approval of a medication with no demonstrated benefit, the integrity of the FDA’s review of Biogen's marketing application for Aduhelm appears to have been dangerously corrupted by documented inappropriately close collaboration between Biogen and the FDA during the data analysis after the termination of the phase 3 clinical trials. Indeed, the HHS OIG has opened a review of FDA's accelerated approval pathway, including interactions between FDA officials and Biogen scientists.

CMS must not compound the FDA’s egregious error in approving Aduhelm. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit — improved cognitive function — in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients.

I urge CMS to issue a national coverage determination that EXCLUDES Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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To: The Food and Drug Administration.
To whom this may concern,
After the Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs; because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials, because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. As a concerned citizen I am urging CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I protest!!!

The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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February 10, 2022

Ms. Chiquita Brooks La-Sure
Administrator
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: CMS Proposed Decision Memorandum on Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease

Dear Administrator La-Sure:

On behalf of the Global Down Syndrome Foundation and our partner organizations striving to improve the lives of Americans with intellectual disabilities and developmental disorders, I am writing to share our public comments on CMS’ proposed National Coverage Determination (NCD) decision memorandum to cover FDA approved monoclonal antibodies that target amyloid for the treatment of Alzheimer’s disease through coverage with evidence development (CED) for beneficiaries enrolled in qualifying clinical trials.

Many individuals have interpreted the proposed decision memorandum’s clinical trial coverage exclusion for individuals with “neurological conditions” apart from Alzheimer’s disease as excluding people with Down syndrome from participating in these trials and by extension from Medicare coverage. As the leading public non-profit dedicated to significantly improving the lives of people with Down syndrome as relates to research, medical care and advocacy, we rigorously oppose any and all efforts to discriminate and exclude individuals with Down syndrome from fully and completely participating in all facets of life including access to clinical trials, research, and medical care. Further, we believe excluding persons with Down syndrome from these proposed clinical trials would establish an unjust and discriminatory precedent at a time when we are making advancements in establishing equitable medical care, research, education, and employment policies.

According to the National Institutes of Health (NIH) and our own internationally recognized researchers at the Crnic Institute for Down Syndrome, an estimated 70% of individuals with Down syndrome will develop dementia due to Alzheimer’s disease as they grow older. By the age of 40, most persons with Down syndrome have beta-amyloid plagues along with other protein deposits called tau tangles which are linked to Alzheimer’s disease although not all individuals with these brain plaques experience dementia.

Given the high prevalence of Alzheimer’s disease among individuals with Down syndrome, Congress and the NIH have recognized the importance of studying this connection, and have made important investments in research to study this co-occurrence including new basic and translational research and clinical trials involving persons with Down syndrome. If CMS were to exclude persons with Down syndrome from these clinical trials, this would say to individuals with Down syndrome that CMS does not value their participation in important science, and will set back efforts to advance important research to improve health outcomes for persons with Down syndrome as well as typical individuals.

Given the significant health challenges facing this vulnerable population, we urge CMS to reconsider this exclusion criteria and promote efforts to ensure that persons with intellectual disabilities and developmental disorders, including Down syndrome, are able to fully participate in all current and future clinical trials and remain eligible for full Medicare coverage. We appreciate the complexity of this issue, and thank you for your kind consideration of these comments.

Respectfully,

Michelle Sie Whitten
President and CEO, Global Down Syndrome Foundation

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

Thank you for your consideration.

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The Association for Frontotemporal Degeneration (AFTD) is the only non-profit organization solely dedicated to improving the quality of life of people affected by frontotemporal degeneration (FTD) and driving research to a cure for all FTD disorders. Aduhelm’s path to approval and potential coverage by Medicare has been fraught with controversy. AFTD appreciates the challenges the Centers for Medicare & Medicaid Services (CMS) faced in navigating the complex and changing environment surrounding the draft National Coverage Determination (NCD) on Aduhelm and other amyloid-targeting monoclonal antibodies. Even though Aduhelm is not an FTD treatment, AFTD is concerned that the draft NCD will discourage the innovative research and prohibit the regulatory flexibility that is critical for the development of therapies for FTD and other rare neurodegenerative diseases.

First and foremost, AFTD is concerned that the proposed coverage with evidence development decision creates new precedents that will either block or discourage the development of new therapies that are approved by the FDA through the accelerated approval pathway. Accelerated approval is an important mechanism for new therapies to be brought to market for severe, rare diseases like FTD. The FDA already requires a Phase 4 trial for any therapies approved through the accelerated approval pathway to show that changes to surrogate outcome measures correspond to clinically meaningful benefits. By requiring additional trials for evidence development, CMS is undermining the FDA’s use of the accelerated approval pathway. Pharmaceutical companies need clarity on the evidence required to bring a product to market. This draft NCD accomplishes the opposite and casts uncertainty on the viability of the accelerated approval pathway, disincentivizing companies to invest in innovative research on rare diseases like FTD.

This uncertainty and discouragement is reinforced by the fact that the NCD applies to the entire class of monoclonal antibodies directed at beta-amyloid. Expanding the draft NCD to cover an entire class of treatment based on the results from studies on a single antibody is unprecedented and constitutes a de facto prohibition on further research on the potential of this therapy for Alzheimer’s disease and other neurodegenerative diseases.

We commend the CMS for requiring that any clinical trials proposed under the draft NCD include a representative sample of all the populations affected by Alzheimer’s disease and especially historically under-represented populations. However, requiring that trials only be held in hospital settings will limit participation primarily to people living in urban areas and able to access a hospital, thus making it more difficult to ensure representative participation. Further, there is a lack of clarity regarding coverage of beta-amyloid PET scans, and other tests, which if not fully covered could make participation in evidence development trials prohibitively expensive for most U.S. citizens. AFTD is concerned that similar requirements placed on clinical trials in rare diseases like FTD will make it impossible to conduct meaningful research. Again, we are concerned that the CMS is setting a precedent that will impose an insurmountable obstacle to developing therapies for other neurodegenerative diseases besides Alzheimer’s.

As it stands, the draft NCD offers a strong disincentive to further investment by pharmaceutical companies and discourages the innovative and creative approaches needed to find the treatments and therapies that are so desperately needed by the people and families impacted by FTD and other adult cognitive diseases.

AFTD urges CMS to first: limit the final NCD to only Aduhelm and not to all beta-amyloid directed monoclonal antibodies therapies for Alzheimer’s. Basing such a broad coverage decision on the results from studies on one antibody is tantamount to financial punishment for the companies that have already committed resources to other monoclonal antibodies for Alzheimer’s and a de facto prohibition on pursuing this research for FTD and other neurodegenerative diseases.

Second, and most importantly, we urge the CMS to provide clarity and reassurance that the draft NCD is not an indictment on the accelerated approval pathway and other Expedited Programs for Serious Conditions at the FDA. These programs are essential incentives for industry to see a return on their investment in the research and development of therapies for rare diseases like FTD, which offers hope to all who are impacted by this devastating disease.

New therapies will undoubtedly create complex and evolving logistical, regulatory, and financial realities. We respect that the CMS is stewarding limited resources for the nation and encourage the agency to find mechanisms to work within the frameworks already developed rather than create new evidentiary standards independent of the FDA. We are grateful to the work of the CMS and for the time and care the agency spent in drafting this National Coverage Determination.

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[PHI Redacted] died January 2021 at age [PHI Redacted] after being diagnosed for 7 years with Early Onset Alzheimer’s. During that time, she participated in 8 drug trials, none of which was successful in obtaining FDA approval. However, among our new network of friends with mild forms of dementia, three of the four had positive responses to the Aducanumab drug trials that we truly believe showed improvement among their cognitive abilities and extended the quality of life for them, their spouses, and families.

I am utterly appalled that the CMS is now rejecting FDA approval for aducanumab (Aduhelm). This will make Medicare support for Aduhelm only available through hospital-based drug trials where the patients who has benefited from this drug is not assured of receiving this medication but forced to participate in duplicative double-blind studies where they may get only a placebo! How CRUEL!! In addition, requiring approved hospital-based administration further restricts how many of the two million Americans currently with Mild Cognitive Impairment and Mild Alzheimer’s live near what likely would be high population dense metropolitan hospitals which become Aduhelm trial distributors. Further, such restrictions for Aduhelm and current/future research and clinical trials that target monoclonal antibodies against amyloids will greatly reduce the participation levels among the Black and Hispanic and women who have a much higher rate of Alzheimer’s.

I urge the CMS to modify their decision on Aduhelm and not create the harsh limitations on anti-amyloid monoclonal antibody drug trials currently in Phase 3 as well as any further similar drug trials. Alzheimer’s and dementia make up the #6 cause of death among Americans and is the ONLY killer without any cure, control, or prevention.

CMS must give the families and patients with Alzheimer’s needed HOPE that through science, research, and participation in clinical trials we can identify ways to suppress, control and cure Alzheimer’s and numerous types of dementia.

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Unfortunately, FDA’s decision to award accelerated approval to aducanumab based on an unproven surrogate endpoint has not only likely falsely raised hope for patients and their families suffering from Alzheimer’s disease, but has also created a much larger and more dangerous precedent. In response to FDA’s approval of aducanumab, other manufacturers have pivoted to investigating other monoclonal antibodies with similar, uncertain mechanisms of action in hopes of also receiving accelerated approval without having to demonstrate any clear clinical efficacy within their pivotal trials. Should these other therapies also receive such approval, manufacturers would only need to confirm its clinical benefit in post-marketing trials. In the case of aducanumab, FDA has awarded the manufacturer an extraordinary nine years – far longer than the median deadline granted to other accelerated approval drugs. This means that the drug will be available for Alzheimer’s disease patients despite continued uncertainty of whether it is effective and the high risk of serious side effects including brain swelling and bleeding, which were found in over 40% of patients who received the higher dosage approved by the FDA.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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As Director of the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU), a research scientist and principal investigator of a lab that studies Alzheimer's disease, and as a physician who evaluates and treats patients and families with Alzheimer's disease, I would like to provide my perspective on the proposed CMS decision regarding “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease”. My comments about the proposed decision are below:

1) Monoclonal antibodies to amyloid-beta have different targets and mechanisms of action, that cause large differences in biologic efficacy, biomarker measurements, and safety profiles. Because each antibody is specific, and has large differences on the biology of the disease in patients, I do not believe that antibodies can be judged together as a class.

The clinical trial data is clear that antibodies remove amyloid plaques to varying degrees (some not at all, while others have large reductions), are dose-dependent, remove amyloid at different rates, have large differences in amyloid related imaging abnormalities (ARIA) rates, and also potentially different cognitive and clinical effects. I believe each needs to be judged separately.

2) If an anti-amyloid beta treatment (or any treatment) meets the standard of clinical trial evidence that demonstrates efficacy (for example, consistent findings of clinical and cognitive benefits for Alzheimer’s disease patients), then CMS should support treatment for Alzheimer’s disease, as it does for other diseases. As written, the current proposal indicates that even successful, well-controlled phase 3 trials would not allow for CMS to support treatment in Alzheimer’s patients, except under additional research trials. I believe it’s important to allow access to effective treatments for Alzheimer’s disease as soon as possible.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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February 10, 2022

The Honorable Chiquita Brooks-LaSure
Administrator
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: National Coverage Determination for Monoclonal Antibodies for the Treatment of Alzheimer’s Disease

Dear Administrator Brooks-LaSure:

On behalf of the Alliance for Patient Access (AfPA), we thank you for the opportunity to offer comment regarding the CMS National Coverage Determination (NCD) draft for the newly created class of monoclonal antibody (mAB) therapies for Alzheimer’s disease, which will require Coverage with Evidence Determination (CED), an unusual step that would significantly limit access for Alzheimer’s patients. We are writing to encourage CMS to bear in mind the considerable burden Alzheimer’s disease poses to patients, caregivers and communities. Several aspects of the draft and its implications concern us as it relates to current and future therapies, including the impact on communities of color, access for patients living in rural areas, and the future implications of this determination based on the precedent it may set. We respectfully ask CMS to take these factors into account and carefully reconsider the draft NCD prior to finalizing it.

Founded in 2006, AfPA is a national network of policy-minded health care providers who advocate for patient-centered care. AfPA supports health policies that reinforce clinical decision-making, promote personalized care and protect the physician-patient relationship. Motivated by these principles, AfPA members participate in clinician working groups, advocacy initiatives, stakeholder coalitions and the creation of educational materials. AfPA hosts the Neurological Disease Working Group, a unique network of clinicians, which works to ensure that the clinician’s perspective informs policy discussions around care for patients living with neurological diseases.

Burden of Alzheimer’s Disease

Alzheimer’s disease is widespread among older adults and as a result, costly to the American health care system. An estimated 6.2 million Americans aged 65 and older are living with Alzheimer’s in 2021.¹ By 2050, this number is expected to more than double to 12.7 million.² The estimated total healthcare cost for treatment of Alzheimer’s disease was $355 billion in 2021.³

However, the burden of Alzheimer’s goes far beyond the economic impacts. One in three seniors dies with Alzheimer’s or another dementia and while mortality from other diseases has decreased significantly, deaths from Alzheimer’s disease have increased.⁴ In addition to the disease impact on patients, caregivers also carry a unique burden with Alzheimer’s disease. More than 11 million Americans provided an estimated 15.3 billion hours of care, typically unpaid, for people with Alzheimer’s disease in 2020.⁵ The financial and health cost of Alzheimer’s will only continue to climb, as this disease impacts more and more people.

Current and Future Implications for Therapy Access

Patients with Alzheimer’s disease have historically had few treatment options, limited to drugs purposed for symptom management. However, the FDA’s approval of aducanumab on June 7, 2021 changed that. Aducanumab is the first FDA-approved treatment to reduce the presence of amyloid beta plaques in the brain, directly targeting the pathophysiology of Alzheimer’s disease. Aducanumab will likely not be the last of its kind; we are aware of three other drugs of this type that are currently in the trial phase. We understand that these treatments have yet to present the data necessary to be considered for approval by the FDA.

However, as the NCD currently stands, if approved, the full class of treatments – including those not yet approved – would be subject to CED requirements in order for patients to gain access. We are concerned that under this CMS proposal, future treatments will be subject to a duplicative trial process based solely on the determination reached through consideration of coverage of aducanumab. Instead of applying a one-size-fits-all approach to an entire class of medications, CMS should recognize the FDA approval of each individual medication and ensure future treatments are not unnecessarily subject to NCD requirements.

We are also concerned that CMS’s decision to implement an NCD with CED poses a challenge to FDA’s role in approving medications. The FDA is tasked with determining the safety and efficacy of medications. It is their responsibility to oversee and approve clinical trial processes and evaluate the data generated. An additional trial conducted by CMS creates a redundancy that will limit access for patients who need treatment.

Impact on Representative and Timely Access

In addition to the above, a CED requirement will limit access for communities of color. Alzheimer’s disease affects Black Americans at the highest rate at 13.8%, with Hispanic Americans making up 12.2% and white Americans 10.3% of patients⁶ over the age of 65. Accurate access and representation is crucial, as much current research suggests that socioeconomic status may be linked to increased instance of dementia in Black Americans.⁷ It is also widely documented that Black Americans experience higher levels of poverty than other racial demographics, earning on average 59 cents to every dollar than white Americans earn.8 Further, we know that socioeconomic status is closely tied to healthy aging; wealthier individuals are more likely to be healthier as they age than poorer individuals.⁹

Each of these factors combines to create a complicated web of access barriers to health care. Black Americans are more likely to develop dementia and are more likely to have trouble gaining access to care based on economic and other compounding factors. While we appreciate CMS’s goal of ensuring diverse clinical trials, we are concerned that a CED will only serve to exacerbate access challenges in communities of color by requiring clinical trials participation to gain therapy access. These requirements are inappropriate for a population of patients whose health may depend on this class of medication. And ultimately, patients may be denied access as the result of factors that are beyond their control.

A major and closely related concern is that a CED will require patients to receive treatment in the hospital-based outpatient setting, limiting clinical trials sites beyond that of current and recent clinical trials for this type of treatment. This requirement will limit access for many patients, as it necessitates favorable geographic proximity to this type of facility. It also may require additional assistance from a care partner for transportation to the medical center. Patients must have reliable transportation and a care partner who can afford absenteeism from employment to transport their loved one to the clinic to receive treatment. These layers of burdens will make it virtually impossible for patients in rural areas, as well as patients with limited financial resources, to participate in a CED trial. Based on available data, this will also mean that Black Americans will be disproportionately affected. If CMS finalizes the CED requirement as currently written, we are concerned CMS will be effectively limiting care for a large portion of Alzheimer’s patients who are simply unable, at no fault of their own, to fulfill the requirements to receive potentially life-extending treatment.

Development of the criteria for the CED will be a time-consuming process that delays access to this treatment for patients who would otherwise be eligible to receive therapy. This delay means patients who would be candidates for current therapy may progress in their disease beyond an appropriate treatment window. Further, a CED could require some eligible patients to take a placebo rather than the FDA-approved therapy, inappropriately denying care to patients and further limiting the number of patients who can receive therapy.

Prioritizing Patient-Centered Care

Patient-centered care is rooted in the relationship that providers foster with their patients, relationships that are built through trust and open communication. A key aspect of this is shared decision-making, which is crucial for patient confidence and adherence and for providers to support the patient with the most appropriate care. When treatment coverage limits the tools at a clinician’s disposal, this can undermine the physician-patient partnership by interfering with the preferred course of treatment and jeopardize the patient’s well-being. Accordingly, we urge you to consider these concerns and work to revise the draft National Coverage Determination in order to reduce barriers between patients and appropriate therapies and ensure appropriate access to current and future therapies for Alzheimer’s patients.

We recognize the challenges CMS is working to address and appreciate the opportunity to provide comment on the proposed NCD. Thank you for your attention to this important topic. If AfPA can provide further details or be of assistance in this matter, please contact us at 202-499-4114.

Sincerely,

Josie Cooper
Executive Director
Alliance for Patient Access

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I have a relative who is now dealing with Alzheimer's disease. But the Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program. Thank you.

Sincerely,
Susan E. Young

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Having read a number of articles about Aduhelm, I believe it should not be supported by Medicare. Medicare is a necessary system to guarantee retired elders access to medical care and should not be in the business of supporting any pharmaceutical company's testing program. Beyond that restriction, this particular drug has not shown positive effects on Alzheimer's, but has shown a very high incidence of side effects. It should never have been okayed by the FDA. It only offers little hope to desperate people at a fantastic cost. Please don't set a bad precedence for Medicare, that will threaten the cost to those who need it for things that do work.

Thank you,

Joel Cohen, age 85

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I strongly support the CMS decision NOT to cover this treatment. I've read the studies and find it frankly embarrassing that the FDA moved this medication forward. Even if the drug were offered at a low cost the harms clearly outweigh the benefits, if there are any real clinically meaningful benefits (I've not seen any evidence that there are). It smacks of corruption and surely CMS will get a lot of input from pharma and paid consultants pretending to be patient advocates. I care for elderly patients. Do not reverse your decision on this. The harm to patients will be real and the cost to the healthcare system will be outrageous. It is primary care doctors like me that will have to try to talk patients out of the medication that will be demanding based on misleading advertisement that will be bombarding them. Thank you.

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I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program. The U.S. Food and Drug Administration (FDA) made a grave error in its June 7, 2021 decision approving Aduhelm on June 7, 2021 for treating Alzheimer’s Disease.

That approval was foolhardy and utterly unscientific. The decision severely undermined both FDA drug approval standards and trust in the agency.

Approving Aduhelm relied on deeply problematic analyses of 2 identical Phase 3 trials that were stopped early after recognition that, if continued to completion, those trials would not likely to show that the drug benefits people with Alzheimer’s. Further, the FDA's unprecedented and shamefully close collaboration with Biogen during data analysis on the key clinical trials makes it impossible to view as trustworthy the FDA’s review of Aduhelm's marketing application.

It would be disastrous in many ways if CMS were to compound the FDA’s appalling and obvious error. Absent any scientific evidence that Aduhelm meaningfully improves cognitive function in people suffering from Alzheimer’s Disease, it is totally unjustifiable to deem Aduhelm reasonable and necessary for Alzheimer's patients.

So again, I urge CMS to make a national coverage determination excluding Aduhelm from Medicare coverage.

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Please do NOT allow the use of Monoclonal antibodies for the treatment of Alzheimer’s, except as part of clinical trials. Because pharmaceutical companies can charge a virtually unlimited amount for their drugs and we can’t negotiate with them, we cannot pass the cost of this treatment on to all other people on Medicare.

If the drug companies take exception with this, remind them of the hundreds of billions in extra profit they make from the American Public.

Thanks for saving Medicare from greedy profiteers

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As a primary care physician who treats patients with Alzheimer's disease and has read the primary studies on aducanumab (Aduhelm), I strongly oppose Medicare/Medicaid coverage of this drug outside the realm of clinical research. The equivocal benefits and clear, potentially fatal harms demonstrated by the two large randomized controlled trials evaluating aducanumab demand further research that evaluates this medication over a longer time frame. It would also be reasonable to abandon it as a pharmacotherapy altogether. Patients with Alzheimer's deserve treatment options that have been clearly vetted and show meaningful benefit. Existing data on aducanumab simply to not justify its routine use, especially at the exorbitant price tag set by the manufacturer.

Please note that my views do not necessarily represent those of my employer

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The Food and Drug Administration’s flawed and highly questionable decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and flouted the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been seriously compromised.
The approval of Aduhelm was based on flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Nevada Chronic Care Collaborative (NCCC) strongly urges the Centers for Medicare and Medicaid Services (CMS) to reconsider its proposed National Coverage Determination (NCD) pertaining to breakthrough Alzheimer's treatments. NCCC makes this request not only on behalf of the millions of Alzheimer's patients, families, and caregivers who would be denied access to this class of drugs, but also because of the far-encompassing precedent it would set. CMS would be putting cost concerns over patient health for Nevadans with Alzheimer's and other chronic conditions. If Medicare goes down the road of sharply restricting access to innovative treatments and cures that have been deemed safe and effective by the Food and Drug Administration, not only will patients suffer but CMS will lose the opportunity to curb health costs in the long term. Importantly, very few Americans have the opportunity to take part in clinical trials. That reality is especially significant for disparate populations. If left as is, the NCD will deny patients access to medications that can save and extend life and provide improved quality of life.

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As organizations committed to scientific integrity, we are providing these public comments on the National Coverage Analysis Proposed Decision Memo from the Centers for Medicare and Medicaid Services (CMS). This decision relates to coverage of Aduhelm and similar unproven medical products for the treatment of Alzheimer’s disease.

We share the view of scientists and researchers across the country that the FDA approval of Aduhelm was not scientifically sound and sets a dangerous precedent for other medical products. The clinical trial data that the manufacturer submitted to the FDA did not meet FDA’s standards of safety and efficacy, resulting in a unanimous vote against Aduhelm by the FDA’s scientific advisory committee. We therefore strongly support the CMS proposed decision to limit the coverage of these Alzheimer’s drugs to patients participating in clinical trials, as a way to determine if the drug is safe and effective for Medicare patients before covering the cost for millions of patients. This will provide the scientific evidence needed so that patients and family members can make informed decisions based on unbiased information – essential criteria for all medical products, and not only those for Alzheimer’s disease.

Our nonprofit organizations also support the scientific importance of diversity in clinical trials used as the basis of FDA decisions. Fewer than 4% of the patients in the Aduhelm clinical trials were Black or Hispanic, making it impossible to determine safety or efficacy for those populations. Moreover, the data from the Aduhelm studies submitted to the FDA were based on patients representing a small minority (15%) of the types of Medicare beneficiaries who have mild Alzheimer’s disease, excluding many with common chronic health conditions.

We recommend the following to ensure unbiased scientific evidence:

1. Enforcement of requirements for diversity

CMS’s proposal mandates that CMS-funded trials must include a nationally representative population of people with Alzheimer’s disease. We urge that this diversity include a substantial number of patients in different racial, ethnic, and age groups to ensure that there is enough statistical power to determine safety and efficacy for each of the major demographic groups. CMS should specify how they will ensure that the study participants represent the co-morbidities typical of Alzheimer’s patients, while protecting patients from harm. Since CMS plans to restrict clinical trials to the most appropriately selected treatment centers, that should ensure the diversity that is needed.

2. Safety Data

In the original Aduhelm clinical trials, 41% of patients experienced brain swelling or brain bleeds. Other side effects included headaches, dizziness, confusion, and an altered mental state. It was unclear which patients were at greatest risk, although there is some evidence that more advanced Alzheimer’s patients might be most likely to experience brain swelling. The final CMS coverage decision must clearly specify how they will protect clinical trial participants, including guaranteeing monitoring with free brain scans.

3. CMS should be consistent in its coverage for other medical products that are not proven to be safe or effective.

When the FDA approves medical products that are not proven to be safe or effective, we urge the CMS to require evidence of meaningful clinical benefit in well-designed clinical trials, as they are proposing to do with Aduhelm and similar Alzheimer’s drugs.

We appreciate the opportunity to provide our views and strongly encourage CMS to consider our recommendations aimed at requiring scientific evidence for important regulatory decisions.

ORGANIZATIONAL SIGN ONS

Government Accountability Project
Government Informational Watch
Jacobs Institute of Women’s Health
National Center for Health Research
Union of Concerned Scientists

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The National Home Infusion Association (NHIA) appreciates the opportunity to provide feedback on the proposed National Coverage Analysis (NCA) decision memorandum, “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease” (CAG-00460N), issued by the Centers for Medicare & Medicaid Services (CMS) on January 11, 2022. NHIA is a trade association that represents companies that provide infusion therapy to patients in their homes, as well as companies that manufacture and supply infusion and specialty pharmacy products. As the leading voice for the home and alternate site infusion community, we write to share our comments regarding the proposed decision.

NHIA is concerned that in order to gain access to monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s Disease, patients would have to participate in a CMS-approved or NIH-supported clinical trial exclusively offered in a hospital outpatient setting. NHIA believes this requirement to limit infusions to hospital settings is unnecessary and inconsistent with the inclusivity goals of CMS. If CMS intends to ensure the diversity and representativeness of populations in Coverage with Evidence Development (CED trials), then the agency should remove this requirement and allow infusions in a wide range of settings, including the home. Limiting the site of care for conducting such trials disenfranchises patients who do not live near a study facility, are not physically able to travel, or simply could not otherwise participate due to situational constraints. During the COVID-19 pandemic, many companies, including those studying monoclonal antibodies for the treatment of Alzheimer’s Disease, successfully modified their clinical trial protocols to include administration of study drugs in the home setting. Collecting real-world data from settings other than the hospital outpatient centers reduces enrollment barriers and contributes valuable insights that improve the final product. NHIA strongly urges CMS to reconsider this requirement if the CED is finalized.

If CMS does not move forward with the CED process, NHIA reiterates its previous recommendations for ensuring that monoclonal antibodies for the treatment of Alzheimer’s disease are accessible to Medicare beneficiaries in the home. NHIA encourages CMS to ensure that all eligible patients have the option to receive infusions in the home setting. Currently, Medicare only offers coverage of home-based drug administration services for a limited subset of drugs – about 30 medications that require an external infusion pump to administer. These limited services are covered under the Medicare Part B DMEPOS benefit. For drugs that do not require a pump for administration – such as monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease – there is no Medicare coverage for home administration of the drugs. As a result, Medicare beneficiaries will be forced to travel to a treatment center or pay out of pocket to receive these services in the home. Vulnerable beneficiaries who cannot access a treatment center and cannot afford to pay out of pocket for home administration will not have access to these drugs.

To address this access issue, NHIA recommends that Medicare beneficiaries have coverage of home infusion services and supplies regardless of whether the drug they need requires an external infusion pump to administer. We propose that home infusion therapy services providers would be allowed to bill a bundled payment to Medicare Part B for services, supplies and equipment and bill separately to Medicare Part D for drugs used in the home setting. This model is consistent with reimbursement in Medicare Advantage programs and has been overwhelmingly effective at lowering overall costs of care for patients and health plans. A similar approach was recently used to successfully establish coverage for home infusion for COVID-19 monoclonal antibody treatments. As a result, most eligible home infusion providers enrolled with Medicare supported the pandemic response by offering these important treatments to patients at home. NHIA believes a similar model could be implemented to cover treatments for Alzheimer’s Disease and other conditions as a demonstration project through the Center for Medicare and Medicaid Innovation (CMMI).

NHIA appreciates the opportunity to provide these comments. If you have questions or need additional information, please contact me at connie.sullivan@nhia.org.

Sincerely,

Connie Sullivan, B.S. Pharm
President and Chief Executive Officer
National Home Infusion Association

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The premise that the approval for this drug was based on its that blocking the growth of amyloid plaques will also slow the progression of Altzheimer’s. But that has never been proven.

The risk of harm is high. 41% of patients on the therapeutic dose of Adhuhelm in clinical trials experienced brain bleeds.

Eventually, Aduhelm may be proven effective at slowing the progression of Alzheimer’s. However, the “accelerated approval” that the FDA granted Aduhelm gives its manufacturer Biogen nine years to produce a study that shows it’s safe and effective, all the the drug is available for doctors to prescribe to any patient. For nearly a decade, an unproven, dangerous drug can be prescribed to people who are desperate for a cure for Alzheimer’s. Patients have the right to assume that a drug approved by the FDA is safe and effective. This approval undermines the entire reason for the FDA’s existence.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

Don't waste the Medicare money! Too many of us already cannot pay for the drugs our doctors say we should have. This is just a give away to Big Pharma

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless (and possibly unethical) action, the agency’s credibility has been further damaged.
Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.
Another grossly over-priced "placebo" to be pushed by physicians indoctrinated in pharmaceutical incentivism.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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February 10, 2022

Submitted electronically via email to CAGinquiries@cms.hhs.gov.

Ms. Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
U.S. Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

RE: Proposed National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-0046ON)

Dear Ms. Jensen:

The Pharmaceutical Care Management Association (PCMA) appreciates the opportunity to comment on the proposed National Coverage Determination (NCD) for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N).¹ PCMA recognizes the burden of Alzheimer’s Disease (AD), especially the heavy toll on patients, their caregivers, and their family members. Our industry supports access to treatments that improve a patient’s quality of life and ability to enjoy more valued time with loved ones.

PCMA supports the Centers for Medicare & Medicaid Services’ (CMS’s) Proposed Decision Memo (PDM). Requiring enrollment of patients in randomized clinical trials (RCTs) will generate evidence to help answer the question as to whether drugs with this mechanism of action improve the lives of AD patients.

PCMA is the national association representing America’s pharmacy benefit managers (PBMs), which administer prescription drug plans and operate specialty pharmacies for more than 266 million Americans with health coverage through Fortune 500 companies, health insurers, labor unions, Medicare, Medicaid, the Federal Employees Health Benefits Program, and through the Exchanges established by the Affordable Care Act. Our members work closely with Medicare Advantage (MA) and stand-alone Part D plan sponsors to secure lower costs for prescription drugs and achieve better health outcomes.

In the PDM, CMS concludes that the evidence for monoclonal antibodies (mAbs) for the treatment of AD is “far from conclusive and more rigorous individual trials (i.e., Randomized Clinical Trials) continue to be needed to determine the clinical benefit of anti-amyloid mAbs for the treatment of [AD].”² Therefore, CMS proposes the use of its Coverage with Evidence Development (CED) policy to restrict coverage for Food and Drug Administration (FDA)-approved mAbs directed against amyloid for the treatment of AD to use of these products in RCTs that satisfy specified coverage criteria and trials supported by the National Institutes of Health (NIH).

PCMA thanks CMS for its comprehensive, evidenced-based, and objective analysis of the clinical evidence, benefits, and potential side effects of this class of therapies. We agree with CMS’s conclusion that there is currently “insufficient evidence to conclude that the use of monoclonal antibodies directed against amyloid is reasonable and necessary for the treatment of Alzheimer’s disease.”³ Furthermore, we agree with CMS that “no trial has been able to demonstrate any meaningful improvement in patient health outcomes,” and that given the “lack of a clear clinical benefit and the frequency of adverse events like amyloid-related imaging abnormalities (ARIA), the evidence does not support that the benefits outweigh the harms” of the therapeutic class.

CMS’s proposed coverage with CED will require enrollment in a clinical trial to facilitate collection of diverse population-level evidence using a consistent approach. This policy will allow for close monitoring and management of potentially serious adverse events associated with the treatment. It will also enable additional development of evidence on the therapeutic class’s efficacy and safety profile in a diverse population representative of the national population diagnosed with Alzheimer’s (e.g., age, gender, disease severity) to proactively avoid potential disparities in care. CMS should only approve clinical trials that are double-blinded and randomized. Such trials are the recognized “gold standard” for assuring unbiased results that evaluate the efficacy of a drug independent of factors that may otherwise influence patient experience and interfere with efforts to understand the role of the studied drug in determining clinical outcomes.

We support CMS’s proposed application of CED to this therapeutic class. Specifically, we support the proposal to apply this NCD to the entire therapeutic class of anti-amyloid-beta mAbs, rather than a specific drug. A uniform approach to this class of drugs in the Medicare program is essential as there are at least three other mAbs currently in development, in addition to the one treatment currently approved by the FDA (aducanumab). As the evidence evolves, CMS can revisit the NCD. Product-level differences, alternative formulations such as self-injectable drugs, and new evidence on the class’s efficacy and safety could change the nature of coverage.

The CED best balances the opportunity to continue to study the effectiveness of drugs in the class while ensuring these drugs are safely administered to patients who could possibly benefit. In addition, the coverage determination provides Medicare beneficiaries consistent and nationwide access to this class of products and related services, while gathering sufficient clinical evidence to support future determinations of whether these drugs are both reasonable and necessary for populations within the program. We appreciate that the initial coverage of mAbs directed against amyloid for the treatment of AD is paid under the Medicare Part B benefit only.

PCMA provides further comments below in support of key elements of the proposed NCD as well as proffers recommendations on additional issues for CMS’s consideration and clarification as you work to finalize the NCD.

Discussion:

The draft NCD states that mAbs “directed against amyloid for the treatment of AD provided outside of the CMS approved randomized controlled trials and trials supported by the NIH are nationally non-covered.”⁴ Therefore, this national non-coverage is class-wide regardless of route of administration. Moreover, CMS states that “[t]o date, no trial of an anti-amyloid mAb has confidently demonstrated a clinically meaningful improvement in health outcomes (i.e., cognition and function) for AD patients. Thus, there is insufficient evidence to conclude that the use of monoclonal antibodies directed against amyloid is reasonable and necessary for the treatment of Alzheimer’s disease under §1862(a)(1)(A) of the Social Security Act.”⁵

We read this statement to say that CMS’s statutory authority allowing it and its partners to deny coverage outside of recognized RCTs extends beyond Medicare Part B. As such, the CED applies in whole to potential coverage determinations requested of MA (MA; Part C) and Part D plan sponsors for existing and future products in this therapeutic class until the CED is closed.

Section 1862 (a)(1)(A) allows Medicare coverage and payment of items and services considered to be medically reasonable and necessary, which is the standard applied in NCDs. The section pertains to Medicare coverage of items and services covered under Parts A (hospital services) or B (outpatient medical services). However, the statute also applies this specific authority to Part D plans in Section 1860D-2(e)(3): drug plans “may exclude from qualified prescription drug coverage any covered Part D drug … for which payment would not be made if section 1862(a) applied to this part.”⁶ Thus, coverage requests made of MA or Part D plans for use of these products outside of a CMS-approved RCT should be denied ipso facto. We request that CMS provide explicit guidance and direction as to how any new formulations, specifically self-injectable forms, will be covered under this therapeutic class-wide coverage decision in the CED in its final form.

Recommendation:

PCMA supports CMS’s proposal to narrowly target coverage within the context of an evidence development process as provided under section 1862(a)(1)(E) of the Social Security Act, which allows CMS to provide coverage for research on a product that otherwise does not meet the “reasonable and necessary” standard. CMS should clarify in the final decision memo that this CED precludes coverage under any other part of Medicare, as well.

Furthermore, because the PDM points to the authority the agency is provided under Section 1860D-2 of the Social Security Act, we request that CMS include additional language in the final decision memo applying the CED to Part D coverage determinations for any product in this therapeutic class.

Discussion:

CMS requires that in order to receive approval, trials must specifically address, at a minimum, research questions regarding meaningful clinical benefit and adverse events. These considerations are and should be important elements of CMS’s conditions of coverage under the CED process. The collected evidence on clinical benefit and adverse events is not only critical to CMS’s assessment of continued coverage of aducanumab and other drugs in this class, but it can also provide information to the FDA to assist in designing the confirmatory trials for any drugs in this class.

As noted previously, we agree with CMS’s conclusion that there is currently “insufficient evidence to conclude that the use of monoclonal antibodies directed against amyloid is reasonable and necessary for the treatment of Alzheimer’s disease.”⁷ We also agree with CMS’s stipulated clinical trial inclusion and exclusion criteria.⁸

In addition to these specified criteria, CMS should require in the final decision memo the criteria from Aduhelm Phase 3 clinical trials (EMERGE⁹: NCT02484547; ENGAGE¹⁰: NCT02477800) to ensure participants are comparable to those in the two Phase 3 clinical trials for aducanumab.¹¹ These criteria will promote safety when administering aducanumab or other products through appropriate imaging, and adequate medical and behavioral monitoring and consenting, including a discussion of risks and benefits with patients.

Recommendation:

We support the inclusion of additional criteria to promote safety when administering products in this class. More expansive criteria will improve the comparative analysis across all mAbs that may eventually be available to treat AD, including aducanumab. As previously stated, we support the use of rigorous clinical studies that are double-blinded, randomized, and case controlled. As CMS considers additional requirements for the structure of CMS-approved clinical trials, it should include these robust requirements as they will provide the most meaningful comparative data on clinical efficacy and safety for this class of drugs. Without these requirements, there will still be uncertainties on the efficacy and safety of the class.

Additionally, the use of a longitudinal registry is a helpful tool for studying the long-term safety profile of a treatment. However, it will not allow CMS to draw additional conclusions on efficacy of these products. Therefore, we’d encourage CMS to allow longitudinal registry type data collection only after the completion of the approved randomized clinical trial (RTC). The longitudinal registries should be focused on the following questions:

• What happens when the drug is discontinued?
• What clinical findings (be it a complication such as ARIA or clinical progression) should prompt discontinuation of the medication?

Beyond inclusion in clinical trials and longitudinal registries, we recommend that CMS clarify expectations for the small number of Medicare beneficiaries who are already receiving aducanumab. Will they need to be enrolled in a trial, or are they allowed to continue coverage since it predated the CED? How about individuals enrolled in other Phase 3 trials that do not end up meeting CMS’s approved criteria?

Discussion:

PCMA supports CMS’s emphasis on the importance of evaluating the safety and effectiveness of treatment on different sub-populations beyond those enrolled in the clinical trials, including minority, underserved, and low-income individuals, many of whom are at greater risk for developing AD and may be more likely to have a missed diagnosis of the disease. Without this additional research, it will be unclear whether access to this treatment, with its accompanying risks, is in the best interests of populations that have been systematically underserved by prior clinical trials. Moreover, a trial population that is representative of the national population diagnosed with AD will promote equitable access to diagnosis and treatment across geographies and sub-populations and enable CMS to evaluate whether the results are generalizable across a broader population.

Recommendation:

We support the requirement that the RCTs reflect “the diversity of patients [and be a] representative [cross-section] of the national population diagnosed with [Alzheimer’s],” (e.g., age, gender, disease severity).¹² This expansion of trial populations will proactively avoid potential disparities in care. This obligation should fall on the drug trial sponsor, and CMS should use it as one criteria in considering approval of the clinical trial for coverage under the CED. CMS should account for this diversity to reflect geographical diversity as well and find ways to include rural and remote providers equal access to the clinical trials and facilitate their participation via development of geographic diversity access protocols and proposals.

In addition to the recommendations and considerations raised above, there are several areas that warrant clarification from CMS. These areas include implications for the MA and Medicaid programs.

MA plans need clear guidance on their coverage obligations under the NCD. It would be beneficial if CMS maintained an updated list of all clinical trials that meet the final requirements under the CED pathway for the MA plans to refer to. CMS should also specify to what extent the Medicare Coverage of Clinical Trials policy applies to MA plans in the context of this NCD.¹³ While we do not expect that under current conditions nor under the proposed NCD that the “significant cost” policy would be triggered, we ask that CMS keep in mind that a broader finalized NCD could do so. We ask the agency to provide guidance on how future updates and modifications to the NCD, due to new evidence or additional FDA-approvals, could alter the estimated impact on the national average per capita cost.¹⁴ Other additional questions include: What are plan obligations for coverage and payment for aducanumab, placebos, and any ancillary treatments or services considered part of a clinical trial; and flexibility for medical management in the event an RCT is converted to a longitudinal study?

Finally, PCMA would like to highlight the potential cost impacts for state Medicaid programs that may be required to cover aducanumab and other products in this class. Focusing on the evidence, benefits, and potential side effects of this class of therapies, CMS should ensure state Medicaid programs have the flexibility to only cover therapies that are proven safe. Moreover, CMS should apply its conclusions that there is a “lack of a clear clinical benefit and the frequency of adverse events,” to Medicaid and ensure a consistent application of coverage guidance across its programs. Therefore, we urge CMS to consider and clarify what types of medical necessity criteria and other flexibilities may be available to state Medicaid programs for these treatments as well. We also agree with the many other commenters that states should not be required to pay first-dollar coverage (along with the Medicaid cost-sharing portion) for Medicare-Medicaid dual-eligible beneficiaries who are not eligible or do not participate in CMS-approved clinical trials.

PCMA thanks CMS for the opportunity to provide comments on the proposed NCD framework regarding coverage for mAbs under CED to develop additional evidence on safety and effectiveness for this novel therapeutic class for the treatment of AD. We agree with CMS that “It is important to first demonstrate that the clinical benefits outweigh the harms within the patient protections and controlled settings of RCTs”¹⁵ and urge CMS to finalize its CED paradigm. We appreciate the extensive and thorough review CMS undertook in its National Coverage Analysis process. PBMs provide affordable access to drugs that show clear evidence of clinical benefit to beneficiaries. We look forward to our continued partnership on these efforts.

If you need any additional information, please reach out to me at tdube@pcmanet.org.

Sincerely,

Tim Dube
Vice President, Regulatory Affairs

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1 NCA. Proposed Decision Memo. “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N)” Available at https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=305
2 Ibid.
3 Ibid.
4 Ibid.
5 Ibid.
6 Cathy Kelly. “Could Alzheimer’s Drugs Avoid Medicare Coverage Restrictions If They Are Covered By Part D?” Pink Sheet. January 17, 2022. Available at https://pink.pharmaintelligence.informa.com/PS145526/Could-Alzheimers-Drugs-Avoid-Medicare-Coverage-Restrictions-If-They-Are-Covered-By-Part-D.
7 Ibid., NCA
8 For details on inclusion and exclusion criteria, see: https://clinicaltrials.gov/ct2/show/NCT01677572
9 A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Aducanumab (BIIB037) in Subjects With Early Alzheimer's Disease (EMERGE). ClinicalTrials.gov identifier: NCT02484547. Updated September 2, 2021. Accessed January 14, 2022. https://clinicaltrials.gov/ct2/show/NCT02484547
10 Disease (ENGAGE). ClinicalTrials.gov identifier: NCT02477800. Updated September 2, 2021. Accessed January 14, 2022. https://clinicaltrials.gov/ct2/show/NCT02477800 Aduhelm [aducanumab-avwa] injection, for intravenous use. Cambridge, MA: Biogen, Inc. July 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761178s003lbl.pdf Accessed January 14, 2022.
11 These additional criteria are: Age 50-85, Clinical Dementia Rating (CDR)-Global Score of 0.5., objective evidence of cognitive impairment at screening, an MMSE score between 24 and 30 (inclusive), must have a positive amyloid Positron Emission Tomography (PET) scan, must consent to apolipoprotein E (ApoE) genotyping, if using drugs to treat symptoms related to AD, doses must be stable for = 8 weeks prior to screening visit 1, must have a reliable informant or caregiver, and CMS should clarify whether or not the current Phase 3/4 trials on monoclonals meet the criteria.
12 FDA Advisory Committee Meeting. “Meeting of the Peripheral and Central Nervous System Drugs Advisory Committee Meeting Announcement.” November 6, 2020. Available at: https://www.fda.gov/advisory-committees/advisory-committee-calendar/november-6-2020-meeting-peripheral-and-central-nervous-system-drugs-advisory-committee-meeting#event-materials Accessed January 14, 2022.
13 NCD. “Routine Costs in Clinical Trials.” July 9, 2007. NCD 100-3. Available at https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=1.
14 42 CFR § 422.109 - Effect of national coverage determinations (NCDs) and legislative changes in benefits. Available at https://www.ecfr.gov/current/title-42/chapter-IV/subchapter-B/part-422/subpart-C/section-422.109.
15 Ibid., NCA

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The Food and Drug Administration’s CRIMINAL decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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After working in public health across state/local agencies, academic institutions, and in community-based settings, I strongly support the limitation of Aduhelm coverage by CMS.

There are many other more cost-effective and evidence-based ways to prevent Alzheimer's and related dementias. The indications for this drug are poorly understood at best as there is no clear diagnostic criteria for MCI and consensus on how useful that diagnosis is. In addition, granting greater approval of this drug would lead to several downstream issues on medical providers: there is no clear guidelines on when/if to take someone off this drug if they transition into moderate/severe Alzheimer's nor are there are contraindications on the current label leaving individual hospitals/practices/physicians to decide for themselves. Proponents of the amyloid hypothesis claim that a large reduction in plaque means this drug is effective and is proved by "science," but this generalization is irresponsible as many people can have high levels of plaque and remain healthy. Therefore, the main mechanism of action of this drug results in an outcome that does not even have a clinical benefit (i.e. stopping cognitive decline) for the patient.

This is particularly harmful since the risk of side effects are high in non-experimentally controlled Alzheimer's population with numerous co-morbidities and vascular complications on top of their Alzheimer's. It is critical to take a holistic and public health approach to Alzheimer's instead such as by supporting caregivers, increasing primary care and mental health care coverage in underserved areas, and preventing chronic disease. The desire for early treatment and detection is valid, but expensive pharmaceuticals are certainly not the only ways to tackle Alzheimer's "early." Therefore, CMS should focus on funding alternatives that are safe (i.e. hearing aids).

It is more dangerous to give patients and their caretakers false hope on a drug that has shown virtually no clinical benefit. Though it is important to balance the voices of patients and "experts," it is the responsibility of CMS, FDA, and other federal agencies to make sure that approval of Aduhelm is based on evidence rather lobbying and profit. Given the lack of evidence on clinical benefit and the high prevalence of side effects, which cannot be dismissed as mild because longitudinal data was limited, CMS should continue to strictly limit Aduhelm coverage. To maintain public trust in these agencies and prevent harm, it is certainly better for CMS to limit coverage while data is lacking rather than go off a single clinical trial at the risk of harming many patients and their families.

Thank you, Naisa Rahman

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As members of the Patient, Consumer, and Public Health Coalition, we are providing these public comments on the National Coverage Analysis Proposed Decision Memo from the Centers for Medicare and Medicaid Services (CMS). This decision relates to coverage of Aduhelm and similar medical products for the treatment of Alzheimer’s disease.

We strongly support the CMS proposed decision to limit the coverage of these drugs to patients participating in clinical trials, because it will provide the evidence needed regarding safety and effectiveness for the Medicare population. We agree with CMS that this will enable patients and family members to make informed decisions based on unbiased information pertaining to the known risks and as yet unproven benefits.

The Food and Drug Administration’s (FDA) approval of Aduhelm (aducanumab) has generated unprecedented controversy. The clinical trials that the manufacturer, Biogen, submitted to the FDA did not meet FDA standards of safety and efficacy, resulting in a unanimous vote against Aduhelm by the FDA’s Advisory Committee. Committee members expressed concern that the drug was not proven to improve memory or cognition, but it did cause brain swelling, brain bleeds, nausea, headaches, dizziness, confusion, and an altered mental state in approximately half the patients.

Unfortunately, FDA approved Aduhelm on the basis of a biomarker that is associated with Alzheimer’s but that previous research has shown does not predict improved memory or cognition.¹

It is especially concerning that fewer than 4% of the patients in the Aduhelm clinical trials were Black or Hispanic, making it impossible to determine safety of efficacy for those populations. In addition, the trials excluded patients who were over the age of 85, as well as individuals with numerous chronic conditions that are common in Medicare beneficiaries, such as heart disease, blood clots, kidney disease, impaired liver function, and individuals taking blood thinner. In fact, the data from the Aduhelm studies were based on patients representing a small minority (15%) of the types of Medicare beneficiaries who have mild cognitive impairment.

We make the following recommendations as CMS finalizes the coverage decision and develops the clinical trial guidance:

1. CMS needs to describe the mechanisms in place to enforce their requirements for diversity.

Biogen has claimed that the CMS decision would limit access to Aduhelm by people of color. However, since the company’s studies had few people of color, it is the company that is at fault for not establishing the safety or efficacy of Aduhelm for people of color.

Fortunately, CMS’s proposal addresses that problem, by mandating that CMS-funded trials must include a nationally representative population of people with Alzheimer’s disease. We urge that this diversity include a substantial number of patients in different racial, ethnic, and age groups to ensure that there is enough statistical power for subgroup analyses to determine safety and efficacy for each of the major demographic groups. CMS should also explain how they will ensure that the study participants represent the co-morbidities typical of Alzheimer’s patients, while protecting patients who might be less likely to benefit. Since CMS plans to restrict clinical trials to the most appropriate treatment centers, CMS should specify how that and other strategies will help ensure the diversity that is needed.

2. Protecting Patients from Adverse Effects

There are significant safety concerns associated with Aduhelm. In the original clinical trials 41% of patients experienced brain swelling or brain bleeds.² Other side effects included headaches, nausea, dizziness, confusion, and an altered mental state. The final CMS coverage decision should be very explicit about how they will protect clinical trial participants, and how they will ensure convenient, free access to brain scans and other safeguards.

3. Drug manufacturers should share the cost of these CMS clinical trials.

Biogen is charging $28,000/patient/year for Aduhelm, which is an outrageous price for an unproven drug. In addition, Aduhelm requires numerous brain scans to determine the presence of amyloid plaques on the brain and possible brain swelling. Biogen should reduce the cost of Aduhelm in the trials and share the costs of brain scans and administrative fees. These costs should be made publicly available.

4. CMS should be consistent in its coverage for similar Alzheimer’s treatments that are not proven to improve memory or cognition.

FDA’s decision to approve Aduhelm despite no clinical evidence of benefit has persuaded several other companies to submit applications to FDA based on similarly weak evidence of efficacy. CMS’ proposal should apply to all Alzheimer’s drugs that fail to provide solid evidence of clinical benefit, requiring well-designed clinical trials representing the diversity of Medicare beneficiaries.

We strongly support the CMS proposed plan, which will protect Alzheimer’s patients, reduce the financial burden on all Medicare beneficiaries, while also helping to keep the Medicare program solvent.

We appreciate the opportunity to provide insight into this decision and strongly encourage CMS to consider our recommendations aimed to protect patients, consumers, and the public health.

ORGANIZATIONAL SIGN ONS

American Medical Student Association (AMSA) UW Madison Chapter
Doctors for America
Jacobs Institute of Women’s Health
MISSD
National Center for Health Research
National Organization for Women
National Women’s Health Network
Our Bodies Ourselves
Patient Safety Action Network
TMJ Association
USA Patient Network
Washington Advocates for Patient Safety
Woody Matters

References

1. Zuckerman, D.M., Jury, N.J., Silcox, C.E. (2015) 21st Century Cures Act and similar policy efforts: at what cost? BMJ ;351:h6122 doi: 10.1136/bmj.h6122
2. Salloway, S., Chalkias, S., Barkhof, F., et al. (2021) Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurol ;79(1):13–21. doi:10.1001/jamaneurol.2021.4161

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In their proposed decision for coverage of aducanumab and other such monoclonal antibodies, CMS has recognized the need for further investigation to protect older and disabled adults. Importantly, CMS has suggested requiring that the drug be tested through well-designed, randomized controlled trials within patients representative of populations most impacted by Alzheimer’s disease, including racial and ethnic minorities. We see this as correcting the precedent set forth by the FDA in awarding accelerated approval for aducanumab. Through this coverage decision, manufacturers will instead have to meet a higher standard when conducting clinical trials for such Alzheimer’s disease drugs by making evident that the treatments show a clear change in patients’ cognition and function and are safe, not just a change in the level of a surrogate marker seen on MRI imaging. So far, in addition to the doubtful reliance on a surrogate imagine marker of effectiveness which does not correlate necessarily with cognitive changes, there has been inadequate investigation of harmful adverse effects of aducanumab such as brain hemorrhage that requires ongoing periodic brain imaging thus adding enormously to costs.

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It is my personal opinion this this drug works based on my interaction with the patients on drug and their family members over the past number of years.. Both patient and families continue to remark about improvements in ADL’s and cognitive areas. This is the first drug EVER to show any real change based on MRI findings.
If patient, families and doctors say they can find a way to work out the logistics of administering, and Biogen is ready and willing to step up and help the patient and families financially with the cost WHY can’t patients be entitled to this drug.
It is HOPE that would be needlessly taken away.

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The following comments are also available at https://www.citizen.org/wp-content/uploads/2618.pdf

Public Citizen, a consumer advocacy organization with more than 500,000 members and supporters nationwide, strongly supports the Centers for Medicare and Medicaid Services’ (CMS’) proposed national coverage decision for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N), under which the Medicare program would cover the drug aducanumab (and any future FDA-approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease) only for beneficiaries who enroll in CMS-approved randomized, controlled clinical trials meeting certain criteria or in trials supported by the National Institutes of Health (NIH).

As we explained in detail in our August 11, 2021, written comments regarding CMS’ National Coverage Determination Analysis for CAG-00460N, the Food and Drug Administration’s (FDA’s) decision to approve aducanumab for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of aducanumab was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for aducanumab was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

Unlike the FDA, the European Medicines Agency and a Japanese Health Ministry expert panel have opposed marketing authorization for aducanumab based on the available data.

Implementation of CMS’ proposed national coverage decision would significantly mitigate the damage done by the FDA’s egregious error in approving aducanumab under the Accelerated Approval pathway on June 7, 2021. Given the lack of scientific evidence that aducanumab provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients and unmistakable evidence that it can cause serious brain injury, the drug cannot be deemed reasonable and necessary for treatment of any patients outside the context of a clinical trial at this time. Unlike the FDA, CMS wisely chose to follow the available scientific evidence in developing its proposed national coverage decision for aducanumab for treatment of Alzheimer’s disease.

Below we provide comments regarding specific provisions of the proposed national coverage decision and responses to some comments submitted by others.

Comments regarding specific provisions of the proposed national coverage decision:

Responses to other comments submitted to CMS regarding the proposed national coverage decision:

In closing, Public Citizen urges CMS to issue a final national coverage decision under which the Medicare program would cover the drug aducanumab only for beneficiaries who enroll in CMS-approved randomized, controlled clinical trials meeting certain criteria or in trials supported by the NIH. The lack of evidence that aducanumab provides meaningful clinical benefit and the fact that the reduction in amyloid-beta plaques following administration of the drug is not an established, validated surrogate endpoint for such clinical benefit, combined with the known risks of the drug, clearly justify such limitation on Medicare coverage for aducanumab.

Thank you for the opportunity to comment on this important public health issue.

Michael A. Carome, M.D.
Director
Public Citizen’s Health Research Group

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

Fill out the required address fields, check the box to affirm that you are not a robot, and press “Submit!”

If the CMS decision goes through, Medicare’s 2022 premium increase for 57 million Americans could be reversed. That’s why your voice is so important right now!

In solidarity,

Mike Phelan
Progress America

1 https://www.youtube.com/watch?v=o8h7aBCvxu0

PAID FOR BY PROGRESS AMERICA

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February 10, 2022

Administrator Chiquita Brooks-LaSure
Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Boulevard
Baltimore, MD 21244

RE: NCD Determination for Aduhelm

Dear Administrator Brooks-LaSure:

The Alliance of Community Health Plans (ACHP) applauds the Centers for Medicare & Medicaid Services (CMS) on its balanced decision regarding the proposed National Coverage Determination (NCD) for monoclonal antibodies targeting amyloid for the treatment of Alzheimer’s disease. The proposed NCD would include coverage for Aduhelm (Aducanumab), the latest treatment developed for Alzheimer’s disease, as well as similar treatments currently under development. The coverage with evidence determination is sound and will allow the opportunity to assess the medical necessity of these types of drugs based upon the collection of additional safety and efficacy data.

As you know, ACHP represents the nation’s top-performing, provider-aligned, community-based health plans for more than 24 million Americans nationwide. We support the development and coverage of novel drugs that improve health outcomes, but monoclonal antibodies targeting amyloid have not demonstrated effectiveness, safety or value. We strongly support the agency’s goal to ensure that access to this treatment is made based upon strong clinical and scientific evidence that will be gathered through further studies and clinical trials. This proposed coverage decision balances that admirable goal while not giving individuals and families facing the everyday challenges Alzheimer's disease presents a false hope.

ACHP offers this detailed input after consulting with top clinical leaders (such as medical directors and pharmacy leaders) from our member plans. This letter is based on their extensive expertise and understanding based on years of experience in the field. It represents our membership’s collective understanding of the available scientific literature and the desire to ensure the best health outcomes for the patients our members are trusted to care for.

Background
Aduhelm was evaluated in two identically designed phase 3 randomized, placebo-controlled clinical trials named Study 301 (ENGAGE) and Study 302 (EMERGE), which had primary objectives to demonstrate efficacy and safety in early Alzheimer’s disease.

In 2019, both studies1 were stopped by Biogen for futility following a planned interim analysis. In 2020, Biogen performed numerous post hoc analyses on the trial data and suggested that in one of the two identical trials there was a small statistical difference in the rate of cognitive decline as measured by one of the clinical scales used in the trials in the highest dosage arm. Importantly, this difference was not identified in the highest dosage arm of the other identical trial. Additionally, there were no differences in the rate of cognitive decline identified in the lower dosage arms of either trial.

Many scientists and biostatisticians have observed that such a finding during post hoc analysis should be hypothesis-generating and requires confirmation in prospectively designed clinical trials. This is of particular importance since one trial had a positive finding and the other did not. It is not an appropriate assumption to label one of the trials as “true” and the other as “false.”

The FDA Advisory Committee charged with reviewing the clinical trial data for Aduhelm all voted against approval due to lack of sufficient evidence of effectiveness on patients. Despite the Advisory Committee’s strenuous objections, the FDA ultimately approved2 Aduhelm under the Accelerated Approval pathway. The agency’s decision was based on a reduction in beta-amyloid plaques in the brain. The FDA cited beta-amyloid plaques as a surrogate endpoint, a reduction of which “is reasonably likely to result in clinical benefit.”

Since its approval, numerous major health plans – including ACHP member Point32Health – announced they will not cover the drug outside of any national requirement to do so given concerns about the effectiveness and safety of the drug. They are joining a list of major health systems and insurers such as the Cleveland Clinic, Mount Sinai and the Department of Veterans Affairs who are rightfully questioning whether prescribing this treatment is in the best interest of patients.

Lack of Efficacy & Significant Safety Concerns
While Aduhelm has not definitively demonstrated benefit in clinical trials, a significant number of participants in both studies suffered from numerous concerning adverse effects. About 41% of patients in the Phase 3 trials suffered from amyloid related imaging abnormalities (ARIA) including brain swelling (ARIA-E) and small bleeds or microhemorrhages of the brain (ARIA-H). Indeed, one patient treated with Aduhelm in the Phase 1b trial died of an intracranial hemorrhage believed to be related to study treatment.

Of note, the phase 3 clinical trials excluded patients who were on anticoagulant drugs (blood thinners) due to the known risk of ARIA-H (brain bleeds) with Aduhelm. The current FDA label does not list concurrent use of blood thinners as a contraindication, precaution or warning.

There are grave concerns that patients may receive Aduhelm and anticoagulants together with disastrous outcomes, including death from bleeding into the brain. ACHP is encouraged that the Centers for Medicare and Medicaid Services made safety and efficacy a priority in the proposed NCD.

The Concern with Beta-Amyloid Plaques as a Surrogate Endpoint
The full role of beta-amyloid plaques in the pathophysiology of Alzheimer’s Disease is not completely understood. While presence of amyloid plaques in patients with cognitive impairment are a hallmark of Alzheimer’s disease, their causative role in development of the disease and whether they are an effective therapeutic target remains in doubt.

Some experts question the validity of using beta-amyloid plaques as a surrogate endpoint to predict likelihood of clinical benefit. This is largely based on the fact that numerous investigational drugs targeting amyloid plaques have failed to demonstrate any improvement in cognitive function decline, despite reducing amyloid plaques.

In addition, it is hypothesized that other markers, including nerve inflammation and tau protein tangles may also play important roles in the disease. Unfortunately, since the controversial FDA approval of Aduhelm was based on beta-amyloid plaque reduction as a surrogate marker, several pharmaceutical companies whose previous anti-amyloid drugs failed to demonstrate any clinical benefit now aim to file for FDA approval of similar drugs. Doubling down on anti-amyloid therapies at this time would likely discourage research for other Alzheimer’s treatment targets, which could provide more useful and proven therapeutic modalities in this devastating disease.

As for the randomized controlled trials, there are measures that must be undertaken by Medicare in order to gather wholesome data. Among people ages 65 and older, African Americans have the highest prevalence of Alzheimer’s disease and related dementias (13.8 percent), followed by Hispanics (12.2 percent), and non-Hispanic whites (10.3 percent)4, American Indian and Alaska Natives (9.1 percent), and Asian and Pacific Islanders (8.4 percent). The final coverage with evidence development must ensure that the enrolled patients reflect the nation’s diverse population diagnosed with Alzheimer’s disease. Patients and families need a clearer understanding of whether a reduction of beta-amyloid plaques provides a clinical benefit that is reflective upon a diverse population and limiting coverage to generate additional evidence is a step in the right direction.

Affordability for the U.S. Healthcare System
There is a well-established prescription drug affordability crisis in the United States, which acutely impacts our nation’s public insurance programs and the populations they serve. We applaud the Biden Administration for its continued focus on the problem of exorbitant drugs. Coverage for high-priced, unproven therapeutics will only exasperate existing cost concerns – and do little to improve the health of the nation.

Even with Aduhelm’s recently announced price cut, an annual price of $28,200 per patient set by Biogen will have staggering effects on patient access, insurance premiums and taxpayers. The Institute for Clinical and Economic Review’s (ICER)4 panel (which included numerous experts in Alzheimer’s disease) unanimously voted against Aduhelm with respect to providing any additional benefits over standard care.

During a cost-effectiveness analysis, ICER’s model generously included an assumption that the post hoc analysis finding of delayed cognition decline in the high dose group in the single trial was true. The analysis identified an appropriate value-based annual price range of $3,000 - $8,400, far from the current Aduhelm annual list price and Biogen’s staggering $56,000 price at release.

With the aforementioned issues in mind, if Congress acts to allow Medicare to directly negotiate drug prices and those prices cannot be accessed by commercial payers, there will be a massive cost shift to the commercial market, which would undoubtedly result in double digit premium increases for employers and working Americans. In addition, due to the significant safety concerns regarding ARIA-E and ARIA-H, numerous brain imaging studies are recommended to monitor for signs of these common adverse effects, which adds to overall costs and patient affordability.

Also, there are concerns that, despite coverage only being available through clinical trials, some costs may be inappropriately pushed onto Medicare. To safeguard the integrity of the trials, CMS should provide guidance to ensure all precisely delineate the conditions under which health care related items and services must be considered as part of the trial, and thus reimbursed by Medicare.

Dr. Lee Fleisher, CMS Chief Medical Officer and Director of the Center for Clinical Standards and Quality noted in the draft decision that due to “the potential for harm, and important questions that remain, we have determined that coverage with evidence development through clinical trials is the right decision for Medicare patients, clinicians, and caregivers.” We applaud the proposed national coverage determination for ensuring that the health care system is paying for a drug that is effective and safe.

We appreciate the continued engagement with you and members of your team. ACHP strongly supports this balanced policy, and we encourage CMS to proceed with finalizing the NCD decision for monoclonal antibodies targeting amyloid for the treatment of Alzheimer’s disease. Please contact Michael Bagel, ACHP Director of Public Policy, at mbagel@achp.org or (202) 897-6121 with any questions.

Sincerely,

Ceci Connolly
President and CEO
ACHP

Cc:
The Honorable Xavier Becerra, Secretary, Department of Health and Human Services
& Mr. Paul Spitalnic, Director and Chief Actuary, Office of the Actuary, Centers for Medicare & Medicaid Services

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

NO, PHARMA SCAMS!!!

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am not yet a medicare recipient but this is important.

The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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February 10, 2022

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore, MD 21244

Re: Proposed Decision Memo National Coverage Analysis (NCA) for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N)

Dear Ms. Syrek Jensen:

The Black Women’s Health Imperative (BWHI) and the Rare Disease Diversity Coalition (RDDC) (referred to collectively as BWHI) appreciate the opportunity to comment on the Centers for Medicare & Medicaid Services’ (CMS’) proposed decision memo referenced above (the proposed NCA). Since its 1983 founding at Spelman College, the BWHI has been the only national organization dedicated to improving the health and wellness of the nation’s 21 million Black women and girls – physically, emotionally, and financially. We are committed to leading the effort to solve the most pressing health issues that affect Black women and girls in the U.S. Through investments in evidence-based strategies, we deliver bold new programs and advocate policies that promote health and equity.

RDDC is a coalition launched by the Black Women's Health Imperative to address the extraordinary challenges faced by rare disease patients of color. For the estimated 30 million Americans suffering from a rare disease, it takes an average of 5 years to achieve a diagnosis. Additionally, only 10% of rare diseases have a treatment approved by the Food and Drug Administration (FDA). For minorities with a rare disease, these challenges are compounded by disparate access to affordable care and underrepresentation in registries, genome-wide association studies and clinical research trials. RDDC brings together rare disease experts, health, and diversity advocates, and industry leaders to identify and advocate for evidenced-based solutions to alleviate the disproportionate burden of rare diseases on communities of color. While Alzheimer’s disease is a relatively common condition, the RDDC has significant concerns that the proposed NCA represents an unprecedented challenge to the validity of the accelerated approval pathway that will widen health disparities and inequities for minorities with rare diseases.

Systemic racism has impacted Black, Latinx, and other people of color with respect to income potential, reliable access to quality health care, representation in clinical trial populations, prevalence of significant comorbidities, and poor health outcomes. BWHI appreciates both the Administration’s recognition that health inequities and disparities are inextricably linked to centuries of systemic racism, and its commitment to policies that move our nation closer to fulfilling its promise of opportunity and equality for all Americans. As you know, there are no easy solutions to “fix” the economic and health care inequities that limit the health and lives of Black women and other people of color. Research, data, and community outreach are clearly essential to identifying the causes and effects of health disparities and addressing the inequities that drive them. When crafting solutions, however, it is paramount that CMS and other government entities reinforce, rather than abrogate, the key principles of dignity, opportunity, and self-determination that our nation’s history of slavery and racism have denied to Black women and other people of color.

We have significant concerns that the proposed NCA places CMS’ assessment of benefits versus risks above the very personal decisions on use of FDA-approved treatments that should be inherently within the practice of medicine and the patient/physician relationship. In addition, BWHI cannot support any public policy conditioning coverage of an FDA-approved treatment on research participation. The proposed NCA is, unfortunately, particularly problematic in that resolving the myriad logistic, ethical, and operational issues associated with its CED paradigm will likely trigger unintended consequences that broaden inequities borne by Black women suffering from Alzheimer’s disease (AD) and their families.

I. Background

Alzheimer’s disease exacts a disproportionate, multi-generational toll on black women that both reflects and perpetuates the longstanding barriers to achieving our full potential. Black women are 2-3 times more likely than non-Hispanic white women to develop AD; Latinx individuals are 1.5 times as likely. It is anticipated that by 2030, nearly 40 percent of all US Alzheimer’s patients will be Black or Latinx. The prevalence disparity for AD risk factors such as diabetes, stress, depression, and cardiovascular disease appears to be widening.

• Individuals with a history of either high blood pressure or high cholesterol levels are twice as likely to get AD. Those with both risk factors are four times as likely to get AD.
• 65% of Black Medicare beneficiaries have hypertension, compared to 51% of white beneficiaries. They are also at higher risk of stroke.
• Black individuals have a 60% higher risk of type 2 diabetes.

The growing AD crisis also exacts a tremendous financial toll on Black families. Black women often face caregiver responsibilities for their children, grandchildren, and parents – all while maintaining primary economic provider responsibilities in a job market that pays less for doing the same work.

• Black women have to work for 579 days to make what white men earn in 365.
• On average, Black women are currently paid only 63 cents for every dollar paid to a non-Hispanic white man. Black working moms are paid just 52 cents on the dollar.
• This amounts to a median wage gap of $2,009 a month, $24,110 a year and $964,400 over a 40-year career, compared to white men. (Black-Women-Retirement-Fact-Sheet_final.pdf (nwlc.org))

The added burden of caring for a family member with AD can create unresolvable conflicts between familial caregiving and financial responsibilities. Interventions offered to newly-diagnosed patients and their caregivers (caregiver coaching, financial planning, support groups and counseling for caregivers) assume that surplus time and/or money can be leveraged to make additional responsibilities easier or more manageable. These supports are not particularly relevant to the needs of Black women who disproportionately work and live without surplus time or money. Although BWHI does not expect that the monoclonal antibodies discussed within the proposed NCA are a magic bullet against AD progression, we believe that steady, incremental progress in treatment options can make a substantial positive impact on the lived experience of Black women and their families. More importantly, we believe that the value of an incremental slowing of AD progression, and the acceptable risks to achieve it, are highly personal and inextricably linked to each patients’ life experience and their perspectives on dignity, autonomy and self-determination.

II. The proposed NCA appears to challenge the validity of the accelerated approval process.

BWHI has significant concerns that the proposed NCA demonstrates an expanded view of CMS’ authority to determine whether health care interventions are reasonable and necessary. The accelerated approval process is a statutory construct that permits FDA to determine that a drug or biologic is safe and effective based on surrogate endpoints. Congress has limited Its use to treatments addressing unmet needs in serious and/or life-threatening conditions. AD is a progressive, fatal disease that has presented tremendous challenges to drug developers due, in part, to the divergence in rate of progression from one individual to the next.

We understand that reliance on surrogate endpoints within the accelerated approval process is inherently inconsistent with the rigorous evidence on clinical benefit CMS applies within its national coverage decision process. We do not, however believe, that CMS has authority to review evidence and decide that FDA was wrong in determining that a surrogate endpoint is associated with likely clinical benefit, or that the potential benefits of a new treatment outweigh its risks. If CMS’ authority were sufficiently broad to permit implementation of the proposed NCA, the Agency could single out any accelerated-approval treatment(s), subject it to the robust evidence requirements needed to convey “national coverage” and predictably find that failure to clear the bar on confirmed clinical benefit should result in “national noncoverage.” This means that each accelerated-approval treatment would, despite addressing an unmet need in a serious or life-threatening disease, be out of reach for all Medicare beneficiaries without the financial resources to absorb the costs of the treatment.

BWHI strongly believes that leveraging the NCA process to deny coverage for on-label use of accelerated-approval drugs and biologicals frustrates Congress’ intent in creating that pathway, i.e., to facilitate early access to promising treatments. We urge CMS to reconsider its approach and exercise its authority under Medicare’s “reasonable and necessary” provision in a manner consistent with Congress’ intent in affirming the accelerated approval pathway. CMS should defer NCA inquiries on accelerated approval treatments until confirmatory trials are completed and/or real world evidence is sufficient to evaluate clinical benefit.

III. The proposed NCA will disproportionately impact Black women and other underserved populations.

BWHI is committed to ensuring that all treatments are developed and studied with the full inclusion of black women and men. The fact that black patients make up just 5% of clinical trial populations is not acceptable. It is, however, where we are. We cannot correct exclusion of black lives in developing treatments by declining or limiting access once these treatments are approved. In addition, conditioning coverage on participation in research is likely to exacerbate the trepidation within our communities, and particularly older Black women and men, toward health care systems.

While we appreciate CMS’ interest in facilitating additional research with full inclusion from people of color, conditioning coverage on clinical trial participation may negate the critical element of informed consent, and could create a tiered system of access. Patients with adequate financial resources have always been able to access treatments that individuals relying on insurance coverage are unable to afford. If implemented, the proposed NCA could result in:

The potential for differential access to on-label treatments is antithetical to the policy preferences driving the accelerated approval pathway, and inconsistent with CMS’ perceived role in “protecting” Medicare beneficiaries.

BWHI fully agrees that failures in enrolling racially and ethnically diverse clinical trial populations increases uncertainties on subpopulation-specific benefits and risks of emerging treatments. Unfortunately, the challenges to enrolling Black patients are complex, multi-factorial, and deeply rooted in our shared historical experience of systemic racism permeating the medical and scientific communities. These challenges cannot be mandated away.

• People of color are more likely to have significant comorbidities that exclude them from clinical trial enrollment
• Patients can face substantial economic challenges associated with transportation to clinical trial sites.
• AD clinical trials impose an additional layer of burdens in the form of caregiver participation requirements.

In addition, medical mistrust among Black women and other people of color has a legitimate basis, particularly with respect to any appearance or perception that participation in research is forced. BWHI asks that CMS recognize that any government-initiated policy conditioning access to treatment on research participation, particularly when the study is designed to randomly withhold an FDA-approved therapy, is likely to further, rather than reduce, medical mistrust.

BWHI also has significant concerns with the study criteria CMS outlined in its proposed NCA. We expect that the requirement that studies exclude patients with comorbidities would disproportionately exclude Black patients. To the extent that CMS intends to rely primarily on data collected through the CED studies in a future coverage decision, Black patients will likely face disproportionate access denials through and beyond the CED studies and confirmatory Phase 4 clinical trials. We urge CMS to:

IV. The proposed NCA appears to be grounded in a CMS determination that the surrogate endpoint is not likely associated with a clinical benefit.

As outlined above, BWHI strongly believes that CMS should align its access decisions with Congress’ intent in affirming the accelerated-approval pathway and avoid implementing coverage decisions that perpetuate and exacerbate differential access to FDA-approved treatments. CMS should reconsider its proposed NCA based on public policy and equity priorities. In addition, we do not view CMS’ discretionary authority as sufficiently broad to permit substitution of CMS’ interpretation of evidence for specific determinations delegated to and actually made by FDA. The proposed NCA appears to undermine both the validity of the accelerated approval pathway in facilitating access and FDA’s authority to determine that a surrogate endpoint is likely associated with clinical benefit.

CMS’ guidance on use of CED outlines a set of governing principles, including that “CED will not duplicate or replace the FDA’s authority in assuring the safety, efficacy, and security of drugs, biological products, and devices.” (Medicare Coverage Document - Guidance for the Public, Industry, and CMS Staff: Coverage with Evidence Development) We note that CMS initiated the National Coverage process shortly after FDA approved Aduhelm® but focused its analysis on all monoclonal antibodies directed at the surrogate endpoint of beta amyloid plaque. The breadth of the proposed NCA clearly suggests that CMS’ primary question is the validity of the surrogate endpoint in predicting clinical benefit. The accelerated approval mechanism intentionally prioritizes early access and defers the question of clinical benefit to Phase 4 confirmatory studies. CMS declined to incorporate Congress’ intent to prioritize early access over evidentiary certainty with respect to Medicare beneficiaries. The primary research question driving the proposed NCA is whether “the evidence [is] sufficient to conclude that the use of monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease improves health outcomes for Medicare beneficiaries?” Predictably, CMS concluded that:

"[t]o date, no trial of an antiamyloid mAb has confidently demonstrated a clinically meaningful improvement in health outcomes (i.e., cognition and function) for AD patients. Thus, there is insufficient evidence to conclude that the use of monoclonal antibodies directed against amyloid is reasonable and necessary for the treatment of Alzheimer’s disease under §1862(a)(1)(A) of the Social Security Act (emphasis added)"

As outlined above, we urge CMS to take a more pragmatic approach to emerging accelerated-approval treatments and decline to engage in a futile NCA inquiry into whether clinical benefit is confirmed. If, however, the Agency determines to pursue and finalize an NCA, HHS’ delegations of authority and CMS’ internally-created guidance documents require it to accept FDA determinations. The proposed NCA fails to do so in several ways:

- FDA has sole authority (pursuant to HHS delegation of authority) to balance evidence on an intervention’s benefits and harms and determine whether a drug or biological is safe and effective for its labeled indication(s). CMS’ proposed NCA appeared to view FDA’s Aduhelm® determination as deficient from an evidentiary perspective. The Agency outlined its rigorous, independent safety and effectiveness analysis and concluded that “due to the lack of a clear clinical benefit and the frequency of adverse events like ARIA, the evidence does not support that the benefits outweigh the harms for mAbs directed against amyloid for the treatment of AD.”

- FDA determined that clearance of amyloid plaques was likely related to clinical benefit and approved Aduhelm® based on that surrogate endpoint. CMS’ determination of national noncoverage (other than within CED studies) for all monoclonal antibodies directed at amyloid plaques was based on its de novo review and independent judgment that “we agree with the conclusion, published by one author reviewing all the trial data, that ‘no biomarker has achieved surrogate status in AD drug development with definite evidence that a change in the biomarker predicts a clinical benefit.’”

- FDA requires completion of Phase 4 confirmatory trials to establish clinical benefit, and there are no indications that the manufacturer has failed to act with diligence toward completing the required clinical trial(s). CMS is “proposing CED to support rigorous trials to answer whether antiamyloid mAbs improve health outcomes for patients.” BWHI is unable to identify any clear rationale that could differentiate the goals of the confirmatory studies from the evidence likely gleaned within the proposed CED studies. In fact, CMS proposes to exclude patients with comorbidities who may be eligible to participate in the Phase 4 study. In addition, it is highly likely that, if finalized, the CED paradigm will frustrate and delay enrollment in manufacturer-sponsored, FDA-mandated confirmatory studies.

V. CMS should no longer limit amyloid PET coverage to CMS-approved clinical trial participants.

CMS issued its final decision memorandum for “Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease” (PET NCA, NCA - Beta Amyloid Positron Emission Tomography in Dementia and Neurodegenerative Disease (CAG-00431N) - Decision Memo (cms.gov)) nearly a decade ago. Throughout the years since its implementation, the CED framework has limited Medicare beneficiary access to a diagnostic tool that, in combination with a clinical finding of cognitive impairment, can provide a greater level of diagnostic certainty than clinical evaluation alone. Clinical certainty in diagnosing AD is, unfortunately, not clinically relevant. As CMS noted in its PET NCS:

"Because clinical diagnosis is poor, and amyloid pathology is seen in other diseases as well as in cognitively normal older persons, the “gold standard” for diagnosis requires both (a) the presence of moderate to frequent Aß plaques and neurofibrillary tangles on autopsy, and (b) clinical documentation of progressive dementia during life (NIA-Reagan Institute 1997, Hyman 1997)."

Medicare beneficiaries cannot meet the gold standard with respect to an AD diagnosis until they have suffered progressive dementia, died, and been autopsied. Patients and the Medicare program, however, have a substantial interest in ensuring that patients have access to diagnostic tools that can be deployed in living patients and before AD progression exerts its devastating toll. Beta amyloid PET is one of the best diagnostic tools available to inform patients and their clinicians on the likely cause and potential progressive course of cognitive impairment/decline in aging patients. Its use enables proactive strategies to seek an FDA-approved treatment, participate in a clinical trial, implement safety and wellness interventions, and develop a care plan while the patient has the cognitive ability to fully participate in their care decisions. In its 2020 Clinical Effectiveness Review entitled “Diagnosis and Treatment of Clinical Alzheimer’s-Type Dementia: A Systematic Review,” (https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/cer-223-clinical-alzheimers-type-dementia_0.pdf ) the Agency for Healthcare Research and Quality (AHRQ) stated that “amyloid PET and MRI were highly sensitive and specific distinguishing autopsy-confirmed AD from non-AD dementia.”

CMS has asserted that its authority to implement CED within its NCA process is grounded in Section 1862(a)(1)(E) of the Social Security Act and its reference to Section 1142 of the Act, which describes AHRQ’s authority to conduct and support research on outcomes, effectiveness, and appropriateness of services and procedures to identify the most effective and appropriate means to prevent, diagnose, treat, and manage diseases, disorders, and other health conditions. To the extent that AHRQ review of the PET NCA at its creation was sufficient authority to implement the CED restrictions, AHRQ’s 2020 report dispositively answers the underlying research questions driving the CED inquiry. Continuing to require that Medicare beneficiaries serve as research subjects to access what AHRQ has determined to be a “highly sensitive and specific” tool for diagnosing AD in cognitively impaired beneficiaries is not only unfair, but contrary to Medicare’s commitment to pay for medically necessary diagnostic services.

VI. The draft NCA raises significant operational and ethical concerns with respect to individuals seeking access to the first FDA-approved treatment with potential to mitigate disease progression

CMS has noted that there are no FDA-approved treatments that impact Alzheimer’s disease progression, other than the recently-approved therapy that is the subject of the proposed NCA. BWHI strongly opposes the proposed NCA and the precedent it will set for Medicare beneficiaries with serious conditions who might benefit from therapies approved through the accelerated approval pathway. We also have significant concerns about implementation in the event that CMS determines to finalize the NCA.

1. It is unclear that any entity, other than a manufacturer, would be willing to undertake the CED studies.
Anti-kickback and beneficiary inducement considerations would likely preclude manufacturer funding. BWHI is concerned that the proposed NCA will, as a practical matter, function as a near-complete bar to treatment access. CMS did not identify the types of entities that it would accept as study sponsors. While manufacturers are generally the most likely sponsors for interventional studies, BWHI is concerned that the link between funding the study and coverage could preclude manufacturer participation. We suggest that CMS outline how it expects to resolve beneficiary inducement and anti-kickback prohibitions that might preclude manufacturer funding of the CED research, including whether manufacturers can fund participant copayments, and assess whether funding CED studies would impermissibly interfere with and delay FDA-required confirmatory studies. In addition, we urge CMS to assess whether, and the extent to which, other entities would fund the research in a manner sufficient to ensure a reasonable level of access to emerging AD treatments.

2. CMS’ requirement that studies be performed within a hospital-based outpatient department will overly burden patients and inhibit access for rural patients.
CMS appeared to determine that Aduhelm® administration and follow-up can only be safely performed in a hospital-based outpatient department. BWHI expects that there are a number of logistic and cost-related factors that could make this setting preferable for CMS, including the potential to incorporate prior authorization processes and reimburse drug costs at ASP minus 22.5% for 340(B) covered entities. The FDA-approved label for Aduhelm® sets forth the follow-up protocols to ensure patient safety and do not limit administration or imaging studies to hospital outpatient departments. From a patient perspective, we are unconvinced that infusion centers, physician offices, and independent imaging centers might better serve as administration and follow-up settings of care. We urge CMS to revisit this proposed requirement with an eye toward balancing patient burdens with safe treatment and follow-up.

3. CMS is not clear on how it would apply its requirement that studies enroll a diverse patient population.
BWHI is committed to public policies and initiatives to increase clinical trial participation among Black women and other under-represented populations. We fully support culturally-relevant outreach and education on the benefits of clinical trial participation, study designs that consider the needs of Black women and other persons of color (e.g., travel and time commitments), increased participation of Black researchers and study providers, and inclusion of clinical trial sites that are likely to be trusted providers for Black patients.

4. The requirements within the proposed NCA do not appear likely to resolve the impediments to enrollment among underserved patient populations.
Conditioning coverage on research participation is likely to increase medical mistrust. Excluding individuals with a set of undefined comorbidities based on their likelihood of increasing adverse events will likely disproportionately exclude Black patients. We urge CMS to assess the differences in likely number of patients screened versus eligible across racial and ethnic subpopulations. To the extent that investigators would find it difficult to meet CMS’ requirements, we are concerned that pressures to enroll Black patients, together with the conditional coverage of an FDA-approved treatment, could impede meaningful informed consent.

Similarly, CMS is unclear on how and when it would evaluate clinical trial enrollment. It would appear that coverage could be delayed until enrollment is completed and evaluated. This would create enormous logistic problems given the progressive nature of AD and the potential that an eligible participant could be ineligible within a year due to cognitive decline. The alternative would be for CMS to cover treatment for enrolled participants as they enter the study, and retroactively assess whether the study has met the diversity requirements. We urge CMS to resolve this important issue before finalizing the NCA, and to clearly communicate whether retroactive denials of coverage would be applied in the event that a study fails to meet the diverse enrollment coverage criteria.

5. The CED paradigm set forth within the proposed NCA appears to be a CMS research study.
The proposed NCA is quite granular with respect to the data CMS seeks and clinical trial requirements, including (1) enrolled population reflecting overall disease demographic; (2) exclusion criteria; (3) randomization of patients to treatment and control arms; and (4) directing the setting of care (hospital outpatient department). CMS will also be reviewing and approving study protocols and intends to gather and review data on patient outcomes. Given that CMS intends to engage in prospective research that contemplates randomizing individuals diagnosed with AD and either providing or withholding an FDA-approved treatment, we believe that it is critical that the Agency obtain a clear and specific assessment of the ethical and patient protection concerns associated with the NCA. We believe this is particularly important within an NCA context that precludes coverage outside of the set of CMS-approved studies.

BWHI similarly urges CMS to clearly outline the evidentiary goals of the CED construct, and contract with an independent entity to perform monitoring functions across all CMS-approved studies to ensure that randomization of research subjects ceases when likely clinical benefit is shown.

6. We strongly urge CMS to prioritize beneficiary access and protections over the data collection interests outlined in the CED proposal.
If CMS finalizes the proposed NCA within the timeframe anticipated, it is likely that an additional year will elapse before the first doses of Aduhelm® are covered within a CED study. BWHI has significant concerns that individuals accessing the drug in advance of NCA finalization and implementation will face interruptions in access or, worse, find that they no longer have access. Some of these patients may have demonstrated a meaningful decrease in amyloid plaque, or even a clinical benefit from treatment. In addition, beneficiaries may be unable to enroll in a CED study by virtue of delays in establishing protocols and enrolling patients, or distance from a CED study site. We suggest that CMS:

- Identify an alternative coverage pathway for Medicare beneficiaries unable to participate in a CMS-approved clinical trial who seek coverage within the FDA-approved labeled indication.

- Limit CED coverage restrictions to “new starts” or develop a clear pathway (e.g., expedited appeal) to coverage for beneficiaries who have received the treatment and not exhibiting significant adverse events, including beneficiaries accessing care before NCA implementation, or through coverage by another payer, expanded access, or self-pay.

7. CMS should review informed consent documents in connection with CMS-approved research studies and ensure that the informed consent clearly articulates:

• The non-experimental, non-investigational nature of the FDA-approved treatment.
• Availability of alternative ways for beneficiaries to access treatment outside participation in clinical trials.
• Clarity on post-trial participation access to treatment for individuals demonstrating a clinical benefit. While CMS appears to prefer conditioning coverage on continued enrollment in longitudinal studies, BWHI believes that beneficiaries should have a choice on continued participation without losing access to treatment.
• Whether the study protocol is blinded or not, and what that means for patients diagnosed with AD who may be randomized to the control arm.
• All costs that participants will be expected to pay, including copayment amounts. This must include disclosure on whether subjects randomized to the control arm will be responsible for copayments associated with the FDA-approved therapy in the treatment arm.
• That individuals unwilling to accept the risk of randomization to the control arm and can access the FDA-approved treatment if it is prescribed and they are able to pay for the treatment. Although BWHI expects that this could result in disparate access, we believe that failing to inform potential research subjects that treatment is available commercially would be unethical.
• Disclosure of research subject responsibilities, including consent to invasive and non-invasive tests and imaging studies, that are associated with data collection rather than connected to treatment monitoring.

Conclusion

Once again, BWHI appreciates the opportunity to respond to CMS’ proposed NCA. We welcome the opportunity to fully engage with CMS to ensure that equity considerations and an intentional focus on eliminating the impact of systemic racism remain at the forefront of CMS’ policy determinations, including Medicare coverage decisions.

If you or your staff would like to discuss these issues in greater detail, please do not hesitate to contact me (tboyd@bwhi.org) by phone or via e-mail.

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There are many aspects of this process that seem worthy of further review, and criticism. Firstly, for a drug whose efficacy is highly limited in scope, and whose determination as successful necessitated post-hoc analysis (WSJ Editorial Board, 2022), I believe Biogen bears responsibility to continue decreasing the price of their drug. I find that a post-hoc analysis is a relatively weak form of evidence to determine efficacy, as opposed to traditional experimental conclusions. Combining that with the potentially negative side effects that some have experienced, which are a far-cry from being outweighed by its alleged benefits (as in most medications,), highlights that the drug in and of itself should likely not have received accelerated FDA approval and should certainly not be approved for regular administration beyond optional experimental research trials. A case of these potentially intense negative outcomes from the drug can be seen in a NY Times article, where a woman had brain swelling intense enough to result in death (Belluck, 2021). Some degree of negative outcomes is typically unavoidable in pharmaceuticals, but it must be asked whether these are outweighed by their positive effects. While of course innovation begets profit, it must be considered as to whether this innovation and its approval truly serve for the primary purpose of improving patients' lives, and not improving the financial standing of the company which has had to jump through several hoops to begin profiteering. The fundamental purpose of medical research and innovation is benefitting either the general, or a specific population who suffers from a particular illness. Alzheimer’s is an illness which has always been followed by despair and hopelessness regarding its inevitable progression; individuals with afflicted loved ones will, of course, vie for any opportunity to improve their standing, however small the chance. I believe the actions of Biogen must at the very least be contemplated as predatory regarding these desperate individuals and their desire for any glimmer of hope. This is not to downplay the awareness of the afflicted regarding the drug’s history and questionable efficacy, but rather highlight the potential reality that they would opt to take a considerable risk in hopes of any change. Given all the reasons for scrutiny that these events seem to justify, I am of a mind with bioethicist Leonard Fleck, who wrote in the Hastings Center Report that the company should have profit margins fractional to their current margins until it can be more definitively proven that Aduhelm does?demonstrably improve the lives of those who take it (Fleck, 2021). This especially applies while it is being administered experimentally in trials, but may not be as significant, should the drug go on to more effectively prove itself. If it is eventually approved for general coverage after doing so, I still believe Biogen’s top priority should be aiding the afflicted, not maximizing profit margins. If lowering its cost could allow it to help more people, the company bears a moral burden to take that into consideration regarding its pricing. Additionally, upon looking back at all of the events that occurred in this drug, and this company’s timeline, further standards should be upheld to prove that transparent practice is taking place, as should be the bare minimum in medical innovation. If these further standards and trials should prove the drug more effective than it has been thus far, and if Biogen is more successful in proving the purity of its intentions, I believe that would be substantial enough evidence to justify a broader coverage by CMS, otherwise, trials should continue to be the extent of its coverage.

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Works Cited

Board, The Editorial. “Opinion | the Alzheimer's Death Panel.”?The Wall Street Journal, Dow Jones & Company, 23 Jan. 2022, https://www.wsj.com/articles/the-alzheimers-death-panel-biogen-aduhelm-fda-cms-medicare-healthcare-access-ration-care-progressives-elderly-senior-citizens-11642958967.

Belluck, Pam. “Concerns Grow over Safety of ADUHELM after Death of Patient Who Got the Drug.”?The New York Times, The New York Times, 22 Nov. 2021, https://www.nytimes.com/2021/11/22/health/aduhelm-death-safety.html.

Fleck, Leonard, “Alzheimer’s and Aducanumab: Unjust Profits and False Hopes,” Hastings Center Report 51, no. 4 (2021): 9-11. DOI: 10.1002/ hast.1264

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s incorrect decision to approve Aduhelm for treatment of Alzheimer’s disease demonstrated poor review of the science. The agency’s credibility has been definitively harmed.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am writing to applaud the Centers for Medicare and Medicaid Services (CMS) for their proposed national coverage decision regarding “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease” issued on January 11, 2022. I am a practicing physician and, like many other clinicians, patients, and experts, I was deeply disturbed by the Food and Drug Administration’s (FDA) recent decision to approve the Alzheimer’s disease drug, aducanumab, despite the significant lack of evidence regarding its efficacy as well as concerns about the drug’s safety. While the FDA has defended this decision by noting that they granted accelerated approval to aducanumab, which only requires the drug to demonstrate an effect on a surrogate marker thought to be predictive of clinical benefit, the agency has failed to note that the particularly surrogate marker underpinning aducanumab’s approval – that of beta-amyloid seen on MRI scans of the brain – has failed in over two dozen clinical trials to show any association with clinically meaningful changes in Alzheimer’s disease patients. In addition, the cost of this medication is prohibitive and will put a tremendous financial strain on Medicare.

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UnitedHealth Group (UHG) is pleased to provide feedback to the Centers for Medicare and Medicaid Services’ (CMS) Proposed National Coverage Determination (NCD) for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N) released for comment on January 11, 2022.

UHG is a mission-driven organization dedicated to helping people live healthier lives and helping our health care system work better for everyone through two distinct business platforms – UnitedHealthcare (UHC), our health benefits business, and Optum, our health services business. Our workforce of 340,000 people serves the health care needs of 140 million people worldwide, funding and arranging health care on behalf of individuals, employers, and governments. We not only serve as one of the nation’s most progressive health care delivery organizations; we also serve people within many of the country’s most respected employers, in Medicare we serve nearly one in five seniors nationwide, and in Medicaid we support underserved communities in 31 states and the District of Columbia.

Many UHC members and Optum patients suffer from Alzheimer’s disease (AD) and, to date, there have not been any proven therapies which alter the pathogenesis of this devastating disease. UHG understands the significant impact of AD on those inflicted with this condition, as well as the loved ones who care for them. As part of our overall senior wellness programs, we ensure that members and caregivers have the resources and support they need to battle this devastating disease including supportive treatment. Of the over 100 therapies currently in clinical trials for AD we remain hopeful that a safe and effective treatment will one day become available.

UHG agrees with CMS’s finding, which is the basis of the proposed NCD, that “To date, no trial of an antiamyloid mAb has confidently demonstrated a clinically meaningful improvement in health outcomes (i.e., cognition and function) for AD patients.” We also agree with CMS’s conclusion that currently there is insufficient evidence to conclude that the use of monoclonal antibodies directed against amyloid is reasonable and necessary for the treatment of AD under the Social Security Act. Given the significant risk of complications with use of these therapies, until there is sufficient evidence that these treatments meet the general standard for coverage under Medicare, UHG supports CMS covering them only under Coverage with Evidence Development. Finally, we recommend that CMS require the clinical trials be randomized, placebo controlled and include beneficiaries that are representative of the national population affected by AD.

UHG appreciates this opportunity to comment, and, if you have any questions, please do not hesitate to contact me.

Sincerely,

Margaret-Mary Wilson, MD, MRCP, FNMCP, MBA
Executive Vice President and Chief Medical Officer
UnitedHealth Group

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Dear Secretary Becerra, Administrator Brooks-LaSure, and Members of Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease CMS NCD Committee:

I am a cognitive neurologist and Alzheimer’s disease (AD) clinician-clinical researcher with over 20 years of experience solely devoted to caring for patients with AD and Related Disorders (ADRD) and their care partners, and serving and leading AD/ADRD diagnostics and therapeutics research/trials, and national care practice, outreach, patient-care partner advocacy, and educational efforts. I also co-chair (non-paid) a national Alzheimer’s Association clinical practice guidelines working group for ADRD detection, diagnosis and disclosure; and serve (un-paid) as the chair of the Alzheimer’s Disease International (ADI) Medical and Scientific Advisory Panel (ADI MSAP). I have been involved with anti-amyloid mAb clinical trials (as site-PI/investigator and consultant) for more than 15 years (please see my disclosure below); have substantial experience and proficiency with detection, monitoring and management of amyloid-related imaging abnormalities (ARIA); with real-world cohort studies to assess long-term clinical effectiveness of approved AD medications (Atri et. al 2008; https://pubmed.ncbi.nlm.nih.gov/18580597/); and with assessing participants and diagnostic formulation (as a site clinical core co-leader), psychometrics and normative data from the National Alzheimer’s Coordinating Center (NACC) Uniform Dataset (UDS) longitudinal observational cohort (Shirk et al. 2011 doi: 10.1186/alzrt94; Weintraub et al. 2018 doi: 10.1097/WAD.0000000000000223) – of note, a study which used NACC UDS data (Andrew et al. 2019) was, in my opinion, wrongly quoted in the CMS CED proposed decision memo regarding “clinically meaningful” outcomes and thresholds. I have also had the great privilege, and challenge, of having served twice as a primary caregiver to very close family members suffering from dementia. I am also part of the authorship team of Cummings J, et al. Aducanumab Appropriate Use Recommendations. J Prevent Alz Dis. 27 July, 2021 – open access https://link.springer.com/article/10.14283/jpad.2021.41.

For many scientific, medical, ethical and health policy reasons and considerations, I have major concerns and strongly urge you to kindly carefully reconsider the current CMS NCD decision memo proposal regarding monoclonal antibodies (mAbs) directed against amyloid for the treatment of Alzheimer’s Disease (AD).

While I applaud CMS for considering safety guardrails; benefit-risk/burden calculus; clinical meaningfulness; diversity, inclusion, equity (DEI); and generalizability of results to CMS-covered clinical populations, I believe that the current proposed decision memo is based on several incorrect assumptions, misinterpretations and misunderstandings, and that it sets a dangerous and discriminatory (against persons with AD) precedent that:

I agree that there should be appropriate inclusion/exclusion criteria and sufficient proficiency of dementia specialist clinicians, with demonstrated knowledge and adequate resources, to advise patients in a patient-centered shared decision-making process that balances potential risk-benefit and burdens, and to mitigate potential safety risks, especially for ARIA. There is a path forward for CMS to provide reasonable and restricted coverage and guardrails (e.g. akin to a template provided in the appropriate use recommendations by Cummings et al. 2021) in a manner that will allow informed patient-centered decision-making that balances beneficence, safety, autonomy and justice (including with respect to diversity, equity, inclusion, access, burden and costs). Such a path could be achieved under CED with an open-label registry that requires proficient clinicians, sufficient system resources, and safety monitoring, plan and reporting. It can lead to better DEI (compared to the current CED under RCT) and, if designed carefully, also to overall better AD/ADRD diagnosis and care and, in the intermediate- to longer-run, to better outcomes and societal savings.

The current “second generation” anti-amyloid mAbs are far from a cure but should not be lumped together. Aducanumab is the first in this class. We will do better in the coming years and decades by sharpening our approaches, informed by biomarkers, and providing personalized care. The current anti-amyloid mAbs provide a foundational stepping stone that is good enough to start. Many patients, with capacity to make informed-decisions about their lives and livelihood when faced with progress and incurable disease (AD), and their families do not want to want to, cannot afford, and should not have to wait until our field generates the perfect data, drug and magic bullet – that is neither realistic, economical nor ethical. We need iterative advances to make larger leaps over the next 1-2 decades – and these anti-amyloid mAbs, in additional to best care practices, can provide that.

Anti-amyloid approaches are and will only be part of a larger equation for combination and add-on multifactorial personalized treatments and care that will be informed by biomarkers, and that will also target “T” (tau), “N” (neurodegeneration), “I” (Inflammation and Immune-mechanisms), “V” (Vascular), E/M “Energetics and Metabolism”, etc. Yet, for those with early stage AD now, a potential slowing of clinical progression that is not guaranteed and may be modest for a group (population), can meaningful to a person with this disease and to her/his loved-ones. To maintain as much function in the MCI or early dementia stages, for months or longer compared to standard of care, would be clinically meaningful to many persons with AD. Finally, the first step to receiving appropriate care involves receiving a timely and accurate diagnosis, and appropriate disclosure, education and counseling; I believe that a reasonably safeguarded and equitable CMS NCD open-label registry coverage(with restrictions as to site dementia specialist proficiency, monitoring resources and plan) can also improve the evaluation, diagnostic and care process for patients and families/care partners, whether or not they ultimately qualify or choose to undergo treatment with aducanumab/anti-amyloid mAbs. Our patients deserve our support to have the autonomy to make such an informed choice.

Thank you for your careful consideration of this nuanced and complex issue and critical determination.

Disclosures: My comments represent my own views and not those of any of my institutions, affiliations or employer. I also served as site-PI for the aducanumab phase 3 EMERGE study at my previous institution, and currently serve as Project Arm Leader (PAL) for the DIAN-TU open label gantenerumab study (contracted research via Washington University St. Louis); and have served as a consultant for multiple pharmaceutical companies including several with anti-amyloid mAbs currently under consideration/being studied (Biogen, Eisai, and Roche-Genentech). An additional list of my recent disclosures can be found the recent appropriate use recommendations publication (Cummings et al. JPAD 2021 https://link.springer.com/article/10.14283/jpad.2021.41).

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

I really do not want medicare premiums to increase especially to pay for an inadiquetly vetted drug. This country needs to help the people. Medicare is health system that can only succeed if we keep the greedy Big Pharmas' hands out. Please think of US retired people and our access to healthcare.

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The National Center for Health Research (NCHR) appreciates the opportunity to provide public comments on the National Coverage Analysis Proposed Decision Memo from the Centers for Medicare and Medicaid Services (CMS). This decision relates to monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease.

As a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, we have a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. Our aim is to ensure that patients and consumers are equipped with information that can help them chose treatments that are proven safe and effective. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.

The Food and Drug Administration (FDA) approval of Aduhelm (aducanumab), a member of this drug class, has generated enormous controversy. The manufacturer, Biogen, submitted clinical trial data that did not meet FDA standards of safety and efficacy. One randomized clinical trial indicated a small benefit that was not clinically significant and the other indicated that the placebo patients did somewhat better. In addition to a lack of efficacy, brain swelling and brain bleeds were experienced by 41% of patients, as well as nausea, headaches, dizziness, confusion, and an altered mental state. Unfortunately, FDA ignored the advice of their Advisory Committee and instead approved Aduhelm on the basis of a biomarker that has not been shown to not be associated with significant improvement in terms of memory or cognition.¹

We strongly support the CMS proposed decision to limit the coverage of this class of drugs while requiring additional clinical trials to ensure safety and effectiveness for the Medicare population. This compromise strategy will help ensure that patients and family members can make decisions based on unbiased information demonstrating the known risks and the lack of certainty about any benefit.

Approximately 1 million American’s are diagnosed with Alzheimer’s disease each year,² which has been found to be more prevalent among older Black and Hispanic communities.³ And yet, less than 4% of the patients in the Aduhelm clinical trials were Black or Hispanic, making it impossible to determine safety of efficacy for those populations. The proposed decision memo takes important steps to protect vulnerable Americans by requiring diversity in the clinical trials.

In addition to excluding patients who were over the age of 85, the Aduhelm trials also excluded individuals with many prevalent chronic conditions such as heart disease, blood clots, kidney disease, impaired liver function, and individuals taking blood thinners. Overall, 85% of Medicare beneficiaries with mild cognitive impairment were not represented in the Aduhelm clinical trials conducted by Biogen.⁴ The new clinical trials should include as many of these co-morbidities as can be done safely.

NCHR recommends the following as CMS finalizes the coverage decision for this class of drugs and develops the clinical trial guidance:

1. The clinical trial guidance must articulate how CMS will enforce their requirements for diversity.
Criticisms of the CMS decision have focused on limiting access of Aduhelm to people of color. These criticisms ignore the fact that Aduhelm was not adequately tested on people of color, so that neither safety nor efficacy has been established in any of the Biogen studies. It also ignores the fact that people of color tend to seek treatment for Alzheimer’s disease at a later stage than Whites, thus making it less likely that they would seek treatment for the mild cognitive impairment for which Aduhelm is approved.³

While numerous racial and ethnic groups have been underrepresented in clinical trials for Alzheimer’s disease, CMS’s proposal explicitly addressed that problem.⁵ The proposed decision memo mandates that CMS-funded clinical trials must include patients that are representative of the national population diagnosed with Alzheimer’s disease. We would suggest a slight revision: Rather than being concerned about the percentage of patients in specific racial and ethnic groups, we propose that CMS include sufficient numbers of patients in different racial, ethnic, and age groups to ensure that there is enough statistical power for subgroup analyses to determine safety and efficacy for each of the major demographic groups. Equally important, CMS should specify how they will ensure that the study participants represent the co-morbidities of typical Alzheimer’s patients, while ensuring that patients at high risk of harm are not included in the trial. Because CMS plans to restrict clinical trials to the best possible treatment centers, they can help ensure the diversity that is needed.

CMS should specify how clinical trial recruitment will overcome barriers such as mistrust, lack of clinical trial awareness, lack of transportation and access to the clinical trial sites, and lack of comfort with the clinical trial process.⁶ Principal Investigators and physicians who have already built trust by serving diverse populations will be key.

2. CMS guidelines must establish a strict monitoring strategy to track and limit adverse effects.
There are significant safety concerns associated with Aduhelm. In the original clinical trials 41% of patients experienced brain swelling or brain bleeds.⁷ Other side effects included headaches, nausea, dizziness, confusion, and an altered mental state. It is critical that there are adequate data monitoring guidelines in the final CMS coverage decision to help protect clinical trial participants, including easy, free access to brain scans and other necessary safeguards.

3. Drug manufacturers should share the cost burden of future CMS clinical trials for this drug class.
The financial burden of these clinical trials studies should not be paid entirely by the American taxpayer through Medicare. The cost of Aduhelm at 28,000/patient/year is far too expensive for an unproven drug in or outside of a clinical trial, and Aduhelm requires numerous brain scans that would be very costly for patients and for Medicare. Biogen should reduce the cost of Aduhelm in the trials and share the costs of brain scans and administrative fees. CMS must ensure transparency in all costs to the public and patients.

4. CMS must uphold this decision with future monoclonal antibody drugs in development that are targeting amyloid.
Several companies decided to submit applications to FDA for similar drugs as soon as Aduhelm was approved. They followed the misguided precedent of defining efficacy as amyloid plaque reduction rather than clinically meaningful benefits to memory and cognition. CMS must uphold this coverage decision so that it applies to all Alzheimer’s treatment drugs pending results from clinical trials.

NCHR strongly supports CMS’s effort to make the best of the bad situation that was created when the FDA ignored the advice of its own independent scientific advisors and instead approved Aduhelm. Rather than have Medicare pay for patients to risk their lives by providing coverage for an unproven drug with clear risks, CMS’s proposed plan would safeguard many Alzheimer’s patients while at the same time protecting the Medicare program from financial ruin. Given the lack of scientific evidence that the benefits of Aduhelm outweigh the risks for most Medicare patients, well-designed clinical trials that ensure patients’ access to brain scans are urgently needed. These trials will eventually make it possible for patients to make an informed decision for their own health and for loved ones. The inclusion of diverse populations, initially excluded from clinical trials of Aduhelm, will ensure safety and efficacy data is representative of all groups with access to drugs within this class.

We appreciate the opportunity to provide insight into this decision and strongly encourage CMS to consider our recommendations aimed to protect the public health.

References

1. Zuckerman, D.M., Jury, N.J., Silcox, C.E. (2015) 21st Century Cures Act and similar policy efforts: at what cost? BMJ ;351:h6122 doi: 10.1136/bmj.h6122
2. Rajan, K.B., Weuve J., Barnes, L.L., Wilson, R.S., & Evans, D.A. (2019) Prevalence and incidence of clinically diagnosed Alzheimer's disease dementia from 1994 to 2012 in a population study. Alzheimer’s Dement;15(1):1-7.
3. Lines, L.M., Sherif, N.A., & Wiener, J.M. (2014) Racial and ethnic disparities among individuals with Alzheimer’s disease in the United States: A literature review.
4. Anderson, T.S., Ayanian, J.Z., Souza, J., Landon, B.E. (2021) Representativeness of Participants Eligible to Be Enrolled in Clinical Trials of Aducanumab for Alzheimer Disease Compared With Medicare Beneficiaries With Alzheimer Disease and Mild Cognitive Impairment. JAMA;326(16):1627–1629. doi:10.1001/jama.2021.15286
5. Indorewalla, K.K. et al. (2021) ‘Modifiable Barriers for Recruitment and Retention of Older Adults Participants from Underrepresented Minorities in Alzheimer’s Disease Research’: 927 – 940.
6. Clark, L.T., Watkins, L., Piña, I.L., Elmer, M., Akinboboye, O., Gorham, M., Jamerson, B., McCullough, C., Pierre, C., Polis, A.B., Puckrein, G., (2019) Increasing diversity in clinical trials: overcoming critical barriers. Current Problems in Cardiology;44(5):148-72.
7. Salloway, S., Chalkias, S., Barkhof, F., et al. (2021) Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease. JAMA Neurol ;79(1):13–21. doi:10.1001/jamaneurol.2021.4161

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Men's Health Network
P. O. Box 77476
Washington, D.C. 20013
202-543-MHN-1 (6461)
Info@menshealthnetwork.org ? www.menshealthnetwork.org

February 10, 2022

Centers For Medicare and Medicaid Services

I am writing on behalf of Men’s Health Network (MHN). MHN is an international non-profit organization whose mission is to reach men, boys, and their families where they live, work, play, and pray with health awareness messages and tools, screening programs, educational materials, advocacy opportunities, and patient navigation.

MHN is very concerned about the new and unprecedented National Coverage Determination (NCD) proposal by the Centers for Medicare and Medicaid (CMS) regarding the use of an FDA fully approved medication for the treatment of Alzheimer’s Disease, Aduhelm.

Alzheimer’s disease has an enormous impact on both the patient and the caregiver. This condition imposes a significant physical, emotional and financial burden on them. It is a condition for which there are few therapeutic options and every new one, including Aduhelm, needs to be made available to patients in a manner that does not impose additional unnecessary burdens on the patient and their caregivers. For this and other reasons we note here MHN does not support the proposed NCD that would require patients to enroll in a clinical trial in order to obtain access for this fully approved FDA product. For CMS, in its role as a payor, to establish such a requirement would significantly increase the burden of treating the condition, require patients, who already are cognitively impaired, and their caregivers, to agree to and complying with the rigors of a clinical research protocol to obtain an already approved medication. This policy is unnecessary because of the broad array of other existing methods for controlling product specification and cost.

This if implemented as proposed, this CMS NCD is likely to result in a myriad of other unintended and dangerous effects. Some of these that are of concern to MHN are: the real potential for other public and private payers also implement their own requirements for enrollment in a clinical trial as a predicate to obtaining an FDA approved product, thus creating a never ending stream of post-approval clinical trials of various rigor; what might this action do to begin to erode the global gold-standard approval process that has been one of the strengths of the US FDA drug, biologic and device approval process and; how will this impact the willingness of companies to develop important and technologically advanced therapeutics for complex difficult to treat conditions.

We strongly encourage CMS to revisit its approach to the NDC for Aduhelm

Respectfully
S. J. Giorgianni, Jr. PharmD
Sr. Science Advisor, Men’s Health Network

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I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program. The excessive costs of this questionable drug undermine the physical and financial health of Medicare recipients.

The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program. The excessive costs of this questionable drug undermine the physical and financial health of Medicare recipients.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am a private practice general neurologist of 15 years working in the New Haven, CT area. I have taken care of Alzheimer’s Patients for that period of time and am excited that there is a treatment for them which met its endpoint of removal of amyloid. The monoclonal antibodies which are still in research phase have demonstrated greater clinical efficacy than did Aduhelm and therefore I generally believe that this class of medications will be clinically affective.

I do not believe that medicare should be involved in running a trial and I do not agree with a policy as it is. Patient’s would have to wait another long period of time. This would shut out private practice physicians. Nonetheless, If it is the decision of medicare to restrict access of this medications to those who enroll in a medicare drive clinical trial, I think that private practicing physicians should be allowed to participate.

M. Joshua Hasbani, M.D. Ph.D.

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As a scientist, I don't think it is my place to comment on federal policy decisions. However, I wanted to bring to the Agency's attention a journal article of my team that was published today in Alzheimer & Dementia. In this article, we estimate that a hypothetical Alzheimer's treatment that reduces progression in early disease stages by 30% will generate $5.5 trillion in gross societal value over 20 years in the U.S. alone.

The full article can be found online: https://doi.org/10.1002/alz.12578

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The Food and Drug Administration’s (FDA’s) decision to approve Aduhelm for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. The integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program. Medicare must absolutely NOT be bankrupted by this ineffective medication!

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

Less

The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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As a Medicare recipient/enrollee I am directly affected by the outcome of the approval decision regarding the drug Aduhelm. Please consider the following statement, and conclude that paying for this ineffective drug must not be forced on our Medicare system.

The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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CMS's increasing recognition of Alzheimer's disease (AD) as a severe and highly prevalent disease process that results in tremendous burden to individuals inflicted with AD, to care givers, and to healthcare systems is heartening. AD represents the 6th leading cause of death in the US and 1/3 of deaths in the USA are associated with dementia. More that 6 million currently have AD in the USA and someone develops AD every 65 seconds in the USA. The current cost of care for AD is over $300 billion in the USA with over 50% paid for by CMS. We all realize the travesty that is AD and there is much well-deserved debate regarding the best way to address continued research, treatment, and manage expectations. Further comment here will be focused on the topics deemed most useful in this period identified by CMS.

https://www.alz.org/aaic/downloads2020/2020_Facts_and_Figures_Fact_Sheet.pdf

Which health outcomes are important, and what degree of improvement in them is meaningful for patients receiving treatment? Expected/important health outcomes should be reflective of the respective disease process and current capabilities for treatment. For instance, many forms of stage IV cancer have low expectations for cure/disease free survival, however advanced chemotherapy, radiotherapy, and surgical care are routinely administered. Likewise, neurodegeneration resulting from AD has been highly recalcitrant to therapeutic intervention, however treatments have ensued. In such, outcome expectations of the first ever FDA approved disease modifying treatment (DMT) for AD, Aduhelm, should be thoughtful. The general population starts losing brain volume and significant neural connections after the age of 40. The decline rate continues until death. As we know neurodegenerative disease processes such as Alzheimer’s disease have a substantially increased decline rate for cognitive loss. When a patient seeks treatment at the stage of mild cognitive impairment (MCI) or AD they have typically already lost significant neural connections/brain volume and thus cognitive power. Monoclonal antibody treatment for removal of amyloid deposition in the brain is not expected to increase brain volume and therefore not likely to increase measurable cognitive ability from the presentation state. The increased decline rate over general senescence that AD pathology causes, however, has been shown to be reduced by treatment with Aduhelm in a dose dependent matter through the recent Engage and Emerge clinical trials. This mitigation of increased cognitive decline rate is the expectation that should be considered for treatment, just as many oncologic treatments seek to stop progression rather than achieve a complete cure. It may take many successes in future regenerative medicine and genomics research to reverse damage that has already been caused by AD pathology and other neurodegenerative processes to increase lost cognitive ability.

https://www.cancer.org/treatment/survivorship-during-and-after-treatment/long-term-health-concerns/cancer-as-a-chronic-illness.html
https://my.clevelandclinic.org/health/diseases/9164-alzheimers-disease
https://www.semanticscholar.org/paper/Atlas-of-Biomarkers-for-Alzheimer's-Disease-Gonz%C3%A1lez/143098454a4d440de2e2478d769f5129ee25740c

What characteristics of patients with Alzheimer’s disease are important to optimizing the likelihood of positive health outcomes from treatment?
Optimizing the likelihood of a positive health outcome from treatment will require coordinated care that works to ensure a healthy diet, regular exercise, adequate sleep, and other social determinants of health are addressed. A positive outcome is less likely if all other determinants of health are not positively addressed.
https://www.cdc.gov/socialdeterminants/index.htm

What issues of equity and inclusion must be accounted for in the diagnosis and treatment of Alzheimer’s disease?
Issues of equity and inclusion have come to significant light over the past several years. The New IDEAS trial, which assays amyloid deposition in the brain highlights decreased rates of diagnosis and treatment that may be associated with limited demographic diversity, as the study seeks to include increased numbers of patients of African ancestry and Hispanics. Furthermore simply living in low population regions and economically depressed areas limits opportunity for research study inclusion, diagnosis, and treatment. There are many reasons for disparity in healthcare, too numerous to go into detail here. In general a holistic broad national approach through existing CMS care pathways would help to reduce disparity and exclusion.

https://www.ideas-study.org/

What health care providers should be included as part of the patient’s treatment team? Should medical specialists be included in the care team of patients receiving treatment? If so, which specialists should be included in the care?
Patient’s with a diagnosis of mild cognitive impairment and/or AD should have access to an entire team tailored to their care coordinated by their primary care physician including dementia specialists such as a neurologist, psychiatrist, and/or psychologist. Geriatricians, genetic counselors, and radiologists may also assist in diagnosis, monitoring, and disease state discussions.

https://www.alz.org/media/Documents/alzheimers-dementia-choosing-a-doctor-ts.pdf

In what setting(s) should treatment and care be given?
The care setting should be as convenient for the patient and caregivers as possible, utilizing existing care networks broadly across the nation. Limiting care to select academic centers in specific cities or states will result to egregious healthcare disparities.
https://www.ncbi.nlm.nih.gov/books/NBK221045/

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As someone whose [PHI Redacted] experiences dementia, it is incredibly disheartening to see CMS limit coverage of an entire class of drugs which could potentially pave the way for new treatments or even a cure. If there is a genetic component to Alzheimer's and dementia, like we believe there might be, it is likely that one of [PHI Redacted] may one day experience the currently incurable and fatal disease. Although my [PHI Redacted] is too far along in the disease process to benefit from an FDA approved drug like Aducanumab, I want those who want to try it to have the ability to do so. I imagine that many people witnessing the slow death of a loved one, like myself, would be willing to try anything for hope. Hope that their loved one might get more time. Hope that we could one day end this terrible disease. Limiting coverage to what is essentially non coverage for this whole class of monoclonal antibodies halts research and progress. Please don't kill our hope. That's all that we're clinging onto.

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February 10, 2022

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Center for Clinical Standards and Quality
Center for Medicare & Medicaid Services

RE: Proposed National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N)

Dear Ms. Syrek Jensen and CMS Colleagues:

On behalf of The Gerontological Society of America (GSA), thank you for the opportunity to provide comments to the Proposed National Coverage Determination for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N).

Our mission at GSA is to cultivate excellence in interdisciplinary aging research to advance innovations in practice and policy. GSA’s 5,400 members include gerontologists, health professionals, behavioral & social scientists, biologists, demographers, economists, and many other disciplines. These experts study all facets of aging with a life-course orientation. The multidisciplinary nature of the GSA membership is a valued strength, enabling the Society to provide a 360-degree perspective on the issues facing our population as we age. GSA is advancing major initiatives related to improving adult immunization rates, earlier detection of cognitive impairment, improving oral, hearing, and vision health, framing our language to improve the public’s understanding of aging, and understanding the impact of the longevity economy.

As a professional membership society with a long-standing commitment to translating research to inform evidence-based care for persons with dementia, GSA has developed The GSA KAER Toolkit (2020 Edition). This work is intended to support primary care teams in implementing a comprehensive approach to initiating conversations about brain health, detecting and diagnosing dementia, and providing individuals with community-based supports. We are currently working with the University of Washington and the Centers for Disease Controls’ Alzheimer’s Disease and Healthy Aging Program to pilot the Toolkit in a primary care system. Likewise, GSA members and staff actively participate in and serve as members federal councils such as the Advisory Council on Alzheimer’s Research, Care, and Services.

GSA appreciates that we are all focused on improving care for persons living with dementia and their loved ones while advancing innovation and access to pharmacologic and non-pharmacologic therapies for prevention and treatment of Alzheimer’s Disease and Related Dementias. GSA focuses our comments in three areas. We respectfully request that CMS consider these recommendations in the coverage determination:

• Reconsider application of the proposed NCD to the entire class of monoclonal antibodies
• Ensure coverage criteria reduces rather than exacerbates already existing issues of equity and access to clinical trials
• Provide specific commitments and define open ended terms of timely and quick approval of protocols

First, we respectfully request CMS reconsider the application of the proposed NCD based on research results published for one specific monoclonal antibody therapy. Several therapies are in clinical development. As with any class of medications, we must recognize variations in therapeutic profiles and improvements in efficacy. Imposing the NCD on the entire class of monoclonal antibodies fails to account for these variations and subjects these therapeutic entities to duplicative studies. Clinicians and patients need to have access to options to better target individualized treatment. Prospectively including all monoclonal antibodies in this NCD may stifle much needed innovation to improve treatment of Alzheimer’s Disease and Related Dementias. We respectfully request that each therapeutic entity be considered individually.

Next, we applaud CMS for recognizing the importance of under-representation of members of racial and ethnic groups in research relating to Alzheimer’s Disease and Related Dementias. The clinical trial requirements and restriction of the trials to only hospital outpatient settings however only further exacerbate the system of inequities as we have seen demonstrated. We respectfully request CMS consider additional options to improve access to monoclonal antibody therapies as well as promote activities to improve access to detection, diagnosis, and treatment for all with dementia. Given limited access to randomized controlled trials, we respectfully request CMS consider additional methods that could be more easily applied in communities across the country, such as registries, that could track the progress of patient groups and subgroups to generate additional real-world data to inform care.

Finally, we respectfully request that CMS further clarifies and provide more specific definitions related to timely response. With the progressive nature of dementias, open-ended timelines for response to protocols and research submitted and determinations of coverage fail to recognize the urgency that persons living with dementia need for access to therapeutic agents. CMS should explore its ability to provide specific time defined commitments to approving clinical trial protocols, consideration of interim results, and providing revised coverage decisions based on the results of these studies.

Pharmacologic treatments for Alzheimer’s Disease and Related Dementias are in their beginning stages. How we approach decision points like coverage determination can have impact on future approaches for prevention, diagnosis, treatment, and ultimately cure.

Thank you for considering our recommendations and we look forward to working with you as this Medicare Coverage Decision advances. We believe by working together we can find a meaningful path forward. Please do not hesitate to contact GSA Vice President of Policy and Professional Affairs, Trish D’Antonio at pdantonio@geron.org or 202-587-5880 if we can provide further assistance.

Sincerely,

James C. Appleby, BSPharm, MPH, ScD (Hon)
Chief Executive Officer

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Chiquita Brooks La-Sure
Administrator
Centers for Medicare and Medicaid Services
7500 Security Boulevard Baltimore, MD 21244

Re: National Coverage Analysis (NCA): Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N)

Dear Administrator Brooks La-Sure:

The National Multiple Sclerosis Society (Society) appreciates the opportunity to provide public comments on the Centers for Medicare and Medicaid Services’ (CMS) proposed National Coverage Determination (NCD) decision memorandum “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease” National Coverage Analysis (NCA). We are concerned with many of the policy elements within the proposed NCD decision memorandum, including the precedent it sets for future policy for treatments that are approved through accelerated approval pathways, barriers to access that may worsen health disparities and patient access, and a lack of a formal patient engagement process with the NCD process.

Multiple sclerosis (MS) is an unpredictable, often disabling disease of the central nervous system, which interrupts the flow of information within the brain and between the brain and the body. Symptoms range from numbness and tingling to blindness and paralysis. The progression, severity, and specific symptoms of MS in any one person cannot yet be predicted but advances in research and treatment are moving us closer to a world free of MS. While MS and Alzheimer’s Disease are different neurological diseases, the Society is concerned that the proposed NCD decision memorandum could have harmful – if unintended - effects on the development or treatments for other neurologic conditions that may be approved via accelerated approval pathways in the future.

The Society believes that better coordination with the FDA and CMS is necessary where it comes to coverage decisions relating to therapies approved through an accelerated pathway, particularly when sponsors are given long time frames to submit confirmatory efficacy evidence, as was the case with aducanumab. We believe that the lack of confirmatory evidence for aducanumab should not impact future coverage decisions for all future therapies in this class of drugs. We urge CMS to consider taking each treatment on a case-by-case basis to evaluate the evidence for that specific treatment, particularly therapies that are approved through accelerated or expedited pathways.

The Society is also concerned that the policy outlined in the NCA of limiting the access to these monoclonal antibodies to only individuals who are clinical trial participants at academic medical centers will contribute to health disparities, both for these treatments and within any trial that CMS may deem necessary through a NCD in the future. We believe this policy does not align or advance the Biden Administration's focus on addressing health disparities and should be reconsidered with health equity in mind. We know that clinical trials at academic medical centers draw from select patient populations with access to these centers, and therefore does not produce data that would reflect performance of the treatment in diverse populations. It is well documented that clinical trials do not typically enroll minority populations in significant numbers to ensure that the results are statistically significant for those populations. Without a sufficiently diverse sample set, the data in the confirmatory studies would not give CMS evidence it needs to make coverage determinations for the Alzheimer’s population. We urge CMS to reconsider this policy, as we are again concerned with the precedent that this sets for other neurologic conditions. People with MS have experienced similar payor policies that limit access to certain therapies based on narrow clinical trial criteria and not on the approved FDA label. Our recommendation to CMS would be that in future NCDs, if CMS determines that access to a product or therapy should be narrower than the FDA label, that it host a public meeting to explain the decision in detail, including evidence or expert opinions used to make the determination and allow public stakeholders the opportunity to respond to the agency via a public comment portal.

Finally, as patient-focused drug development continues to evolve, it is important that patients are not only consulted in the development of new therapies but also in cost and coverage determinations. Therefore, we urge CMS to establish a formal process to solicit stakeholder and patient engagement for future coverage determinations. Through this process, CMS will be able to gain an understanding of patient and caregiver priorities in terms of quality of life and what clinical and additional outcomes are important to individual patients and their care partners.

Thank you again for your consideration of these comments on the NCA. We look forward to working with you to ensure that the needs of patients are prioritized within any coverage determination process. If you have any questions, please contact Leslie Ritter, AVP of Federal Government Relations at Leslie.Ritter@nmss.org.

Sincerely,

Bari Talente, Esq.
Executive Vice President, Advocacy and Healthcare Access
National MS Society

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefited Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Lewy Body Dementia Association (LBDA) is writing to submit public comment in response to the Centers for Medicare and Medicaid Services (CMS) proposed National Coverage Determination (NCD) for monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease.

Lewy body dementia (LBD) is the second-most common progressive dementia after Alzheimer’s disease, affecting approximately 1.4 million Americans and their families. Approximately one-third of those with dementia with Lewy bodies, one form of LBD, have sufficient co-existing pathology for an Alzheimer’s disease diagnosis. There are no disease-modifying therapies for Lewy body diseases currently available. As such, regulatory decisions in Alzheimer’s disease are highly relevant for LBD; the decisions may even be precedent-setting for future regulatory decisions that will impact people with Lewy body dementias. As such it is imperative for LBDA to comment on behalf of those we serve.

We appreciate the complexity of considerations CMS must balance on behalf of society, regarding the potential clinical benefit versus potential harms of any new treatment and thank CMS for the efforts required to make the proposed NCD. The access CMS has made to their personnel through various events, for the purpose of learning more about the NCD and how it could be modified when more compelling evidence emerges has been very helpful to informing our public comment.

Alzheimer’s disease (AD) is a fatal disease with an average duration of 8 years, which unlike most other fatal conditions, robs individuals of their ability to think and reason, and steals from entire families the persona and presence of the person diagnosed. This loss of self, intensely and indescribably painful to entire families, not just the person diagnosed, ruins many families financially due to the cost of care in late-stage disease, and places undue burden and poor health outcomes on family caregivers without the resources to supplement the care they provide. For communities already affected by health disparities, a diagnosis of Alzheimer’s may make the burden truly immeasurable.

We would like to highlight several points we feel warrant reconsideration of the recently proposed CMS NCD.

• A public comment opportunity truly does not reach the public. It largely only reaches the professional stakeholders for any disease and tiny proportion of people directly affected. Decisions on a new class of drugs for Alzheimer’s disease, the first that may halt progression, should be done in greater consultation with the patient community, not just the scientific, clinical care and advocacy community, which is not representative of the diversity of the Alzheimer’s community. Focus groups with members of the public who are diagnosed with, or caring for a person diagnosed with, Alzheimer’s disease and that are representative of the diversity of the Alzheimer’s community, should be immediately convened to gain real world insights on perspectives on the potential risk/benefit ratio of anti-amyloid interventions, and delve further into what the Alzheimer’s community considers to be clinically meaningful benefit. The insights gleaned from the focus groups should be made publicly available as part of any final NCD.
• The draft NCD establishes two distinctly separate tiers of access. Wealthy individuals who qualify for the drug can pay out of pocket. The rest of those who may benefit from such a treatment can only access the drug through clinical trial participation. This widens the considerable economic disadvantages born by people living with Alzheimer’s disease who do not have the logistical and financial resources required to participate in a clinical trial. Further, communities disproportionally affected by AD, such as African Americans and Hispanic/Latino communities, are underrepresented in clinical trials. Limiting coverage to clinical trial participants may worsen health disparities.
• In the case of fatal diseases lacking disease-modifying treatments, an NCD that impacts coverage for an entire class of drugs is overly restrictive and counter to the purpose of the FDA’s accelerated approval of aducanumab. We strongly recommend amending the NCD to be limited only to aducanumab.
• The concept of CMS analyzing published data of failed trials of anti-amyloid interventions as a means to determine cumulative evidence of clinical benefit from the only FDA-approved treatment in that class is concerning. Through its memorandum of understanding with the FDA or under confidentiality agreement with the sponsor, CMS should evaluate the same data on aducanumab evaluated by the FDA, before finalizing the NCD. Clinical Trial Requirements
• The proposed NCD includes a requirement that delivery of these therapies be restricted to “hospital-based outpatient settings.” LBDA urges CMS to reconsider this limitation, as this was not a requirement for the clinical trials of aducanumab. Other appropriate settings should be considered, such as infusion centers and clinical research centers that are not designated as “hospital-based outpatient settings.”
• The concept that “the diversity of patients included in each trial must be representative of the national population” is a critical step towards equity and inclusion. However, if clinical trials are the only pathway to obtaining treatment with anti-amyloid interventions, CMS should be more specific on its expectations. The final version of the NCD should be either a) be more explicit about the required diversity of the cohort or b) require the trial protocol provide details on how it will achieve its diversity goals.

Lastly, the United States has a national strategy to address Alzheimer’s disease and related dementias. The first goal of the plan is to prevent and effectively treat Alzheimer's disease and related dementias by 2025, such as by slowing down progression or delaying the onset of dementia. The CMS NCD as it is currently written is at odds of achieving this national goal.

In closing, because anti-amyloid therapies are directly relevant in LBD which commonly co-occurs with Alzheimer’s disease, the Lewy Body Dementia Association recommends further revisions to the NCD.

We thank CMS for its diligence and hope these public comments will be given serious consideration as part of finalizing the NCD.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

It's just too soon to give the public hope. Wait until it's definite.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Center for Science in the Public Interest (CSPI), an organization that promotes independence, scientific rigor, and transparency, submits the following comments regarding the Centers for Medicare and Medicaid Services’ (CMS) National Coverage Determination (NCD) memorandum on Aduhelm (aducanumab), released on January 11, 2022.

CSPI shares the belief of many scientists and researchers that FDA approval of aducanumab was not based on adequate scientific evidence of the drug’s effectiveness. The clinical trial data submitted to the FDA were based on one favorable study of the two conducted, and that study only showed a 0.4 point improvement on an 18-point scale. This is less than half of what surveyed patients and caregivers stated was the minimum improvement to be clinically meaningful. This implicit benefit was only seen for the high dose. As a result, FDA’s Peripheral and Central Nervous Systems Drugs Advisory Committee unanimously voted, with one member uncertain, that it was not reasonable to consider the one study as primary evidence of the drug’s effectiveness for the treatment of Alzheimer’s Disease. Further, the approval of aducanumab was widely criticized for the uncommon involvement of the drug’s sponsor in the preparation of briefing materials for the advisory committee, questionable use of amyloid plaques as a surrogate biomarker, and harmful side effects of the drug that include minor brain swelling and bleeding, which occurred in 40% of patients.

Although aducanumab received FDA approval, it’s important to note that CMS has a more restrictive standard for coverage under Medicare. Under the Food, Drug, and Cosmetic Act, a drug must demonstrate “reasonable assurance of...safety and effectiveness” for FDA approval. In contrast, the Social Security Act allows for reimbursement by Medicare only if the drug is deemed “reasonable and necessary.” Thus, FDA approval alone does not guarantee coverage of the drug under Medicare’s more rigorous standard.

For these reasons, if aducanumab is to be covered at all under the Medicare program, we strongly support CMS’ proposal that Medicare will not pay for aducanumab or similar FDA-approved monoclonal antibodies that target amyloid for the treatment of Alzheimer’s Disease unless patients are participating in qualifying clinical trials (i.e., follows a “Coverage with Evidence Development” provision). As stated by CMS, qualifying trials must include a nationally representative sample of participants diagnosed with Alzheimer’s Disease and demonstrate a clinically meaningful difference in cognition and function. Only such trials can provide the information that is currently lacking and that is critical before aducanumab can be prescribed to other Medicare patients.

In addition to supporting CMS’ NCD, we recommend the following:

1. Qualifying clinical trials include a nationally representative sample of patients diagnosed with Alzheimer’s Disease with respect to age, comorbidities, race, and ethnicity.
2. Qualifying clinical trials should place equal focus on safety and efficacy and include free brain scans for monitoring adverse effects.

The “Coverage with Evidence Development” provision is a valuable tool that can be leveraged by CMS to apply a more rigorous scientific standard beyond FDA’s standard for approval. Given the limitations of FDA’s approval process in this instance, this seems like the ideal opportunity to use this unique authority and place CMS squarely on the side of scientific rigor – while sparing many patients the dangers of ineffective and potentially harmful drug use.

Stephanie Rogus, Ph.D, R.D.N
Campaign Manager, Scientific Integrity
the Center for Science in the Public Interest

Peter Lurie, M.D., M.P.H.
President
the Center for Science in the Public Interest

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Dear Secretary Becerra:

The National Grange is America’s oldest agricultural and rural life advocacy organization. Since its founding in 1867, the Grange has been the leading voice in advocating for sound public policy impacting rural and small-town citizens. Today, with nearly 1800 state and local chapters in 38 states, the Grange continues its mission to bring attention to issues of concern to rural America, to shed light on the health, economic, and resource disparities which impact approximately 22% of the US population that live there, and to work together with all interested parties to identify and implement viable solutions.

We appreciate the opportunity to comment on the proposed National Coverage Determination (NCD) regarding the use of monoclonal antibodies against for the treatment for Alzheimer’s disease. We believe it is important for the Centers for Medicare and Medicaid Services (CMS) to reconsider this proposed policy. More than 6 million people in our country suffer from this unforgiving and relentless disease. This proposed policy will keep many of them and their families from access to the medicine and the hope it brings with it.

Research conducted by Dr. Ambar Kulshreshtha, MD, PhD from Emory and reported in 2021 has shown that the mortality rate for Alzheimer’s and related dementias is higher in rural areas than it is in urban centers. One of the major contributors to this is thought to be the lack of access in much of rural America to health care professionals with experience in treating Alzheimer’s and dementia. The Food and Drug Administration’s approval of the breakthrough treatment, Aduhelm, brought hope to families dealing with Alzheimer’s that a long-awaited therapy might be at hand.

CMS’s proposed NCD was a crushing development for these patients and their loved ones. Restricting access to Aduhelm to patients involved in approved clinical trials is inequitable to rural citizens. Most clinical trials take place at health care institutions in major population centers. Americans who live hours away from a major city will be frozen out of these trials and, thus, denied access to a drug that could address their condition.

It also can’t be denied that this proposed NCD will quite likely have a chilling effect on future research into Alzheimer’s treatments. If CMS establishes a precedence that it can preclude the creation of a market for FDA-approved products, it will cast doubt over investment in continuing research and development.

In the interest of essential medical research and greater health equity for those living in rural regions and remote areas of the United States, we request that CMS reconsider this draft determination and provide access to innovative treatments that millions of current and future Alzheimer’s patients and caregivers desperately need.

Sincerely,

Betsy Huber
National Grange President

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I have learned from reading articles and participating in presentations on Aduhelm and Aduhelm trials and studies that, based on recent studies, the very low, statistically insignificant study numbers that purport to show beneficial action of Aduhelm on neural plaques should not be the basis of any approval of the use of Aduhelm. The study numbers that purport to show efficacy are so low, and so statistically insignificant, that no inference should be drawn between the drug and reduction in plaques. And certainly, no inferences or connection should be drawn between the reduction in plaques and any alleviation in Alzheimer's symptoms. It would be thoroughly and scientifically irresponsible to draw any conclusions of Aduhelm's efficacy based on these recent and extremely limited study results. Any FDA approval of Aduhelm based on these recent studies, that are clearly inconclusive regarding Aduhelm's efficacy, would seriously compromise any public trust in FDA to act responsibly and in the public interest. If the FDA approval of Aduhelm, even for limited use, were to proceed, it would call into question whether FDA is properly following and adhering to any legal protocols or regulatory requirements for all drug approvals. FDA approval of Aduhelm for any purpose at this time, based on such flimsy, inconclusive efficacy data would seriously undermine the public trust in FDA's ability to execute its mission to protect public health and safety.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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[PHI Redacted]

I feel that people living with Alzheimer’s disease are being treated unfairly by requiring that they participate in a clinical trial in order to receive CMS coverage of monoclonal antibody treatments for Alzheimer's Disease. Please revise your NCD to make CMS coverage for these treatments available to anyone who is eligible as soon as possible.

CMS has never before limited Medicare coverage like this for any other FDA-approved medication. CMS needs to treat coverage for this class of drugs the same way it has treated FDA-approved medication for all other diseases. Alzheimer's disease is the only major fatal disease without a cure and until now, it did not even have a treatment.

This drug has given us hope that there is a way to slow down the progression of this disease. And there are other treatments close behind it in the research pipeline showing even greater promise. But with CMS’s proposed decision limiting coverage to those in clinical trials, access will be severely restricted to only those few who live near research institutions, or can afford to pay out-of-pocket. For those who get into the trial, there is only a 50/50 chance that they will actually get the drug. It is a randomized trial so half of the participants would get a placebo! For those of us who do not get into a trial, denying us access to this treatment is guaranteeing us a very unpleasant death for a drug that is at our fingertips.

[PHI Redacted]

While there has been much debate about the efficacy of the FDA-approved drug in this class, Aduhelm, Alzheimer's disease will likely need to be treated using a variety of different drugs, just as cancer usually needs to be treated with more than one approach. Drugs like Aduhelm will very likely become one of many strategies used to tackle the disease. Aduhelm reduces amyloid beta plaque – which is associated with Alzheimer's disease. This is a stepping stone in the path for a cure. We need to start with something reasonable and take small positive steps forward and work this path to get to a day when we can live with this disease – not die from it.

[PHI Redacted]

I also believe that if the CMS requires an additional clinical trial, it will set back future research and development of potential treatments for Alzhiemer's disease. This would be unfortunate because Alzheimer's and other dementias are an urgent public health issue. More than 6 million Americans have Alzheimer’s and it is one of the most expensive diseases in America. Alzheimer's disease costs to Medicare and Medicaid was an estimated $239B in 2020. It is expected to more than double to $536B by 2040. Doing more today to slow down the progression of this disease and collect real-life data to accelerate Alzheimer's research will save CMS billions of dollars in the long run.
If finalized as currently structured, this NCD will negatively impact both scientific progress and families facing Alzheimer’s disease. We have the ability to slow down the progression of this deadly disease – we just need access to this class of drugs to begin that process.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

Fill out the required address fields, check the box to affirm that you are not a robot, and press “Submit!”

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#4: I only treat HMO patients
Many of them are senile or might be losing it.
Many have memory loss from statin drugs.
This drug sounds like a Grab.
I applaud CMS’s proposal to restrict coverage of anti-amyloid monoclonal antibodies such as aducanumab for the treatment of Alzheimer’s disease only in the setting of randomized-controlled trials under Coverage for Evidence Development (CED) as such a coverage decision prioritizes and protects patients above all else. As a practicing physician, I urge CMS to adopt this proposal as their final national coverage determination to ensure that our patients have access to truly effective and safe medications.

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In their proposed decision for coverage of aducanumab and other such monoclonal antibodies, CMS has recognized the need for further investigation to protect older and disabled adults. Importantly, CMS has suggested requiring that the drug be tested through well-designed, randomized controlled trials within patients representative of populations most impacted by Alzheimer’s disease, including racial and ethnic minorities. We see this as correcting the precedent set forth by the FDA in awarding accelerated approval for aducanumab. Through this coverage decision, manufacturers will instead have to meet a higher standard when conducting clinical trials for such Alzheimer’s disease drugs by making evident that the treatments show a clear change in patients’ cognition and function and are safe, not just a change in the level of a surrogate marker seen on MRI imaging.

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I am writing to support the Centers for Medicare and Medicaid Services (CMS) proposed national coverage decision restricting payment for “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease” issued on January 11, 2022. As a physician and clinical researcher, I was deeply disturbed by the FDA's decision to approve aducanumab for treatment of Alzheimer's disease, despite the lack of evidence regarding its clinical efficacy and major concerns about safety. The FDA's h accelerated approval of aducanumab was based on efficacy for reducing beta-amyloid plaque on MRI brain scans, despite the fact that efficacy in reducing this biologic marker has failed to show clinical benefit in multiple other trials of drugs that reduce amyloid plaque. In addition, this drug is dangerous, causing intracranial hemorrhages in a substantial proportion of patients, and it will be ridiculously expensive.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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On behalf of Point32Health, the combined organization of Harvard Pilgrim Health Care and Tufts Health Plan, we thank the Centers for Medicare and Medicaid Services (CMS) for putting patient safety first by proposing to provide Medicare coverage for monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease exclusively in the context of approved clinical trials. We strongly agree that the Coverage with Evidence Development (CED) designation is appropriate and necessary, and we urge CMS to finalize the National Coverage Decision (NCD) as proposed.

Point32Health is a leading health and wellbeing organization. Building on the quality, nonprofit heritage of our founding organizations, Tufts Health Plan and Harvard Pilgrim Health Care, we leverage our experience and expertise to help people find their version of healthier living through a broad range of health plans and tools that make navigating health and wellbeing easier for our 2.2 million members across New England.

Alzheimer’s disease is a progressive and debilitating condition that affects memory, thinking and behavior. Point32Health is committed to supporting our communities in their fight to end Alzheimer’s. We invest in efforts that help expand awareness, that advance research on preventative care and treatment solutions, and that identify and implement systemic and innovative programs to improve the lives of those living with Alzheimer’s and their caregivers. Our past and current leaders have served on the Alzheimer’s Association Board of Directors, and we are consistently a top fundraiser for the Association, with many of our colleagues participating in their annual awareness walk. We also have Alzheimer’s Association staff embedded into our organization to help families navigate their health care needs when a family member is impacted by this debilitating disease.

While we are eager for a treatment that will slow or even reverse the impacts of this disease, as explained below and in the attached letter, monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease have not yet met this threshold. Until sufficient clinical evidence is available, all monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease must, therefore, be nationally non-covered when provided outside of the CMS-approved randomized controlled trials and trials supported by the National Institutes of Health (NIH) are nationally non-covered.

Alzheimer’s disease is a particularly impactful disease, affecting many Medicare beneficiaries and the CED paradigm provides the most appropriate pathway to provide Medicare coverage while sufficient evidence regarding safety and efficacy is developed. As outlined in CMS’ proposed decision memo, under CED, CMS would cover FDA-approved monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease in CMS-approved randomized controlled trials, and in trials supported by the NIH. A trial must be a multicenter randomized controlled trial with an appropriate control representing the standard of care and conducted in a hospital-based outpatient setting. If a beta amyloid positron emission tomography (PET) scan is part of the protocol, one beta amyloid PET scan will be covered per patient if the patient did not previously receive a beta amyloid PET scan. A CMS-approved randomized controlled trial may be extended to a prospective longitudinal study if the findings demonstrate a clinically meaningful benefit in cognition and function.

Studies of anti-amyloid antibodies for the treatment of Alzheimer's disease points to a surrogate marker rather than clinical improvement as an endpoint. The treatments reduce beta amyloid in the brain as shown by imaging studies or analysis of cerebrospinal fluid. However, surrogate markers as evidence of impact on disease must only be used when that biomarker has clearly and definitively been shown to be the cause of the disease or to be a clear marker of clinical improvement. There is no clear evidence that a reduction in amyloid produces cognitive improvements and the aducanumab studies conducted to-date have failed to clearly demonstrate improved functional abilities. Instead, these treatments have been associated with serious safety risks to patients receiving the monthly infusions of aducanumab, including swelling and bleeding in the brain. Additional randomized controlled trials, particularly more longitudinal studies, are critical to evaluating the success of these treatments. We thank CMS for allowing manufacturers to extend their trial to a prospective longitudinal study when the randomized controlled trial is completed and the findings demonstrate a clinically meaningful benefit in cognition and function, as longer studies are designed to assess true clinical markers, such as memory, language, and functional abilities.

The draft decision memo takes care to recognize and address the lack of diversity among the original trial population. The aducanumab studies failed to demonstrate safety and efficacy across diverse patient populations, including minorities, underserved, and low-income individuals, many of whom are at greater risk for developing Alzheimer’s disease and may be more likely to have missed diagnoses of the disease. Consistent with the draft decision memo, the final CED must explicitly require manufacturers ensure the diversity of patients included in each trial must be representative of the national population diagnosed with Alzheimer’s disease. We recognize there may be challenges in achieving robust Black and Brown patient participation in clinical trials, including hesitancy and accessibility, and we urge CMS to establish study requirements that require manufacturers to address such barriers.

Consistent with other CEDs, the NCD final decision memorandum must detail the required makeup of the trial, including the aforementioned participant diversity requirements as well the conditions under which health care related items and services must be considered as part of the trial. For example, ancillary testing associated with the trial may be needed to assess an adverse impact. The final decision memo must require all such services be outlined in the study protocol so they will not be inappropriately billed to the Medicare program.

The health and well-being of our members is at the heart of every decision Point32Health makes and Alzheimer’s disease is very personal to many of us at Point32Health. Our priority is to provide our members with coverage for effective and safe treatments that are based on scientific evidence. Accordingly, we take careful consideration of the risks associated with any drug before moving forward with a coverage decision. After thorough review of the available clinical data on the efficacy and safety of aducanumab, Point32Health concluded that it is experimental and investigational. We consulted with our internal resources, as well as our regional providers who offer extensive expertise in this area, in making this clinical determination. The external experts we consulted with were unanimous in their recommendation that helped inform our decision. Further, the low utilization of the treatment and the paucity of requests to our health plan for coverage to date confirms that the neurological community does not view this treatment as proven to be beneficial to their patients.

While the need for an effective new treatment for Alzheimer’s disease is indisputable, shortcuts to solutions are not a fair response to the patients and families impacted by this terrible condition. Utilizing the CED paradigm would allow safe access to all FDA-approved anti-amyloid monoclonal antibodies while developing additional evidence to substantiate the efficacy of the treatment for all populations.

For reference, pasted below please find a copy of the detailed comments Point32Health submitted to CMS on August 11, 2021 in response to their initiation of the NCD analysis for monoclonal antibodies directed against amyloid for the treatment of Alzheimer’s disease. The attached letter includes a cover letter from Point32Health’s Chief Medical Officer for Commercial Products and Neurologist, Claire Levesque, MD, as well as the following sections:

I. Point32Health and its Support of Alzheimer’s Patients
II. Safety Concerns with Aduhelm
III. Lack of Efficacy in Aduhelm
IV. Medicare’s Prohibition from Covering Unsafe, Unproven Treatments

We appreciate your consideration of this feedback and look forward to additional dialogue on this important matter.

Sincerely,
Claire Levesque, MD
Chief Medical Officer, Commercial Products
Point32Health

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The Food and Drug Administration’s (FDA’s) decision to approve Aduhelm for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs.

Two identical phase 3 trials were stopped early because a preliminary review of the data found that these trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients.

However, an unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data after the termination of the phase 3 trials is what lead to the approval of Aduhelm on June 7, 2021, damaging the reputation of the FDA.

Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients.

I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The California Chronic Care Coalition (CCCC) strongly urges the Centers for Medicare and Medicaid Services (CMS) to reconsider its proposed national coverage determination regarding the breakthrough Alzheimer's treatments. We make this request not only on behalf of the millions of Alzheimer's patients, families and caregivers who would be harmed by the draconian access restrictions CMS proposes to apply to this class of drugs, but also because of the distressing and potentially far-reaching precedent it would set in placing cost concerns over patient health.

The nation is entering dangerous territory if CMS begins making coverage decisions that supplant the medical and scientific expertise of the Food and Drug Administration. Roughly half of the U.S. population — 150 million people — has at least one chronic disease with direct treatment costs of over $1 billion annually (Alzheimer's represents 17 percent of this aggregate treatment expenditure.) If Medicare begins sharply restricting access to innovative treatments and cures that have been deemed safe and effective by the FDA, not only will patients suffer but the opportunity to curb health costs in the long term will be lost. Very few Americans have the opportunity to take part in clinical trials. It is unfair and counterproductive to deny those patients access to medications that can save and extend their lives.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease suggests that the FDA is taking orders from the drug's maker, Biogen, rather than responsibly following the science. The FDA is irreparably damaging its reputation in the service of Biogen's greed.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Social Justice and Peacemaking Ministry Unit of College Hill Community Church of Dayton, Ohio urges CMS and the Congress to make sure that health care, including drugs that are FDA approved for treatment of Alzheimer’s disease, be covered by Medicare and Medicaid and not limited to “control groups” that will inevitably exclude the poor and minorities.

Our Church is a racial and cultural rainbow that values all people. We contact you because our faith tradition expects justice from the powerful, care for the needy and vulnerable, and love for the worth of all people in all their diversity. Accordingly outsiders and the poor are to be valued, health care should be available to all, workers are to be paid a fair wage, a fair marketplace is required, and greed and exploitation are to be prevented. These values are not limited to our Judeo-Christian faith tradition but are found throughout American society.

We are located in a mostly African American neighborhood in northwest Dayton, Ohio, one of the nation’s most racially segregated cities. Many around us are low or moderate income. Our community has been a target for numerous kinds of disinvestment, and is often described as a food desert, a retail desert, and a healthcare desert. In particular the hospital serving our community was recently closed and demolished, depriving many in the area of care, while the same provider built numerous facilities in wealthy white suburbs. We experience health care disinvestment daily.

The existing health care system has been shown to deliver lower quality care to those on the lower end of the income scale and particularly to minorities. The difference in quality between high quality private insurance and the Medicare and Medicaid on which many ordinary Americans depend, remains a barrier to all Americans getting the health care they deserve. CMS should not make things worse by excluding enormous numbers of people from coverage, and only providing better treatments to a favored few.

Alzheimer’s disease is a scourge to all, including minorities. There has never been an Alzheimer’s study that has closely approximated the percentage of African Americans or Latinos that have Alzheimer's. Everyone should have equal access to breakthrough drugs and treatments

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February 10, 2022

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore, MD 21244

Re: National Coverage Analysis (NCA) for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N)

Dear Ms. Syrek Jensen:

The undersigned members of the Council of State Bioscience Associations, a coalition of forty-six state bioscience associations across the United States, wish to submit comments to the Centers for Medicare & Medicaid Services regarding the recent National Coverage Analysis (NCA) for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N).

Introduction

On January 11, 2022, the Centers for Medicare & Medicaid Services (CMS) issued a proposed decision memo in its National Coverage Analysis (NCA) for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (AD) (Proposed National Coverage Determination (NCD)).

CSBA has serious concerns about CMS’s proposed NCD. If finalized, the NCD would set a dangerous precedent, restricting access to a promising class of new amyloid-focused therapies, both current and future. This would have life-altering implications for the over five million Americans struggling with AD. It also would also have far-reaching implications for a variety of patient populations living with unmet medical needs — patients who stand to benefit from therapies approved for difficult-to-treat diseases, notably those approved by the Food and Drug Administration (FDA) under the Accelerated Approval pathway.

CMS’s proposal to limit coverage only to patients enrolled in government-approved Randomized Control Trials (RCTs) is also troubling. It means that the vast majority of individuals suffering from AD will have no meaningful access to an approved medicine simply because of where they live and where they go for care.

CMS’s Proposal Will Harm Patient Access to Safe and Effective Drugs

Patients will bear the consequences if CMS’s Proposed NCD is finalized. As drafted, the Proposed NCD will have dramatic ramifications for access—not just for the currently approved beta-amyloid for AD but also the entire pipeline of new beta-amyloid AD treatments to come. Moreover, finalization of the Proposed NCD will undoubtedly limit investment in this historically challenging clinical area.

CMS’s proposal is fundamentally unworkable for patients living with AD today. AD is a degenerative medical condition; each year an AD patient goes without treatment means the potential for permanent and progressive loss of cognitive ability. Patients with AD cannot afford to wait a year or more for CMS-approved clinical trials to be available.

Further, even when approved trials are initiated, patients will still face the risk of being placed on a placebo. It is untenable for CMS to force patients to make this kind of choice, especially after FDA has determined the drug’s safety and efficacy. Beyond this basic premise, CMS is imposing new and stringent clinical trial criteria which strongly suggest that the number of clinical trials approved will be extremely limited. CMS’s RCT requirement only compounds the fundamental inequity and risk of harm to patients. Even if a patient is fortunate enough to have reliable access to a CMS-approved trial, they may end up being assigned to a placebo while still being forced to bear out-of-pocket cost-sharing obligations as if they had been guaranteed access to the anti-amyloid therapy. This is simply unacceptable.

CMS’s proposed coverage with evidence development (CED) standards also will compound existing inequities in health care delivery. AD disproportionately impacts African American and LatinX populations—who are, respectively, two and 1.5 times more likely than Caucasian Americans to have AD and other dementias—but are nonetheless significantly less likely to be diagnosed with AD. CMS’s CED criteria will only add to these existing problems of access for already under-served populations.

CMS’s Proposal Undermines FDA Authority and Invalidates Sponsor Commitments

Beyond the issue of anti-amyloid treatments discussed in this NCD, CSBA is concerned that the current proposal inappropriately undermines FDA’s Accelerated Approval pathway. This pathway enables therapies for serious, life limiting conditions to be approved and available to patients more expeditiously and relies on scientifically validated surrogate endpoints. Such approvals require a commitment from the manufacturer to conduct a confirmatory Phase 4 study. As such, CMS’s Proposed NCD not only undermines FDA, but it also invalidates the sponsor’s commitment to important post-approval research.

CMS’s Proposal Could Chill or Even End Research into Conditions with Serious Unmet Medical Needs

The risk of CED restrictions would make it untenable for developers of novel therapies to pursue the FDA Accelerated Approval pathway. Developing a new drug requires billions of dollars in research and investment. Further, the investment required is exponentially higher for difficult to treat medical conditions like AD. To promote research in difficult-to-treat conditions like AD, manufacturers and investors need certainty that CMS will cover drugs for on-label indications once FDA has determined the therapy to be safe and effective. CMS’s Proposed NCD threatens to chill research and investment in new drugs targeting challenging disease states and to reduce reliance on a key mechanism that patients rely on to get faster access to desperately needed new therapies.

Conclusion

We believe that taken together, the imposition of restrictions on access to therapies for patients with serious unmet needs, CMS’s unprecedented actions questioning the FDA, and the demand for narrow RCT coverage with evidence development (CED) makes this proposed determination troubling. CMS should be encouraging development of new and innovative treatments for conditions like AD—not adopting restrictions on coverage that threaten to chill the development of an entire class of therapies for a degenerative condition that has no viable treatment option. Ultimately, we believe any national coverage policy should help ensure consistent patient access for vulnerable patients – not introduce inappropriate barriers to care.

We thank the Agency for its consideration of these comments and look forward to further engagement with CMS on these issues in the future.

Sincerely,

BioAlabama; Arizona BioIndustry Association, Inc. ; Southern California Biomedical Council; California Life Sciences; Biocom California; Colorado BioScience Association; BioCT; Delaware BioScience Association; BioFlorida; Georgia Bio; Idaho Technology Council; Illinois Biotechnology Innovation Organization; Indiana Health Industry Forum; Iowa Biotechnology Association; BioKansas; Kentucky Life Sciences Council; Louisiana BIO; Bioscience Association of Maine; Maryland Technology Council; Massachusetts Biotechnology Council; Michigan Biosciences Industry Association; Medical Alley Association; Missouri Biotechnology Association; Montana BioScience Alliance; Bio Nebraska; Nevada Biotechnology & Health Science; BioNJ; New Mexico Biotechnology & Biomedical Association; NewYorkBIO; North Carolina Biosciences Organization; Bioscience Association of North Dakota; BioOhio; Oklahoma Bioscience Association; Oregon Bioscience Association; Life Sciences Pennsylvania; INDUNIV; Rhode Island Bio; South Carolina BIO; South Dakota Biotech Association; Texas Healthcare and Bioscience Institute; BioUtah; Virginia Biotechnology Association; Bioscience Association of West Virginia; BioForward Wisconsin

Endnotes:
1. Alzheimer’s Association, “2021 Alzheimer’s Disease Facts and Figures,” March 2021

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

Less

The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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February 10, 2022

VIA ELECTRONIC DELIVERY

Tamara Syrek Jensen
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Blvd
Baltimore, MD 21244

Re: National Coverage Analysis for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N) – Proposed Decision Memo

Dear Ms. Syrek Jensen,

Genentech, a member of the Roche Group, appreciates the opportunity to submit comments on the proposed national coverage determination (NCD) for anti-amyloid monoclonal antibodies for the treatment of Alzheimer’s Disease (AD).

As a leading biotechnology company that discovers, develops, and manufactures novel medicines to treat patients with serious and life-threatening medical conditions, we are committed to improving patients’ lives through new innovations, investing $15 billion globally in research and development in 2021 alone. As a result, in the past twelve years, we have delivered to patients 21 new medicines that treat serious conditions like cancer, multiple sclerosis, hemophilia, and spinal muscular atrophy. We have a longstanding history in AD research that spans more than a decade – during this period, we have made and shared exciting new discoveries and experienced setbacks, but have persisted through each step. Together with the scientific community, we have learned lessons and thoughtfully applied them to optimize the work we have done and continue to do. To that end, our AD therapeutics pipeline encompasses investigational medicines for different targets, types, and stages of AD, including two anti-amyloid monoclonal antibodies – gantenerumab and crenezumab.

Gantenerumab, an investigational anti-amyloid monoclonal antibody, is being evaluated for subcutaneous administration in people with early AD (i.e., mild cognitive impairment and mild dementia) in two global Phase III studies – GRADUATE I (ClinicalTrials.gov/NCT03444870) and GRADUATE II (ClinicalTrials.gov/NCT03443973).

• On October 8, 2021, the FDA granted Breakthrough Therapy Designation to gantenerumab, which, if approved, would be the first subcutaneous medicine for the treatment of AD with the potential for at-home administration.¹
• The GRADUATE studies include close to 2,000 individuals and have a 27-month treatment duration, with data readouts expected in Q4 2022.
• Patients completing the GRADUATE studies may enter a two-year open label extension study to assess long term safety and tolerability of gantenerumab (ClinicalTrials.gov/NCT04374253).
• In collaboration with Washington University, gantenerumab is also being investigated in two studies in autosomal dominant AD – DIAN-TU-001 for secondary prevention (ClinicalTrials.gov/NCT01760005) and DIAN-TU-002 for primary prevention.
• Finally, the SKYLINE study is a secondary prevention trial in AD aiming to enroll amyloid-positive, cognitively normal individuals between 60–80 years old, and treat them with gantenerumab or placebo for 4 years.

Crenezumab, an investigational anti-amyloid monoclonal antibody, continues to be evaluated in the Phase II/III Alzheimer’s Prevention Initiative (API) Colombia trial in autosomal dominant AD. We remain committed to following the science and exploring multiple approaches and molecules that may address key pathways of AD, including amyloid beta and tau, with the hope that our scientific research will lead to impactful progress for millions of people with this disease.

We are proud to work closely with people living with AD and their families and care partners, advocacy groups, health care providers, and others in the AD community to listen carefully and learn so we can contribute to a better future for everyone touched by this disease. Because of the profoundly negative impact it would have on patients and their families, we are discouraged by and disagree with the approach CMS has taken in its proposed NCD for anti-amyloid therapies, which would limit coverage of all FDA-approved products in the class to Medicare beneficiaries enrolled in qualifying randomized controlled trials (RCTs) via Coverage with Evidence Development (CED).² Specifically, our concerns are as follows:

• In tying this proposal to an expressed need for additional data to confirm if the benefits of these therapies outweigh the harms, we are concerned that CMS's reliance on its own risk/benefit evaluation to restrict coverage for this class of drugs disregards the role of the FDA, and threatens to undermine the FDA's credibility as the agency statutorily tasked with evaluating the benefits and risks of prescription drug products. Most importantly, restricting coverage on these grounds is detrimental to people living with AD, many of whom are likely to progress beyond the stage of disease eligible for treatment initiation while access to FDA-approved therapies is denied or delayed.
• Limiting utilization to RCTs hampers the development of real-world evidence that is essential for filling in data gaps related to real-world treatment patterns and answering other questions that cannot be addressed in RCTs. Such data is important to build upon the evidence base for FDA-approved therapies to inform the development of clinical guidelines and accelerate future innovations; as such, preventing or delaying this type of data generation is likely to set back continued advancement in research and clinical practice in this space.
• CED presents barriers to patient access that disadvantage people living in rural and underserved communities; those who lack the means to participate in clinical studies, especially RCTs, as these types of trials are typically conducted in urban, academic medical centers; and those whose access to medical care is limited by transportation challenges, ability to travel, or other social determinants of health. CMS’s proposed decision appears bound to exacerbate well-documented health disparities in AD that predominantly affect people of color. While we appreciate and share CMS’s goal of reducing health disparities, we are concerned that this proposal reinforces disparities instead of improving them.
• We believe that by including anti-amyloid therapies still undergoing Phase III clinical trials within the scope of this policy, CMS is jeopardizing individuals' access to products that may be approved in the future and that might be appropriate for their specific treatment needs, without even considering the evidence for those products.
• Finally, this proposal fails to update a now outdated and overly restrictive coverage policy for beta amyloid positron emission tomography (PET) imaging as an important confirmatory diagnostic tool for AD, which further negatively impacts the ability for individuals to receive timely diagnosis and treatment.

Genentech stands with the AD community in seeking broad and equitable access to FDA-approved anti-amyloid monoclonal antibodies for all eligible Medicare beneficiaries living with this devastating disease. In light of the many concerns we have around this proposed decision, which are further detailed below, we strongly urge CMS to reevaluate and revise their position in the final NCD.

I. CED is Unnecessarily Restrictive and Detrimental to People Living with AD

CMS has proposed to cover FDA-approved anti-amyloid monoclonal antibodies only when they are administered as part of a CMS-approved RCT that conforms to narrow criteria (e.g., in a hospital-based outpatient setting), or in trials supported by the NIH. CMS’s proposal is based on its conclusion that “there is insufficient evidence to conclude that the benefits outweigh the harms for mAbs directed against amyloid for the treatment of AD.” However, it is notable that this is the same assessment FDA conducts to make an approval decision about a prescription drug product or biologic.³ We are concerned that CMS’s proposal to itself conduct a benefit-risk assessment for an FDA-regulated product for the same FDA-assessed use encroaches on FDA’s expert, scientifically-driven decision-making process. And by reaching the opposite conclusion as FDA, CMS could erode public trust in the FDA’s judgements, which is critical for public health and patient safety, as has been clearly demonstrated during the COVID-19 pandemic.⁴ Moreover, individuals with AD would bear the most severe consequences because many would lose access to an entire class of potential therapies that have been deemed safe and effective by the FDA, even if the individual's healthcare provider advises that the treatment is right for them, and even if that individual has previously initiated treatment successfully.

Even if CMS believes that additional evidence is needed for broad coverage, we are concerned that the proposed NCD would unduly restrict access because there is no indication in the proposed decision memo that CMS will reevaluate or lift the CED restrictions promptly after such evidence becomes available. Based on past CMS actions, such as the NCD for beta amyloid PET imaging that has been in effect since 2013⁵, CED restrictions imposed by CMS have remained in place for years with no definitive end point, and CMS historically has not reconsidered such policies in a timely manner following relevant, emerging evidence. This means many Medicare beneficiaries with AD who might have been eligible for anti-amyloid therapies would likely progress to more severe stages of the disease and suffer devastating effects while waiting for access to be expanded, if at all. Caregivers – who already provide an average of 24 hours a week of uncompensated care, with an estimated economic value of over $250 billion⁶ – also will endure additional physical, emotional, and financial stress. Beyond the suffering experienced by people living with AD and their families and caregivers, the disease represents an enormous and growing public health challenge, costing more than $180 billion annually for Medicare alone, and the broader economy an estimated $305 billion in 2020 (predicted $1 trillion by 2050 as the population ages).⁷

We believe CMS’s specific, proposed criteria for qualifying CED studies are also unnecessarily restrictive and discouraging for patients living with this destructive disease. The cost and logistical complexity of conducting an RCT present challenges for many smaller institutions and those that have not previously participated in trials. As a result, participation in RCTs that meet CMS’s proposed CED requirements will very likely be skewed toward larger academic institutions concentrated in urban areas. Given the high prevalence of AD and likely capacity/resource constraints at these facilities, which are limited in number, CMS’s proposal would effectively deny opportunities for the vast majority of eligible Medicare beneficiaries with AD to receive treatment with FDA-approved anti-amyloid monoclonal antibodies. Needless to say, this would be a highly distressing outcome for individuals with AD who deserve the option of receiving FDA-approved disease-modifying treatments, and yet would be denied access to those treatments due to seemingly arbitrary geographic limitations.

Finally, in addition to denying the majority of eligible individuals access to FDA-approved therapies for a progressively debilitating condition, this decision would also hamper the development of real-world evidence. Important data gaps are often filled through post-approval real-world evidence generation – collecting data through registries, electronic medical records and insurance claims. These data sources require real-world utilization to provide insight on real-world treatment patterns, adherence/persistence, and efficacy and safety in both non-RCT settings and key subgroups not controlled for or adequately powered for in RCTs. Restricting utilization to hospital-based RCTs would limit the ability to answer these and other important remaining data gaps. As CMS stated, “there is also benefit in assessing whether the results of successful trials can be replicated in broader community practice, outside the rigor of clinical trials performed in relatively few academic medical centers.” In so doing, CMS acknowledges the shortcomings of hospital-based RCTs, and thus should recognize that taking such a narrow approach could stunt our collective ability to build upon the scientific knowledge base in this emerging therapeutic class to inform and accelerate advancements in research and clinical practice.

II. The Proposed Coverage Criteria Would Exacerbate Health Disparities in AD

We support CMS’s stated goal of ensuring that underrepresented groups are engaged, recruited, and retained in clinical research; however, we are concerned that the proposed CED requirements will actually inadvertently exacerbate inequities in access to treatment rather than further the goal of diversifying clinical trial populations in AD.

First, the requirement that studies be conducted as hospital-based RCTs would severely limit the participation of individuals who live in rural communities, where access to hospitals participating in this type of research is limited.⁸ Those without the means to travel long distances – disproportionately minority groups⁹ – would be effectively excluded from participating in a CED study, and therefore denied access to this class of therapies. Second, CMS’s proposal to exclude patients with any non-AD condition “likely to increase significant adverse events” or “that may significantly contribute to cognitive decline” would also disproportionately shut out historically underrepresented groups. A recent review of AD studies showed that some of the most common exclusion criteria related to medical conditions were for conditions more prevalent in non-Latinx Black, Latinx, or American Indian/Native Alaskan patients relative to non-Latinx White patients.¹⁰ This means that individuals in these historically underrepresented groups will be disproportionately made ineligible for treatment, even if they would otherwise be eligible under the FDA-approved indication for use.

By making it harder for these historically underrepresented groups to participate, the requirements above are counter to CMS’s additional requirement that CED studies include a diverse population that is representative of the national population diagnosed with AD. These dueling requirements would result in significant delays in trial recruitment and completion, lengthening the time for which the inequities in access to treatment imposed by the CED requirement would persist. At the same time, CMS’s proposal to require new RCTs to support broad coverage may actually serve to de-value the participation of individuals with AD (including those from underrepresented groups) in clinical research altogether, which could further compound the mistrust that is a well-documented barrier to minority patients’ willingness to participate in clinical trials.¹¹ If different RCTs were to be required for FDA approval, post-approval confirmatory requirements, and/or Medicare coverage, the value of the time, cost, and patient participation in each of those trials would be diminished.¹²

Instead, we would encourage CMS to consider ways to promote and support broader initiatives to overcome the significant systemic barriers to recruiting and retaining diverse populations in clinical trials. For example, at Genentech, we are already undertaking efforts to improve diversity in our AD trials by attempting to reduce the logistical burden on study participants, including providing door-to-door transportation, childcare, mobile nursing, as well as leveraging telehealth and digital solutions for data collection. However, given the scale of the challenges we collectively face on this front, CMS could augment individual stakeholder efforts by implementing programs to better address the social determinants of health (SDOH) impacting Medicare beneficiaries living with AD, and particularly those from underrepresented groups.

III. Limiting Access to an Entire Class of Therapies Based on Incomplete Data is Inappropriate and Harmful to Medicare Beneficiaries with AD

In assessing whether the use of monoclonal antibodies directed against amyloid for the treatment of AD improves health outcomes for Medicare beneficiaries, CMS determined that there is “insufficient evidence to conclude that the use of [these therapies] is reasonable and necessary for the treatment of AD.” However, we note that CMS’s conclusion is based on two underlying determinations that cannot reasonably be extrapolated to the entire class of anti-amyloid therapies, particularly those that are still undergoing Phase III clinical trials:

• “To date, no trial of an anti amyloid mAb has confidently demonstrated a clinically meaningful improvement in health outcomes (i.e., cognition and function) for AD patients.”
  • The Phase III trials that CMS reviewed in Table 1, Section VII.B, to justify this statement do not include the latest pipeline of investigational anti-amyloid monoclonal antibodies, including donanemab (Eli Lilly & Co.) and lecanemab (Biogen, Inc. and Eisai Co., Ltd.), nor do they account for the latest, ongoing Phase III trials of drug candidates such as gantenerumab that, based on key learnings from previous studies, have been optimized to maximize exposure for all trial participants. While we understand that CMS has to make a determination based on the evidence available at the time of review, we do not believe it is appropriate to prematurely apply that determination to an entire class of drugs when most of them are still being investigated and the final results have yet to emerge.
• “With conflicting results from two RCTs (EMERGE and ENGAGE), and a secondary analysis that did not resolve the difference between the two RCTs, CMS believes that the available evidence is insufficient to establish that [Aduhelm™] is reasonable and necessary under section 1862(a)(1)(A) of the Social Security Act.”
  • CMS’s view of whether Aduhelm is reasonable and necessary is based on the evidence available for this specific product, and not evidence for any other anti-amyloid monoclonal antibody. Without such evidence, CMS’s determination on Aduhelm cannot reasonably be applied to the entire class, especially when there are potential mechanistic differences across the products that could result in differential safety and efficacy profiles.

We understand that CMS has a desire to adhere to precedent in developing a class-based NCD. However, we urge the agency to fully consider the broad ramifications and significant unintended consequences of prematurely placing unduly severe restrictions on the entire class of anti-amyloid monoclonal antibodies – the majority of which have ongoing Phase III trials that are expected to read out within the next year, after this NCD has already been finalized. Not only would CMS’s proposal require potentially duplicative post-approval studies that would further delay patient access, but it is also likely to discourage continued research, investment and future innovation in this space by preemptively setting unreasonable standards for Medicare coverage of FDA-approved drugs in the class. Ultimately, the consequences would be borne by Medicare beneficiaries living with AD, who would have limited access to fewer therapeutic options for this devastating disease.

IV. Access to Beta Amyloid PET Imaging Remains Inappropriately Restricted Under an Outdated Policy

We strongly recommend that CMS reconsider NCD 220.6.20 and remove the CED requirements to ensure broad access to beta amyloid PET imaging for appropriate patients clinically diagnosed with AD.

There is consensus among the scientific community that individuals most likely to benefit from treatment with anti-amyloid therapies are those with 1) a clinical diagnosis of mild cognitive impairment or mild dementia due to AD, and 2) confirmation of amyloid pathology objectively identified via evidence-based diagnostic tools such as beta amyloid PET imaging.¹³ We agree with this consensus, and thus support confirmation of AD pathology via PET or other evidence-based methods, such as cerebrospinal fluid (CSF) testing, as a condition for coverage before initiating treatment with an anti-amyloid monoclonal antibody.

Timely and early diagnosis has important physical, emotional, and financial benefits for people living with AD as well as their families and care partners, and could allow these individuals to live an independent life for longer and reduce the significant burden that AD places on the healthcare system.¹⁴ The Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study, which included 11,409 Medicare beneficiaries with MCI or dementia of uncertain etiology evaluated by dementia specialists, demonstrated that the use of amyloid PET was associated with changes in clinical management within 90 days.¹⁵ The value of confirming an AD diagnosis goes beyond the opportunity to initiate treatment with FDA-approved drugs/biologics, as it also enables the individual to make informed decisions on diet or lifestyle changes that may slow cognitive decline, retirement and financial planning, and seek access to support services and resources.¹⁶ Giving Medicare beneficiaries access to the information necessary to take these types of actions following what is currently a fatal diagnosis, one that many consider to be worse than being diagnosed with cancer, should not be dependent on how CMS decides to cover any FDA-approved therapies.

Since 2013, coverage for beta amyloid PET imaging has been restricted under the NCD for Beta Amyloid Positron Tomography in Dementia and Neurodegenerative Disease (220.6.20)¹⁷, impairing accurate and timely diagnosis of AD. In our previous comments to CMS, we noted the importance of broad access to appropriate diagnostic technologies, and urged CMS to acknowledge the important role future diagnostic technologies/modalities will have in properly identifying patients most likely to benefit from anti-amyloid therapies. However, regardless of how CMS ultimately chooses to cover these therapies, we believe that the agency can and should take action to ensure broad access to the diagnostic tools available to confirm AD pathology and support timely and accurate diagnosis, starting with beta amyloid PET imaging.

V. Revisions to CMS’s Proposed Decision are Necessary to Mitigate the Impact on Patients and Support Future Innovation

We have significant concerns about broadly limiting access to anti-amyloid monoclonal antibodies via CED for the reasons described above, and firmly believe that it is not in the best interest of Medicare beneficiaries with AD for CMS to place such unprecedented restrictions on access to current and future FDA-approved drugs for this chronic, progressive, and debilitating disease. If CMS nonetheless moves forward with CED, we strongly urge the agency to, at a minimum, implement the following revisions to the proposed decision:

1. Clarify that CED does not apply to FDA-approved anti-amyloid therapies that have demonstrated clinically meaningful improvement in the primary outcome(s) of well-designed RCTs, including pivotal trials and post-marketing studies. Instead, products in the class that meet this criterion should be nationally covered to their respective FDA-approved labels.
   • With regards to what constitutes “clinically meaningful” improvement in a given trial’s primary outcome, we agree with CMS that the threshold should be supported by the peer-reviewed, published literature.
2. When applicable, CED requirements should be broadened to include other, less burdensome, yet acceptable and valid, methods of data collection beyond RCTs, including real-world evidence generation approaches and inclusion of sites beyond the hospital-based outpatient setting. This would help to lower the barriers to provider participation and patient recruitment, which in turn could better address geographic, economic, and social disparities in access to care that predominantly affect minority communities.
   • As CMS stated, “there is… benefit in assessing whether the results of successful trials can be replicated in broader community practice, outside the rigor of clinical trials performed in relatively few academic medical centers.” If CMS recognizes that requiring hospital-based RCTs would significantly curtail the number of Medicare beneficiaries with AD who have access to anti-amyloid therapies, it then stands to reason that this would also directly contravene the agency’s stated commitment to health equity by limiting access for rural and underserved communities, and impair the ability for sponsors to achieve diverse and representative study populations.
3. As explained above, reconsider the NCD for beta amyloid PET imaging and remove the CED restriction in order to enable timely and accurate diagnosis for all eligible Medicare beneficiaries who have been clinically diagnosed with AD.

Thank you for the opportunity to provide our feedback on the proposed NCD for anti-amyloid monoclonal antibodies for the treatment of AD. Please do not hesitate to contact David Burt, Executive Director, Federal Government Affairs, at burt.david@gene.com should you have any follow-up questions.

Sincerely,

David Burt
Executive Director, Federal Government Affairs
Genentech, Inc.

REFERENCES:

1. Genentech press release. October 8, 2021. https://www.gene.com/media/press-releases/14931/2021-10-08/genentechs-anti-amyloid-beta-antibody-ga
2. Centers for Medicare and Medicaid Services. NCA - Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease - Proposed Decision Memo. Accessed at:
https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=305 3. 21 USC 355(d) (drugs), F.D.C.A. 505(c); 21 USC 356(h)(8), F.D.C.A. 506(h)(8); 42 USC 262(a), P.H.S.A. 361(a) (biologics).
4, Daly, M. et. al. Public Trust and Willingness to Vaccinate Against COVID-19 in the US From October 14, 2020, to March 29, 2021. JAMA. 2021;325(23):2397–2399.
5. Centers for Medicare and Medicaid Services. NCD - Beta Amyloid Positron Tomography in Dementia and Neurodegenerative Disease. Accessed at: https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?ncdid=356&ncdver=1
6. Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures - Special Report: Race, Ethnicity, and Alzheimer’s in America. Accessed on August 2, 2021, at: https://www.alz.org/media/documents/alzheimers-facts-and-figures.pdf
7. Seidler, EM, et al. Geographic distribution of clinical trials may lead to inequities in access. Clin. Invest. (2014) 4(4), 373–380.
8. Probst, J. et al. Effects of residence and race on burden of travel for care: cross sectional analysis of the 2001 US National Household Travel Survey. BMC Health Serv Res. 2007 Mar 9;7:40.
9. Franzen, S., et al. Diversity in Alzheimer's disease drug trials: The importance of eligibility criteria. Alzheimer’s Dement. 2021;1–14.
10. Clark, LT, et al. Increasing Diversity in Clinical Trials: Overcoming Critical Barriers. Curr Probl Cardiol. 2019 May;44(5):148-172.
11. Arad, N, et al. Medicare Coverage of Monoclonal Antibody Treatments for Alzheimer’s Disease: Key Issues from the CMS Proposed Coverage Decision. Accessed at: https://healthpolicy.duke.edu/sites/default/files/2022-01/AD%20mAbs%20Key%20Issues%20CMS%20Draft%20Decision%20Memo%20Analysis.pdf
12. Decourt B, et al. Critical Appraisal of Amyloid Lowering Agents in AD. Curr Neurol Neurosci Rep. 2021 Jun 10;21(8):39.
13. Weimer, DL, et al. Early identification and treatment of Alzheimer's disease: Social and fiscal outcomes. Alzheimers Dement. 2009 May; 5(3): 215–226.
14. Rabinovici, G et al. Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia. JAMA. 2019;321(13):1286-1294.
15. ACT on Alzheimer’s. Alzheimer’s disease often goes unrecognized. Why? Accessed at: https://www.actonalz.org/timely-detection#:~:text=Timely%20detection%20and%20diagnosis%20of,diagnosis%20and%20post%20diagnostic%20care.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

Less

The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am 76 years old [PHI Redacted]. I rely on Medicare as my primary health insurance. It's critical to my existence that Medicare remain fiscally sound, with only reasonable increases to recipients. I urge CMS not to approve Aduhelm which cannot be deemed reasonable and necessary for most patients with Alzheimers. My [PHI Redacted] lived with us with Alzheimers. I don't take this lightly. But millions rely on Medicare and the approval of this drug risks Medicare's financial security. Thank you.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Centers for Medicare & Medicaid Services should not approve the use of Aduhelm to treat Alzheimer’s based upon the mere theory that the drug, by reducing amyloid plaque, will benefit patients —- when there is no proof of its actual efficacy. An approval of this drug in the absence of successful trials on the effects of Alzheimer's will (1) harm patients and their families and give them false hopes; (2) cost Medicare (and therefore its participants) millions of wasted dollars; and (3) further undermine the credibility of the federal government’s decision-making process at a time when right-wing media are waging a rather successful campaign against federal agencies. We need to have confidence that when the FDA and CMS approve the use of drugs for treating specific illnesses, that there is a firm basis for those decisions based upon reliable evidence, rather than enticing theories.

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The FDA’s Adminis decision to approve Aduhelm for treatment of Alzheimer’s disease is corrupt, disregarded science, and mocked the agency’s standards for approving new drugs. This reckless action badly damaged, the agency’s.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was corrupted by the disgustingly close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The FDA’s approval of Aduhelm, a new, ineffective & very expensive ‘Alzheimer’s drug’, appears political and/or hypocritical. Why should the Food and Drug Administration decide to approve Aduhelm which has not produced verifiable success, corrupting the FDA’s own standards for approving drugs?

Such action makes the public wonder what is motivating drug approval at the FDA; certainly something other than a drugs value for health, given this case. The integrity of the FDA, since it is widely funded by pharmaceutical companies, is already doubtful. This rushed approval only highlights there are serious questions as to motivation for drug approval at the FDA.

The 2 trials of Aduhelm were halted because the studies already showed the drug was of no benefit to the patients. Nonetheless, the FDA rushed to approve Aduhelm, although it was unsuccessful in trials.
Aduhelm’s approval disregarded science & was founded on flawed, questionably motivated analyses of the 2 phase 3 trials. This rush to approve Aduhelm did manage to underscore the unwholesome connection between the developer of the drug, Biogen, and the FDA in their after-the-fact marginalized analyses of the phase 3 trials, which had already shown the drug as ineffectual.
For this drug, which does not afford any proven benefit to patients, (while many other drugs that do help variou patients are not approved by Medicare) to be covered by Medicare would be a travesty, corrupt.
Aduhelm is not necessary for treatment of Alzheimer’s, does not improve mental ability and is outrageously expensive in addition to being ineffective.
The CMS must not include Aduhelm in its national coverage for Medicare. Doing so would not only put the FDA’s motives for drug approval in more serious question, it would do the same for the CMS’s decisions.

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I am writing this solicited commentary concerning Medicare Coverage of Aducanumab in the hope the Center for Medical Services will correct an egregious wrong and protect the American Public specifically — patients suffering from Alzheimer’s disease and their families.

My name is David B. Ross, M.D. I am a board-certified neurologist. I completed my neurology residence at the Longwood Area Training Program in 1983. I had the privilege to train with some of the most famous neurologists in the world. Dennis Selkoe, M.D. [world renowned expert in Alzheimer’s disease and Amyloid]. I have practiced neurology, participated in multiple pharmaceutical trials, and own an award-winning patent. I have attached my curriculum. I will be 69 years old in a few months and will be retiring within the foreseeable future. I have no vested interest in the outcome of this CMS decision except to protect the integrity of Medicine and to protect the future.

I was formally an active member of the American Academy of Neurology, but stopped. I felt that the academy was increasingly promoting academic and financial self-interest rather than patient well-fare and community benefit. The AAN’s comments regarding Aducanumab egregiously demonstrate that shameful trend. There are three major concerns.

1. The fallacies surrounding ARIA-edema and ARIAS-micro-hemorrhage. These concerns are based on many fallacies.

A. Misnomers. The very terms are misrepresentative. There is no such thing as Amyloid-Related Imaging Abnormalities - Edema or Microhemorrhage. If these findings were related to Amyloid itself [whether aggregated or not]; then they would be present in all patients with CNS Aggregated Amyloid beta 42; it would not require the added presence of another agent such as Aducanumab.

The verbiage is therefore overtly misleading. It conflates a natural therapeutic process and impute as an abnormal process attributable brain protein. As discussed below, any brain protein linked to an immunological process will create inflammation with edema and microhemorrhage. The terminology creates disinformation.

B. A Historical Approach. The existence of brain “edema’ has been known for known for over a century. The term was first used by M. Reichardt in 1905. In fact, edema occurs locally in all body tissues. It has two types – vasogenic or cytotoxic. Cytotoxic edema occurs whenever tissue becomes irritated or damaged. The concept of cytotoxic edema was set forth by Rudolph Virchow in the 1860’s. He realized that edema and micro hemorrhage. [and other signs of inflammation] were ubiquitously present when the body was subject to tissue injury. Thus, the concept of non-specific inflammation-related edema and microhemorrhage has been established for over 150 years.

C. Nineteenth century physicians quickly realized that edema and microhemorrhage occur during pathological and therapeutic processes. Many therapeutic processes require tissue injury and promote cytotoxic reactions as part of that intervention. Prominent examples include all surgeries, all radiation therapies, and many chemotherapy agents. To the best knowledge of this physician, therapeutic-related asymptomatic edema and/or microhemorrhage never been called an adverse effect in the annals of Medicine. If so, then this adverse effect has been negligently disregarded by all surgeons, radiation therapies, oncologists and many others.

D. Monoclonal antibodies against tissue proteins are a new class of therapeutic agents that provoke a directed immune response to remove pathogenic proteins from the body [usually associated with cancers]. There are more than a dozen agents that have been approved by the regulatory bodies in the United States and/or Europe. A good faith review failed to identify any study using advanced imaging to monitor the possibility of asymptomatic localized edema or microhemorrhage. None of those FDA approved research protocols or reviews found it relevant to find something that must occur but is very usually harmless.

The ARIA-E and ARIA-H are egregious red herrings. Patients with Alzheimer’s disease are confronted with an inexorably fatal disease that will rob them of their cognition and memory [i.e., their very humanity]. The following facts show the clinically relevant [i.e., symptomatic] side effects with their placebo-adjusted incidence [taken from the prescribing information]

	Aducanumab	Placebo	Adjusted
Headache	21	16	5
Falls	15	12	3
Diarrhea	9	7	2
Confusion	8	4	4

I am confident that, if asked, patients would accept a one in twenty risk of side-effects [usually reversible] to get a treatment that would remove the toxic substance causing them to lose their brain function; there are very few who would refuse. Millions of cancer and surgical patients undergo far worse. Patients must be given the opportunity to understand the facts and make their own informed conclusion. Patient should not be denied their rights by a small group of people who seeking to ignore 150 years of Medical Science and the promise of a better future.

II. The Use of Biomarkers: General Considerations. The AAN has decried that the FDA approved aducanumab based on its biomarker findings. For the first time ever, Biogen showed that aggregated beta amyloid could be safely removed from the human brain as long as it was used early in the course of Alzheimer’s disease. That is an august triumph with profound implication for the future treatment of all neurodegenerative and other degenerative diseases. It follows many well-known precedents.

Diabetes II, dyslipidemia, and hypertension are all actually biomarkers. The historical facts are straightforward. Myocardial infarction, stroke, and kidney disease have been known for a long time.

• Descriptions of heart disease date back to ancient Greece discussed by Hippocrates
• Stroke descriptions date back to similar ancient cultures worldwide.
• Kidney disease as an independent condition was described by Richard Bright in 1827.

Modern treatments for diabetes, hypertension, and dyslipidemia all have the same goal – reducing the rate of their known complications. We do not medically treat gray hair, wrinkles, and other presbyopia because they do not cause disease states. Most modern pharmaceutical trials for these major biomarkers do not wait to prove that strokes and/or heart attacks are reduced. They accept that an improvement in the biomarkers will have an important therapeutic effect.

In the field of neurology, the clinical goal Multiple Sclerosis of treatment is to reduce long term disability. Multiple medications are FDA approved and covered by CMS. The facts are that all those trials used biomarkers as end points: number of attacks, an arbitrary scale of true-world disability [the EDSS] and MRI findings. The fact that there was little “real world” proof of efficacy does not prevent neurologists from ordering expensive and potential toxic medications for the Multiple Sclerosis patients. The factual bases for these actions is explicit. In 2020, a multi-center consortium retrospectively looked at their experience [30 departments] reported their experience: The abstract is compelling.

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (=18 years), adult-onset (18-49 years) and late-onset multiple sclerosis (=50 years).

The abstract makes the point that the true impact of Multiple Sclerosis treatment had to wait 30 years after the introduction of interferon beta-1b to establish the reality that these treatments offer a moderate impact in the reduction of real-world disability.

The actual fact is the all-medical science frequently use biomarkers and non-real-world measurements to evaluate new treatments. It is frankly hypocritical to criticize Biogen or any pharmaceutical company for using biomarkers in their studies. If one had to wait until real word prove, one might have to wait decades and the cost would be astronomical. Medicinal therapy would advance at a snail’s pace to the detriment of millions of suffering patients and their families.

III. Biomarkers: Specific Considerations. Aggregated Amyloid Beta 42 as a very precise biomarker for Alzheimer’s disease. Unlike the biomarkers used above, aggregated amyloid beta 42 is pathognomonic for Alzheimer disease. Tau peptide accumulation can lead to multiple entities. Amyloid beta 40 leads to something different. Inflammatory responses occur non-specifically in many conditions. This neurologist is unaware of any other human condition associated with aggregated amyloid beta 42.

Logic states that if a variable is essential in the creation of an outcome, removing that variable must prevent the outcome. What specific role Amyloid beta 42 aggregation plays in the cascade of events leading to Alzheimer’s disease is incompletely understood. Studies of hereditary Alzheimer’s disease show that altered Amyloid beta 42 aggregation results from dysregulation of the body’s homeostatic control over its production versus breakdown. When those two opposing processes are not properly in concert, then a toxic accumulation of aggregates occur. These aggregates then promote a cascade of events leading to extracellular accumulation and brain tissue dysfunction and finally neuronal cell injury and death. There are many well respected scientific reviews on the subject. Selkoe and Hardy authored such a review in 2016 to robust approval; it has been cited over 3500 times with wide acceptance.

This logic is explicitly documented by the Aducanumab trials. The scientists who designed the subject identification process required that each subject have a sufficient level of CNS Amyloid to be entered into the trials. The study used quantitative PET-scan Amyloid and/or spinal fluid levels of Amyloid/Tau as entry criteria. This unequivocally proves that the trial’s designers felt that certain levels of aggregated Amyloid Beta are causally associated with Alzheimer’s disease; if not, then these quantitative levels should not have been a core requirement.

This reliance on biomarkers for the identification of diseases is used for many other conditions. For example, PET scans and laboratory levels are used to follow cancer treatment responses. I doubt that oncologists who identify the presence of malignancy using this marker would then reject the active treatments that improve those PET scan and laboratory levels by more than 80%. Such abnegations fly in the face of common sense. Yet the AAN sets forth such ridiculousness despite that such biomarker changes are accepted by all branches of medicine including neurology.

IV. The Issue of Cognitive Stability or Improvement. I fully endorse the AAN’s stance that more data is needed regarding the cognitive outcomes of treatment, but not for the reasons that so-called pundits propose. The actuality is that cognitive performance as all human performance is a complex mixture of biological, psychological, educational and ethnic/social factors; there are also dietary, family, and exercise factors that influence presentation and treatment outcome. Simone Biles proved to the world that mental health can dramatically impact performance even for the world’s best trained athletes. This truism impacts all people especially the elderly in our polyglot, polyethnic, educationally diverse country.

People assessing and treating the elderly with cognitive complaints need better tools to analyze and treat such individuals so that biological advances such as Aducanumab can be incorporated meaningfully with other medications, psychological and social support, and cognitive rehabilitative efforts. Awell-designed multidimensional approach to a complex human phenomenon deserves the clarity of a well-designed multidimensional analysis that can implement the accurate biological, supplementary medical, psychological and other interventions. If Pharma is truly interested in individual and social welfare, a percentage of its profits should be reinvested into understanding these phenomena and promoting the general welfare. The AAN has not recommended or supported such endeavors to the best of my knowledge.

V. The High Cost Argument. This argument is hypocritical and false. With the implicit agreement and facilitation, Joseph Berger, M.D. [at the University of Pennsylvania] has argued that MS-specialty Neurologists should receive greater compensation because the high cost of MS medications generated greater revenues for their employers [academic departments]. His articles have been published in many national neurological periodicals and are in mainstream media. MS infusion therapies are extremely expensive. The real-world cost of treatments for MS infusions have been studied and are $80,582, $121.053, and $93, 807 per annum. The following facts apply.

• The cost per infusion is far higher for multiple sclerosis treatments is far higher than that proposed for Aducanumab.
• The annual cost of treatment for multiple sclerosis is far higher.
• The MS treatments are ostensibly less effective [and are called disease modifying] whereas Aducanumab will probably result in disease reversal [i.e., no evidence of disease].
• The MS treatments continue for decades [i.e., the life of the patient in many cases] to the profitability of the treating physician and hospital center.
• Aducanumab treatments will probably last 2 to 3 years for most patients.

Other neurological treatments are even more cost prohibitive. Spinraza costs $375K to $700K per annum; Radicava costs $145,000 per year. Yet there are no outcries from neurologists or the American Academy of Neurology. The current cost concerns are specious, hypocritical and incorrect.

When one considers that the lifetime cost of caring for a person with Alzheimer’s disease is estimated at $357, 000. Estimating the cost of Aduhelm at about $150K, that means that successful treatment will save about $200K per patient [since most of the expense comes late in the disease] over the patient’s lifetime. Given the estimate that there are 500,000 new cases of Alzheimer’s disease per year. The implication is clear, properly implemented monoclonal antibody prevention will save the nation about $100 billion dollars per year in the long run.

VI. Conclusions. The AAN arguments constitute a disservice to science, the Alzheimer’s community and the nation. They should be summarily rejected. Some will argue that the Amyloid hypothesis is not a certainty. This is true; some doubt is part of the scientific adventure and can only be certain in hindsight. When a theory has been dominant for 30 years and accumulated evidence for thirty years, it deserves credence and a planned implementation.

The solution is straightforward. CMS should cover the cost of Aducanumab in its phase IV research. There should be several emphases. Pharma and CNS should reinvest some of the profits into improved, cost-effective methods to evaluate and follow the multidimensional nature of cognitive decline. Reinvested money should develop non-medicinal care for the educational, cognitive rehabilitative, and social aspects of cognitive changes. Some of the money should go to developing new medications to deal with some of the additional aspects of cognitive decline [depression, anxiety, pseudobulbar affect and others]. These investments will improve the science and treatment of all-cause dementia meaning that patients and society win.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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I am writing to applaud the Centers for Medicare and Medicaid Services (CMS) for their proposed national coverage decision regarding “Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease” issued on January 11, 2022. I am a practicing and academic neurologist and, like many other clinicians, patients, and experts, I was deeply disturbed by the Food and Drug Administration’s (FDA) recent decision to approve the Alzheimer’s disease drug, aducanumab, despite the significant lack of evidence regarding its efficacy as well as concerns about the drug’s safety. While the FDA has defended this decision by noting that they granted accelerated approval to aducanumab, which only requires the drug to demonstrate an effect on a surrogate marker thought to be predictive of clinical benefit, the agency has failed to note that the particularly surrogate marker underpinning aducanumab’s approval – that of beta-amyloid seen on MRI scans of the brain – has failed in over two dozen clinical trials to show any association with clinically meaningful changes in Alzheimer’s disease patients. We should have better, clear evidence that this medication helps patients clinically before making this applicable to all patients— and therefore including those in clinical trial makes sense. In addition, this is a very expensive medication without clear benefit, and the decision to cover it by CMS appropriately is being carefully made.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The proposed decision to require additional clinical trials for Amyloid treatments - already approved by the FDA - is unprecedented and unfair. It is not a requirement for other FDA-approved drugs, including those for cancer, heart disease, HIV/AIDS, and other serious and fatal diseases. If the proposed decision stands, most likely other payers beyond MCS will not cover payment for current and future FDA-approved treatments for Alzheimer’s, unless individuals are enrolled in qualifying clinical trials. The decision would severely limit coverage and access to the first FDA-approved treatment to slow the progression of Alzheimer’s. Finding and enrolling in a clinical trial can take months. This is precious time that people with Alzheimer's Disease do not have. The proposed decision should be withdrawn.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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February 10, 2022

Tamara Syrek Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Electronically Submitted

RE: Proposed Decision Memo for Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease

Director Jensen:

In my training as a neurosurgeon, I have seen the devastation neurological conditions bring to patients and their families. I have also seen how lives can be changed through new treatment breakthroughs. I am a venture capital investor in early stage biotechnology companies, making investments to ensure these breakthroughs can continue. The proposed National Coverage Determination to only cover anti-amyloid monoclonal antibody treatments (mAbs) for Medicare patients enrolled in clinical trials is incredibly concerning, and will have disastrous effects on future medical innovation and investment into new Alzheimer’s treatments. Therefore, I believe this decision must be withdrawn.

Historically, venture capitalists incur losses on investments into Alzheimer’s treatments because these drugs have a less than 1% chance of making it through clinical trials. However, we continue to invest because we know new treatments do not start from square one – we can learn from and build on those initial failures and inject capital into therapeutic area research and development to spur future successes. Research into a certain area of drug development leading to eventual approval and coverage for one drug, such as an Alzheimer's drug, could open the door to many others down the line.

From an investor’s perspective, the decision to apply this proposal to the entire class of mAbs will have a chilling effect on innovation in this area of drug development. Investors will struggle to justify risking capital in Alzheimer’s research if there is uncertainty around whether CMS will cover FDA approved drugs. In turn, biotech companies in this space will be unable to raise funding, and will move into other areas of research, leaving Alzheimer’s patients with no options.

This decision also undermines the FDA’s gold-standard system by restricting access to drugs that have already undergone the Agency’s review and approval process. By law, Medicare Part B must cover medicines that are “reasonable and necessary” for treatment. Covering mAbs only for patients who are enrolled in clinical trials goes against CMS’s commitment to covering medicines that all patients need to access.

Pharmaceutical investment comes with a great deal of risk, yet the benefit to patients nationwide is unmatched when the system works properly. On behalf of my colleagues in the venture capital community, and on behalf of the patients we aim to help, we ask that this decision be changed. Thank you for the opportunity to comment on this matter.

Sincerely,

Gaurav Gupta, MD, MS
Founder and Managing Partner of Ascendant BioCapital

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Apparently, from what several sources have confirmed, there is lack of scientific evidence that Aduhelm even works, as shown in clinical trials.

Worse, according to Physician, Dr. Geoff Rutledge's post on LinkedIn: "'The FDA Neurological Drugs Advisory Panel had strongly advised against approval, voting 10-1, and 3 members subsequently resigned to protest a far broader use than intended. One former member expressed 'probably the worst drug approval decision in recent U.S. history.'"

Worse, "Aduhelm has not been proven to be effective, except on scans that show a reduction in amyloid deposits. Unfortunately, so far there is no evidence that a reduction in amyloid will stop the disease process. Forty percent (4 out of 10 people!!) of patients treated with the drug developed either swelling or small hemorrhages in the brain. The studies were halted prior to completion due to a lack of benefit from the medication.

"The recent rise in Medicare premiums were due in part to the anticipated cost of this medication." - Dr. Douglas Nathanson, Neurologist.

Worse: During a pandemic where all of a sudden prices are going up for everything, and many of us "little people," including the elderly, are worried about affording a roof over our heads and food on our tables and clothes on our backs, Medicare's premium was raised a LOT. I was shocked when I saw my Part B premium soar. To bug-eyed purveyors of lucrative gain like Big Pharma, this isn't "soaring" whatsoever, is it? But we may be small. But each and every one of our voices counts exactly the same as that drug company's CEO's. And, especially the many among us who aren't crooks.

This is a disgrace and a blot on our Government's good name, let alone an exercise in inefficient haphazard endangerment of... what was it? 40 percent of people who take this potentially lethal concoction.

Thank you.
Please give us back our $$ which you took out of our Social Security checks.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.
The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented collaboration between Biogen and the FDA in analyses of data from clinical trials after phase 3 clinical trials were futile and terminated.

Please do not compound the FDA’s error by approving Aduhelm. My Medicare rates are already too high and the unprecedented costs for an unproven drug are unwarranted.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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February 10, 2022

The Honorable Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: CMS Draft NCD on Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease.

Dear Administrator Brooks-LaSure:

The National Health Council (NHC) thanks the Centers for Medicare & Medicaid Services (CMS) for the opportunity to comment on the draft national coverage determination (NCD) on anti-amyloid monoclonal antibodies (mAb) directed for the treatment of Alzheimer’s disease.

Created by and for patient organizations over 100 years ago, the NHC brings diverse organizations together to forge consensus and drive patient-centered health policy. We promote increased access to affordable, high-value, sustainable health care. Made up of more than 145 national health-related organizations and businesses, the NHC’s core membership includes the nation’s leading patient organizations. Other members include health-related associations and nonprofit organizations including the provider, research, and family caregiver communities; and businesses representing biopharmaceutical, device, diagnostic, generic, and payer organizations.

Our comments are informed first and foremost by the NHC’s concern for both patient access and safety. Thus, we urge CMS to consider the following perspectives regarding the draft NCD:

1. The draft NCD’s wide-sweeping application to future FDA-approved mAbs in the same class as aducanumab could limit Medicare’s flexibility to appropriately cover future products with similar product profiles but different demonstrations of value and/ or confirmatory data.
2. The draft NCD’s limitation of drug coverage to patients participating in a CMS/National Institutes of Health (NIH) randomized controlled trial (RCT) in the hospital outpatient department (HOPD) setting creates patient access, affordability, and health disparity concerns.
3. The draft NCD sets an alarming precedent for the coverage of future innovative products by signaling CMS’s reluctance to cover FDA-approved, on-label treatments.

Sweeping Application of NCD Could Limit Medicare’s Flexibility to Cover Future Products in Class

If finalized as proposed, this NCD is likely to significantly limit access to anti-Aß mAbs for the treatment of Alzheimer’s disease for a number of patients who may benefit from such products. While CMS’s decision was based mostly off its review of the first-to-market product in this class, aducanumab, the NCD has significant implications for a robust pipeline of similar drugs (10 additional products currently in Phase 2 and 3 trials) that provide promise and hope for the U.S.’s large Alzheimer’s patient population. These products will each have a unique risk-benefit clinical profile supported by separately collected data from different clinical trial populations.

It will be important that these products be assessed by CMS independently, on their own merits, to ensure that Medicare coverage is sufficient for the specific patient populations demonstrated, via clinical trial data and thorough FDA review, to safely benefit from each product. While the NHC appreciates that CMS’s concern with patient safety informs the agency’s decision to implement such restrictive guardrails, the NHC urges CMS to ensure that Medicare coverage determinations do not preemptively subject future medical innovations to restrictive use and encourages CMS to outline this NCD with the flexibility to evolve with new evidence, patient perspectives, and market developments. To achieve this objective, the NHC requests that the final NCD speak clearly to the applicability of the NCD to future drugs and how differences in efficacy data will be factored into agency decision making.

CMS has previously demonstrated its ability to adjust a draft NCD to accommodate considerations related to expansions in a drug class and market developments, for example, removing coverage with evidence (CED) requirements from its final NCD decision for CAR-T therapies. The NHC asks CMS to consider, and potentially replicate, this precedent.

Site of Care and RCT Requirements Create Patient Access, Affordability, and Equity Concerns

The draft NCD includes a CED component that limits Medicare coverage for aducanumab only to situations where the drug is administered as part of an RCT approved by CMS or supported by the NIH. Additionally, Medicare coverage is restricted to the HOPD setting. Such narrow site of care and RCT requirements create specific concerns regarding patient access, affordability, and equity. Moreover, under the current public health emergency (PHE), the hospital setting continues to serve as the front line in addressing the COVID-19 pandemic. This and other PHEs can put pressure on hospital capacity, limiting their ability to facilitate access to the product through the RCT process.

Access: Such significant restrictions on the setting of care presents problems related to patient access. Notably, Medicare patients in rural settings who live at significant distances from the large, academic medical centers with HOPDs that usually support RCTs are likely to have disproportionately less access to trial participation and be inadvertently denied coverage. Disparities in access will make it difficult to ensure treatment is provided to a diverse population.

While the NHC applauds CMS’s effort to ensure drug efficacy and safety with the RCT requirement, particularly for racial minority patient populations who were underrepresented in the initial clinical trial, the decision would mean that a significant number of patients would not be able to receive the drug due to randomized placement in the placebo group, while going through the burden of a trial without receiving any benefit. The NHC questions the feasibility and fairness of a coverage decision that, by inherent design, denies a portion of the population access to the product despite that population meeting all of the patient eligibility qualifications under the NCD. Given these patient access concerns, the NHC urges CMS to re-evaluate site of care and RCT requirements.

Affordability: The NHC also urges CMS to consider the implications of the NCD’s HOPD requirement on patient affordability. Unless CMS provides further clarification, the NCD as proposed would subject Medicare patients enrolled in the required RCTs to pay standard Medicare Part B cost-sharing (i.e., 20% coinsurance) on the drug, or the placebo, and services related to its administration. Given that Medicare services are typically more expensive in the HOPD setting compared to physician office or infusion clinics, the decision to limit access to HOPD only could put unnecessary strain on patient out-of-pocket expenses, especially, given the RCT requirement, which could require patient spending on services and scans without even the guarantee of receiving the drug. Even more troubling is the potential study design that would require patients pay coinsurance to receive a placebo to maintain the blinding of the control arm.

Equity: The draft NCD also raises broader health disparity concerns for minority and other potentially disadvantaged patients. The NHC applauds CMS for its commitment to health equity initiatives and for the agency’s efforts to address uncertainty pertaining to the impact of monoclonal antibodies on minority populations. The NHC has long been an advocate for increased diversity in clinical trials and hopes to work with HHS and FDA to further advance this priority. However, given the historical underdiagnosis of Alzheimer’s in minority populations, the NHC questions whether the RCT requirement alone is the best approach for advancing CMS’s intended goals related to health care quality and access. While the NCD outlines a process to improve clinical trial data for minority populations and requires that RCTs are representative of the national population diagnosed with Alzheimer’s disease, CMS has not acknowledged that minority patients are consistently underdiagnosed in this disease space. Agency efforts to improve the diagnosis of Alzheimer’s in minority populations coupled with community-led initiatives to better inform minority and other disadvantaged populations about RCT participation and associated benefits and risks could alleviate this concern. Without these additional activities, we are concerned the required benchmarks included in the NCD will be difficult to meet, while at the same time limiting access to individuals who do not have access to HOPD settings (as referenced above).

The NCD Would Create a Precedent that Jeopardizes Access to Future Innovative Drugs

CMS has historically limited the use of Medicare NCDs and relied on Medicare Administrative Contractors (MACs) to make localized coverage decisions. While the NHC recognizes that NCDs are often intended to ensure more uniform and equitable coverage across the Medicare program, the NHC worries about a shift to a system where NCDs are instead used to control costs by restricting access to new, innovative, and/or expensive drugs or drug classes coming on to the market.

The NHC asks CMS to consider the precedent, if finalized, that the NCD could set in making Medicare beneficiaries meet new, and potentially difficult-to-achieve requirements to access FDA-approved products, particularly when the requirements may misalign with the drug’s label or interfere with patients’ ability to engage in shared clinical decision making with their provider to determine appropriate treatment. The expanded use of NCDs with significant coverage restrictions would likely widen existing disparities between underserved populations already having challenges accessing clinical trials and other care.

Additionally, this precedent could create disincentives against manufacturers using the accelerated approval pathway or surrogate endpoints in the future, leading to delays in bringing new therapies, that are intended to fulfill high unmet needs, to patients.

The NHC strongly upholds its commitment to advancing equitable patient access to innovative products while also advocating for the implementation of proper safeguards to ensure product safety and efficacy. The NHC also maintains its position that clinical decisions are best when patients can engage in decision making with their providers. Thus, the NHC urges CMS to carefully consider these comments for this, and future NCDs, and assess the need to adjust the final NCD for aducanumab accordingly.

We appreciate the opportunity to provide input on this process. Please do not hesitate to contact Eric Gascho, Vice President of Policy and Government Affairs, if you or your staff would like to discuss these issues in greater detail. He is reachable by phone at 202-973-0545 or via e-mail at egascho@nhcouncil.org.

Sincerely,
Randall L. Rutta
Chief Executive Officer

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This appears to be the worst of our governmental bureaucracy being bought by Big Pharma! The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged. The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.
CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s (FDA’s) decision to approve Aduhelm for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Dear Center for Medicare and Medicaid Services (CMS):

We are writing on behalf of [PHI Redacted], who has Down syndrome.

According to McCarron,M, McCallion, P, et al., people with Down syndrome have a 90% probability of being diagnosed with Alzheimer’s disease. Let us take a moment to think about what this statistic means in term of quality of life and how we value life. For [PHI Redacted] and people like her with Down syndrome, their families, friends, loved ones, caregivers, and communities who are deeply invested in their success – the clock is ticking.

CMS issued a proposed National Coverage Determination (NCD) decision memorandum published on January 11, 2022 that sets a new precedent for restricting coverage of all Food and Drug Administration (FDA)-approved drugs using monoclonal antibodies directed against amyloid for Medicare beneficiaries suffering from Alzheimer’s Disease.

If finalized, this decision will impact more than 6 million American families suffering from Alzheimer’s disease, including those with other neurological or medical conditions such as Down syndrome. They may be prohibited from receiving Alzheimer’s disease treatments such as the recently FDA-approved Aduhelm, because people like [PHI Redacted] were excluded from and therefore discriminated against participating in the CMS-approved trials.

Let us reflect upon what this means for the individuals who have struggled their entire lives to learn basic skills, seek education, find gainful employment, achieve independence, and fight for inclusion and representation into society only to have their achievements and success taken away prematurely by a diagnosis of Alzheimer’s disease.

Let us also reflect upon the families, friends, caregivers, and communities who have invested their time, money, and compassion in these individuals with Down syndrome and other neurological conditions. The impact is far greater than the 6 million American families referenced above.

Our hope is that these and other comments may shed some light on certain aspects of the NCD determination process that if changed, could markedly improve the lives of individuals like [PHI Redacted] and mitigate the negative impact on their caregiving network as well.

We urge you to reconsider and repropose the NCD to provide reasonable access to FDA-approved AD treatments for a broader population of Medicare beneficiaries, including those Americans suffering from other neurological diseases and medical conditions such as Down syndrome like [PHI Redacted].

Thank you for your consideration.
Margot and Chris Rhondeau

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The Honorable Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Dear Administrator Brooks-LaSure,

I appreciate the opportunity to comment on the draft NCA regarding Monoclonal Antibodies Directed Against Amyloid for the Treatment of Alzheimer’s Disease (CAG-00460N). I am a Professor of Neurology, Radiology & Biomedical Imaging at the University of California San Francisco (UCSF) and Co-Director of the NIH-funded UCSF Alzheimer’s Disease Research Center (ADRC). I am a board-certified neurologist with sub-specialty training in behavioral neurology and over 20 years of clinical experience caring for patients with AD and related disorders (ADRD). I serve as Study Chair of the New Imaging Dementia-Evidence for Amyloid Scanning (New IDEAS) and was Study Chair of the original IDEAS study, working closely with the Coverage and Analysis Group on Coverage with Evidence Development (CED) evaluating beta-amyloid PET. I currently serve as principal investigator or co-investigator on over twenty active research studies funded by NIH or private foundations related to ADRD. The opinions expressed here are my personal opinions and do not represent my university.

Based on my evaluation of the evidence regarding anti-amyloid monoclonal antibodies, I respectfully ask that CMS reconsider the following points in the draft NCA.

First, I recommend that CMS restrict this NCA to aducanumab, the sole approved drug in this class. Anti-amyloid monoclonal antibodies target different epitopes on the Abeta peptide and different conformations of monomeric or aggregated Abeta. Given these distinct biological effects, it is likely that different drugs within this class will have different efficacy and safety profiles. For example, Solanezumab targets monomeric Abeta and is not associated with Amyloid Related Imaging Abnormalities (ARIA), in contrast with other antibodies that target oligomeric or fibrillar Abeta aggregates. While the limitations of the clinical data from the aducanumab Phase 3 studies EMERGE and ENGAGE are well documented, Phase 3 randomized controlled studies are currently underway for four additional antibodies in this class. If these trials meet their clinical endpoints and receive full approval from the FDA, they should be fully covered by CMS and not subjected to CED. Therefore, I recommend CMS limit this NCA to aducanumab and determine coverage for future antibodies based on the totality of evidence available at the time of that specific drug’s accelerated or full approval.

Second, I recommend that CMS reconsider the criteria for CED put forth in the draft NCA. The current proposal to limit CED to “randomized controlled trials (RCT)” represents an unprecedented bar for an approved therapy of a common and devastating disease, and stands in stark contrast to CMS coverage of hundreds of drugs that have been approved via the FDA accelerated pathway for other diseases (e.g., HIV, cancer). The RCT requirement seems redundant to the confirmatory RCT required by the FDA for aducanumab, which Biogen has announced will launch in May 2022. Furthermore, based on my experience running CED studies, it is hard to imagine how CMS could ethically expect beneficiaries to be financially liable for co-payments for treatments and associated procedures (e.g., safety MRI scans) when they are enrolled in a study and may be randomized to an arm that does not receive the full therapy. Importantly, I fear that by holding AD to a different standard compared to other devastating illnesses, this CMS decision will exacerbate the nihilism around diagnosing and treating ADRD, which unfortunately is pervasive throughout our healthcare system.

A more reasonable and productive path forward would be to acquire CED via a broad, open-label, longitudinal registry, which would address critical questions regarding clinical response and safety in “real world” specialty practice, as we await complementary results from the pharma-sponsored confirmatory RCT. As you are aware, the Alzheimer’s Association is currently developing a National Registry which would capture longitudinal clinical and safety outcomes in patients treated with novel AD therapies. The Network is being developed rapidly with active engagement of multiple academic and private stakeholders, many of which have previously collaborated with CMS on similar efforts. Importantly, the registry will promote “best practice” recommendations regarding careful selection of patients for treatment and conservative ARIA monitoring and management, as put forth in the Updated Appropriate Use Recommendations being developed by Cummings and colleagues. This approach would be consistent with previous CMS coverage decisions and build on successful collaborations pursuing CED in the ADRD space via open-label study designs in IDEAS and New IDEAS.

Finally, I recommend that CMS work collaboratively with FDA to define “clinically meaningful improvement” in early-stage AD. Current cognitive and functional scales show little progression over the course of a clinical trial in patients with MCI or mild dementia due to AD. For example, the placebo groups in EMERGE and ENGAGE showed a mean change in the CDR-SB of 1.74/1.55 units respectively on this 18-point scale. The example provided in the NCA suggests a 1-2 point decline in CDR-SB would be required to meet the bar for “clinical meaningfulness.” This threshold, which is derived from a single study in a highly selected population (Andrews 2019), is highly unrealistic is it would require a therapy to completely halt (rather than slow) clinical progression. Substantial slowing of decline at this early stage of disease would still provide patients with benefit and is a more realistic goal for this initial generation of drugs that modify the biology of AD.

In summary, I am hopeful that CMS will consider these points and reach a more balanced final national coverage decision. By enabling coverage via a broad, open-label, longitudinal registry, CMS would provide the coverage that beneficiaries with early-stage AD need and deserve, while generating real-world evidence of clinical response and safety as we enter the modern era of AD therapies.

Sincerely,

Gil D. Rabinovici, MD

Disclosures: The New IDEAS study receives funding from Avid Radiopharmaceuticals, GE Healthcare and Life Molecular Imaging. I receive research funding through my institution from NIH, Alzheimer’s Association, American College of Radiology, Rainwater Charitable Foundations and Genentech. In the past 3 years I have received personal fees for serving on Scientific Advisory Boards for Eisai, Eli Lilly, Genentech and Roche. I receive personal fees from serving on a Data Safety Monitoring Board for Johnson & Johnson.

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Amyloid Reduction is a Scientifically Well-grounded Approach to Slow Alzheimer’s Disease

CMS is clearly committed to the welfare of patients in reaching a coverage decision for aducanumab and subsequent amyloid lowering antibodies. A central challenge in weighing the evidence for this approach is the longstanding debate about the scientific validity of b-amyloid as a target for achieving disease modification and clinical benefit. While a large majority of experts on AD pathobiology recognize the strength of evidence for a pathogenic role of abnormal Ab accumulation, one continues to hear from some individuals inside and outside the Alzheimer field that this target is not sound or of little relevance. This persistent debate ignores or misunderstands some key aspects of the overwhelming body of evidence supporting this target that has emerged over 4 decades from hundreds of independent laboratories and clinics worldwide. To help clarify this sometimes-contentious topic, I summarize here eight salient findings – all of them confirmed multiple times in peer-reviewed journals — that support this therapeutic concept and underpin the steady march toward slowing of Alzheimer’s disease.

1) Down’s syndrome represents a lifelong progression of typical AD brain lesions and subsequent clinical decline that is caused by increased gene dosage of the wildtype APP gene.

2) All autosomal dominant cases of AD are caused by mutations in the substrate (APP) or the protease (presenilin) of the biochemical reaction that generates Ab throughout life.

3) A specific APP mutation that decreases Ab production by ~30% lifelong prevents AD and even lessens the likelihood of age-related cognitive impairment.

4) Apolipoprotein E4 is the major genetic risk factor for LOAD, and it decreases Ab clearance in vivo.

5) Soluble Ab oligomers (oAb) isolated from AD cortex induce neuritic dystrophy and tau hyperphosphorylation in rodent hippocampus and in iPSC-derived human neurons. CNS injections of oAb impair memory in healthy adult rats. All of these are prevented by Ab antibodies.

6) Human biomarker studies show that falling CSF Ab (signifying its aggregation into plaques) precedes rising CSF tau, decreased FDG-PET, vMRI loss, and tau regional spread as seen on tau-PET.

7) Clinical data across trials of four Ab antibodies indicate that they can all clear plaques, and 3 have produced statistically significant slowing of decline in cognition and ADL. They have recently been reported to lower tau in brain, CSF and/or plasma, signifying disease modification.

8) Other human amyloidoses, e.g., transthyretin (TTR), occur both genetically and sporadically. TTR- lowering agents were approved and covered by CMS with little controversy and modify that disease, with published clinically-meaningful benefit on both morbidity and mortality.

Based on over four decades of basic scientific study and clinical care of AD patients, I wish to convey to my CMS colleagues that amyloid lowering is very well-grounded scientifically and has produced evidence of disease modification for both amyloid and tau, the undisputed defining lesions of Alzheimer’s disease. I cannot explain the deep-seated resistance to this concept in limited quarters, while the same has not arisen in the study of any other organ-limited human amyloidosis, some of which have now been successfully treated or prevented. Although many factors contribute to AD pathogenesis, A? dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target. Carefully qualified patients should be allowed access to these agents as soon as possible, before suffering the inexorable progression that they know lies just ahead.

In addition to these comments, I have submitted a joint statement with Drs. Paul Aisen, Jeffrey Cummings, Howard Fillit, and Marwan Sabbagh. I also urge you to read the individual comments submitted by these individuals, with whom I am aligned.

Dennis J. Selkoe, MD
Brigham and Women’s Hospital and Harvard Medical School

CONFLICTS OF INTEREST: Dr. Selkoe is a Director and provides consulting to Prothena Biosciences and has served on an advisory board for Eisai.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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Medicare must have the freedom to set prices for drugs and other medical services, and Medicare premiums must be as low as possible. People should continue to pay into Social Security and Medicare for the full amount of their incomes. Also, they should not have access to Social Security payments or services through Medicate until their net worth falls before a certain amount.

If premiums for Social Security and Medicare are going to rise, they should be means tested so that the people at the bottom of our economy do not have to pay higher premiums. This is especially true if the reason for the increase in premiums is the high cost of drugs that may not be effective.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a stunning disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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With Drs. Paul Aisen, Jeffrey Cummings, Howard Fillit, and Dennis Selkoe, I have submitted a statement that speaks to scientific concerns about this draft national coverage determination, including concerns about the science that informed the determination as well as its broad nature and requirements for future research that I believe will negatively affect patients. I write now to share a more personal anecdote.

Today, I saw a patient in the clinic. She is in the EMBARK study which is the open label extension of the aducanumab trials. She was enrolled in the ENGAGE study in 2017 and the EMBARK study in 2021. Her diagnosis of MCI was confirmed by Amyloid PET in 2017. In the five years since she has been my patient, she is still in the MCI stage and continues to drive, shop, cook and remain independent. Her total progression in the five years has been minimal. While we cannot speculate what her life would have been without treatment, I can say this is the first time I have seen an amyloid positive confirmed patient not progress to full dementia in that period of time.

Patients understand what it means to have a terminal uniformly progressive brain disease. AD is what people fear most. Many or most are highly motivated to see a future that does not end up with loss of independence or personhood. We owe it to our patient to give them every opportunity to maximize their remaining life. Restricting treatments that have a chance of meaningful change in slowing decline is regressive and will commit millions to suffer as they have. This is reiterated in the conversations I have every day in the clinic. I urge CMS to follow the recommendations of our expert panel, and to carefully consider these comments as well as the individual comments submitted by Drs. Aisen, Fillit, and Selkoe, with whom I am aligned.

Marwan Noel Sabbagh MD, FAAN
Professor of Neurology, Alzheimer's and Memory Disorders Division, Barrow Neurological Institute;
Clinical Professor of Neurology, Creighton University

CONFLICTS OF INTEREST: Dr. Sabbagh provides consulting for Eli Lilly, Eisai, Biogen and Roche.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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The Food and Drug Administration’s corrupt decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

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The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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As a former Alzheimer’s researcher and former FDA medical officer, I was not surprised when the FDA approved aducanumab, despite its lack of efficacy and serious safety concerns. We’ve seen this coming with the declining standards of the FDA; having Medicare pay for this drug would be an example of waste and abuse of government funds at its worst.

Medicine is littered with therapies that “should” work because a mechanism says they should—just as clearing amyloid makes sense to many in the Alzheimer’s disease field who built their careers and bank accounts on it. Literally all of those who support Medicare recipients paying for Aduhelm are taking money from the company that makes it (or a company with a related drug). It’s another example of the Sacklerization of academics, “advocacy” organizations with CEOs that make over a million dollars a year, and the FDA.

As a practicing psychiatrist, I would never prescribe this drug to a patient; it should be withdrawn from the market. The Japanese and European regulators made an honest assessment of it. In real-world populations too, as opposed to clinical trial samples, I would expect adverse events to be even higher, as co-comorbidities will be higher, especially in black and Latino people on average, with their higher prevalence of diabetes and other cardiovascular risk factors.

Many, many other interventions would go a lot further in helping older people, including those with mild cognitive impairment – hearing aids are one.

Some of those taking money from the corporation are saying that it wouldn’t be right to do a placebo-controlled trial. I think it would be much more in the public health interest to do a comparison group that included lifestyle changes—as in the FINGER study for example. This won’t happen though—it’s too risky for profits.

Thanks for trying to do the right thing.

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I have been following the news about the Alzheimer's drug Aduhelm and don't believe the studies warrant its approval.

The Food and Drug Administration’s decision to approve Aduhelm for treatment of Alzheimer’s disease showed a galling disregard for science and eviscerated the agency’s standards for approving new drugs. Because of this reckless action, the agency’s credibility has been irreparably damaged.

The approval of Aduhelm was based on seriously flawed post hoc analyses of two identical phase 3 trials that were stopped early because a preliminary review of the data found that the trials, if continued to completion, were unlikely to show the drug benefitted Alzheimer’s disease patients. Moreover, the integrity of the FDA’s review of the marketing application for Aduhelm was dangerously corrupted by the unprecedented and inappropriately close collaboration between Biogen and the FDA during the analyses of data from the key clinical trials of the drug after the termination of the phase 3 clinical trials because of futility.

CMS must not compound the FDA’s egregious error in approving Aduhelm on June 7, 2021. Given the lack of scientific evidence that Aduhelm provides any clinically meaningful benefit in terms of cognitive function outcomes in Alzheimer’s disease patients, the drug cannot possibly be deemed reasonable and necessary for treatment of such patients. I urge CMS to issue a national coverage determination that excludes Aduhelm from coverage under the Medicare program.

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