Clinical Trial Policy

Boston Scientific supports CMS’s goal of revising the Clinical Research Policy to ensure coverage of appropriate technologies that are part of a clinical research study and to expand Medicare beneficiary access to new technologies. We applaud CMS’s proposal to maintain the distinction of Medicare coverage according to the regulations on Category A and Category B investigational device exemption (IDE) trials.

However, Boston Scientific is concerned about several elements of the proposed Clinical Research Policy (CRP):

• The proposed definition of “Clinical Research” is too broad and appears to impose a significant burden on company-sponsored, post- market clinical studies in which Medicare beneficiaries are furnished items and services that would otherwise be covered outside the context of the study.

• The exclusion of “Humanitarian Use Devices” (HUDs) is not consistent with the Medicare Evidence Development & Coverage Advisory Committee’s (MedCAC’s) recommendations, with CMS’s “overarching goals” of revising the CRP, nor with Congressional intent in granting this special approval pathway to achieve humanitarian medical care purposes for very small, carefully targeted classes of patients.

• The proposed “Medicare-specific standards for clinical research studies” impose disclosure and subpopulation requirements that are not clear in scope and applicability to device studies that may fall under the revised CRP.

As discussed below, the proposed policy will have a substantial impact on Medicare beneficiaries, hospitals, and medical device companies. Therefore, we urge CMS to consider alternatives and use the notice and comment rulemaking process to identify a process for company-sponsored, post-market studies, as described below, to be reviewed and approved. All other aspects of the CRP, including CMS’s policy on HUDs, could be finalized within the July timeframe. Our comments are discussed in more detail below.

1. Company-sponsored, post-market studies of devices used in procedures that are available to Medicare beneficiaries outside the study

We appreciate CMS’s effort to clarify the definitions of “clinical research”; “routine clinical services”; and “investigational clinical service” to include a more well-defined scope of Medicare covered research activities. However, we are concerned that the proposal creates substantial challenges for company- sponsored studies of FDA-approved products used for procedures that are available to Medicare beneficiaries outside the study. Currently, there are literally hundreds of company- sponsored, post-market studies involving thousands of Medicare patients. Outcomes of such studies often include technical assessments on device features, comparisons with predicate or competitor products, procedure time, anesthesia requirements, length of stay, quality of life, etc. CMS’s draft guidance appears to require all such studies carried out in the United States (i.e. non-deemed) to be compliant with applicable CRP requirements.

However, CMS’s intent is unclear because the proposed policy does not clearly state that such company-sponsored, post-market studies must meet the requirements of the proposed policy in order for Medicare beneficiaries enrolled in such studies to be treated as receiving covered services. Importantly, patients would be receiving services that Medicare would otherwise cover outside the context of a study. Because of the proposal’s ambiguity and public statements by CMS officials, developing comments within the 30 day deadline used in the national coverage process has been extremely challenging.

If CMS intends to make all such studies subject to CRP standards, then these requirements would constitute a major new private sector mandate, potentially imposing millions of dollars of new costs on the private health care sector that CMS has not properly identified and estimated the impact of, as would be required under the Administrative Procedures Act. Nor has CMS identified and provided estimates of the potential impact upon Medicare beneficiaries of potentially widespread loss of coverage when their otherwise covered care is undergoing additional study, due to the new requirements and burdens being placed upon manufacturers, clinical investigators and providers.

Third, the unclear but potential reach of this guidance has major implications for federal resources and the government’s ability to review and approve hundreds of studies that are not currently subject to routine government review and approval requirements. We believe that the approval processes described in the proposed policy will not be sufficient to approve, in a timely manner, the hundreds of company- sponsored, post-market studies currently underway as well as future planned studies. Without such approval, hospitals and other clinical research sites may be subject to false claims risk if they submit Medicare claims for patients enrolled in company-sponsored, post-market studies because the study is not in an approved study under the CRP. Such an outcome will not promote clinical research and runs counter to the policy’s intent of expanding Medicare beneficiary participation in clinical research studies.

Additional pathways for approval for industry sponsored studies
In the final decision, assuming that CMS does intend for non-deemed studies to meet all of the proposed CRP requirements, it would be helpful for CMS to elaborate more fully on the potential mechanisms by which these studies could be reviewed and approved for coverage of routine costs under the CRP.

In the proposed decision, CMS adopted the AHRQ recommendation that federally-funded research centers could approve studies for CRP coverage if the processes used by those Centers were reviewed and approved by a Federal agency.

However, such process review mechanisms do not exist, to our knowledge, and the final policy should therefore be more specific about a timeline for creation of this capacity, and also be explicit that these process review mechanisms should not be overly burdensome. Furthermore, the concept of “same level of protocol review as provided by the supporting Federal Agency” strikes us as a formidably high standard in terms of complexity and resource requirements. The final policy should clarify that the protocol review mechanisms should be “adequate to ensure that the general and Medicare specific study standards have been met.”

As the proposed decision mentions, there is also a need to develop additional mechanisms for review and approval of study protocols in order to certify that they are eligible for CRP coverage.

In the absence of explicit exclusions of company- sponsored studies from the CRP requirements, we support the need for self-certification and alternative third-party review processes that would be recognized by CMS as sufficient to qualify for CRP coverage of industry-sponsored studies, and other studies that are not federally funded. The dialogue should take place quickly, since the CRP policy will not provide substantial additional access to industry-sponsored clinical studies until these mechanisms are in place. However, as discussed above, if it is CMS’s intention to pursue this approach, we firmly believe the implications for hospitals, patients, and trial sponsors and requirements for new federal procedures and resources, all point to a need for using the formal rulemaking process to require CRP standards for industry-sponsored, post-market studies.

Recommendation:
We urge CMS to include language in the final CRP that explicitly grants Medicare coverage for beneficiaries participating in company- sponsored, post-market studies of items and services that are available to beneficiaries outside of the study but exclude such studies from the requirements outlined in the CRP.

While we believe that the impact on hospitals, beneficiaries, sponsors, and research outweighs the potential benefits of subjecting such studies to the CRP requirements, if CMS chooses to proceed, we urge CMS to revise the proposal and explicitly grant Medicare coverage for company-sponsored, post-market studies until CMS develops timely, practical approval process(es) for such studies. In addition, we urge CMS to use the notice and comment rulemaking process to develop the mechanisms by which these studies could be reviewed and approved. Under such an approach, we believe that all other elements of the proposed CRP, as revised based on public comments, could proceed with a final policy issued no later than July.

2. Humanitarian Use Devices (HUD)

We appreciate CMS’s efforts to consider Medicare policy for HUD technology within the CRP National Coverage Determination (NCD), including the Agency’s request for input from the MedCAC. We believe including the HUD objective within CRP is consistent with CMS’s overarching goal “to allow Medicare beneficiaries to receive care that may have a health benefit, but for which evidence for the effectiveness of the treatment or service is insufficient to allow for full, unrestricted coverage.” We, however, are concerned by CMS’s recommendation not to establish an explicit coverage framework on HUDs within the CRP, particularly under circumstances where an HUD with HDE approval is subject to a pre-existing national non-coverage policy.

We believe that CMS’s proposed approach misses opportunities for timely real world clinical evaluation of potentially life-saving treatments and impedes beneficiary access to these promising last resort therapies.

The current CMS recommendation runs counter to the Congressional intent behind the HUD provision of the 1990 Safe Medical Devices Act. Specifically, Congress enacted this HDE approval path because they recognized that for rare conditions affecting small patient populations, a device manufacturer’s considerable research and development costs would pose a significant obstacle to technological innovation. The FDA HDE approval process, finalized in 1996, requires demonstration of safety and probable benefit, but waives the effectiveness requirement. Applicants must demonstrate that the device intervention legitimately encompasses an orphan disease population of no more than 4,000 individuals in the U.S. annually. HUD use is subject to strict, protective controls via IRB approval process, and manufacturers must submit annual post approval reports to FDA on device volumes.

The FDA approval process reflects rigorous, but balanced evidentiary requirements for innovations for rare diseases. In analogous fashion, CMS should leverage the CRP’s theme of expansion of Medicare coverage for clinical research to explicitly define an HDE coverage pathway paired with reasonable data collection requirements. That is, CMS should provide in the CRP a coverage path for such HDE-approved technologies, even if otherwise not available to Medicare beneficiaries because of a previously existing national non-coverage policy.

Instead, CMS has proposed in the CRP to address HDEs via a separate NCD process with use of Coverage with Evidence Development (CED) to meet long term clinical evidentiary questions. One concern and question with this separate NCD approach is that it runs counter to considerations CMS has already made on development of HDE coverage framework (see CMS Decision Memo, CAG-0085R2, Intracranial Stenting and Angioplasty with HUD, November 6, 2006). When finalizing this NCD, CMS opted not to apply the CED process to open up conditional coverage to the HDE patient population associated with the HUD, the Wingspan® Stent System with Gateway™ PTA Balloon Catheter.

If CMS moves forward now with the proposed CRP as currently drafted, we request that CMS proactively revisit the non-coverage decision for the intracranial stenting and angioplasty HUD by expeditiously reconsidering the November 2006 decision. We believe that an expeditious reconsideration is achievable given the diligent discussions on clinical review and proposed observational study protocol, which have already taken place on this intracranial angioplasty and stenting coverage policy.

However, we continue to believe that CMS can also build a coverage path for certain HDEs within the CRP itself. If CMS is concerned that this approach would unduly broaden coverage to HDE technology with insufficient evidence, CMS could provide CRP coverage to HDEs used in procedures that are nationally non-covered but are covered when furnished in Category B IDE trials. This builds upon the coverage that CMS has already provided within a more controlled trial setting, and ensures that additional CRP coverage is tied to CMS’s determination that coverage is already viewed by CMS to be reasonable and necessary within the context of a Category B IDE study.

Recommendation: We urge CMS to provide within the final CRP explicit coverage for HUDs subject to national non-coverage policies consistent with the intent of the MedCAC. Such HDE technologies should be considered eligible for national Medicare coverage as part of an observational study that is reviewed and approved by CMS. Specifically, we suggest the following language:

3. Medicare-specific standards for clinical research studies

We support CMS’s efforts to ensure that studies covered under the revised policy are scientifically and technically sound. The proposed implementation of the Medicare-specific standards serves as the mechanism to accomplish this goal but also causes us concern. We urge CMS to provide clarification around the proposed standards, which are unclear as to their application in the context of developing scientifically sound statistical designs and protocol requirements. Specifically, we urge CMS to provide clarification on the following Medicare-specific standards:

• The research study protocol specifies and fulfills method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early.

  Recommendation: Clarify the above standard regarding acceptable and alternative methods of public disclosure and clarify that the intention of this standard is not to require public release of data that would jeopardize FDA and journal publication restrictions on the dissemination of study results before pre-market approval or clearance.

• The research study protocol must have explicitly discussed inclusion criteria and considered relevant subpopulations (as defined by age, gender, race/ethnicity, socioeconomic or other factors).

  Recommendation: Clarify the above standard and provide guidance recognizing that some studies may not be able to address subpopulations or such information may not be obtainable under current patient privacy rules.

• The research study protocol contains a discussion of how the results will generalize to the Medicare population to infer whether Medicare patients may benefit from the intervention. In particular, the protocol describes the potential impact of age-specific and other factors on outcomes and whether the research study is powered sufficiently to draw conclusions with respect to the Medicare population.

  Recommendation: Clarify what CMS considers the definition of “powered sufficiently to draw conclusions with respect to the Medicare population”. We urge CMS to provide guidance on the above standard recognizing that some studies may not be able to address age-specific outcomes.

Boston Scientific appreciates the opportunity to comment on CMS’s efforts to finalize the revised national Clinical Research Policy. We urge CMS to consider our recommendations in this comment letter, and welcome the opportunity to discuss our responses to CMS’s proposal. Please contact me at (508) 652-7492 or parashar.patel@bsci.com, or Scott Reid, Director of Health Policy and Payment, at (202) 637-8021 or reids@bsci.com if you have any questions.

Sincerely,

Parashar Patel
Vice President, Health Economics & Reimbursement
Boston Scientific Corporation

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The SGO understands the desire to provide Medicare beneficiaries greater understanding regarding the results of clinical trials and that clinical services provided during a trial that is covered by Medicare should produce results that can be demonstrated to be relevant to the Medicare population. Since cancer is a leading cause of morbidity and mortality for both men and women older than 65 years of age in the U.S., the results of any cancer clinical trial are obviously applicable to Medicare beneficiaries as a whole. The lack of a mechanism to implement these requirements will slow protocol development and decrease access for Medicare beneficiaries with cancer to clinical trials.

The Food and Drug Administration (FDA) and in the case of trials operated by NCI funded clinical trials cooperative groups, the NCI – not CMS – are responsible for protocol approval. We see no evidence in this proposed policy that CMS has discussed the impact of these proposed additional requirements the NCI funded clinical trials cooperative groups or with the FDA.

The SGO has significant concerns that CMS’ proposed additional Medicare-specific standards, including but not limited to mandating whole new sections of clinical trials protocols be developed with no guidance as to acceptable standards of compliance, will decrease Medicare beneficiaries’ access to cancer clinical trials

The Role of IND-exempt trials

The SGO joins with our colleagues from the American Society of Clinical Oncology (ASCO) and the Cancer Leadership Council (CLC) in urging CMS to re-consider this policy change, or at a minimum make an exemption for clinical cancer studies.

For women with ovarian cancer, studies using various combinations of FDA-approved drugs in an “off-label” fashion have produced significant improvements in progression-free and overall survival over the last decade For many women this has meant literally the difference between life and death. . Ovarian cancers, although highly chemosensitive, develop resistance after initial treatment. Thus, ovarian cancer researchers, including many SGO members, have conducted numerous trials where differing dosages and combinations of chemotherapy drugs have been studied with the intent to find the best drugs to overcome resistance and prolong women's lives, not change the FDA label. The SGO is concerned that if IND-exempt trials are no longer covered by Medicare programs, the gains that we have seen in increasing survival for women with ovarian cancer and other gynecologic cancers that depend on these type of studies will be lost.

It is unclear what benefit would be derived from burdening the FDA with requests for INDs for trials that are now considered exempt. The disruption this would cause for completion of existing trials and patients’ treatment will likely decrease access to cancer clinical trials for Medicare beneficiaries.

Conclusion

The Society of Gynecologic Oncologists appreciates the opportunity to share with CMS our comments regarding the proposed changes to the Clinical Research/Trials Policy. We commend CMS on proposed changes that will increase access for Medicare beneficiaries with cancer to participate in clinical trials, but we have significant concerns about proposed changes as outlined above that will decrease access. We look forward to working with CMS to further develop the CRP. Please do not hesitate to contact our Washington office at 703-486-4200 or email at Jill_Rathbun@galileogrp.com

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These recommendations are detailed below.

IMPLEMENTATION OF THE CRP

Almyra urges CMS to provide greater detail on howthe final CRP will be implemented, particularlywith respect to the approval process, if any, forqualifying trials. It is not clear from theProposed CRP whether there will be a centraloffice within CMS that will process approvals ofclinical trials that fall under the list of“deemed” studies, or if some determination of awhether a trial has met the CRP’s criteria will bedone on a retrospective basis. Also, Almyra urgesCMS to clarify that trial sponsors may decide toforgo any national process that is established andmay continue to seek approval through localcontractors instead for Food and DrugAdministration (FDA) post-market surveillance foran approved indication. We request that a studyon the list of “deemed” studies only be consideredcovered by the CRP upon request of the researchstudy’s sponsor. This would help to clarify thatthe CRP requirements apply only to trials in whichthe sponsor has sought or intends to pursueMedicare coverage recognizing that many clinicaltrials are not conducted for the purpose ofseeking a Medicare coverage decision. We alsoseek clarification that routine clinical servicesfor Category A devices are covered and whetherthis coverage is subject to the local coverageprocess or the national process; as well as seekclarification that sponsors of IDE trials onCategory B devices may choose to seek coverageunder the CRP instead of pursuing local coveragedeterminations.

With regard to the Medicare-specific criteria, werequest that CMS provide sufficient guidance onhow these criteria will be evaluated so that trialsponsors have adequate information to assurecompliance. Without a greater level ofspecificity on how trial sponsors are to meetthese criteria, study designs will be delayed andenrollment of Medicare beneficiaries into researchstudies could be affected negatively. This isparticularly critical if trials are reviewed on aretrospective basis. It will be difficult toenroll Medicare beneficiaries and ensure theparticipation of providers without certainty ofcoverage for routine care for which they wouldotherwise receive outside of a clinical trial. Almyra also would appreciate additional guidanceregarding the role Medicare contractors have inany approval process. Generally, the task ofevaluating whether a research study meets therequirements set forth in the Proposed CRP is notin the realm of responsibility of Medicarecontractors. Currently, Medicare contractors donot routinely review research study protocolsunder the existing Clinical Trial Policy. Furthermore, using the contactors for any approvalprocess could result in different determinationsin different regions for routine care that wouldnot be subject to coverage outside of the trial. Obviously, this would not be appropriate forstudies with trial sites in different parts of thecountry.

Also, with respect to implementation of the finalCRP, Almyra requests that CMS clarify theoperational requirements in a manner thatdistinguishes any special coding and claimsprocessing requirements used to identify patientsparticipating in studies under the CRP from thoseoperational criteria used for IDE trials in orderto avoid any confusion. It is our experience thatstudy sites continue to receive incorrect codingand claims processing information fromcontractors, or have claims processingdifficulties for correctly coded claims under theexisting policies.

ALTERNATIVE APPROVAL PROCESS FOR STUDIES NOT “DEEMED”

Almyra urges CMS to develop an alternativeprocess for those trials not considered “deemed.” Many worthwhile and rigorous research studieswill not fall within the set of studies proposedas “deemed”, such as studies for 510(k) devicesthat are not separately reimbursed or otherdevices not being studied as part of an IDE. Failure to provide an alternative approval processfor these studies could limit Medicare beneficiaryaccess to well-designed research studies and havea detrimental effect on medical research that canimprove the lives of Medicare beneficiaries. Theestablishment of an alternative approval processwould further the development of medical devicesrelevant to the Medicare population. Almyrarequests that CMS expedite develop for such aprocess so as not to further delay beneficiaryaccess to these important research studies.

COVERAGE OF INVESTIGATIONAL CLINICAL SERVICES

Research Studies Involving Humanitarian Use Devices

Almyra is concerned that CMS has not provided forpayment for trials involving humanitarian usedevices (HUDs) in the Proposed CRP. This proposedapproach is contrary to CMS’ own recommendationsas well as recommendations of the MedicareEvidence Development and Coverage AdvisoryCommittee (MedCAC). Specifically, Almyra stronglyurges CMS to include HUDs that have receivedHumanitarian Device Exemption (HDE) status in thedefinition of “investigational clinical services.” In the Proposed CRP, CMS describes its ownrecommendation that the newly proposed definitionof “investigational clinical services” includecircumstances in which “[t]he item has beendesignated by the FDA as an HUD, has received HDEstatus and is the investigational item or servicein a study that meets the requirements of thepolicy.” At its December 2006 meeting on thesubject of the CRP, MedCAC supported CMS’ proposedcoverage of a HUD with an HDE when the HUD is thesubject of the research study and expresslyrecommended that HUDs be covered in this contexteven when the item is not covered nationally. Inthe Proposed CRP, however, CMS has declined toextend this coverage to HUDs with an HDE.

Coverage of routine clinical services inclinical trials for HUDs, as well as coverage ofthe device itself, is critical to assuring thatsmall device companies are able to continue tobring these new and innovative medicaltechnologies to market. We urge CMS to includecoverage of HUDs with a HDE as part of thedefinition of investigational clinical services. Although in theory HUDs could be covered throughthe CED process, this may not always be anappropriate option because of amount of resourcesnecessary and the small population involved. While CED may make sense for some HUDs, such asthose subject to a national non-coveragedetermination, in other cases reliance on CED maynot be practical. Almyra urges CMS not to rely onthe CED process to cover HUDs that have receivedHDEs, and instead to adopt MedCAC’s recommendationto cover these devices as investigational clinicalservices. This would reflect Congress’ intent tomake HUDs available to patients who need them. Finally, Almyra again urges CMS to clarify thatparticipation in the CRP is at the option of themanufacturer seeking Medicare coverage for routineand investigational services relate to theresearch study.

Consistent Coverage of Investigational ClinicalServices

More generally, Almyra supports CMS’ proposedcoverage of investigational items and serviceswithin a research study when coverage of thoseitems and services is available to beneficiariesoutside the study. Almyra requests that CMSclarify that this coverage applies where coverageof the investigational item or service isavailable to any Medicare beneficiary notparticipating in the study. Thus, where an itemis covered by many – but not all – localcontractors, coverage for the investigational itemwould be available as part of the research study. This would allow research studies conducted inmultiple sites to operate under the same coveragerules and would further the CRP’s goal of assuringMedicare beneficiaries access to research studies.

ROUTINE CLINICAL SERVICES

Almyra supports CMS’ efforts to establish adefinition of “routine clinical services” and toclarify the services covered for Medicarebeneficiaries enrolled in research studies. It iscritical to the success of research studies thatbenefit the Medicare population that beneficiariesare encouraged to participate without concern thattheir routine medical costs will not be covered. Without certainty about their access to routinecare, Medicare beneficiaries and potentiallyresearch sites will be reluctant to participate inresearch studies. With respect to many medicaldevices, however, it is not clear how CMS will payfor the routine clinical services in circumstancesin which the cost of these services outside theresearch context is bundled into a payment withthe costs of the investigational item or service. This is particularly true for medical devicesthat are not being studied as part of a Category BIDE.

In the proposed definition of “routine clinicalservices,” CMS states that such services willinclude “items or services required solely for theprovision of the investigational item or services(e.g., administration of a non-coveredchemotherapeutic agent).” Almyra asks CMS toclarify that in the context of a medical device,the items or services necessary for the provisionof the investigational item or service also willbe covered. Again, because medical devicestypically are provided in a care setting in whichpayment for administration or implantation is notreimbursed separately from the device itself, weask that CMS clarify that this proposal applies tomedical devices and provide real world examples ofhow this would work.

POST-APPROVAL STUDIES

Almyra supports CMS’ efforts to clarify thatpost-approval studies are “deemed” to have met thestandards of the CRP. Post-approval studies fordevices routinely are required and approved byFDA. It is critical that Medicare beneficiariesparticipating in these studies have their routineclinical services covered. Because coverage ofroutine clinical services already is available toMedicare beneficiaries in many types ofpost-approval studies, Almyra seeks clarificationthat CMS is not intending to permit Medicarecoverage of routine clinical services in apost-approval study only pursuant to the CRP. This type of routine care currently is covered,and we are concerned that CMS may be seeking tosubject these studies to the CRP unnecessarily.

At any given time, there are Medicarebeneficiaries participating hundreds of ongoingpost-approval studies. These studies may includestudies of the amount of time a procedure takes,the length of stay associated with a procedure, ortechnical assessments of particular aspects of amedical device. We urge CMS to clarify that itdoes not intend for sponsors of these studies tonow come into compliance with theMedicare-specific standards. At a minimum, such arequirement would pose a significant burden on anyapproval process, as well as the researchsponsors. Again, we urge CMS to include in theCRP those research studies for which the sponsorsseek compliance with the CRP and not limitexisting coverage already available outside thecontext of the CRP.

CMS SHOULD LIMIT THE IMPOSITION OF ADDITIONAL DATACOLLECTION AND OTHER REQUIREMENTS

Almyra urges CMS to work carefully withstakeholders in determining any additional dataactivities or other requirements imposed onclinical trials beyond those required by FDA. Itis critical to the survival of the medical deviceindustry that additional requirements, if any, areminimal. In order to minimize the financialimpact of any such requirements, clinical trialsponsors, and in particular start up companies,must have certainty about the duration and scopeof such requirements.

Although Almyra supports the development ofrigorous evidence on the value of our innovations,we ask that CMS be cognizant of the burdens onstart up device manufacturers and clinical trialsites that agree to work with small companies inconsidering the range of data collectionactivities, methodology requirements, or otherrequirements it imposes on clinical trialseligible for Medicare coverage. Such standardsshould be predictable and should be establishedprior to the onset of a trial. The possibility ofadditional costs imposed by CMS’ requirements is aparticular concern for small companies who mustinvest a significant percentage of their resourcesto get a new technology through the FDA approvalprocess and typically have few available resourcesleft to collect data beyond that required by FDA. Unlike large manufacturers who can spread thecost of additional requirements across manyproducts, small manufacturers may have only one ortwo products on the market and are not able toabsorb such costs. We ask that CMS consideradditional data collection costs imposed by a NCDwith CED as covered administrative servicesaccordingly.

ALMYRA SUPPORTS LISTING ON THE NIH WEBSITE

Almyra supports CMS’ proposal to require clinicaltrials to be listed on the National Institutes ofHealth (NIH) clinical trials registry website whenactive patient recruitment is being conducted. Weencourage CMS to continue to seek alternative waysto make beneficiaries more aware of this site andof the availability and importance of clinicaltrials generally without requiring thatmanufactures provide information that would beconsidered Trade Secret or would otherwisecompromise the intellectual property of themanufacturer. These efforts will further the goalof making more robust clinical trial informationavailable to Medicare beneficiaries that, in turn,will lead to the development of better evidenceregarding the appropriate use of new technologiesin the Medicare population.

PUBLICATION REQUIREMENTS SHOULD BE CLARIFIED

With respect to the Medicare-specific standardrequiring that a research study protocol specifythe method and timing of release of study results,Almyra requests that this requirement beimplemented in a manner that appropriatelyreflects the nature of the research study and thesize of the study. Under the definition of“research” CMS proposed, a wide range of researchstudies could participate in the CRP. For many ofthese research studies, formal publication ofstudy outcomes is not realistic, nor is it withinthe control of the study sponsor, particularly amanufacturer. Small companies, particularly startups do not have the level of exposure within themedical societies that manage these publicationsand the publication process is often longer thanfor companies that more frequently publish inthose journals. In implementing thisMedicare-specific standard, we urge CMS to clarifythat a range of approaches to publication ofresults may be appropriate, provided that theguiding principle of transparency of study resultsis met, and that for many studies, publication ofresults on a sponsor’s web site may be sufficientto meet this standard.

ALMYRA SUPPORTS THE CRP APPROACH TO MEDICAREPOPULATIONS

Almyra supports CMS’ proposed standard thatresearch sponsors discuss the study’s relevance tothe Medicare population. We believe this approachappropriately reflects the need to consider thestudy’s application to the Medicare population,without imposing participation requirements forMedicare beneficiaries that would be extremelydifficult to meet. This proposed standardfurthers the CRP goals of promoting Medicarebeneficiary participation in research studies andfostering research outcomes that benefit theMedicare population, and we encourage CMS tofinalize this proposed standard.

CMS SHOULD FURTHER CLARIFY THE MEDICARE SECONDARYPAYER ISSUES

CMS sometimes has taken the position that if aclinical trial sponsor agrees to cover adverseevents not covered by another payer, then thatsponsor becomes the primary payer for medicalcosts arising out of the clinical trial. Becauseof this uncertainty, trial sites are reluctant toinclude Medicare beneficiaries because Medicarepayment is uncertain and unpredictable. Asurprising number of medical institutions limit,restrict or other implicitly or explicitly avoidenrolling Medicare beneficiaries in clinicaltrials specifically due to concern over complianceon this issue. The result is that Medicarebeneficiaries frequently are under-enrolled inclinical trials, denying beneficiaries theopportunity to receive the most appropriate careand discouraging future innovation that benefitMedicare patients. We strongly urge CMS toclarify that the clinical trial sponsor is thepayer of last resort in these circumstances, andnot an insurer who may be treated as a primarypayer under the Medicare Secondary Payer rules. This is a critical aspect of a successful CRP, andwe believe it is appropriate to address this issuein the context of the final CRP.

CONCLUSION

Almyra urges CMS to finalize and implement theCRP in a manner that furthers the goal ofincreased participation of Medicare beneficiariesin clinical trials by expanding the range oftrials for which coverage is deemed available. Wealso urge CMS to cover HUDs as investigationalclinical services and to provide real worldexamples of how routine clinical services will bereimbursed in the context of medical devices. Inaddition, we support the inclusion ofpost-approval studies in the list of “deemed”studies, but seek to clarify that this will notresult in the imposition of extra requirements forstudies in which routine care already is covered. We ask CMS to limit the burdens of additionaldata collection. Overly burdensome datacollection and operational requirements orconcerns on the part of the clinical trial siteabout compliance with onerous standards will limitMedicare beneficiary enrollment and access toinnovative therapies. Almyra also supportsrequiring sponsors to include their studies onclinicaltrials.gov. We ask that CMS implement thepublication requirement by clarifying that postingof outcomes on a sponsor’s web site meets thisstandard. We also support the proposal to includea discussion of a study’s applicability to theMedicare population in a study protocol. Finally,we believe that it is essential that Medicareclarify for Medicare beneficiaries and health careproviders that Medicare reimbursement will beprovided for clinical trials and other studies andthat the clinical trial sponsor will be the payerof last resort.

Almyra thanks CMS for the opportunity to commenton the Proposed CRP. As always, Almyra looksforward to working with the agency in the future. Sincerely,

Jo Ellen Slurzberg
Vice President Reimbursement and Health Policy
Almyra, Inc.

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One of the Medicare-specific standards in the proposed Clinical Research Policy states that research studies “whose protocols commit to measuring therapeutic outcomes as one of the objectives, may meet this standard only if the disease being studied is chronic, life threatening, or debilitating.” We believe that this is an improvement over the current policy, which requires “therapeutic intent.” Particularly given that clinical research may study diagnostic services, it is important that therapeutic intent not be a requirement of the Clinical Research Policy because this may be interpreted to limit the policy’s application to studies of diagnostic technologies.

One of the general standards for scientifically and technically sound clinical research is that the research study “does not unjustifiably duplicate existing studies.” As we stated in our comments to the MEDCAC, in situations where a number of studies of a particular medical intervention are being planned (or where new studies are being planned and where literature already exists), we think it would be unwise for CMS to restrict the number of studies that receive support, or to assume that only one study should be supported. There may be appropriate reasons for duplicating a study. For example, methodological issues may arise that require an additional study to confirm the conclusions of a given trial. The Medicare program should support multiple studies. We recommend that as CMS implements the Clinical Research Policy that it take an inclusive approach to judging the merits of a given study.

We recommend that on page 33 of the proposed Clinical Research Policy, under “General standards for a scientifically and technically sound clinical research study:” that the introductory language be changed from “A clinical research study that meets the general standards are listed below:” to:

“A clinical research study that meets the general standards below is considered an approved research study:”

This change will clarify the requirements of the proposed Clinical Research Policy.

* * * * *

Thank you again for the opportunity to comment on the proposed Clinical Research Policy. Given the complex nature of this topic, we would like to meet with you and your staff to discuss our concerns and recommendations. Should you or your staff have any questions, please contact Teresa Lee (via e-mail at tlee@advamed.org, or via phone at 202/434-7219) of my staff. We look forward to continuing to work with you and your staff on the Clinical Research Policy.

Sincerely,

Ann-Marie Lynch
Executive Vice President

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4) FDA-required IDE post-approval studies should be specifically included within the Item 8 IDE exemption, whether conducted under the IDE or under protocol for a required stand-alone post –approval study.

We appreciate CMS’s consideration of these comments, and look forward to the continued opportunity to work collaboratively to bring this important issue to closure.

Sincerely,

Don Goffena
W.L. Gore and Associates, Inc.

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These recommendations are detailed below.

IMPLEMENTATION OF THE CRP

MDMA urges CMS to provide greater detail on how the final CRP will be implemented, particularly with respect to the approval process, if any, for qualifying trials. It is not clear from the Proposed CRP whether there will be a central office within CMS that will process approvals of clinical trials that fall under the list of “deemed” studies, or if some determination of a whether a trial has met the CRP’s criteria will be done on a retrospective basis. Also, MDMA urges CMS to clarify that trial sponsors may decide to forgo any national process that is established and may continue to seek approval through local contractors instead for Food and Drug Administration (FDA) post-market surveillance for an approved indication. We request that a study on the list of “deemed” studies only be considered covered by the CRP upon request of the research study’s sponsor. This would help to clarify that the CRP requirements apply only to trials in which the sponsor has sought or intends to pursue Medicare coverage recognizing that many clinical trials are not conducted for the purpose of seeking a Medicare coverage decision. We also seek clarification that routine clinical services for Category A devices are covered and whether this coverage is subject to the local coverage process or the national process; as well as seek clarification that sponsors of IDE trials on Category B devices may choose to seek coverage under the CRP instead of pursuing local coverage determinations.

With regard to the Medicare-specific criteria, we request that CMS provide sufficient guidance on how these criteria will be evaluated so that trial sponsors have adequate information to assure compliance. Without a greater level of specificity on how trial sponsors are to meet these criteria, study designs will be delayed and enrollment of Medicare beneficiaries into research studies could be affected negatively. This is particularly critical if trials are reviewed on a retrospective basis. It will be difficult to enroll Medicare beneficiaries and ensure the participation of providers without certainty of coverage for routine care for which they would otherwise receive outside of a clinical trial. MDMA also would appreciate additional guidance regarding the role Medicare contractors have in any approval process. Generally, the task of evaluating whether a research study meets the requirements set forth in the Proposed CRP is not in the realm of responsibility of Medicare contractors. Currently, Medicare contractors do not routinely review research study protocols under the existing Clinical Trial Policy. Furthermore, using the contactors for any approval process could result in different determinations in different regions for routine care that would not be subject to coverage outside of the trial. Obviously, this would not be appropriate for studies with trial sites in different parts of the country.

Also, with respect to implementation of the final CRP, MDMA requests that CMS clarify the operational requirements in a manner that distinguishes any special coding and claims processing requirements used to identify patients participating in studies under the CRP from those operational criteria used for IDE trials in order to avoid any confusion.

ALTERNATIVE APPROVAL PROCESS FOR STUDIES NOT “DEEMED”

MDMA urges CMS to develop an alternative process for those trials not considered “deemed.” Many worthwhile and rigorous research studies will not fall within the set of studies proposed as “deemed”, such as studies for 510(k) devices that are not separately reimbursed, or other devices not being studied as part of an IDE. Failure to provide an alternative approval process for these studies could limit Medicare beneficiary access to well-designed research studies and have a detrimental effect on medical research that can improve the lives of Medicare beneficiaries. The establishment of an alternative approval process would further the development of medical devices relevant to the Medicare population. MDMA requests that CMS develop such a process in as expeditious a manner as possible so as not to further delay beneficiary access to these important research studies.

COVERAGE OF INVESTIGATIONAL CLINICAL SERVICES

Research Studies Involving Humanitarian Use Devices

MDMA is extremely concerned that CMS has not provided for payment for trials involving humanitarian use devices (HUDs) in the Proposed CRP. This proposed approach is contrary to CMS’ own recommendations as well as recommendations of the Medicare Evidence Development and Coverage Advisory Committee (MedCAC). Specifically, MDMA strongly urges CMS to include HUDs that have received Humanitarian Device Exemption (HDE) status in the definition of “investigational clinical services.” In the Proposed CRP, CMS describes its own recommendation that the newly proposed definition of “investigational clinical services” include circumstances in which “[t]he item has been designated by the FDA as an HUD, has received HDE status and is the investigational item or service in a study that meets the requirements of the policy.” At its December 2006 meeting on the subject of the CRP, MedCAC supported CMS’ proposed coverage of a HUD with an HDE when the HUD is the subject of the research study and expressly recommended that HUDs be covered in this context even when the item is not covered nationally. In the Proposed CRP, however, CMS has declined to extend this coverage to HUDs with an HDE.

A HUD is a “medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year.” FDA considers a HDE when no comparable device is available to treat or diagnose the condition or if a comparable device is available under an approved HDE application or being studied under an approved investigational device exemption (IDE). HUDs are used by a very small number of patients, even though they often are essential to preserving and enhancing the health and well-being of the patients for whom they are designed.

In order to encourage the development of innovative technologies for those vulnerable patients with rare diseases and conditions, adequate payment is essential. This is particularly crucial for the smaller device companies that drive medical device innovation. FDA regulations expressly limit the amount that a manufacturer may charge for a HUD, and device manufacturers are prohibited from making a profit on HUDs. Innovation in HUDs is negatively affected by the fact that many smaller companies do not have the financial resources to support the nationwide marketing and distribution of rarely used technologies the same way that larger, well-recognized companies in the medical industry do. Many companies, especially small companies, simply cannot afford to undertake the research that leads to life-saving technologies for rare diseases and conditions because payment for these devices frequently does not cover the costs of bringing such technologies to market.

Coverage of routine clinical services in clinical trials for HUDs, as well as coverage of the device itself, is critical to assuring that small device companies are able to continue to bring these new and innovative medical technologies to market. We urge CMS to include coverage of HUDs with a HDE as part of the definition of investigational clinical services. Although in theory HUDs could be covered through the CED process, this may not always be an appropriate option because of amount of resources necessary and the small population involved. While CED may make sense for some HUDs, such as those subject to a national non-coverage determination, in other cases reliance on CED may not be practical. MDMA urges CMS not to rely on the CED process to cover HUDs that have received HDEs, and instead to adopt MedCAC’s recommendation to cover these devices as investigational clinical services. This result is sound public policy that would reflect Congress’ intent to make HUDs available to patients who need them. Finally, MDMA again urges CMS to clarify that participation in the CRP is at the option of the manufacturer seeking Medicare coverage for routine and investigational services relate to the research study.

Consistent Coverage of Investigational Clinical Services

More generally, MDMA supports CMS’ proposed coverage of investigational items and services within a research study when coverage of those items and services is available to beneficiaries outside the study. MDMA requests that CMS clarify that this coverage applies where coverage of the investigational item or service is available to any Medicare beneficiary not participating in the study. Thus, where an item is covered by many – but not all – local contractors, coverage for the investigational item would be available as part of the research study. This would allow research studies conducted in multiple sites to operate under the same coverage rules and would further the CRP’s goal of assuring Medicare beneficiaries access to research studies.

ROUTINE CLINICAL SERVICES

MDMA supports CMS’ efforts to establish a definition of “routine clinical services” and to clarify the services covered for Medicare beneficiaries enrolled in research studies. It is critical to the success of research studies that benefit the Medicare population that beneficiaries are encouraged to participate without concern that their routine medical costs will not be covered. Without certainty about their access to routine care, Medicare beneficiaries will be reluctant to participate in research studies. With respect to many medical devices, however, it is not clear how CMS will pay for the routine clinical services in circumstances in which the cost of these services outside the research context is bundled into a payment with the costs of the investigational item or service. This is particularly true for medical devices that are not being studied as part of a Category B IDE.

In the proposed definition of “routine clinical services,” CMS states that such services will include “items or services required solely for the provision of the investigational item or services (e.g., administration of a non-covered chemotherapeutic agent).” MDMA asks CMS to clarify that in the context of a medical device, the items or services necessary for the provision of the investigational item or service also will be covered. Again, because medical devices typically are provided in a care setting in which payment for administration or implantation is not reimbursed separately from the device itself, we ask that CMS clarify that this proposal applies to medical devices and provide real world examples of how this would work.

POST-APPROVAL STUDIES

MDMA supports CMS’ efforts to clarify that post-approval studies are “deemed” to have met the standards of the CRP. Post-approval studies for devices routinely are required and approved by FDA. It is critical that Medicare beneficiaries participating in these studies have their routine clinical services covered. Because coverage of routine clinical services already is available to Medicare beneficiaries in many types of post-approval studies, MDMA seeks clarification that CMS is not intending to permit Medicare coverage of routine clinical services in a post-approval study only pursuant to the CRP. This type of routine care currently is covered, and we are concerned that CMS may be seeking to subject these studies to the CRP unnecessarily.

At any given time, there are Medicare beneficiaries participating hundreds of ongoing post-approval studies. These studies may include studies of the amount of time a procedure takes, the length of stay associated with a procedure, or technical assessments of particular aspects of a medical device. We urge CMS to clarify that it does not intend for sponsors of these studies to now come into compliance with the Medicare-specific standards. At a minimum, such a requirement would pose a significant burden on any approval process, as well as the research sponsors. Again, we urge CMS to include in the CRP those research studies for which the sponsors seek compliance with the CRP and not limit existing coverage already available outside the context of the CRP.

CMS SHOULD LIMIT THE IMPOSITION OF ADDITIONAL DATA COLLECTION AND OTHER REQUIREMENTS

MDMA urges CMS to work carefully with stakeholders in determining any additional data activities or other requirements imposed on clinical trials beyond those required by FDA. It is critical to the survival of the medical device industry that additional requirements, if any, are minimal. In order to minimize the financial impact of any such requirements, clinical trial sponsors must have certainty about the duration and scope of such requirements. Data collection or methodology requirements would be particularly burdensome for HUD trials. As discussed above, device manufacturers are not permitted to profit on these devices, and the addition of burdensome requirements would further hinder the development of innovative technology for rare diseases or conditions.

The medical device industry only has existed as a regulated industry since 1976, yet it is one of the major contributors to advances in health care. Our industry is characterized by small innovators who are struggling to finance the rising costs of higher and higher standards of evidence that can lead to longer times to market. Although MDMA supports the development of rigorous evidence on the value of our innovations, we ask that CMS be cognizant of the burdens on small device manufacturers and clinical trial sites that agree to work with small companies in considering the range of data collection activities, methodology requirements, or other requirements it imposes on clinical trials eligible for Medicare coverage. Such standards should be predictable and should be established prior to the onset of a trial. The possibility of additional costs imposed by CMS’ requirements is a particular concern for small companies who must invest a significant percentage of their resources to get a new technology through the FDA approval process and typically have few available resources left to collect data beyond that required by FDA. Unlike large manufacturers who can spread the cost of additional requirements across many products, small manufacturers may have only one or two products on the market and are not able to absorb such costs. We ask that CMS consider additional data collection costs imposed by a NCD with CED as covered administrative services accordingly.

MDMA SUPPORTS LISTING ON THE NIH WEBSITE

MDMA supports CMS’ proposal to require clinical trials to be listed on the National Institutes of Health (NIH) clinical trials registry website when active patient recruitment is being conducted. We believe this will increase participation of Medicare beneficiaries in clinical trials. We encourage CMS to continue to seek ways to make beneficiaries more aware of this site and of the availability and importance of clinical trials generally without requiring that manufactures provide information that would be considered Trade Secret or would otherwise compromise the intellectual property of the manufacturer. These efforts will further the goal of making more robust clinical trial information available to Medicare beneficiaries that, in turn, will lead to the development of better evidence regarding the appropriate use of new technologies in the Medicare population.

PUBLICATION REQUIREMENTS SHOULD BE CLARIFIED

With respect to the Medicare-specific standard requiring that a research study protocol specify the method and timing of release of study results, MDMA requests that this requirement be implemented in a manner that appropriately reflects the nature of the research study and the size of the study. Under the definition of “research” CMS proposed, a wide range of research studies could participate in the CRP. For many of these research studies, formal publication of study outcomes is not realistic, nor is it within the control of the study sponsor, particularly a manufacturer. In implementing this Medicare-specific standard, we urge CMS to clarify that a range of approaches to publication of results may be appropriate, provided that the guiding principle of transparency of study results is met, and that for many studies, publication of results on a sponsor’s web site may be sufficient to meet this standard.

MDMA SUPPORTS THE CRP APPROACH TO MEDICARE POPULATIONS

MDMA supports CMS’ proposed standard that research sponsors discuss the study’s relevance to the Medicare population. We believe this approach appropriately reflects the need to consider the study’s application to the Medicare population, without imposing participation requirements for Medicare beneficiaries that would be extremely difficult to meet. This proposed standard furthers the CRP goals of promoting Medicare beneficiary participation in research studies and fostering research outcomes that benefit the Medicare population, and we encourage CMS to finalize this proposed standard.

CMS SHOULD FURTHER CLARIFY THE MEDICARE SECONDARY PAYER ISSUES

CMS sometimes has taken the position that if a clinical trial sponsor agrees to cover adverse events not covered by another payer, then that sponsor becomes the primary payer for medical costs arising out of the clinical trial. Because of this uncertainty, trial sites are reluctant to include Medicare beneficiaries because Medicare payment is uncertain and unpredictable. The result is that Medicare beneficiaries frequently are under-enrolled in clinical trials, denying beneficiaries the opportunity to receive the most appropriate care and discouraging future innovation that benefit Medicare patients. We strongly urge CMS to clarify that the clinical trial sponsor is the payer of last resort in these circumstances, and not an insurer who may be treated as a primary payer under the Medicare Secondary Payer rules. This is a critical aspect of a successful CRP, and we believe it is appropriate to address this issue in the context of the final CRP.

CONCLUSION

MDMA long has supported expanded beneficiary access to important new medical technologies and procedures. MDMA urges CMS to finalize and implement the CRP in a manner that furthers the goal of increased participation of Medicare beneficiaries in clinical trials by expanding the range of trials for which coverage is deemed available. We also urge CMS to cover HUDs as investigational clinical services and to provide real world examples of how routine clinical services will be reimbursed in the context of medical devices. In addition, we support the inclusion of post-approval studies in the list of “deemed” studies, but seek to clarify that this will not result in the imposition of extra requirements for studies in which routine care already is covered. We ask CMS to limit the burdens of additional data collection. Overly burdensome data collection and operational requirements or concerns on the part of the clinical trial site about compliance with onerous standards will limit Medicare beneficiary enrollment and access to innovative therapies. MDMA also supports requiring sponsors to include their studies on clinicaltrials.gov. We ask that CMS implement the publication requirement by clarifying that posting of outcomes on a sponsor’s web site meets this standard. We also support the proposal to include a discussion of a study’s applicability to the Medicare population in a study protocol. Finally, we believe that it is essential that Medicare clarify for Medicare beneficiaries and health care providers that Medicare reimbursement will be provided for clinical trials and other studies and that the clinical trial sponsor will be the payer of last resort.

MDMA thanks CMS for the opportunity to comment on the Proposed CRP. As always, MDMA looks forward to working with the agency in the future to improve access to the best and innovative technologies that our industry has to offer.

Sincerely,

Mark Leahey
Executive Director
Medical Device Manufacturers Association

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STANDARDS FOR CLINICAL TRIALS

The proposed NCD would establish seven general standards that a clinical trial would need to meet to be considered scientifically and technically sound; these are similar to the standards in the current NCD. In addition, the proposal includes a number of new Medicare-specific standards. The Medicare-specific standards would authorize Medicare coverage of a study only if the study (a) has certain therapeutic objectives, (b) is registered on ClinicalTrials.gov, (c) has a protocol that provides for release of the study results through publication in a journal or in a sponsor-supported database, (d) addresses all relevant subpopulations (age, gender, race/ethnicity, socioeconomic, etc.), and (e) has a protocol that addresses how the results will generalize to the Medicare population.

Our comments relate to the proposed Medicare-specific standards.

In General

We are concerned that the proposed Medicare-specific standards reflect a major and unwarranted change in the purpose of the NCD. The original intent of Medicare coverage of the routine services in clinical trials was patient-oriented. A White House news release stated that the purpose of the initiative was “to promote the participation of Medicare beneficiaries in clinical trials.” The President highlighted that “Too few seniors participate in clinical trials,” “Current Medicare reimbursement policies often discourage seniors from participating in clinical trials,” and “Increased participation is likely to have significant rewards.” (The White House, “President Clinton Takes New action to Encourage Participation in Clinical Trials” (June 7, 2000), available at http://clinton4.nara.gov/WH/New/html/20000607.html.)

By contrast to the original purpose of the policy – making clinical trials accessible to Medicare beneficiaries – the proposed decision memorandum now appears to view the primary purpose of Medicare coverage as supporting research. Allowing Medicare beneficiaries to participate in research studies remains a goal, but it seems subordinate to the new goal of “encourag[ing] the conduct of research studies that add to the knowledge base about the efficient, appropriate, effective, and cost-effective use of products and technologies in the Medicare population. . . .”

Although the proposed Medicare-specific standards generally reflect worthy goals, making Medicare coverage dependent on the sponsor’s compliance with all of these standards threatens to make many clinical studies once again unavailable to Medicare beneficiaries. Research objectives should not take precedence to the exclusion of providing Medicare patients with the best possible care. In some cases the best possible care will be participation in clinical trials even if the trials are not designed to serve all of the Medicare-specific research objectives set forth in the proposed policy.

We urge CMS to reconsider each of the Medicare-specific standards carefully. Some of the proposals, such as trial registration, are objective standards, relatively easy for sponsors to comply with, and may be sufficiently important to warrant denying Medicare patients access to non-compliant trials. Other aspects of the proposal, such as the requirement that the study must be designed to reach conclusions about various subpopulations, including the elderly, will often be difficult to satisfy and are likely to result in many trials being closed to Medicare patients. The desirability of meeting research objectives should be balanced against the desirability of affording Medicare patients access to clinical trials.

Therapeutic Intent

The current NCD requires that therapeutic intent must be the primary objective of the trial and specifies that the trial cannot be exclusively designed to test toxicity or disease pathophysiology. The revised policy would not require therapeutic intent to be the study’s primary objective and instead would read as follows:

“The clinical research study is not designed to exclusively test toxicity or disease pathophysiology. Research studies, including some Phase I trials, whose protocols commit to measuring therapeutic outcomes as one of the objectives, may meet this standard only if the disease being studied is chronic, life threatening, or debilitating.”

The accompanying CMS discussion indicates that the requirement for a therapeutic outcome to be stated in the protocol as a study objective, as opposed to a less defined requirement for therapeutic intent, is intended to provide an operating policy that is easily understood by providers and enforceable by Medicare contractors.

Comments:

Read literally, this provision makes the entire Clinical Research Policy apply only if the disease being studied is chronic, life threatening, or debilitating, which is clearly not CMS’s intent. In addition, the reference to “some Phase I trials” leaves unclear whether that phrase means those trials “whose protocols commit to measuring therapeutic outcomes as one of the objectives,” or instead is broader. Finally, use of the phrase “protocol commits” to refer to whether the protocol includes a study metric is unusual language and may cause confusion. To clarify these points, we suggest revising the second sentence to read as follows:

“A Phase I trial meets this standard only if (a) its protocol includes measuring a therapeutic outcome as one of the study’s objectives and (b) the disease being studied is chronic, life threatening, or debilitating.”

Trial Registration

The proposal points out that the National Institutes of Health/National Library of Medicine established a clinical trials registry (ClinicalTrials.gov) to comply with a requirement in the Food and Drug Administration Modernization Act of 1997 (“FDAMA”). The proposal would require a study to be registered with ClinicalTrials.gov prior to the enrollment of the first subject.

Comments:

We support the proposal to provide greater transparency to clinical trials by requiring their registration with ClinicalTrials.gov. The timing of the registration, however, should be made consistent with the requirement under FDAMA. The FDAMA provision, 42 U.S.C. § 282(j), applies to trials of drugs for serious and life-threatening conditions and requires registration with clinicaltrials.gov within 21 days after the approval of the study protocol.

We recommend that, for trials subject to the FDAMA provision, the FDAMA deadline for registration should apply even if it is later than the date on which the first subject is enrolled. Government registration deadlines should be consistent, and a deadline established administratively by the Medicare program should not override the deadline enacted by Congress. In the case of trials not subject to the FDAMA requirement, the proposal to require registration before the first subject is enrolled could be retained.

Release of Study Results

The proposal would require the study protocol to specify the method and timing by which all pre-specified primary and secondary outcome measures would be released to the public, and these plans would have to be fulfilled. The outcomes would have to be publicized “as the analyses are completed.” Dissemination could be in peer-reviewed journals or in a suitable public web-based database, including, at least initially, a sponsor-supported database.

Comments:

We support the public dissemination of study results, including negative results, as CMS has proposed. We suggest, however, that CMS clarify how this requirement will be interpreted, since retroactive denial of Medicare coverage would be the apparent enforcement mechanism.

In terms of timing, how soon after “the analyses are completed” would results have to made available? If the sponsor seeks journal publication, and that process takes an extended period of time, and is possibly unsuccessful, will that effort be considered to comply with the requirement?

If the sponsor and principal investigator of the study is a practicing physician not associated with an institution, is it sufficient that the study results be posted on any website, or are there specific requirements that the website must meet?

In the case of a peer-reviewed journal article, the content of the disclosure is clear by virtue of how such articles are written, but the required content of a disclosure made through a web-based database is not at all evident in the proposed decision memorandum. For example, does the web-based disclosure require the same detailed description of the study as would appear in a journal article? Does the presentation of data on the primary and secondary endpoints require a full statistical analysis, including p-values, confidence intervals, etc.? On these and similar points, we recommend that CMS provide detailed publication rules to help sponsors avoid retroactive coverage denials.

Health Disparities

The proposed standards require studies to enroll sufficient numbers of relevant subpopulations defined by age, gender, race/ethnicity, socioeconomic, or other factors to ensure a valid analysis of the studied intervention with respect to those subpopulations. If evidence does not already exist that there are no differences among the subpopulations, then the protocol must discuss how the study will address these issues, such as being of sufficient size to measure the outcomes in each subgroup.

Comments:

We strongly oppose this proposed requirement. This standard appears to assume that all clinical studies are trials involving large patient populations that are designed to generate definitive data for final resolution of safety and effectiveness issues. In reality, many studies currently covered by the NCD are small studies, such as Phase II trials of new drugs and new uses of approved drugs, which may involve only 20-30 patients. Small trials are incapable of allowing results to be assessed in subpopulations. CMS’s proposal is tantamount to withdrawing Medicare coverage of clinical trials except for the relatively small proportion of large Phase III trials that might conceivably be designed to meet this rigorous requirement.

Many small studies serve an important purpose, and Medicare patients should not be denied access to them. For example, when a cancer patient has not responded to the standard therapies, the patient may be enrolled in a small Phase II study of a promising new anticancer agent. We do not understand why CMS is proposing to end Medicare beneficiary access to these trials simply because they are not large enough to assess outcomes in various subpopulations.

To the extent that this requirement is retained, it would benefit from clarification. For example, does the requirement for study of age subpopulations require the inclusion of pediatric patients in studies? Can the elderly subpopulation be defined as age 62 and older, as it often is, or, in conjunction with the requirement for study of the elderly Medicare population, must it be defined as age 65 and older? If sponsors are to comply with a requirement related to study of subpopulations, there needs to be additional explanation of the details of the requirement.

Medicare Populations

CMS states that the results of all studies covered by Medicare should benefit the elderly Medicare population. Therefore, the proposed standard would require the study protocol to discuss “how the study results will generalize to the Medicare population to infer whether Medicare patients may benefit from the intervention.” The protocol must also describe the potential impact of age-specific factors on outcomes and whether the study is sufficiently powered to draw conclusions with respect to the Medicare population.

Comments:

The meaning of this standard is not clear. Although on its face the standard requires simply a description of how the study results will generalize to the Medicare population, the accompanying discussion suggests that, to be acceptable, the study must be designed such that the results will in fact be generalizable to the elderly Medicare population and that the number of elderly patients in the study must be large enough to allow conclusions to be drawn with respect to that subpopulation.

As in the case of the proposed standard on other subpopulations, we believe that this standard will mean the end of Medicare coverage for many types of currently covered trials. It is unreasonable to demand that every trial include a large number of elderly patients so that conclusions can be drawn with respect to that subpopulation.

APPROVAL PROCESSES

The current NCD deems trials approved by various federal agencies, as well as trials supported by nongovernmental centers funded by those agencies, to meet the requirements for Medicare coverage. In addition, trials conducted under an investigational new drug application (IND) and IND-exempt trials are deemed covered. The NCD provided a self-certification process for other trials, but CMS has not implemented this provision.

The proposed NCD would somewhat enlarge the number of federal agencies whose trials would be deemed approved. Coverage of trials supported by the federally funded centers would continue if the funding agency determines that the centers provide the same level of protocol review as the agency itself. Although studies under an IND would continue to be covered, IND-exempt trials would no longer be covered. Post-approval studies required and approved by FDA would be covered, as would studies required under the Coverage with Evidence Development process. The never-implemented self-certification process would be deleted.

Centers and Cooperative Research Groups Funded by Federal Agencies

The current NCD automatically covers trials supported by centers and cooperative groups that are funded by certain federal agencies. Under the proposal, trials supported by these centers and groups would be automatically covered only if the federal agency “reviews and approves the applicant research centers’ or cooperative groups’ subcontract and subgrant funding requirements, selection procedures and oversight measures, and determines that those processes provide the same level of protocol review as provided by the supporting Federal agency.”

Comments:

While we have no objection to the substance of the proposed change, we are concerned about the timing of the process by which federal agencies will investigate the procedures used by the centers and cooperative groups and determine whether their procedures meet the new standard. CMS should not permit a gap in Medicare coverage of the important trials conducted by these centers and groups simply because the federal agencies need time to review their procedures.

We suggest that the current policy on automatic coverage of trials continue until the federal agencies have determined whether the centers and groups they support comply with the new standard. Alternatively, we suggest an extended period of time, such as one year, before the new policy goes into effect to permit the federal agencies to complete the review process.

IND-Exempt Studies

FDA regulations, 21 C.F.R. § 312.2(b), exempt certain clinical studies involving approved drugs from the requirement for an IND. In essence, a trial with an approved drug is IND-exempt if the use of the approved drug in the trial does not significantly increase the risks to patients and the trial is not intended to support labeling or advertising claims.

IND-exempt trials are currently covered by Medicare. The proposed decision memorandum would end that coverage on the ground that IND-exempt trials do not have FDA oversight ensuring that the studies are being conducted under scientifically and technically sound principles. An IND-exempt trial would be covered by Medicare only if it met the other criteria in the proposal, such as being funded by a federal agency.

Comments:

We believe that this proposal is a seriously mistaken change in policy. This is another example, as discussed above, of CMS converting the NCD from a patient-support policy to a research-support policy.

The reason that FDA exempts certain trials from IND requirements is that they so closely resemble ordinary medical practice that no FDA oversight is needed. The trials involve approved drugs used in a manner that, while outside the terms of the FDA approval, poses no significant additional safety risk. In such circumstances, the case for Medicare covering the routine services furnished to the patient would seem to be even stronger than when the drug or device being studied is completely experimental, yet the proposal would cover the truly experimental treatment while refusing to cover the treatment resembling ordinary medical practice.

One of the reasons that CMS adopted the current NCD was the seemingly inexplicable nature of the previous policy under which coverage of routine services surrounding the use of an investigational drug or medical device was denied. For example, if a cancer patient was receiving an investigational drug, the previous policy denied Medicare coverage of the supportive care drugs (e.g., anti-nausea drugs) and drug administration services even though those services would have been necessary and covered if the patient had received standard treatment. Now, CMS is proposing to return to the pre-2000 policy of denying routine care costs merely because they were furnished in conjunction with an approved drug used in an unapproved manner.

We urge CMS to place patient needs above its desire for proof that the research protocol is rigorous. Medicare should continue to cover IND-exempt trials.

Compliance with Medicare-Specific Standards

As discussed above, the proposed NCD would include several new Medicare-specific standards. The proposal states that the Medicare contractors will use “routine processes” to determine whether particular clinical studies meet those standards.

Comments:

We are greatly concerned about the proposed enforcement mechanism for the Medicare-specific standards. Under the current NCD, the standards for determining whether a particular clinical trial is covered by Medicare are objective, and compliance with those standards is easily determined. The proposal, however, would adopt a set of standards that are open to interpretation and with respect to which compliance cannot readily be determined. In particular, compliance with the requirements regarding subpopulations would undoubtedly be the subject of much dispute.

The proposed decision memorandum apparently contemplates that the Medicare contractors, using their normal tools such as post-payment audits, will determine whether particular studies met the Medicare-specific standards. If a study is determined to be out of compliance because, for example, it was not adequately powered to assess outcomes in all of the subpopulations deemed relevant by the contractor, the contractor would determine that the study was not covered by Medicare. Prior Medicare payments for services furnished in the study would be recouped unless the provider and patient could demonstrate that they were without fault, and if the study was on-going, future payments would stop.

The combination of complex and ill-defined Medicare-specific standards and after-the-fact enforcement by the Medicare contractors would have potentially severe consequences. Providers will be reluctant to participate in trials if their Medicare payments could be taken back years later when a Medicare contractor finds an alleged flaw in the study design. Patients may refuse to participate in trials if they understand that, in such a case, financial liability could shift to the patient. Medicare coverage might end in the middle of a trial, thereby forcing the trial to terminate before usable results are obtained.

The vague requirements of the proposed Medicare-specific standards are ultimately the source of the problem. All Medicare-specific standards should be drafted such that trial sponsors can determine with certainty that they comply with the standards.

COVERED SERVICES

Definition of “Routine Clinical Services”

The current NCD defines the routine costs that are covered by Medicare in a confusing way. By contrast, the proposed Clinical Research Policy defines covered routine clinical services as, in essence, items and services that are (a) available to Medicare beneficiaries outside of a clinical study, (b) not investigational clinical services, and (c) used for patient management within the study.

Comments:

We believe that this change is an important and very helpful improvement that should significantly reduce confusion by making the question of whether a particular service is “used for patient management” the key test of whether it is covered by Medicare. We have two suggestions for further clarification. First, the definition of routine clinical services uses the term “patient management,” while the definition of administrative services uses the term “direct patient management” to describe what we believe is the same thing. We suggest using the term “patient management” in both definitions.

Second, the bullet points in the proposed definition of routine clinical services are somewhat confusing. As we understand CMS’s intent, the first two bullets define what is covered and the next three bullets are examples of covered services. If that understanding is correct, we suggest revising the definition to read as follows:

Definition of “Routine clinical services”: Items and services that (a) are available to Medicare beneficiaries outside of a clinical study, (b) are used for direct patient management within the study, and (c) do not meet the definition of investigational clinical services.

Routine clinical services include the following types of items and services:

Definition of “Investigational Clinical Services”

Under the proposal Medicare would not cover “investigational clinical services,” which would be defined as “those items and services that are being investigated as an objective within the study.” In a change from the current policy, however, Medicare would cover any investigational clinical services that would be covered if furnished outside the trial.

Comments:

The proposal to cover investigational services that would be covered outside a trial is a useful change in policy. The new policy would, for example, make clear that approved drugs used for their approved purposes in a trial as a comparator to an investigational drug, or as a basic therapy to which an investigational drug is added, are covered by Medicare.

Humanitarian Use Devices

Under section 520(m) of the Federal Food, Drug, and Cosmetic act, 21 U.S.C. § 360j(m), FDA may allow a medical device to be marketed without full proof of the device’s effectiveness if, in essence, (a) the device is designed to treat or diagnose a disease or condition that affects fewer than 4,000 individuals in the United States, (b) there is no other comparable device available to treat or diagnose the disease or condition, (c) the probable benefit outweighs the risk, and (d) the risk is not significant. If FDA grants a humanitarian device exemption (“HDE”) to permit the sale of such a humanitarian use device (“HUD”), the manufacturer’s charge is limited to the costs of research, development, fabrication, and distribution.

CMS is proposing not to cover HUDs furnished under an HDE. Coverage of an HUD could be available under the proposal, however, if a trial in which an HUD is being investigated is the subject of a national coverage determination on Coverage with Evidence Development.

Comments:

The discussion in the proposed decision memorandum regarding HUDs is confusing because it sometimes appears to be addressing HUDs in general and at other times addresses HUDs being studied in clinical trials. Under the law establishing their status, HUDs subject to an HDE are not investigational devices, and their use is not restricted to clinical trials. As FDA noted when it issued the regulations to implement the HUD statute:

“FDA has decided that a humanitarian device exemption, which provides for temporary marketing approval, does not constitute ‘research’ or an ‘investigation,’ which would normally require informed consent. A HUD is intended to benefit patients who have a rare disease or condition rather than to generate data to support a finding of effectiveness.” 61 Fed. Reg. 33231, 33235 (June 26, 1996).

Congress decided that HUDs should be available to the public outside of clinical trials for treatment of orphan conditions for which no other treatment is available. In light of that policy, Medicare should in every case cover HUDs being used for their approved purposes. It would be inconsistent with congressional intent for Medicare to deny coverage of HUDs that the law allows to be marketed, especially in light of the lack of treatment alternatives that underlies the HUD approval. If a HUD is studied in a clinical trial, that context should not cause denial of coverage because under the proposal, an item covered outside a trial would be covered even if it is being studied in a trial.

The proposal to cover HUDs only if Coverage with Evidence Development applies is too limited and not appropriate. Since a device can obtain HUD status only when a very small number of individuals need it, there is a strong possibility that there will not be a sufficient number of Medicare patients to support Coverage with Evidence Development. More important, as noted above, Congress intended to make HUDs available to patients without further proof of effectiveness, and the proposal to deny Medicare patients access to HUDs except as part of an evidence-development process is inconsistent with the statute’s purpose.

Post-Approval Studies

One of the categories of clinical trials that would covered under the proposal is studies “required and approved by FDA as a post-approval study.”

Comments:

Post-approval studies required by FDA are ordinarily, if not always, studies of the approved product for its approved use. (Typically, a post-approval clinical study examines safety issues in the larger patient population than was involved in the clinical trials or gathers data on long-term safety and effectiveness.) The reference in the proposed decision memorandum to this type of study is somewhat confusing in light of the new policy that items that are covered outside of a trial will be covered in a trial. The specific mention of post-approval trials “required and approved by FDA” might be read as denying coverage of post-approval trials that are not required and approved by FDA even if the trials involve approved products used for their approved indications.

For example, one type of post-approval study not required by FDA but sometimes conducted is a head-to-head trial of competing products to assess their comparative safety and effectiveness when used for their approved purposes. Since both products in such a study would be used for their approved purposes, it seems clear that the products and all the patient-management services furnished in the study should be covered. The CMS policy should be clarified to provide that all post-approval trials of products for their approved purposes are covered.

ADDITIONAL ISSUES

Medicare as Secondary Payer

The proposed decision memorandum does not deal with the important issue of whether and how the Medicare secondary payer rules apply in situations where clinical trial sponsors offer to pay certain unreimbursed patient costs. We are disappointed that CMS has not yet clarified its policy in this area. An NCD on coverage of clinical trials is incomplete as a practical matter if there is a significant unresolved issue about how the secondary payer rules apply to sponsorship of clinical trials, which is in fact the current situation.

It has been common for sponsors of clinical trials to assume financial responsibility for the treatment of injuries and other adverse effects resulting to study subjects from participation in the study to the extent that the treatment is not covered by the subject's health insurance. An April 2004 CMS letter, however, has come to light and caused great consternation in the research community. That letter stated that a study sponsor's commitment to cover the costs of injuries resulting from clinical trials constituted a “liability insurance policy or plan (including a self-insured plan)” under which “payment . . . can reasonably be expected to be made” within the meaning of the Medicare secondary payer provisions in 42 U.S.C. § 1395y(b)(2)(A)(ii). Thus, Medicare coverage is denied if the sponsor has made such a commitment.

We question the applicability of the Medicare secondary payer rules in this situation. The applicability of § 1395y(b)(2)(A)(ii) rests on the assumption that sponsors of clinical trials are legally liable for injuries or other adverse effects of the trial incurred by patients being treated by the study investigators. Under this assumption, trial sponsors are viewed as self-insuring against their legal liability and therefore within the terms of the Medicare secondary payer statute. It is far from clear, however, that trial sponsors are legally liable in all or even many cases for the side effects of the treatment furnished by the study investigators. Any legal liability of the sponsor would generally need to be based on a showing of the sponsor's negligence. Injuries or other adverse effects may occur in a clinical trial even if the sponsor is not negligent. Consequently, the assumption underlying the April 2004 CMS letter is unfounded, and its conclusion that a sponsor's commitment to pay for research-related injuries constitutes a self-insured liability plan is not correct. CMS should withdraw the policy expressed in the April 2004 letter and make clear that sponsors may limit their payments for research-related injuries to costs not covered by the subject's health insurance. It is important for this issue to be resolved concurrently with revision of the policy on coverage of clinical trials.

Effective Date

The proposal does not address the effective date of any changes in policy that may be adopted. We believe that the effective date of any changes should be delayed significantly so that there is adequate time to determine whether particular planned trials conform to the new requirements and, if necessary, to obtain approval of revised protocols when revision is necessary to comply the new conditions for coverage. The effective date should be at least six months after publication of the final revised NCD. Moreover, as discussed above, there should be potentially even additional time for federal agencies to determine whether the centers and groups that they fund comply with the new standards.

Also, the revised NCD should not apply to any trials initiated before its effective date. It would be confusing and disruptive if Medicare coverage of particular trials ceased mid-trial because the coverage standards changed. The current rules should continue to apply to on-going studies.

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Thank you for the opportunity to comment on the proposal.

Sincerely,

Suzanne Seferian
Senior Counsel

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One of the general standards for scientifically and technically sound clinical research that CMS proposes to adopt is that the study “does not unjustifiably duplicate existing studies.” In situations where a number of studies of a particular medical intervention are being planned (or where new studies are being planned and where literature already exists), St. Jude Medical believes that it would be unwise for CMS to restrict the number of studies that receive support, or to assume that only one study should be supported. There are circumstances in which it is appropriate to conduct similar or even what some might consider “duplicate” studies. It may be important to “duplicate” a study in order to understand how a specific patient population responds to a particular medical intervention. Methodological issues may arise that require an additional study to confirm the conclusions of the initial trial. Indeed, it would be virtually impossible to implement a policy that excludes duplicate clinical studies because no two clinical studies are exactly the same with regard to methodology and patient populations studied. Thus, in implementing the Clinical Research Policy, we recommend that CMS takes an inclusive approach to judging the merits of a given study.

St. Jude Medical remains concerned that even with revisions and clarifications to the clinical trials policy, the outstanding questions regarding the interaction of this policy with the Medicare Secondary Payer (MSP) rules remain a barrier to Medicare beneficiaries’ participation in clinical trials. While we understand that these concerns extend beyond the scope of the NCD, we urge the Office of Financial Management to provide guidance to the public through a transparent process directed at removing MSP as a barrier to access. We appreciate the opportunity to comment on the proposed Clinical Research Policy and would welcome the opportunity to work with CMS on this and other related Medicare coverage issues.

Sincerely,

Susan Walker
Sr. Director, Health Policy and Reimbursement

Cc: Leslye K. Fitterman, Ph.D.

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Investigational Device Exemption Studies and Humanitarian Use Devices Medtronic supports the maintenance of contractor discretion in determining coverage for Investigational Device Exemptions (IDEs) and Humanitarian Use Devices (HUDs) with a Humanitarian Device Exemption (HDE). We are pleased with CMS’ decision not to implement national provisions that would unnecessarily limit beneficiary access to these types of devices. We believe the current local coverage process affirms individualized clinical decision- making in the context of the physician-patient relationship, allows for flexible decision- making for innovative new therapies, and encourages the appropriate diffusion of HDE and IDE technologies to Medicare beneficiaries.

We recommend clarification in two areas of the proposed NCD regarding HUDs. The proposed NCD states:

“…[W]e are proposing that the revised policy not include a separate provision for HUDs. This would allow for coverage of HUDs under the same standards as outlined in this policy for other items or services under study. We believe that the most appropriate coverage of HUDs would be through the CED process in an NCD.”

First, the decision memorandum is generally clear that HUDs are subject to the Clinical Research Policy (CRP) under the same standards as other items or services under study. However, the language should be tightened to clarify that only HUDs involved in clinical research are subject to the CRP guidelines.

Second, the decision memorandum is potentially confusing regarding future coverage policy for HUDs. An HUD device is intended to treat patients with rare diseases and limited treatment options. The patient populations are small, unique, and difficult to study, and the conditions treated by HUDs are complex, making case-by-case consideration an important aspect in determining appropriate coverage.

We believe CMS’s intent is to maintain the local coverage process for HUDs not addressed by NCDs. We also believe it is CMS’s intent to make the CED process available to HUDs subject to future NCDs. We find that while CED may be a reasonable approach for some HUDs, particularly those subject to a national non-coverage determination, CED may not always be practical. For the unique patient populations that have no alternatives, the CED process may impede timely access to HUDs.

The CRP should be implemented in a way that does not impact coverage available under the existing local coverage process. To prevent any misinterpretation of the coverage policy on HUDs, we recommend revising the final decision memorandum to state more explicitly the circumstances and parameters under which local and national coverage processes (including CED) would apply or be promoted.

We believe the following new language, in bold, should be included in the final decision memorandum (in place of the text from the proposed decision memorandum) to address the two issues raised above:

“…The revised policy does not include a separate provision for HUDs. As a result HUDs that are both the subject of clinical studies and non – covered by Medicare are covered under the same standards as outlined in this policy for other items or services under study. The local coverage process will be used for HUDs that do not have NCDs in place or when an existing NCD allows for local contractor discretion. In certain circumstances, the most appropriate process for coverage of HUDs that have national non-coverage determinations may be through the CED process in an NCD.”

In addition, Medtronic recognizes there are some concerns regarding the timeframe of the NCD reconsideration process for HUDs subject to a national non-coverage determination. For those few devices subject to national non-coverage, we would support an expedited review process.

Privately-Sponsored Studies Involving Medicare Covered Items and Services As indicated above, Medtronic supports CMS’s goal of increasing Medicare beneficiary access to quality clinical studies. However, we believe the language in the proposed CRP is unclear regarding how the policy should be reconciled with other existing coverage statutes, regulations, and determinations. The lack of clarity in the CRP has the potential to have far- reaching, unintended consequences to beneficiary access to quality clinical research of items and services that have existing coverage under the Medicare program.

In order to be consistent with CMS’s overarching goals, the CRP should provide for an elective process which would offer an opportunity for Medicare beneficiaries participating in clinical studies to qualify for additional coverage, without restricting coverage that might otherwise exist outside a clinical study. In other words, the CRP would only be applied at the election of the trial sponsor in instances when national or local non-coverage policies exist that impede coverage of an item or service under study. The application of the CRP in these very limited circumstances is in keeping with CMS’s overarching goals of increasing beneficiary access to and participation in quality clinical studies. Any other application would have a prohibitive affect on beneficiary access to clinical research and potentially cause a chilling effect on innovation, ongoing research and evidence generation.

Medicare-Specific Standards CMS proposes to revise the Medicare-specific standards that qualify a clinical study for Medicare coverage by adding a number of Medicare-specific requirements including the following:

Related to the registration of the study on the ClinicalTrial.gov website, Medtronic believes the language regarding the timing of registration should be changed from "prior to the enrollment of first study subject" to "not later than 21 days after the first study subject is enrolled". The management of a clinical trial involves many competing priorities, particularly at the start of a study when multiple sites are being initiated and qualified in parallel to begin study enrollment. Study staff could easily miss the registration timeline as currently defined (prior to first enrollment) without any intention to be out of compliance with the policy. Therefore, we feel a 21-day grace period establishes a reasonable window of acceptable registration and is consistent with the current ClinicalTrials.gov timeline. FDA guidance interprets the FDAMA 113 timeline for registration as no later than 21 days after the trial is opened for enrollment. “Opened for enrollment” is subject to interpretation as a discrete point in time in the clinical trials process. Our proposed language provides further clarification and promotes consistency as enrollment initiation can be clearly delineated by enrollment of the first study subject. Medtronic also believes a change in language is necessary regarding the public release of pre- specified outcomes. We feel it is important to clarify that the intent of this standard is not to provide access to specific health outcome data (e.g., raw data file). In order to further clarify this point, we propose the following new language, in bold, to be included in the final decision memorandum (in place of the text from the proposed decision memorandum):

“The research protocol specifies and fulfills method and timing of public release of study results on all pre-specified outcomes to be measured including release of results if outcomes are negative or study is terminated early.”

Regarding the discussion of how the results will generalize to the Medicare population, Medtronic appreciates that CMS has not specified a number or percentage of Medicare beneficiaries required to participate in trials for coverage under the policy. It is important that access to the clinical benefits of new products and therapies not be limited by potential subpopulation enrollment. Well-designed clinical trials can provide useful information relevant to Medicare beneficiaries even when the study is not powered to address this subpopulation. We appreciate the opportunity to provide these comments to CMS during the public comment period. Please feel free to contact me directly at (763) 505-2660 with any questions, or if you need additional information on our above comments.
Sincerely,

Alexandra T. Clyde
Vice President, Health Policy and Payment
Medtronic, Inc.

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3. Therapeutic Intent

UC supports the effort to clarify which early phase clinical trials will qualify under the Clinical Research Policy. UC recommends that CMS permit beneficiaries with chronic, life threatening or debilitating illness to participate in any deemed Phase I or II trial, so long as a physician certifies that all other conventional care has been ineffective, regardless of whether the protocol measures therapeutic outcomes.

4. Research Comparing the Effectiveness of Standard of Care Treatment

It is our understanding that CMS intends to require clinical research comparing the effectiveness of two or more covered, standard of care treatment options (i.e., items or services currently covered by Medicare rules) to comply with the Clinical Research Policy. UC strongly opposes the application of the Clinical Research Policy requirements to this type of clinical research. CMS is statutorily required to cover items and services reasonable and necessary for the treatment of its beneficiaries. Although “investigational” or “experimental” therapies may be excluded from Medicare coverage, this exclusion should not apply when a beneficiary decides to enroll in a study comparing the effectiveness of treatments that Medicare otherwise would cover outside of a research protocol.

5. IND-Exempt Research

Although UC acknowledges CMS’s concern that the self-certification of IND-exempt research may lack sufficient federal oversight, this concern should not apply to research conducted by universities, academic medical centers and/or research institutions that demonstrate a strong record and/or history of conducting scientifically valid research. UC recommends that CMS deem these types of entities to conduct IND-exempt studies pursuant to the Clinical Research Policy. IND-exempt research may provide important results beneficial to the Medicare program and its beneficiaries comparing the cost- effectiveness of FDA approved products, ensuring effective post-marketing surveillance even when not required by FDA, and demonstrating new and potentially cost saving applications for generic drugs.

6. Medicare Secondary Payer Rule

UC strongly encourages CMS to exclude clinical research from the reach of the Medicare Secondary Payer (“MSP”) statute. Although both for-profit and non-profit entities may sponsor clinical research, these entities should not be considered primary payers under the MSP statute and regulations. The Medicare Benefit Policy Manual, section 40.2, has long recognized that a non- profit research sponsor may pay for uninsured or underinsured research participants, while intending to bill third party payers for covered services. The Manual directs intermediaries and carriers to pay for Medicare covered services in the research context, notwithstanding the fact that research sponsors may cover other groups of individuals. CMS should apply the same reasoning in concluding that all research sponsors are not secondary payers.

Finally, there are a number of other issues raised in the comment letter submitted by the American Association of Medical Colleges (AAMC), which the UC supports.

Thank you for the opportunity to comment on the proposed rule. If I can answer any questions or provide any additional detail, please contact me at 510-987-9062 or santiago.munoz@ucop.edu or Dan Stein at 510-987-9793 or Dan.Stein@ucop.edu.
Sincerely,

Santiago Muñoz
Associate Vice President – Clinical Services Development

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This indication limits the availability and use of AbioCor® to patients with end stage cardiac failure who are at imminent risk of death and for whom other treatment options are not available.

The HDE approval was obtained based upon findings from a 14-patient, 4-center clinical trial conducted between 2001 and 2004 which showed survival benefits, improvement in organ system function, and overall improvement in health-related quality of life, based upon assessment of patients and family members. The clinical trial was conducted under a IDE Category A designation.

In addition to the limitations under the HDE approval, ABIOMED and FDA have agreed to a rigorous 25 patient post-HDE-approval study that includes Institutional Review Board review, an Anticoagulation Review Committee, a patient advocate and collection of multiple outcome measures, including patient outcomes. ABIOMED intends to initiate the post-approval study later in 2007 and anticipates that enrollment of the 25 patients will take 2 to 3 years. No patients in the United States will receive AbioCor® outside the post-approval study until the study is completed.

Identifying a viable coverage pathway for the AbioCor® has been challenging due to a national non-coverage decision for artificial hearts issued in 1986 by the Health Care Financing Administration. Although CMS has provided no documentation, correspondence or data analysis on which the decision was made, it is historically perceived to have been a policy decision made to distinguish coverage from that available for human heart transplants. Considering the limited and targeted use of the device, it is unreasonable to expect that sufficient evidence would be obtained to warrant re-opening the national coverage decision. As a result, alternative coverage pathways are essential to the viability to the program.

II. Humanitarian Use Devices and Humanitarian Device Exemptions

In 1996, FDA issued a Final Rule to implement the Safe Medical Devices Act of 1990 provisions regarding HUDs. HUDs are devices that are intended to benefit patients by treating or diagnosing a disease or condition that affects fewer than 4, 000 individuals in the United States per year. The HUD designation and pathway was created to provide an incentive for the development of devices for use in the treatment or diagnosis of diseases affecting small populations—much like the highly successful orphan drug program created by Congress under the Orphan Drug Act of 1983. Under FDA regulations , an HUD may be marketed following submission and approval by FDA of an HDE, which is similar in both form and content to a premarket approval application (PMA). Because of the limited size of the target population for an HUD, FDA recognized that it may not be feasible for sponsors to provide data to support the effectiveness of an HUD meeting the standards for approval of a PMA (i.e., scientifically valid clinical investigations demonstrating that the device is effective for its intended purpose). Therefore, to obtain approval of an HUD under an HDE, a different regulatory standard is applied to assess risk/benefit. To be approved, an HDE application “must contain sufficient information for FDA to determine that the device does not pose an unreasonable or significant risk of illness or injury and that the probable benefit to health outweighs the risk of injury or illness from its use, taking into account the probable risks and benefits of currently available devices or alternative forms of treatment. Additionally, the applicant must demonstrate that no comparable devices are available to treat or diagnose the disease or condition, and that they could not otherwise bring the device to market.” s/cfHDE/HDEInformation.cfm>(accessed May 3, 2007).

In addition to obtaining an HDE, an HUD may be used only after approval by an IRB for use of the device for the FDA approved indication. FDA has approved only 41 HDEs since the final regulations were effective just over10 years ago. Although these approvals are an indicator of the success of the HDE program, this pathway is not viewed by industry as a short-cut pathway to market. FDA closely monitors to assure that the population receiving an HUD under an HDE is, in fact, less than 4,000-per year as required for HUD designation. IRB review and approval is required even on a post-approval basis. Furthermore, for patient understanding and transparency, FDA requires the posting of results on a post-market website not dissimilar to that recommended in the Decision Memo for clinical trials. At a recent device development conference, the consensus among investigators, medical device manufacturers, FDA leadership and investors was that the HUD/HDE pathway should be reserved for true orphaned indications and should not be viewed strategically as part of the clinical development plan to access a large market. Current utilization of HUDs under HDEs supports this consensus.

As noted above, ABIOMED obtained an FDA-approved HDE for AbioCor® in September 2006 and plans to commence commercial use of the device under a 25 patient FDA-approved post-approval study later in 2007. The agreed upon post-market study includes a rigorous review of patient characteristics, adverse event reporting requirements, coagulation consensus, health- related quality of life assessments, patient discharge protocols, and other protocols.

III. CMS Should Clearly Articulate Coverage Pathways for HDEs under the Clinical Research Policy

Although Congress provided for the designation of HUDs and approval of HDEs in 1990 and although FDA issued final regulations implementing this provision in 1996, CMS has never developed a policy for how these devices are to be covered under the Medicare program. This has allowed for coverage of HDEs to be determined at a local level by regional Medicare contractors, a process that has generally worked well. However, questions and concerns have remained as to how HUDs under HDEs may be covered when these are included in clinical studies and/or when these may be subject to pre- existing National Coverage Determinations (NCDs). These concerns have reduced access to HUDs because providers are unwilling to adopt and use these devices when they are uncertain that coverage will be provided by Medicare. We are particularly eager that CMS articulate a coverage pathway for HDEs under the CRP due to the lack of coverage options available to patients who are candidates for the AbioCor® and who are expected to obtain benefit from the device in the face of the 1986 national non- coverage determination that pre-dates the AbioCor® technology.

Therefore, we were very encouraged when CMS indicated in opening the reconsideration of the CRP that it intended to discuss Medicare policy for the payment of HUD costs. We were further encouraged and very pleased by the discussion and recommendations of the Medicare Evidence Development and Coverage Advisory Committee (MedCAC) at its December 13, 2006 meeting about coverage for HUDs. At that meeting CMS recommended coverage of HUDs as investigational clinical services under the CRP when “The item has been designated by the FDA as an HUD, has received HDE status and is the investigational item or service in a study that meets the requirements of this policy.” (Decision Memo, at 35.)

As noted in the Decision Memo, the MedCAC “discussed HUDs in detail . . . [and] recommended that HUDs with an HDE be covered when they are the investigational item in covered research studies both when the item is noncovered nationally and in all other circumstances.” (Id.) CMS also noted that public comments supported coverage of HUD costs in clinical studies of these devices when they have been granted HDEs.

However, the Decision Memo does not provide for coverage as recommended by CMS to the MedCAC or as recommended by the MedCAC or public commenters. Instead, CMS has proposed not to provide for coverage of HUDs in the CRP and would instead leave coverage of HUDs to follow pathways open to any other device. In addition, CMS stated that it believed the most appropriate coverage of HUDs would be through the Coverage with Evidence Development (CED) process under an NCD. We respectfully disagree with this proposal and urge CMS to articulate clearly the pathways for coverage of HDEs in a final decision memorandum.

The Decision Memo suggests that the coverage pathways for HUDs can fit neatly under established coverage pathways and that no specific policy is needed. However, this is not the case for all HUDs. Some HUDs are furnished under HDEs outside of any specific clinical studies. Other HUDs are furnished solely under clinical studies under IDEs or post-market studies under HDEs. At the same time, some HUDs are subject to NCDs while others are not. We see no reason why the CRP should apply when an HUD is furnished outside a clinical study and we see no reason why well-established HUDs furnished under HDEs outside a clinical study would require coverage only under an NCD following a CED pathway. An important role for the CRP, however, is to establish coverage for an HUD when it is furnished under an FDA- approved HDE in the context of a study that meets the criteria for coverage under the CRP. We would recommend that CMS consider the following scenarios under which HUDs are offered—

This pathway allows for both local and national coverage processes to proceed as they have always proceeded and is fully consistent with Medicare law and coverage policy. Articulating the alternative pathways clearly in a final decision memo under the CRP will provide clarity, predictability and assurance as to under what circumstances, when and how HUDs may be covered. This will facilitate provider determinations about adoption of HUDs and will make coverage clearer for the Medicare contractors.

Providing coverage for HUDs under the pathways identified above will not create incentives to pursue the HUD pathway as an expedited route to coverage because HUD designation and obtaining and HDE are difficult. As noted above, FDA has approved only 41 HDEs in over 10 years and FDA monitors closely to assure that the incidence limitation of the HUD designation is not abused. In addition, coverage would be available under the CRP only for those HDEs that are subject to clinical studies meeting the criteria set forth under the CRP, such as participation in an FDA-approved post-approval study.

IV. FDA-Approved Post Approval Studies

Should be Deemed as Approved Studies for the CRP In the Decision Memo, CMS discusses its recommendation “that in those instances in which FDA has required and approved a post-marketing study that those studies be added to the list of approved studies” (Decision Memo, at 28). CMS indicated that the MedCAC and AHRQ both supported this recommendation. ABIOMED also strongly endorses this recommendation. As described above, ABIOMED has committed to an intensive post-approval study of the AbioCor® device that includes a very limited patient population (25 patients), tight controls (patient advocate, IRB review, anticoagulation consensus, discharge and other protocols) and collection of multiple outcome measures (include health-related quality of life measures). Such a study would appear otherwise to fit under the general and Medicare-specific standards of the CRP as described in the Decision Memo, however, we believe the deemed status as an FDA-approved post-approval study will provide an imprimatur that will facilitate coverage for these devices.

We appreciate the opportunity to provide comments on the Decision Memo for the CRP. We look forward to discussing our recommendations regarding coverage for HUDs and working with CMS toward a viable coverage pathway for patients who may benefit from the AbioCor® device.

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In both cases, it seems that the beneficiary would be responsible for the costs associated with standard care that would otherwise be covered if the beneficiary were not in the study.This could preclude Medicare beneficiaries from participating in research evaluating the safety and efficacy of widely available treatments where the pharmaceutical industry does not stand to benefit directly but for which significant public health concerns remain such as studies involving over the counter medications or dietary supplements. The exclusion of Medicare beneficiaries from these clinical studies appears to run counter to CMS’s stated intent in guidance issued in July 2006 on Coverage with Evidence Development (CED), which states:

“The purpose of CED is to generate data on the utilization and impact of the item or service evaluated in the NCD, so that Medicare can a) document the appropriateness of use of that item or service in Medicare beneficiaries under current coverage; b) consider future changes in coverage for the item or service; c) generate clinical information that will improve the evidence base on which providers base their recommendations to Medicare beneficiaries regarding the item or service

In addition, It is important to note that many institutions require that research investigators submit to the FDA for determination of whether an IND is required or not. To unequivocally state that these research studies have not been reviewed by the FDA is to paint with too broad a brush. Many IND exempt protocols have in fact been reviewed by the FDA; it is the FDA who determined that an IND was not needed. To penalize the research study for a decision made by FDA seems counter to the intent of the proposed decision, that studies should have some degree of federal oversight, when the federal agency did not want to assume oversight. We would not be opposed to requiring all investigator initiated studies involving a drug or biologic to be submitted to the FDA, but concur with the previous public comment that FDA and CMS issue joint guidance in this event.

In the discussion under drug trials that are exempt from having an IND, the decision memo states, “…that studies that are IND exempt meet the other criteria in this policy”. However with the elimination of self certification no other viable alternatives are presented in this policy. In fact the decision memo recognizes this problem and goes on to state that CMS will engage the public in a discussion of various supportable options. In the interim, institutions will have no other option than to inform prospective Medicare subjects that by enrolling in longitudinal research studies conducted without federal funding they will be responsible for the costs associated with their routine care and treatment. This would create the opposite effect of the proposed rule by providing a coersive disincentive to prospective research subjects. The prospect of losing Medicare coverage for standard care will severly limit the willingness of Medicare beneficiaries to participate in studies and thereby limit the generalizability of the results to the Medicare population as a whole. Additionally, the ethical imperative to participate in medical research for societal benefit will be undermined by a loss of benefits that the Medicare beneficiaries would otherwise have, had they not enrolled in the research study.

We would also like to comment on public comments regarding use of Institutional Review Boards (IRB) and the MedCAC recommendation for an alternative procedure to deem a study eligible for Medicare reimbursement. The types of alternatives discussed include establishing reviews at academic health centers or use of university scientific review panels with the caveat that they should include representatives of the patient and provider community. The discussion portion states that IND exempt trials have no external process for ensuring that the standards of this Medicare policy are being met. Yet, the responsibility for ensuring that Medicare specific protocol requirements articulated in this policy are met will most likely fall to each institution’s Institutional Review Board. IRBs functioning under a Federal-wide Assurance are empowered by the federal regulations to review all clinical research and are mandated to enforce federal regulations at the institutional level. This de-centralized system is a federally recognized and codified mechanism for the government to regulate research which occurs outside federal agencies. IRBs review both IND and IND exempt protocols and are required by regulation to include representatives of the community. In addition it is in the interest of human subject protections to ensure that subjects do not inappropriately bear the costs of conducting research. Therefore it would appear to us that any IND exempt protocol which complies with the Medicare standards articulated and approved by an IRB as conforming to those regulations should be considered a “deemed” clinical research study.

It is our opinion that the proposed decision as written will deny Medicare beneficiaries access to clinical research and that potential subjects enrolled in clinical research studies would have to pay for the costs of procedures that would normally be covered outside the context of the research proposal. As a result we respectfully request that CMS clarify the following before a final decision is issued:

Patti Ariel
Chief Compliance Officer
NS-LIJ Health System
200 Community Drive
Great Neck, NY 11021

Cynthia Hahn
Administrator, Research Compliance
The Feinstein Institute for Medical Research
350 Community Drive, 4th floor
Manhasset, NY 11030

Kevin Tracey, MD
Vice President, Research
NS-LIJ Health System
The Feinstein Institute for Medical Research
350 Community Drive, 4th floor
Manhasset, NY 11030

Mt Sinai School of Medicine

Dennis S. Charney, M.D.
Dean, Mount Sinai School of Medicine
Executive Vice President for Academic Affairs, The Mount Sinai Medical Center
Anne and Joel Ehrenkranz Professor
Departments of Psychiatry, Neuroscience, and Pharmacology & Systems Therapeutics
Mount Sinai School of Medicine
One Gustave L. Levy Place, Box 1217
Annenberg Building, Room 2186
New York, NY 10029

Marshall Lieberman, HEM
Director, Research Compliance Program
The Mount Sinai School of Medicine

St. Vincent Catholic Medical Centers

Steven Lascher, DVM, MPHVP, Research and Clinical Trials
Saint Vincent Catholic Medical Centers
170 W.12th Street
Staff House
New York, NY 10011

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Our detailed comments and recommendations to the proposed CRP language are outlined below:

I. Medicare-Specific Standards

1. Therapeutic Intent

Genentech supports CMS’ proposal to clarify therapeutic intent. However, CMS’s proposed language for the first Medicare-specific standard distorts the intent of the recommendations made by the Medicare Evidence Development and Coverage Advisory Committee (MedCAC) and the Agency for Healthcare Research and Quality (AHRQ) and creates confusion because CMS’s proposed language could be interpreted to limit coverage to only those research studies that are studying a chronic, life threatening, or debilitating disease. Accordingly, we recommend that the second sentence of the proposed standard be modified to more closely track the recommendations of MedCAC and AHRQ by deleting the phrase “Research studies, including some” and the words “may” and “only,” so that the proposed standard would read:

The clinical research study is not designed to exclusively test toxicity or disease pathology. Phase I trials, whose protocols commit to measuring therapeutic outcomes as one of the objectives, meet the standard if the disease being studied is chronic, life threatening, or debilitating.

2. Trial Registration

Genentech supports efforts to ensure that information about clinical trials is made available to physicians and potential clinical research participants; however, we also believe it is important to balance the interest in transparency with appropriate regard for the protection of confidential and proprietary information in Phase I clinical trials. We therefore urge CMS to exclude Phase I studies from the requirement to register on Clinicaltrials.gov.

It is not uncommon for a single study to be designed as a combined Phase I/Phase II study, including distinct Phase I and Phase II portions within a single study protocol. If CMS adopts the clinical trial registration requirement for Phase I studies in the CRP, we encourage CMS to revise the standard to provide that in the case of a single combined Phase I/Phase II study, that this standard would be met if the study is registered prior to the enrollment of the first subject in the Phase II portion of the study.

Balancing the need for transparency in clinical trials with industry’s concern of public disclosure of confidential information in early stage trials, we recommend that CMS revise to the trial registration by adding the underlined language as follows:

The research study is registered on the ClinicalTrials.gov website prior to the enrollment of the first study subject. In the case of a single combined Phase I/Phase II research study, this standard would be met if the study is registered on the ClinicalTrials.gov website prior to the enrollment of the first study subject in the Phase II part of the study.

3. Research Study Protocol Requirements

The Proposed Decision imposes several new requirements on the design, development and content of the written research study protocol. The proposed Medicare-specific standards would require that the study protocol (1) specify and fulfill the method and timing of the public release of study results and that the results be published; (2) consider relevant subpopulations; and (3) discuss how the results may benefit the Medicare population.

As we indicated in our comments to CMS dated August 9, 2006 regarding its proposal to revise the existing clinical trial NCD, the FDA—not CMS—is the federal agency principally responsible for regulating the conduct of clinical trials. As such, CMS should not be creating policy related to clinical trial protocol design and conduct and should eliminate these requirements in the Proposed Decision.

In addition, there are a number of practical concerns with CMS’s proposed Medicare-specific standards as these requirements are too vague to be implemented effectively, as currently written. For example, it is not clear what a satisfactory discussion of inclusion criteria would be or what consideration of subpopulations would satisfy CMS’s proposed requirement. It may not feasible to consider relevant subpopulations in Phase I studies and some Phase II studies that involve only a small number of subjects. Similarly, it is not realistic for CMS to expect a statement can be made at the protocol drafting stage regarding how the results of the study can be generalized to the Medicare population. Such analyses are more appropriately conducted following completion of the study.

CMS’s lack of clarity in the details surrounding implementation of the proposed Medicare-specific standards will cause confusion in the clinical trial community and result in inconsistent application of the CRP. Specifically, it is not apparent from the Proposed Decision how clinical trial sponsors, study sites, or Medicare beneficiaries will know when a particular trial has met the CRP criteria and therefore been approved for coverage. As a result, we urge the Agency to provide greater detail on the specifics of the proposed approval process.

Role of Contractors in Reviewing Medicare-Specific Standards

CMS indicates in its Proposed Decision that “CMS will use routine processes to ensure that the Medicare-specific standards and any standards required through the NCD process using CED are met.” It is not clear, however, what CMS means by “routine processes” and how such an approval process will be implemented in a consistent and unbiased manner.

Moreover, under the Proposed Decision, Medicare contractors will be charged with ensuring that these Medicare-specific standards are met. Although Medicare contractors frequently make medical necessity determinations, they are not accustomed nor trained to make assessments regarding research study protocol requirements. As a result, contractors are likely to be inconsistent and vary in their determination of whether a study meets the Medicare-specific standards. Such inconsistency and variation could have a detrimental impact on Medicare beneficiaries’ access to and participation in clinical trials, particularly multi-site studies conducted in different contractor jurisdictions.

If Medicare contractors are going to be held responsible for determining whether Medicare-specific standards are met, at minimum, CMS should issue a standardized checklist for contractors that includes instructions to ensure each contractor’s review is similar. Furthermore, contractors should be required to conduct the review before the first study participant is enrolled so study sponsors, research sites, and Medicare beneficiaries are all aware that a particular trial has been approved for coverage prior to participating in the study.

Health Disparities and Medicare Populations

Genentech agrees with CMS that analysis of relevant subpopulations is appropriate and often critical in conducting clinical research; however, requiring sub-population analyses in all studies eligible for coverage under the CRP is too restrictive, particularly for studies involving a small number of patients or a specific disease where conducting a sub-population analysis may not be feasible. If CMS implements this standard as written, Medicare beneficiaries may be denied access to otherwise appropriate trials.

Release of Study Results

While Genentech supports the publication of study results, regardless of the outcomes, we urge CMS to clarify in the CRP that the public release of study results can occur in any format available to the public, including, but not limited to, public websites, newsletters, or other paper or electronic announcements. Often, the specific nature of the public release of results cannot be described in detail at the protocol design stage because of the many factors that affect where and how the results of a given study will be released. As such, the decision of where to publish study outcomes does not occur until after the completion of the study. As long as a study sponsor indicates in the study protocol that the results will be publicly released, in some format, it should be sufficient for fulfilling this requirement for purposes of the CRP.

Overall, CMS should consider other ways to achieve its objectives and should not condition coverage for clinical trial costs on meeting standards based on protocol design. Instead, CMS should encourage enrollment of Medicare beneficiaries by clarifying the terms of the NCD and removing barriers to participation in clinical trials.

II. Approval Processes

The following comments address CMS’s proposed changes to the options for ensuring that covered trials meet the general standards outlined in the policy—deeming and self-certification.

1. Trials Conducted Under an IND

In the Proposed Decision, CMS adds language to expressly require that coverage of clinical services for Medicare beneficiaries participating in a study conducted under an IND is only effective after the FDA has reviewed the protocol and the “IND has not been put on hold.” The language proposed by CMS is confusing, because FDA may place a clinical study on hold, but it does not place INDs on hold.

A clinical hold is an order issued by FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. The clinical hold may apply to one or more clinical studies covered under an IND. FDA may remove a clinical hold if the sponsor satisfactorily responds to the issue(s) identified in the clinical hold order. At that time, the investigator may resume the conduct of the study. We therefore propose the following revisions to CMS’ suggested language in the Proposed Decision:

The following processes will assure that the standards of scientifically and technically sound clinical research are met and assure that the research is conducted with AHRQ support pursuant to section 1142 of the Act: Studies conducted under an Investigational New Drug (IND) when the FDA has reviewed the protocol and the clinical study is not on clinical hold by the FDA.

2. IND-Exempt Trials

Under the Proposed Decision, IND-exempt studies would no longer be deemed as qualifying trials, and the self-certification process for coverage in connection with non-deemed trials would not be implemented. As a result, Medicare patients would find themselves excluded from many important trials sponsored by academic medical centers and community hospitals, especially in the area of oncology, that are appropriately conducted without an IND. We strongly urge that CMS continue to consider IND-exempt trials as automatically qualified to receive Medicare coverage under the CRP, or alternatively, retain the self-certification process.

Many important studies exploring new uses for marketed products are conducted by investigators who are not required to conduct such trials under an IND and are in fact discouraged by FDA from filing an IND. This is particularly true in the area of oncology.

The U.S. Food and Drug Administration (“FDA”) launched its Reinventing the Regulations of Cancer Drugs initiative in 1996 with the goal of accelerating the approval of cancer therapies and encouraging new uses of marketed products in cancer treatment. As part of that initiative, FDA explained that many sponsors were submitting INDs for trials of marketed products in off-label indications when no such INDs were required, and stated that the agency would no longer accept INDs that were exempt under the applicable regulations. In 2004, FDA issued a guidance document to clarify the circumstances when no IND is required for studies of marketed products in cancer research. FDA noted in that guidance document that oncologists commonly modify labeled dosing recommendations as part of their clinical practice. FDA further stated that off-label use of cancer therapies in the context of clinical trials does not appear to significantly increase risk to patients, and that an investigator could conclude that such a study could be conducted without an IND.

In oncology, IND-exempt trials are part of an established federal regulatory mechanism designed to expedite the approval of cancer therapies and encourage new uses of marketed products in cancer treatment. However, even outside the oncology setting, IND-exempt trials play an important role in exploring new uses for marketed products. The current NCD covers the routine costs of a clinical trial conducted under an IND, even when the study is purely investigational and involves drugs or biologicals that have not been approved by the FDA. It is therefore incongruous that CMS would not extend the same degree of coverage to IND-exempt trials which involve lawfully marketed drug or biological products.

Failure to automatically grant IND-exempt trials “deemed” status would undermine the goals of the Medicare clinical trials NCD. IND-exempt trials represent an important category of clinical trials. In the area of oncology, thousands of cancer patients are enrolled in studies that are not required to be conducted under an IND. If deemed status is not extended to IND-exempt investigations, Medicare beneficiaries will be discouraged from participating in the many valuable clinical trials exploring investigational cancer treatment options using drugs that are already available. CMS must ensure that the new CRP continues to provide coverage for clinical studies that are exempt from the IND regulations.

In the Proposed Decision, CMS expressed its concern that IND-exempt trials lack FDA oversight, and thus there is no external process for ensuring that the CRP standards are being met. However, IND-exempt trials are, in fact, regulated by FDA and subject to oversight by Institutional Review Boards (“IRBs”). A clinical study that is exempt from the requirements of an IND is not exempt from regulatory oversight. In addition to meeting the specific regulatory requirements to be considered exempt from the IND regulations, such studies must be conducted in compliance with IRB and informed consent regulations (set forth at 21 C.F.R. Parts 50 and 56). By definition, IND-exempt trials are generally not intended to support FDA approval of a new indication or a significant change in product labeling. Nonetheless, these IND-exempt trials commonly meet rigorous standards for trial design, data collection and reporting of results in order to pass IRB scrutiny, attract research funding, and qualify for presentation and publication.

In revising the NCD, CMS should focus on providing clarification and eliminating the obstacles to greater participation in clinical trials by Medicare beneficiaries, and not assume the obligations of the FDA in the regulation of clinical trials. CMS should continue to consider all IND-exempt trials as automatically qualified to receive Medicare coverage under the CRP.

3. Health Care Research Center and Cooperative Group Studies

Under the current NCD, clinical trials supported by health care research centers or cooperative groups funded by designated Federal agencies are deemed to qualify for Medicare coverage. However, as the proposed CRP is currently drafted, CMS would impose a new layer of review requirements in order for these studies to meet the general standards for a scientifically and technically sound clinical research study. Under those standards, the federal agencies funding the centers or cooperative groups would have to review and approve the subcontract and sub-grant funding requirements of the centers and cooperative groups and determine that those processes provided the same level of protocol review as provided by the supporting federal agency.

This requirement introduces yet more uncertainty and confusion into the clinical trial coverage policy and would be extremely difficult for clinical trial sites to determine whether it was appropriate to bill clinical study expenses to Medicare. The proposed CRP gives no direction to Federal agencies regarding the nature of the review that would be required or what standards to apply in considering whether protocol review processes are sufficiently the “same” as those of the funding federal agency. Moreover, to the extent that CMS is requiring other agencies to engage in additional review and auditing functions, it is overstepping its authority in this area. More importantly, the study sites seeking to bill Medicare for clinical trial related expenses would not in a position to assess whether these centers and cooperative groups have adequate procedures.

These review requirements create uncertainty and pose an unwarranted hurdle to access to beneficiaries’ participation in clinical research studies. The proposed restrictive review requirements for health care research center and cooperative group studies should be eliminated in the final decision memorandum.

4. Other Options, Including Self-Certification

CMS proposes deletion of the self-certification option in the new policy, yet fails to offer any alternative for approving other types of studies, including IND-exempt studies. This approach would be extremely detrimental to bona fide clinical research efforts and further discourage participation in trials by Medicare beneficiaries.

If CMS elects to exclude non-IND studies from coverage under the CRP, it is critical that it either retains and implements the self-certification process or creates an alternative process that provides a mechanism through which non-IND studies may qualify for coverage under the CRP.

III. Covered Services

1. Coverage of Routine Clinical Services

The Proposed Decision provides a definition of “routine clinical services.” As written, the second bullet (“Only those items and services used for patient management within the study”) could be interpreted as excluding the other bulleted items. For clarity and consistency, we recommend that CMS delete “only those” from the second bullet point such that the bullet point reads “items and services used for patient management within the study.”

2. Coverage of Investigational Clinical Services

In general, Genentech supports CMS’s proposed revision to cover investigational clinical services in Medicare-covered research studies as an appropriate incentive for Medicare beneficiaries to enroll in clinical trials. However, we are concerned that CMS intends to use the proposed provisions outlined in the CRP to fund certain trials with the intent of inappropriately limiting coverage or reimbursement based on the trial results. Specifically, CMS should not use the CRP to limit coverage for items and services currently covered by Medicare outside the context of a research study, nor should it use the CRP as a method for making coverage decisions based solely on comparative effectiveness data gathered under the CRP.

Medicare currently reimburses for drugs and biologicals under Medicare Parts A and B in a range of settings and for a range of uses. For example, Medicare provides coverage for on-label indications as well as off-label indications for cancer therapies when the indication is listed in an approved compendium and for medically accepted uses of other drugs and biologicals at the discretion of each Medicare contractor. CMS should not use the CRP to narrow existing coverage or to require these covered uses to be part of CED or another study subject to the CRP. In sum, Medicare coverage of approved therapies should not change depending on whether the therapy is part of a research study. These therapies must continue to be covered consistent with existing coverage rules when provided as part of a research study that meets the requirements of the CRP.

In order for the CRP to be implemented appropriately and consistently across multiple Carrier jurisdictions, CMS should clarify that when coverage for an item or service is available to any Medicare beneficiary pursuant to local contractor coverage policies, then coverage for that item or service will be available under the CRP. Failure to adopt this approach would require sponsors to seek coverage at the contractor level for each Medicare participant involved in an appropriate study. If an item or service is covered by several local contractors but not covered by others, coverage under the CRP for a particular study would be inconsistent and could create access barriers to Medicare beneficiaries who want to participate in such a study. Clarifying that coverage for investigational items and services is available if coverage is available to any Medicare beneficiary is necessary to facilitate the enrollment of Medicare beneficiaries into research studies.

The primary intent of CMS’s policy on Medicare coverage of clinical trials is that Medicare beneficiaries should not be denied coverage of medically necessary care simply because that care was provided in the context of a clinical trial. Genentech is concerned that CMS intends to use the proposed CRP as a means to restrict coverage for medically necessary items or services based on comparative effectiveness data. As mandated by Section 1013 of the Medicare Prescription Drug, Improvement, and Modernization Act (MMA), CMS is explicitly prohibited from using data obtained from AHRQ’s comparative effectiveness research to withhold coverage of prescription drugs. Therefore, CMS should not use the CRP as a means to obtain this data for use in making coverage determinations.

While it is the appropriate role of government to promote and augment the overall body of evidence available upon which physicians should make treatment decisions, it is inappropriate for government to supplant its decision-making for that of a physician. Using the results of comparative effectiveness research to base Medicare coverage and payment decisions is tantamount to the government making clinical decisions on behalf of physicians. Enforcing CMS preferred treatment decisions through coverage and payment policies not only undermines the physician/patient relationship, it also violates the well-accepted and understood prohibition against federal regulation of the practice of medicine, and could result in denying Medicare beneficiaries access to new and medically appropriate therapies, including those being studied in a clinical research setting.

3. CED

Although CMS has indicated that CED will be used infrequently, Genentech supports the proposed standard that investigational items or services required pursuant to an NCD using CED be covered. We believe this proposal is consistent with the underlying goals of Proposed Decision to promote Medicare beneficiary participation in research studies as well as to further clinical research that benefits the Medicare population.

IV. Conclusion

Genentech appreciates the opportunity to comment on the Proposed Decision. In making its final determination, CMS must avoid making changes to the NCD that create additional confusion about Medicare coverage for clinical studies. Changes to the NCD should seek to expand the opportunities for Medicare beneficiaries to participate in clinical trials by reducing the barriers to participation rather than by enacting vague and impractical new requirements on clinical trial sponsors and sites. We urge CMS to fulfill its commitment to implement policy changes that remove barriers to Medicare beneficiary participation in clinical studies that are exploring new therapies for serious and life-threatening conditions.

Respectfully submitted,

Walter Moore
Vice President, Government Affairs
Genentech, Inc.

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ASH commends CMS on this proposed standard. Phase I trials represent a valid treatment option for patients and are extremely important in cancer research and treatment. The proposed standard is more flexible than the current standard and allows for Phase I trials that include assessment of therapeutic benefit.

ASH believes that the proposed standard is problematic. While ASH agrees that it is important to share outcomes to help expedite knowledge and translational research, the Society strongly believes in the peer review practice to verify the scientific legitimacy of the results before publication. The peer review process is well established and has proven itself as a method for weeding out inappropriate or inaccurate publication of outcomes. However, the timeline for the public release of a study in a peer reviewed journal is difficult to determine because of the peer review process itself. The Society is concerned that if outcomes are released without appropriate vetting through the peer review process, it could lead to disseminating results that could be a source of confusion for many and could potentially lead to inappropriate conclusions.

ASH also recognizes that if the research is not published through a peer reviewed journal, there needs to be an alternative mechanism for the sharing of information. Therefore, the Society suggests that the principal investigator of any clinical study be required to submit a summary paragraph to a site linked to ClinicalTrials.gov. This summary paragraph would include key study elements and intended outcomes such as: the number of patients recruited, the outcomes as defined in the study, whether outcomes reached statistical significance, and a listing of toxicities. Further, a detailed explanation needs to be included in this summary if the study closes without accruing the targeted number of patients.

ASH proposes changing the proposed standard to state that research studies should undergo a peer review process and all data found to be scientifically sound must be made available to the public. The standard should also state that it would only apply to the parent organization in a multi-site trial, rather than each individual site.

This proposed standard is problematic, particularly as there are Medicare beneficiaries younger than age 65 who may be eligible for clinical trials. Additionally, there are studies that are beneficial to the overall population, but for which Medicare beneficiaries are a minority subpopulation. Not every study may be generalizable to the 65-year or older Medicare population, but these types of studies may be very important to the population at large.

ASH believes that a Medicare beneficiary eligible for the study, even though he/she may be in the minority, should not be denied coverage for his/her standard of care items because the study did not meet this proposed standard. Such an example would be a study involving allogeneic hematopoietic stem cell transplantation. Because of the toxicities to older individuals, such a study may be restricted to younger patients who are dual eligible Medicare beneficiaries and younger (ages 65-67) standard Medicare beneficiaries.

ASH proposes amending the proposed standard to allow the researcher to state the reasons why a particular study may not be generalizeable to the entire Medicare population. ASH suggests including adding the following language: “The research study protocol contains a discussion of how the results will generalize to the Medicare population to infer whether Medicare patients may benefit, including those dually eligible, from the intervention.”

**Proposal 6, regarding coverage of routine costs

ASH believes CMS needs to address the definition and arbiter of research-related injury. The lack of a definition and the lack of establishing who is the "definer" presents a major problem in clearly establishing when an event is "research-related" or when it could be from the disease or the standard treatment. The Society believes language should be included to state that that a research-related injury is defined as "something that would not reasonably be expected outside of participation in the study.”

**Proposal 8, regarding investigational costs or services

ASH supports the new proposed circumstances under which investigational clinical services would be covered because it liberalizes the current policy. Medicare providing coverage for services that would otherwise be covered outside of a clinical research study ensures that all Medicare beneficiaries are treated equally in terms of coverage, regardless of whether they are enrolled in a clinical research study.

**Proposal 9, regarding clarification of the processes that ensure Medicare-specific standards and general standards for a scientifically and technically sound clinical research study are met

ASH agrees that it is important to ensure that general standards for scientifically and technically sound clinical research are met, and applauds the delegation of that authority to several appropriate bodies. ASH would like CMS to clarify whether trials approved through an institution’s NIH Clinical Translational Science Awards (CTSA) Program would apply to this standard. ASH would encourage the inclusion of the CTSA administration as an approval body.

**Proposal 10, regarding deeming and self-certification for qualifying clinical trials

This proposal raises several concerns and questions. First, the Society is concerned with the removal of the self-certification process in the proposed revised policy. ASH believes there is value to Medicare beneficiaries in currently non-qualified trials (such as IND-exempt studies) and that forgoing standard of care benefits to enroll in a clinical trial would be a disincentive for patients to enroll in these trials. Further, disincentives for initiation of and enrollment in these studies as a result of not meeting Medicare standards may slow down the pace of clinical research.

Second, ASH is concerned with the CMS proposal to remove IND-exempt studies. We note that many IND-exempt trials involve new combinations of drugs or new uses of drugs that may be of direct benefit to the Medicare population. We believe that the exclusion of most IND-exempt studies from Medicare payment would be an impediment to much useful research. ASH recommends developing criteria for self certification which include establishing local Protocol Review Committees whose membership would consist of clinical investigators, biostatisticians and basic scientists. The review process would determine if the study met the criteria of both the “General Standards for a Scientifically and Technically Sound Research Study” and the “Medicare-Specific Standards.” ASH supports this idea as an alternative to the elimination of most IND-exempt studies from Medicare coverage and would be pleased to work with CMS and others to implement it.

**Other Proposal adding Exclusions Language

ASH is also seeking clarification regarding one of the exclusion criteria in the proposed revision stating that “Prospective studies in which natural human behavior is observed in a way that does not intentionally or unintentionally change or potentially change the behavior of patients, physicians and other clinical staff, control subjects, healthy volunteers, or caretakers; in which there is no assigned or pre-specified intervention that intentionally or unintentionally changes or potentially changes the behavior of patients, physicians and other clinical staff, control subjects, healthy volunteers, or caretakers; and in which there is no assigned or pre-specified intervention that changes or potentially changes medical care, medical decision-making or any medical treatments.” In this exclusion definition, ASH would like guidance from CMS to define what an “intervention” means. For example, we would like clarification that randomization of patients into two different treatments arms, both accepted as reasonable standard of care, would not be considered an intervention. ASH proposes that all types of studies that do not alter patient management or health outcomes should be excluded from adherence to the standards outlined in the CRP. ASH proposes defining an ‘intervention’ to be something that changes the clinical management of the patient as a result of the research study.

**Additional Issues

ASH understands that all studies initiated before the effective date of the revised policy will be not required to adhere to the revised standards. Because protocols and budgets would have been written assuming the current policy, ASH also recommends that CMS give grandfathering consideration for trials submitted to an agency before the effective date, but not awarded until after the date to avoid unnecessary confusion and administrative burden in adhering to the revised policy.

Thank you for your attention to our comments on the proposed revisions to the CRP.

Sincerely,

Andrew I. Schafer, MD
President

Samuel Silver, MD, PhD
Chair, ASH Reimbursement Subcommittee
Councilor, ASH Executive Committee

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UMHS commends CMS on the expanded flexibility regarding the types of trials eligible for coverage and the position that an objective stated in the protocol needs to measure a therapeutic outcome. This more flexible language may allow for certain Phase I studies to qualify for Medicare coverage.

UMHS understands and supports the CMS goal of reporting both positive and negative results, agreeing that both can be valuable to the medical decision making process when properly presented and vetted. Further, UMHS supports the transparency and sharing of outcomes among institutions and researchers in order to help expedite knowledge and translational research. However, we caution that disseminating incomplete, insignificant or inaccurate outcomes data can result in confusion for many and potentially lead to abuse and inappropriate conclusions being drawn from the outcomes. UMHS believes in the peer review practice to verify the scientific legitimacy of the results before publication or other public presentation. The peer review process is well established and has proven itself as a method of weeding out inappropriate or inaccurate data thus preventing inappropriate publication of outcomes.

UMHS proposes deletion of the “fulfill” requirement of the standard and changing the standard to state that the study protocol specifies that research study results/outcomes should undergo a peer review process and all data, including negative data, found to be scientifically sound will be made available to the public. In the context of multi-site trials, the standard should also state that it would apply only to statistically valid aggregated multi-site data, rather than data for each individual site.

Additionally, the obligation to “fulfill” method and timing of public release presents a variety of challenges beyond the control of the billing institution:

o Publication in peer review journals is ultimately controlled by third parties. The process is variable and it is difficult to predict the timing and certainty of public release. UMHS supports an alternative to Peer Review Publication, but only with certain controls on the alternative mechanism as identified below:
-Pre-specified outcomes data are made available to other researchers as appropriate and necessary.
-Not all research studies are amenable to simple release of pre-specified outcomes data. UMHS proposes that the content should include a summary paragraph that addresses the key study elements and outcomes such as: the number of patients recruited to the study, the outcomes as defined in the study, whether these outcomes reached statistical significance and a listing of toxicities. If the study closes without accruing the targeted number of patients, a detailed explanation should be included in the content of the summary.
o Agreements with Sponsors of industry-sponsored trials typically dictate the method and timing of the release of results. Not all study sites have the leverage to define how to “fulfill” the method and timing of public release.
o An institution participating in a multi-site trial may not always have control of the data and outcomes of the entire study. The timing and release of results must occur in a coordinated manner for these multi-site trials.

There are studies that are beneficial to the overall population, however Medicare beneficiaries may be the minority subject population in the particular study. Not every study may be generalizable to the entire Medicare population, however these types of studies may be very important to the population at large and subsets of Medicare beneficiaries. UMHS proposes amending the standard to state that “the study must not specifically exclude Medicare beneficiaries.” Additionally, the standard should be clarified to indicate that if a particular study is not generalizable to the entire Medicare population, the reasons must be stated.

Proposal 9, regarding Clarification of the Processes that ensure Medicare-specific standards and general standards for a scientifically and technically sound clinical research study are met.

UMHS would like to comment on the approval process outlined below:

UMHS agrees that it is important to ensure that general standards for scientifically and technically sound clinical research are met, and applauds the delegation of that authority to several appropriate bodies. UMHS assumes that CMS would agree that an institution’s NIH Clinical Translational Science Awards (CTSA) body would meet this standard and receive delegated authority for approval of studies. Furthermore, UMHS proposes that funding of a health care research center or cooperative health care research group provided by a federal agency should implicitly provide the necessary approval of the protocol review process.

Furthermore, UMHS strongly agrees and supports a proposal similar to the Medicare Evidence Development and Coverage Advisory Committee’s (MedCAC) recommendation to consider entities such as “professional societies, private foundations, academic health centers and university scientific review panels” as entities with delegated approval authority for IND-Exempt studies. We believe that these entities outlined above by MedCAC should be extended as approval bodies for all studies, and not limited only to IND-exempt studies.

Proposal 10, regarding Removal of Self-Certification and IND-Exempt Studies for ‘Deeming’ studies.

UMHS is concerned with both the proposed removal of the self-certification process and the removal of IND-Exempt studies from their current ‘deemed’ status.

UMHS remains concerned with the removal of the self-certification process in the proposed revised policy because it omits valuable studies that have no other approval mechanism and can have benefit to Medicare beneficiaries. Furthermore, the advancement of medicine and the clinical research enterprise rely on studies that often begin as small investigator-initiated studies that lead to larger federally funded grants. We are concerned that the disincentives for initiation and enrollment of these studies as a result of CMS deciding that these studies do not meet Medicare standards may slow down the pace of clinical research enterprise nationally.

UMHS has reviewed comments submitted by the American Society of Clinical Oncology and supports their comments and recommendations regarding the removal of IND-Exempt studies.

Other Proposal adding Exclusions Language

UMHS would like to comment on the proposed exclusions to the CRP outlined below:

“Prospective studies in which natural human behavior is observed in a way that does not intentionally or unintentionally change or potentially change the behavior of patients, physicians and other clinical staff, control subjects, healthy volunteers, or caretakers; in which there is no assigned or pre-specified intervention that intentionally or unintentionally changes or potentially changes the behavior of patients, physicians and other clinical staff, control subjects, healthy volunteers, or caretakers; and in which there is no assigned or pre-specified intervention that changes or potentially changes medical care, medical decision-making or any medical treatments.”

UMHS would like guidance from CMS to define what an “intervention” means. For example, we would like clarification that randomization of patients into two different treatments arms, both accepted as reasonable standard of care, would not be considered an intervention. Similarly, data collection that involves the addition of a diagnostic investigational clinical service (such as a research MRI, which would not be billed to Medicare) following routine care treatment but not influencing patient management or health outcomes, would not be an intervention so that the routine care provided prior to the investigational diagnostic service would remain a covered benefit. UMHS proposes that all types of studies that do not alter patient management or health outcomes should be excluded from adherence to the standards outlined in the CRP. UMHS proposes defining an ‘intervention’ to be something that changes the clinical management of the patient as a result of the research study.

Effective Date and Grandfathering

UMHS understands that all studies initiated before the effective date of the revised policy will be not required to adhere to the revised standards. UMHS would like consideration for trials submitted to an agency before the effective date, but not awarded until after the date. The protocol and budget would have been written assuming the current policy, therefore requiring adherence to the revised policy would be administratively burdensome, causing unnecessary confusion and rework.

In addition, we identified a few areas of concern that were not addressed in the revised policy. Specifically, these relate to the Medicare Secondary Payer rules and the compassionate use of drugs that we understand are out of scope for this particular NCD. However, we are looking forward to further guidance from CMS regarding these outstanding concerns.

Thank you for the opportunity to comment on the proposed revisions. We hope you consider our input in the final version of the CRP.

Sincerely,

The UMHS Clinical Research Billing Lead Team

Deborah Biggs
Chair, Clinical Research Billing Lead Team
Director of Business and Regulatory Affairs
Chief Compliance Officer
University of Michigan Medical School

Constance Bridges
Director of Administration for Research and Graduate Studies
University of Michigan Medical School

Elaine Brock
Associate Director, Division of Research Administration and Development
University of Michigan

Thomas Daly
Contract Officer
UMHS Contracting and Business Development

Benjie Johnson
Director of Professional Fee Billing
Faculty Group Practice, University of Michigan Medical School

Susan Livingston
Director of UMH Billing and Third Party Collections
University of Michigan Hospitals and Health Centers

Raymond Hutchinson, M.D.
Associate Dean, Research and Regulatory Affairs
University of Michigan Medical School

Dorene Markel
Director of Clinical and Translational Research
Managing Director, Michigan Institute for Clinical and Health Research
University of Michigan Medical School

Thomas Marks
Senior Director of Finance, Revenue Cycle
University of Michigan Hospitals and Health Centers

Kristin Scarcella
Director of Faculty Group Practice Operations
Faculty Group Practice, University of Michigan Medical School

Samuel Silver, M.D., Ph.D.
Professor, Internal Medicine
Assistant Medical Director,Faculty Group Practice, University of Michigan Medical School

Jeanne Strickland
Chief Compliance Officer
University of Michigan Health System and
University of Michigan Hospitals and Health Centers

Julie Wietzke
Manager of Clinical Research Billing Unit
University of Michigan Medical School

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The existing Medicare language was written with the intent to exclude Phase I and most Phase II trials from eligibility for coverage of routine clinical services provided within these studies. The new language dissolves this important boundary and would give strong incentives to manufacturers and developers to frame their earliest research as measuring a “therapeutic outcome.” Under the proposed language the measurement of even a single therapeutic outcome could be construed as qualifying a Phase I trial for coverage of its clinical costs. The act of measuring a therapeutic outcome, however, should not be allowed to obscure the fact that Phase I and most Phase II trials are primarily intended to answer basic toxicity and dosing questions. Investigators and patients should be aware that such early studies pose risks and may lack any significant therapeutic intent. The proposed new language would present a substantial risk of inappropriate confusion over this key distinction.

AHIP is very concerned that the proposed new language would lead to a significant shift in the costs of drug, device, biologic, and procedure development to public and private insurers. Since many, if not most, interventions undergoing Phase I and Phase II trials do not ultimately prove clinical benefit compared to existing alternatives, it is inappropriate to shift the costs for this research away from developers. A formal cost analysis of the budgetary impact on Medicare expenses should be performed by CMS and provided for public discussion before any change to this section of the existing policy is contemplated. AHIP believes that state regulators will follow any CMS mandates for coverage of early phase research and thus the economic impact will extend into the private sector, adding to increases on health care premiums for all privately insured Americans.

Suggested Alternative to Proposed Language

Despite our concerns expressed above, AHIP believes that CMS can maintain the important distinction between early phase research and research of more direct potential benefit to patients while broadening the scope of clinical research studies considered for coverage of routine clinical services. We recommend the following language for this section of “Medicare-specific standards”:

“The clinical research study is not designed primarily to test toxicity or disease pathophysiology. Phase I trials are thus ineligible. Phase II and other research studies may meet these standards if they fulfill all of the following criteria:

1)The study has a predominant intent of measuring meaningful differences in outcomes of clinical significance to the patients involved.

2)Protocols commit to measuring therapeutic outcomes as a primary objective.

3)Protocols include power calculations that demonstrate that the study will be able to measure with statistical precision meaningful differences in therapeutic outcomes."

Thank you for the opportunity to comment on these important issues.

Sincerely,
Carmella Bocchino, MBA, RN
Executive Vice President, Clinical Affairs & Strategic Planning

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I. Drug Trials that Are Exempt From Having an IND.

CMS’s proposal to remove this category of “deemed” trials with limited discussion despite unanimous comments to the contrary is very troublesome, as is CMS’s failure to address concerns raised about the impact of the policy change upon innovation. This recommendation deserves significantly more extensive consideration and discussion than the three sentences afforded to it in the Proposed Decision Memorandum.

In 2000, CMS approved coverage of IND-exempt trials pending the creation by CMS of a self-certification process, which was never developed. The Medicare Evidence Development & Coverage Advisory Committee (MedCaC), while recommending deleting the deemed status of these trials, also urged “developing another process for reviewing and approving these trials.” However, CMS rejected this approach, as well as any recommendation by MedCaC and others that certain entities such as “professional societies, private foundations, academic health center, and university scientific review panels” might be appropriately qualified to “deem” research studies. CMS’s rejection of these suggestions appears to be based on the premise that only federal agencies, or federally-funded centers or groups can judge whether a trial is “conducted under scientifically and technically sound principles” to justify Medicare coverage. However, we believe that a number of organizations are in a position to fulfill this important responsibility in a rigorous fashion should CMS elect not to provide such a function internally.

A. A Federally-Mandated External Process Currently Exists to Assess Whether IND-Exempt Studies Satisfy Scientifically and Technically Sound Principles

CMS’s concern about a lack of an available external process to review non-federally funded, IND-exempt studies for scientific merit is based on the premise that because the Food and Drug Administration (FDA) and other federal agencies do not oversee trials, there is no way to “ensur[e] that the standards of this Medicare policy are met.” CMS’s assertion that only the FDA, or other federal agencies, or federally-funded centers and cooperative groups can sufficiently assess compliance with the requirements of the Clinical Research Policy is puzzling given that these organizations’ primary role with respect to these studies is to ensure that they have sufficient scientific merit. In fact, these agencies are not in a unique position to provide external reviews of research studies for scientific merit. An Institutional Review Board (IRB) is a time-honored, federally-mandated impartial review mechanism which provides the same, if not higher level of scrutiny of the scientific and technical principles of all studies.

The IRB at Partners, as at other academic institutions performing clinical research, is specifically charged with the responsibility to determine the scientific merit of clinical research studies as part of its obligation to protect human subjects. This oversight has long been recognized and encouraged by the FDA for IND-Exempt clinical trials. No study is approved by the IRB without a thorough review of the scientific principles of the study. To do so would place research subjects at unnecessary and unethical risk. Therefore, it follows that if the IRB, an impartial federally-required review mechanism, finds that a study is based upon scientifically and technically sound principles to justify the risk involved in relation to the potential benefit to the subjects, then Medicare should join FDA in recognizing that review as sufficient to fulfill the obligations for justification of Medicare coverage.

B. Removing Coverage for All Non-Federally Funded IND-Exempt Studies is Inconsistent with CMS’s General Standards and Will Stifle the Development of Innovative Care

One of the General Standards required by both the 2000 Clinical Trial Policy and the Proposed Decision Memorandum is that the study must be “well-supported by available scientific and medical information or it is intended to clarify or establish health outcomes of interventions already in common clinical use.” Many IND-exempt trials involve investigator-initiated research projects studying the impact of clinical interventions through the off-label use of FDA approved drugs. In fact, in some cases, the off-label uses of these drugs have become so common that they are listed in the U.S. Pharmacopeia. These represent trials for which pharmaceutical companies may provide the study drug free-of-charge, but have no immediate intent to sponsor a full-scale multi-site effort to seek FDA approval for the off-label use. As a result, the company will not pursue or agree to allow an investigator to pursue an IND application with the FDA.

While a pharmaceutical company’s reluctance to study certain trials through the IND process may be related to scientific factors, often the failure to pursue such action is primarily due to lack of perceived commercial opportunity. These studies commonly involve off-label uses of FDA-approved drugs, which, as generally IND-Exempt, would not qualify for coverage under the proposed Clinical Research Policy or medications whose patent protection has expired. Yet, they are important, medically innovative studies. Oftentimes they study novel indications of less common diseases, and/or involve such small populations that the pharmaceutical industry will not undergo the rigorous and costly IND drug approval process. For example, statin drugs are increasingly used to test their anti-inflammatory/anti-infective properties in various chronic diseases like diabetes or osteoporosis, especially as these drugs go “off patent” and there is no longer a financial incentive for pharmaceutical sponsors to pursue new or expanded indications. Such studies help us demonstrate where additional benefits of these drugs may be found, preventing costly complications of these chronic diseases.

Routine clinical services provided to Medicare beneficiaries who participate in these studies are billed to CMS, while the Partners’ institutions or sponsors pay for the costs of any investigational items or services. If CMS removes coverage for non-federally funded IND-Exempt trials, providers will exclude CMS beneficiaries from scientifically meritorious research studies that could provide effective treatment and inform future coverage decisions solely because the trials were initiated by investigators without federal funding or pharmaceutical sponsor support. This is particularly troublesome because in many cases, the costs of providing routine clinical services to treating the patients through the off-label use of approved drugs would be covered by Medicare. Thus this policy is antithetical to societal interest in identifying effective interventions for improving the treatment and prevention of disease among it citizenry.

This is best illustrated with examples which address questions of important unmet medical needs: (i) A study which evaluates the use of Bactrim in addition to a standard antibiotic to treat cellulits, which is increasingly known to be caused by methicillin resistant Staphylococcus aureus, involves a well known FDA approved drug administered by the standard route, in a standard dose, to a population in which the drug has been tested for other indications. Yet, this would not be covered by CMS under the new Clinical Research Policy. (ii) A study which evaluates one of two standard FDA approved blood pressure medications would also not be covered by CMS under the new Clinical Research Policy.

The potential long-term result is of even more concern. Partners’ experience has been that most third party payers generally follow CMS’s lead in deciding whether to pay for routine clinical services in trials. While CMS is certainly not responsible for other third party payers’ coverage decisions, it should be aware insurers will likely adopt CMS’s position with respect to these trials magnifying the negative impact on investigator-initiated clinical research studies. The availability of research studies to Medicare beneficiaries, and ultimately to the general public, will become dependent upon whether the studies are funded by a federal or pharmaceutical company sponsor, and as federal funding for research continues to decline, responsibility for the development of innovative care through clinical research will shift from the medical providers to the pharmaceutical industry and its interests.

C. Recommendation.

Partners strongly urges CMS to remove IND-exempt research studies from the list of “deemed” trials. Barring that decision, we urge CMS to postpone implementation of this policy position and engage the academic research community in a thorough discussion about the importance of such trials to the development of innovative care. Partners would welcome the opportunity to participate in any such discussion and proposal review process.

II. Requirement of a Written Protocol

Partners strongly agrees with CMS’s statement that “[i]t is impossible to evaluate the adequacy of trial design without a written protocol…” and appreciates the fact that CMS intends to leave the content of the protocol to the providers. However, Partners believes clarification is needed. Many IRB applications are referred to as “protocols.” The IRB application/protocol serves as the primary source of knowledge of the proposed study design and includes a detailed plan for study management. CMS should clarify that such a protocol in the form of an IRB application would satisfy its requirement for a written protocol under the new Clinical Research Policy. Cutting and pasting the same information into a separate document simply to comply with the strict interpretation of this rule would be redundant and unnecessarily burdensome.

III. Registration of Studies with ClinicalTrials.Gov

As you are aware, the International Committee of Medical Journal Editors (ICMJE) has required registration of clinical trials on ClinicalTrials.gov since July 2005. Partners currently registers trials consistent with the ICMJE’s Statement on this issue. However, CMS should be aware that (i) the ICMJE’s Statement does not require the registration of Phase I, and some Phase II studies, and (ii) the obligation to register a trial under the ICMJE’s Statement does not always rest with the provider. In trials involving an IND, the obligation to register rests with the IND-sponsor, usually the pharmaceutical company. Oftentimes, academic health centers and investigators are not notified when such registration has been completed. This may place providers at risk to the extent that registration prior to enrollment is strictly required by the CMS Clinical Research Policy. Partners recommends that the CMS Clinical Research Policy requirement on this topic mirror the requirements of ICMJE’s Statement to avoid conflicting requirements. Further, to the extent that academic health centers and investigators rely in good faith upon an IND-sponsor’s representation that registration of the trial will occur and it does not for reasons beyond the providers’ control, an exception should be created if they can demonstrate that the IND-sponsor represented that it would register the trial.

IV. Health Disparities

Partners commends CMS’s efforts to ensure that all subpopulations are appropriately included in clinical research studies, but seek clarification on one point. FDA and the National Institutes of Health (NIH) are currently attempting to reconcile and unify their policies on many clinical trials requirements in order to minimize the confusion to research communities caused by conflicting operating definitions and policy requirements. NIH already requires that institutions ensure that certain subpopulations are afforded access to clinical research studies. Partners strongly encourages CMS to adopt a policy that is consistent with NIH’s current requirement, and join with FDA and NIH to explore a uniform approach to this issue.

Further, in the discussion section of CMS’s Decision Memorandum in this area, CMS stated that if “convincing evidence” existed to indicate that there are no differences between identified subpopulations, that information should be noted in the protocol in place of a specific analysis of the impact of the research upon subpopulations. Partners recommends that CMS clarifies what “convincing evidence” might involve to assist in preparing for anticipated Medicare audits in this category.

V. Medicare Populations

Partners also appreciates CMS’s efforts to ensure that the results of clinical research studies will generalize to the Medicare population. Partners recommends that the second sentence of this Medicare-specific standard be deleted. Despite changes in the language CMS originally considered, it still implies that the design of any research study include statistically significant numbers of Medicare beneficiaries. As MedCAC and other commenters noted, strict adherence to this requirement could impact the scientific validity of a clinical research study, particularly if it becomes difficult to enroll the specified number of Medicare beneficiaries. While investigators should use their best efforts to enroll Medicare beneficiaries into clinical research studies, failure to reach statistically identified numbers of such beneficiaries will not prohibit the ability to generalize the results to the Medicare population, and coverage for routine clinical services provided to the Medicare beneficiaries who participate should not be withheld.

VI. Effective Date

The Effective Date of the new Clinical Research Policy is July 10, 2007. This is an extremely tight timeline by which to revise all protocols, informed consent documents, and study budgets to comply with the requirements of the new law. Partners recommends that the effective date be revised to include all clinical research studies initiated one hundred eighty (180) days after the publication of the final Clinical Research Policy. This would not only grandfather existing studies that have been designed and budgeted consistent with the 2000 Clinical Trial Policy, but also allow institutions time to review, redesign, and implement internal administrative processes to ensure that all studies meet the General and Medicare-Specific Standards set forth in the new Clinical Research Policy. The administrative burden of conducting Medicare coverage analyses, budgeting, contracting, regulatory review, and trial registration is substantial. Even an organization of Partners’ resources will find one hundred eighty (180) days an extremely challenging deadline by which to revise its existing process, and create the new processes and controls that this new Clinical Research Policy will ultimately require.

Thank you for the opportunity to comment upon CMS’s Proposed Clinical Research Policy. My colleagues and I would welcome the opportunity for further discussion of these comments and concerns and if helpful, hope you will not hesitate to contact me.

Very truly yours,

Daniel K. Podolsky, M.D.
Chief Academic Officer
Partners HealthCare System, Inc.

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Further detail on each of these issues is provided below: Language and DefinitionsWe appreciate that the new CRP attempts to clarify terminology that has created unnecessary confusion. However, we still find the document to be fraught with vagueness and contradiction that needs to be addressed, particularly with regard to standards for a good clinical trial and the Medicare specific standards.

Clinical research
There is considerable confusion about why the CMS definition of clinical research differs from that already in use by the Food and Drug Administration (FDA) and the U.S. Department of Health and Human Services (HHS). How does the CMS definition now relate to other existing definitions which determine the standards for clinical trials?

Establishing a definition of clinical research, while laudable, serves as an example of the imperative for CMS to work with other federal agencies that sponsor research to promulgate and use uniform, standard definitions.

A CMS definition for research may be unnecessary. Such a definition risks excluding important research studies that do not fall within the definition and thereby may not be covered by the CRP. By falling outside the definition of clinical research, coverage of the items and services of such studies would be jeopardized. Rather than imposing a detailed definition of clinical research, we suggest that CMS state that the CRP addresses clinical research studies that are reviewed and approved by an Institutional Review Board (IRB). This would be more in keeping with CMS’s goal to cover studies that meet the applicable standards but not confine covered studies to “clinical trials.” We are concerned that adding a definition of clinical research may continue to sow confusion, create inconsistencies with definitions of clinical research from other federal agencies, and may inadvertently restrict coverage.

Alternatively, we believe CMS should stipulate that research meeting the definitions of research under 45 CFR Part 46 and 21 CFR Parts 50,56 and satisfying the criteria for "deemed" approval under the CMS policy will meet the definition of research under the CMS policy.

General Standards
In meeting the general standards for a scientifically and technically sound clinical research study as outlined on page 33, the AAHC recommends that the standard requiring that “All research studies have a written protocol” be amended to read: “All research studies have a written protocol that clearly addresses, or incorporates by reference, both the general and Medicare-specific standards.” Without this revision, adding the standard for a written protocol is superfluous and redundant since all deemed studies already require a written protocol under non-CMS federal regulations.

Medicare Specific Standards
Therapeutic Intent
CMS has proposed: “The clinical research study is not designed to exclusively test toxicity or disease pathophysiology. Research studies, including some Phase I trials, whose protocols commit to measuring therapeutic outcomes as one of the objectives, may meet this standard only if the disease being studied is chronic, life threatening, or debilitating.”

We appreciate the clarification of therapeutic intent, which now takes account of some Phase I trials that previously did not fall within Medicare’s definition. However, the definition may still not permit coverage of some Phase I trials of diseases that are not chronic, life threatening, or debilitating, but still pose substantial public health risks, particularly to elderly populations (e.g., treatments for non-life-threatening respiratory illnesses). In addition, it is still not entirely clear whether all Phase I trials are considered as having met the therapeutic intent requirement.

The AAHC recommends that CMS make perfectly clear whether Phase I cancer trials are considered as meeting the therapeutic intent requirement and whether they are covered or not covered under this policy. In addition, the wording should be changed to say that a Phase I study may meet this standard if it studies “acute conditions that pose substantial public health risks or diseases that are chronic, life threatening, or debilitating.” In this way, trials that study conditions which include infectious diseases and make significant contributions to science and the health of Medicare beneficiaries will not be eliminated from coverage.

Alternatively, if CMS does not add “acute conditions” to this standard, we suggest that CMS adopt a definition of “chronic, life threatening, or debilitating” consistent with current definitions of these terms from the FDA and the National Institutes of Health. Registering Trials and Transition ProvisionsOne of the Medicare-specific standards proposed requires that the research study be registered on the ClinicalTrials.gov website prior to the enrollment of the first study subject. This requirement raises questions about the transition provisions for implementing this policy with regard to trials that are underway at the time the policy becomes effective. Such provisions are not addressed and are greatly needed.

The AAHC recommends that all research studies which are qualifying clinical trials under the current Clinical Trials Policy (CTP) and in which subjects have been enrolled, be conducted according to the CTP until completion of the studies. This will waive requirements for registration on the website, as well as all other new standards of the CRP. Any standards that require look-backs or the need to redesign elements of the protocol or reenrollment of subjects would necessarily entail suspension of all research activity with respect to Medicare beneficiaries and re-consenting all participants. This could endanger patients, would be onerous, burdensome, and harmful to a significant segment of the research enterprise, as well as Medicare patients searching for new treatments and cures for illness and disease. In the worst case scenario, Medicare beneficiaries currently enrolled in clinical trials would have to pay for all trial-related care or be dropped from the trials. Neither option will benefit the patients.

The AAHC also notes that this requirement does not address trials that are conducted at multiple sites. In such cases, would each site have to register the research study? What is the process for ensuring registration? The AAHC urges CMS to provide direction on registration with regard to multi-site studies. The AAHC recommends that the provision be amended to ensure that as long as one site has posted the research study or if the sponsor has registered the trial, then the research study should be considered to have met this Medicare-specific standard.

Public release of pre-specified outcomesThe AAHC supports efforts to ensure unbiased recording of research and public dissemination of health outcomes that advance clinical awareness of new and innovative therapies. However, requiring that the outcomes of Medicare-covered research studies be publicly released may prevent beneficiaries from receiving coverage for reasonable and necessary treatment during a research study if the individual health care provider does not have control over decisions about public release of results or the timing of such a release.

In addition, the proposed policy does not make clear what is considered “fulfillment” of plans for public release of health outcomes. Often, sponsors are responsible for releasing results, which may or may not be posted on a sponsor’s website. Results may also be released through publication in peer reviewed journals; the timing of such publications is not within the researcher’s control and not all studies are published. Given that publication of a study’s results can rarely be supervised by a research site and that no central repository for such information currently exists, the AAHC recommends that this fulfillment standard be deleted.

Generalizing the results to the Medicare population
The AAHC understands the desire to determine the impact of age-specific and other factors on research outcomes and the importance of knowing as much as possible about the benefits of studies for Medicare beneficiaries. However, the AAHC must point out that there is no clear sense of how to determine what threshold CMS is seeking when it requests that the research protocol describe “whether the research study is powered sufficiently” to draw conclusions with respect to the Medicare population. We recommend that this terminology be deleted given that it can only create confusion for all concerned. The AAHC requests the use of simple, direct, and unambiguous language in this and all other standards.

The AAHC would recommend that CMS state precisely whether it desires the research study to be designed to provide results that can be generalized to the principal Medicare population (persons 65 years or older) or whether it is sufficient to have a general discussion in the protocol that identifies whetherthe study does or does not hope to seek conclusions about the Medicare population.

The AAHC recommends adding a statement that the protocol include a brief discussion of benefits to Medicare beneficiaries when such benefits are known or can reasonably be expected. We strongly encourage a study in which the design may not be tailored to reach specific conclusions about the Medicare population not have its coverage jeopardized.

Routine clinical services
The AAHC is very pleased the term routine clinical services has replaced the ambiguous and confusing term, routine costs, in the new policy.

Approval Process
The processes for meeting the general standards are described in an ambiguous and unclear manner. The term “approval process” likely is part of this confusion. It appears that the term “approval process” merely refers to CMS having deemed certain types of research studies to meet the general standards, because the research studies have been through an “approval process” that would assure CMS that the research study meets the general standards. While this is understandable from a policy perspective, the term “approval process” is misleading.

Rather than highlighting the “approval process” that the deemed studies have been subjected to, the AAHC suggests that CMS merely refer to the studies that have been through acceptable approval processes as “deemed studies.” This is a term with which the industry is familiar. To the extent that the general standards are designed to replace the “highly desirable characteristics,” this would minimize re-educating the industry on this new term, given that the current term—deemed—is sufficient and still used within the proposed CRP.

The AAHC also recommends that CMS establish a certification process to inform investigators, providers, and sponsors that “health care research centers or cooperative health care research groups” funded by HHS, the Veterans Administration, or the Department of Defense have met all regulation requirements. The AAHC suggests that CMS post a list or create a registry of organizations that meet all the CRP criteria as a funded “health care research center or cooperative health care research group.”

Another ambiguity which should be clarified in the CRP is the posture assumed by CMS and the Agency for Healthcare Research and Quality (AHRQ) related to deemed studies under the policy. In the past, CMS has acted in the role of third-party payor with respect to routine clinical services provided in the context of a clinical trial. The proposed CRP's new requirements reflect obligations heretofore reserved for the role of a sponsor of research. Indeed, the terminology used in the proposed policy "conducted or supported by" is the very definition of sponsored research. Thus, we would like some clarity before implementation of this policy given the questions that emerge at this time. Is CMS and/or AHRQ acting as a sponsor of research under this policy? If so, the AAHC recommends that these agencies clearly adopt and develop the regulatory infrastructure mandated by HHS regulations, which, for example, include receipt of reports of unanticipated problems and adverse events related to human subjects. If this is not clarified, we fear that CMS and AHRQ will receive and/or be overwhelmed by such reports.

Exceptions
CMS states that should the agency find that a study no longer qualifies for coverage, Medicare payment would be denied under 1862(a)(1)(E) of the Social Security Act. Again, this situation raises critical questions about the transition period, how currently open studies would be handled, and how this process (and others) would unfold. The AAHC requests that clear and detailed guidance and clarification be given on this issue.

Furthermore, this provision is critically important for the requirement to publish results of the study. Generally, billing to CMS for services by health care providers is contemporaneous with delivery of service. If the condition for publication of results will not be fulfilled for several years after the time of service, then the billing provider becomes at risk for return of all CMS payments related to the trial and possibly allegations of fraud. Waiting to bill CMS for services until the trial is completed will lead to stale claims that are not allowable. In the current health care climate, providers may likely chose to forego research activity altogether rather than assume a risk out of their control.

IND-exempt clinical trials
The majority of IND-exempt studies are investigator-initiated studies that take place in academic health centers. Most of these studies would not qualify for coverage under the proposed CRP. Excluding such trials, which may be directed at new combinations or uses of approved drugs and often involve new scientists and physicians, would be highly detrimental to the U.S. research establishment. If CMS refuses to pay for medically necessary services during investigator-initiated studies, there will be a dramatic drop in this type of study. The long-term effects of this rule will exacerbate current workforce problems, discourage students and researchers from entering into or remaining in the medical research arena, and severely limit researcher participation in investigator-initiated trials that provide many benefits to furthering science and improving health.

Investigator-initiated IND-exempt studies play an important role in the public health of the country as they enable dissemination of innovative therapies. Many of these trials are studies of off-label uses of FDA approved drugs that investigators have already seen to be effective in the non-research context of their clinical practice. However, in order for the outcomes to be discussed in most peer reviewed journals, the results must be verified in an organized clinical trial. Withdrawing coverage for these types of research studies not only will discourage Medicare beneficiaries from enrolling in the research study because the services may be covered outside the research study, but also will thwart the ability of clinicians to bring to the public’s attention safe and effective off-label uses of FDA approved drugs.

CMS acknowledged these same concerns in the comments to the proposed rule and noted the need to develop solutions to address them. Thus, the AAHC is concerned that CMS decided to change the current policy covering such trials when time and again the agency has recognized the benefits to be gained from such trials and the benefits and consequences of a changed policy are yet to be determined.

Given that the benefits of such trials far outweigh any arguments to the contrary, there appears to be little reason to deny coverage of IND-exempt trials. The burden of changing policy more than once will be clearly excessive and very disruptive and costly to all stakeholders. We recommend that CMS not change such coverage until sufficient time is spent in gathering information and assessing the best way to proceed.

Humanitarian Use Devices
Finally, the AAHC would like to recommend that CMS provide some clarity regarding Humanitarian Use Devices (HUDs) related to clinical trials. The current policy creates confusion for IRBs and investigators. It would help greatly if CMS could provide some explicit language about coverage for these devices. Is coverage for HUDs decided by the local medical director? Is there any change regarding coverage for HUDs with the new CRP? We believe that CMS could provide additional comments in this area and confirm when such coverage exists.

Thank you for considering these recommendations. Please note that we have a broad consensus on these issues and were guided by comments from a wide range of institutions with a steering committee chaired by Samuel J. Tilden, MD, JD, LLM, Deputy Provost for Human Subjects Research, Research Compliance Officer, and Professor of Pediatrics at the University of Alabama at Birmingham.

We look forward to continued work and collaboration with CMS regarding the publication of the revised Clinical Research Policy. Please know that the AAHC is eager to offer its assistance to CMS as a bridge to the academic health center community.

Sincerely,

Steven A. Wartman, MD, PhD
President/CEO

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Protocol Summary
This Phase III randomized trial will evaluate the effectiveness of partial breast irradiation (PBI)compared to whole breast irradiation (WBI) in providing equivalent local tumor control in thebreast following lumpectomy for early stage breast cancer. The study will compare the overallsurvival, recurrence-free survival, and distant disease-free survival between women receiving PBIand WBI. It will also look at quality of life (QOL) issues related to cosmesis, fatigue, treatment related symptoms, and perceived convenience of care.” The eligible subject population will have stage 0 (DCIS – ductal carcinoma in situ), I, or II breast cancer resected by lumpectomy with a tumor size ≤ 3.0 cm and no more than 3 histologically positive nodes.

The trial is sponsored by the National Cancer Institute (NCI) and conducted by two cooperative groups, The National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Radiation Therapy Oncology Group (RTOG).

1. Name the standards of a research study that must be met for a Medicare coverage consideration of routine care associated with the study. Scientifically and technically sound standards:

This study identifies the post-lumpectomy standard of care treatment for stage 0, I, and II breast cancer as whole breast irradiation and has established this treatment as the control arm of the study. The investigational arm of the study involves partial breast irradiation as the treatment strategy post lumpectomy and the study is designed to compare various outcomes of these two treatment groups. The National Comprehensive Cancer Network (NCCN) publishes professional practice guidelines in Oncology specific to breast cancer. This guideline confirms whole breast irradiation in this clinical setting as the standard of care. Further review of the medical literature indicates that the standard of care for local management is breast-conserving surgery to excise the tumor with adequate margins (lumpectomy), followed by whole-breast external-beam radiation therapy (WB-EBRT).

Accelerated partial breast IRRADIATION (APBI) differs from WB-EBRT in two ways. First, the radiation targets only a segment surrounding the tumor rather than the entire breast. Second, since the duration of treatment is four to five days rather than five to six weeks, radiation is delivered in fewer fractions at larger doses per fraction. APBI comprises severaltechniques, including interstitial brachytherapy via catheters, the MammoSite radiation treatment system, accelerated external beam radiotherapy, and intra-operative radiotherapy delivery.

When compared with whole breast IRRADIATION, APBI offers the potential advantages of convenience and decreases radiation dose to healthy breast tissue. However, published studies are limited in patient size and follow-up period.The protocol describes a schedule for data analysis based on numbers of enrolled subjects who complete their randomized treatment assignment. There does not appear to be any description of sponsor publication or anticipated timeline or strategy to publish the study results or post for public access. There is discussion in the protocol about recruitment with consideration for sub-populations in the anticipated subject pool. This information is described in the protocol as follows:“Potential for the enrollment of minority patients in this protocol is enhanced by the NSABP's recognition of the importance of increasing minority accrual. To this end, we provide opportunities for greater participation by underrepresented racial and ethnic groups. In similar studies, the racial/ethnic composition for the study population is approximately 87% white, < 1% American Indian or Alaskan Native, 2% Asian or Pacific Islander, 8% black (not of Hispanic origin), 3% Hispanic, and < 1% other. It is anticipated that this distribution will be maintained for this protocol. The prognostic effect of race/ethnicity will be evaluated using statistical models. Because of sample size limitations, we will not be able to compare effects separately for the different cultural or racial groups.”There does not appear to be any language in the protocol addressing the application of the study findings to the general Medicare population.

2. Does this study meet the standards and qualify for coverage consideration? This trial is sponsored by the National Cancer Institute (NCI) and conducted by two cooperative groups, The National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Radiation Therapy Oncology Group (RTOG). This trial is supported by cooperative groups funded by NCI, a federal agency of the NIH and thus would be automatically deemed a qualifying trial for consideration of coverage of routine care costs. To be a qualifying trial, the study would need to meet all the listed criteria mentioned.Scientifically and technically sound standards:

Medicare-specific standards:

The CRP (April 2007 proposed revisions to the NCD) would suggest that studies reviewed and approved by health care research centers or cooperative health care research groups, funded by one of the above Federal Agencies would qualify IF that Federal Agency reviews and approves the applicant research centers’ or cooperative research groups’ subcontract and sub-grant funding requirements, selection procedures and oversight methods, and determines that those processes provide the same level of protocol review as provide by the supporting Federal Agency. Under the new CRP, do I need evidence that NCI has reviewed and approves the NSABP and RTOG funding requirements, selection procedures and oversight methods and has determined that those processes provide the same level of protocol review as NCI? If so, what does that evidence look like, how do I get it and who do I give it to and in what forum? Can we deduct that once the CRP is effective, cooperative groups (and other sponsors for that matter) will include content relative to method and timing of public disclosure, consideration for subpopulation enrollment and how the study results will generalize to the Medicare population?

3. Define “covered” services according to the proposed CRP

4. Define “noncovered” services according to the proposed CRF

The National Comprehensive Cancer Network (NCCN) publishes professional practice guidelines in Oncology specific to breast cancer. This guideline confirms whole breast irradiation in this clinical setting as the standard of care and goes so far as to state, “Partial breast irradiation should be performed only as part of a high quality prospective clinical trial.” This guideline establishes that partial breast irradiation is not “routine care” and is considered the “investigational treatment” in this study.Medicare has not issued an NCD specific to Partial Breast Irradiation and Mutual of Omaha has not issued a local coverage policy for partial breast irradiation, however a number of other contractors have. First Coast Service Options, Inc. (FI) sets coverage parameters for the appropriate treatment population:“…Given access to care issues, a local coverage determination (LCD) has been developed to define the indications and limitations of coverage, establish a procedure to diagnosis relationship, and clarify the appropriate use of APBI after breast-conserving surgery for early stage breast cancer. In addition, a coding guideline has also been developed to assist in billing this type of service.

APBI after breast-conserving surgery is considered medically necessary for patients with early stage breast cancer when all of the following criteria are met:

Wisconsin Physician’s Service Insurance Corporation has also indicated coverage for partial breast irradiation without any specified parameters stating, “Several prospective studies have shown breast brachytherapy to produce results equivalent to those achieved with conventional external beam radiation therapy in carefully selected patients. The advantage of breast brachytherapy is that treatment can be completed in 4-5 days compared to up to 6 weeks for conventional radiation therapy. Therefore, Medicare Part B will now cover breast brachytherapy for the treatment of early-stage breast cancer after lumpectomy.”

Blue Cross and Blue Shield of Arkansas and National Heritage Insurance Company include similar background information and rationale in their LMRPs and include a slight variation in their parameters in that the lesion size must be less than or equal to 2 cm for a coverage consideration. “Therefore, APBI after breast-conserving surgery for early stage breast cancer is only considered a medically appropriate treatment option with strict selection criteria:Selection Criteria (ALL must be present)Age: ≥50 yoDiagnosis: Invasive ductal carcinomaSize: ≤2cmMargin status: Negative - at least 2 mm in all directionsNodal status: Negative axillary lymph node dissection or sentinel lymph node evaluation”

Note that this carrier does not include DCIS (ductal cancer in situ – stage 0 breast cancer) as a covered diagnosis. In this case, the DCIS eligible subject would have no coverage provision for PBI.

The “sponsor’s” budget is usual and customary NCI reimbursement. A small payment is made for each subject recruited and treated within the study protocol, and itemized reimbursement for quality of life data and pathology services required to submit tissue (blocks, cores or slides). There is no payment provision for patient care items and services performed within the protocol guidelines.

The consent for this study contains the following language: “"Before you begin the study, You will need to have the following exams, tests and procedures to find out if you can be in the study. These exams, tests and procedures are part of regular cancer care and may be done even if you do not join this study. If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor… You and/or your health plan/insurance company will need to pay for some or all of the costs of treating your cancer in this study. Some health plans will not pay these costs for people taking part in studies. Check with your health plan or insurance company to find out what they will pay for. Taking part in this study may or may not cost your insurance company more than the cost of getting regular cancer treatment…You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health plan will be charged for this treatment. The study will not pay for medical treatment.”

5. Using the CRP definitions of administrative service (A), investigational clinical services (I), and routine clinical services (R), classify each of the study activities below as A, I or R.

H&P (within 4 months of randomization) R1breast exam (postop prior to randomization) R1weight Abra cup size Amenopausal status ACBC with diff and platelet count (may be preoperative or postoperative) R1alkaline phosphatase R2AST R2serum Beta HCG I3chest imaging (chest CT or xray) R4Ipsilateral breast CT (within 14 days following surgery however, any time following surgery and before entry is acceptable) R4bone scan (if alkaline phosphatase is elevated or personal s/s of mets R6Abdominal CT scan if AST, bilirubin or alkaline phosphatase is elevated or hepatomegaly R5bilateral mammogram (within 6 months prior to randomization) R7serum collection (after randomization but before treatment) A8tissue blocks (submit within 3 months of randomization) A81Baseline H&P within 4 months of randomization, breast exam CBC with diff and platelet count (may be preop or postop with no other specified time parameters). These activities are part of the usual care of a patient undergoing diagnostic testing for breast cancer with a treatment plan for lumpectomy. The protocol is not stringent with the timing of these tests so that so long as these tests were performed as a part of the usual care of the patient, data from these standard of care tests can be used to satisfy the protocol. Any tests repeated to accommodate the protocol are not billable to Medicare. Breast and physical exams at the frequency required by the protocol are consistent with NCCN treatment guidelines. 2Alkaline phosphatase and AST as required at baseline are indicated as appropriate “work-up” for stages I & 2 breast cancers according to NCCN guidelines. Medicare lab NCDs do not address alkaline phosphatase or AST so that general Medicare guidelines for “reasonable and medically necessary” suggest that if these tests are performed solely to obtain data for subjects with stage 0 breast cancer or repeated solely to accommodate the protocol, they no longer meet the definition of routine clinical services but become administrative services and would not be billable to Medicare. 3Pregnancy testing within 2 weeks prior to randomization for women of childbearing potential is performed within a strictly specified time period as an eligibility requirement. This meets the definition of an administrative service and is not billable to Medicare4Chest imaging – chest CT or chest x-ray – The protocol requires CT scan after lumpectomy or re-excision of margins and CT-imaging of the ipsilateral breast is required prior to study entry. It is recommended that the pre-randomization CT be performed within 14 days following surgery; however, it will be acceptable as long as it is performed within 42 days following surgery. Technical feasibility for PBI techniques will be determined by size, shape and location of the lumpectomy cavity and the lumpectomy cavity/whole breast volume ratio which is required to be ≤ 30%. Medicare has issued an NCD on Computerized Tomography indicating that, “Diagnostic examinations of the head (head scans) and of other parts of the body (body scans) performed by computerized tomography (CT) scanners are covered if you find that the medical and scientific literature and opinion support the effective use of a scan for the condition, and the scan is: (1) reasonable and necessary for the individual patient; and (2) performed on a model of CT equipment that meets the criteria in C below.” This baseline CT would be a covered service required to monitor the effects of the investigational treatment (partial breast irradiation). 5Abdominal CT is to be performed if the subject has hepatomegaly or elevated alkaline phosphatase, AST or bilirubin. There is a published NCD for CT scans that stipulates coverage so long as medical literature supports the scan as reasonable for the condition. The NCCN guidelines recommend abdominal CT, US or MRI for elevated alkaline phosphatase or abnormal LFTs. This scan would be the clinically appropriate monitoring for the subjects’ disease or condition; it meets the definition of routine clinical care and is thus billable to Medicare. 6Bone scan is required by the protocol if the subject has an elevated alkaline phosphatase or personal S/S of skeletal metastasis. Medicare’s NCD for Bone Mineral Density studies including Single Photon Absorptiometry and Photodensitometry (radiographic absorptiometry) but excluding Dual Photon Absorptiometry which Medicare considers investigational states, “Bone (mineral) density studies are used to evaluate diseases of bone and/or the responses of bone diseases to treatment…” There is no frequency limitation noted in this NCD and the indications for performing this scan are consistent with NCCN guidelines. This scan meets the definition of a routine clinical service so long as Dual Photon Absorptiometry is not the technique used to perform this test. 7Bilateral mammography is required at baseline, at 6 months following study entry and annually thereafter. Medicare has issued an NCD on Mammography stating, “A radiological mammogram is a covered diagnostic test under the following conditions:A patient has distinct signs and symptoms for which a mammogram is indicated;A patient has a history of breast cancer; or A patient is asymptomatic but, on the basis of the patient’s history and other factors the physician considers significant, the physician's judgment is that a mammogram is appropriate.” NCCN guidelines indicate annual mammography for this patient population. In addition, the 6 month mammogram would be considered routine care as indicated by the NCCN recommendation as noted: “Patients with mammographically detectable DCIS who elect breast conservation therapy should undergo post excision mammography of the involved breast and specimen radiography to ensure that all mammographically detectable disease has been excised.” Given that the NCD has no frequency limitations on mammography and professional guidelines support such testing at the protocol specified intervals, these examinations meet the definition of routine clinical care and are billable to Medicare8Quality of life and cosmesis study with digital images are not separately billable patient care services and are performed solely for data collection. These activities meet the definition of administrative services. Serum and tissue block collections are also performed for data collection and deposit into a central repository. They are diagnostic collections beyond those required to make a diagnosis and manage patient care. These collections also meet the definition of administrative services.

The CRP contains the following statement: Local Coverage DeterminationsThis policy does not withdraw Medicare coverage for items and services that may be covered according to local coverage determinations (LCD). For information about LCDs, refer to http://www.cms.hhs.gov/Medicare/Coverage/DeterminationProcess/04_LCDs.asp#TopOfPage, a searchable database of Medicare contractors' local policies.

6. What is the investigational treatment in this protocol and according to the CRP, is it covered?

The National Comprehensive Cancer Network (NCCN) publishes professional practice guidelines in Oncology specific to breast cancer. This guideline confirms whole breast irradiation in this clinical setting as the standard of care and goes so far as to state, “Partial breast irradiation should be performed only as part of a high quality prospective clinical trial.” This guideline establishes that partial breast irradiation is considered the “investigational treatment” in this study. Further, if whole breast irradiation is the control or standard treatment, there would be no research question without the comparator investigational treatment PBI. The CRP indicates that investigational clinical services (including the investigational item or service itself) are covered so long as the service is:

* Without a Medicare NCD for PBI, coverage for this treatment is left to the local contractor discretion. Some contractors appear to cover this treatment but with limitations that are more restrictive than the protocol I&E. There is enough coverage evidence published by other contractors to suggest that providers should seek a coverage statement from any contractor that is silent prior to submitting claims for PBI for subjects in this study. The contractor should be asked to comment on coverage for this treatment and should be asked to reference their coverage limitations considering study inclusion and exclusion criteria as well as the 3 study permitted techniques for PBI.

In reference to commercial claims submissions, Susan Granucci, a claims coverage specialist has commented on partial breast irradiation as follows:“APBI differs from whole breast external beam radiation therapy in several ways. Treatment is delivered via HDR brachytherapy. The radiation targets only a segment surrounding the tumor rather than the entire breast. Since the duration of treatment is 4 to 5 days rather than 5 to 6 weeks, radiation is delivered in fewer fractions at larger doses per fraction. APBI features:_ interstitial brachytherapy (high dose rate) via balloon catheters placed into lumpectomy cavity usually immediately after surgery, but can follow later_ the MammoSite radiation treatment system_ 3-D conformal planning_ two treatments each day for five days (BID treatments require modifier 59)_ breast conserving therapyCoverageMedical necessity is supported with the following criteria:Age: Equal to or greater than 50 years old, (I&E for this trial includes all subjects greater than or equal to 18 years of age)Diagnosis: Invasive ductal carcinoma, (this trial includes invasive ductal carcinoma and DCIS)Size of tumor: Less than or equal to 2cm, (I&E for this trial requires a tumor less than or equal to 3 cm) Margin status: Negative - at least 2 mm in all directions, (I&E for this trial puts no specific parameters on the margin status other than the expectation that the margins are histologically free of tumor.)Nodal status: Negative axillary lymph node dissection or sentinel lymph node evaluation.(I&E for this trial have more specific parameters for “negative” node status)

An extensive internet search did not reveal any payer guidelines other than Medicare's. The following from Blue Cross-Blue Shield is now three years old, and although denial is implied, it does not specifically so state. At this time, it would appear most insurers are paying for APBI claims.Based on the available evidence, the Blue Cross and Blue Shield Association Medical AdvisoryPanel made the following judgments about whether accelerated partial breast irradiation usingbrachytherapy meets the Technology Evaluation Center criteria to decrease recurrence afterbreast-conserving surgery for early stage breast cancer.Accelerated partial breast irradiation using brachytherapy as the sole radiation treatment afterbreast-conserving surgery for early stage breast cancer does not meet the TEC criteria. Nov.,2002TEC Assessments are scientific opinions, provided solely for informational purposes. TECAssessments should not be construed to suggest that the Blue Cross Blue Shield Association,Kaiser Permanente Medical Care Program or the TEC Program recommends, advocates,requires, encourages, or discourages any particular treatment, procedure, or service; anyparticular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.” You explain the complicated coverage scenario to the PI and are told, “We submit claims for PBI all the time and payers cover this treatment for all kinds of patients. We participated in the clinical device trial that led to FDA approval of the MammoSite device; this is an FDA approved treatment, it is ridiculous to suggest that it cannot be billed to a third party payer.”

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