Response to Comments: MolDX: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis

The following comment was submitted to Palmetto GBA, CGS, WPS, and Noridian and was received from multiple stakeholders:

Letters of support for a coverage policy for Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis.

During the comment period, we received many letters supporting a coverage policy for Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. Of note, we have acknowledged the need for testing to help physicians and patients avoid a trial-and-error based approach to care. However, we have also acknowledged the limitations of the currently available clinical and laboratory tools to support this effort, as noted in the draft policy that evaluated the data available in the published literature. For example, the molecular biomarker tests had not adequately demonstrated that they can reliably identify responders and/or non-responders to a particular class of therapies beyond what is already known at baseline (i.e. uninformed by the test), given that (a) the overall prevalence of non-response to TNF inhibitors (TNFi), a mainstay of therapy, is so high in this population (~60-70%) and (b) multiple clinical and laboratory data also provide some information regarding the likelihood of response to these therapies. Since then, additional data/newer publications addressing these issues have been published and were provided during the comment period. The policy was therefore modified as an outgrowth of the comments received.

We appreciate the many comments received in support of a coverage policy. We agree that despite the many limitations of predictive biomarker tests, a review of the evidence supports their limited use given their demonstrated validity and utility. Specifically, when a non-response (NR) signature is obtained by the molecular signature response classifier (MSRC), nearly 90% of those patients will prove to not clinically respond to TNFi therapies using multiple validated disease response criteria including the ACR50 and CDAI. For these patients, a change in management would ultimately serve to avoid time on an unnecessary therapy and shorten the time to an appropriate therapy.

However, we also highlight some important points about the evidence regarding these tests to-date: 1. They have only demonstrated their utility in a subset of the RA population (only half of the TNFi non-responders), 2. They are only informative about one particular class of therapies (TNFis), 3. The use of this testing does not guarantee improved disease activity and/or remission outcomes (because many of these patients will also not initially respond to the alternate therapies) and 4. It is not appropriate that patients continue classes of therapy that they have already failed due to payor preference and/or lack of consideration of national guidelines (that support switching over cycling). As a result, it is likely that future tests will add substantially more benefit than the current services offered and reviewed by this contractor, and we will continue to monitor new evidence as it becomes available.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with over 15 years of experience. Without a predictive test, I am left with a trial-and-learn/error approach. PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. PrismRA is intended for use by physicians to guide medical management decisions in RA adult patients (18 years or older) with moderate to high disease activity who have either not reached treatment disease activity objectives 1) on csDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change (including dose escalation or cycling-to another TNFi).

I strongly support the coverage of PrismRA for my patients and would like to see this decision overturned.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 30 years of experience.

Currently (in the absence of PrismRA), I must choose a first-line biologic therapy without the appropriate tools that will help me match therapy to a patient’s unique disease biology. With currently available resources and clinical assessments, I am limited in my ability to start a patient on the correct drug based on their disease biology. Without a predictive test, I am left with a trial-and-learn/error approach. PrismRA is the only test of its kind that is commercially available to prevent a trial-and-learn/error approach to treating patients with a biologic and informing me of the best therapy option. I do not have a test or clinical assessment to inform me of the right biologic for my patients. I utilize the PrismRA test to inform me which biologic is the best start. Without this valuable tool, I am left with prescribing based on what is dictated by the patient’s insurance. We will be wasting valuable time in my patients' lives if we must use trial-and-error approaches to determine what to prescribe next versus incorporating a tool that helps inform TNF inhibitor non-response.

I strongly support the coverage of PrismRA for my patients.

Thank you for considering my comments.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing in support of coverage for the PrismRA molecular signature response classifier test that predicts which patients with rheumatoid arthritis are unlikely to respond to treatment with a TNF inhibitor. I am a practicing rheumatologist with almost 40 years of experience. I am also a Clinical Professor of Medicine. Beginning in the year 2000 we have had remarkably effective, immunologically targeted therapies for this disease.

However, physicians have no tools to predict which patient will respond to which treatment, leading to patients being treated empirically and sequentially. This results in unnecessary expense as well as potential injury to the patient in terms of side effects that might have been avoided as well as disease progression that might be prevented. The PrismRA test has been studied and validated to predict nonresponse to anti-TNF therapies. I have used the PrismRA test to aid in my treatment decisions and I feel that it has helped me to get my patients on more effective therapy sooner. I strongly support coverage of the PrismRA test for my patients. I believe that there is strong evidence to support its use in rheumatology practice so that we can stop the trial-and-error approach to targeted therapy selection for patients with rheumatoid arthritis.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing to express my medical opinion of Prism RA. As you are aware, rheumatoid arthritis is a complex disease, presenting itself in varied ways depending on the individual patient. Additionally, response to therapy is often patient specific and not all categories of medication demonstrate adequate response. This often forces a trial-and-error approach that can subject patients to sub-optimal outcomes. When initiating a biologic treatment for RA, TNFis are chosen 90% of the time. Prism RA identifies those patients likely to have an inadequate response to TNFis, ensuring optimized treatment that reduces pain, inflammation and irreparable joint damage.

I have been using Prism RA for over a year in my medical practice and have found it invaluable and have incorporated Prism RA into my treatment protocol.

I urge you to provide coverage for Prism RA and reverse the current LCD/non-coverage decision.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 5 years of experience.

Currently (in the absence of PrismRA), I do not have a test or clinical assessment to inform me of the right biologic for my patients. I need the PrismRA test to inform me which biologic is the best start. Without this valuable tool, I am left with prescribing based on what is dictated by the patient's insurance. More than 25% of my patients do not reach low disease activity with how I currently practice. We are wasting valuable time in my patients' lives, as we use trial-and-error approaches to determine what to prescribe next versus incorporating a tool that helps inform TNF inhibitor non­response.

Rheumatoid Arthritis is a devastating autoimmune disease. Treating patients with this potentially deadly and debilitating disease early is important, as joint damage caused by RA generally occurs within the first two years of diagnosis. Up to 70% of patients with RA that are inadequately treated become disabled within 10 years (Burton W, 2006). This is because rheumatologists and patients do not have a precision medicine tool to determine which targeted biologic therapies a patient should initiate that will work best for their disease.

Using a precision medicine test, like PrismRA, to predict therapy response to biologics for patients with rheumatoid arthritis saves patients from unnecessary active disease period, progressive damage to joints with time, and expensive medication costs (Johnson KJ, 2019; Boytsov N, 2016; Strand V, 2018).

As published in clinical validation (CV) studies, the PrismRA test can accurately predict non-response to all TNFi therapies. In 174 samples from the prospective observational in the NETWORK-004 study of patients treated with TNFi therapies, the PrismRA test demonstrated (Jones A, 2021):

Positive Predictive Value (PPV): 87.7% (95% Cl 78- 94%). This describes the percent of patients with a molecular signature of non-response who will NOT reach ACR50 on a TNFi.

Sensitivity (true positive rate): 60.2% (95% Cl 50-69%). This describes the percentage of true TNFi non­responders (those who do not respond, defend as having a 50% improvement/ACR50 within 6 months on ACR50) who are identified by PrismRA testing having a molecular signature of non-response.

Specificity (true negative rate): 77.3% (95% Cl 65- 87%) This describes the percent of true TNFi responders (those who respond based on AR50) who did NOT have a molecular signature of non-response.

I support utilizing and implementing the PrismRA test into my practice and have firsthand experience in seeing how a therapy selection test like PrismRA can improve outcomes for patients struggling with RA. I believe there is strong evidence and clinical need to overturn this NCO to an LCD so that we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner.

Thank MolDx for considering your comments and any other closing remarks.

References were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA and Noridian:

I am a practicing Rheumatologist. I would like to provide you a letter in support of PrismRA. Rheumatologist such as I have been waiting for a tool to help guide decisions when it comes to prescribing bDMARDs. At present, rheumatologists like me have no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies without the use of the PrismRA test. Moreover, because RA is a progressive disease, patients that ultimately fail bDMARDs may have increased disability by the time they are able to move to the next mechanism of action (MOA). PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs.

I support utilizing and implementing the PrismRA test into my practice and have firsthand experience in seeing how a therapy selection test like PrismRA can improve outcomes for patients struggling with RA. I believe there is strong evidence and clinical need to have PrismRA available to help guide decisions so we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner for better outcomes.

I fully support the coverage of PrismRA to help guide treatment decisions to help patients get better sooner to avoid disease progression and cost to the patient and health care system.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

Below are my formal comments on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am writing in support of coverage for PrismRA as this test meets a critical need for the treatment of my patients with rheumatoid arthritis (RA).

I am a practicing rheumatologist and an Assistant Clinical Professor. I have over 25 years of research experience focusing on chronic inflammatory diseases, such as RA and psoriatic arthritis, with an emphasis on connective tissue components, inflammatory mediators, and cytokines. Prior to returning to private practice, I was an Associate Medical Director.

Without PrismRA, we as rheumatologists must choose a first-line biologic without guidance to match therapy to a patient's specific disease biology. Our colleagues in the oncology space have benefited from advances in precision medicine for years; this is now a critical need for those treating rheumatic diseases. Currently, I do not have a clinical assessment tool to guide me to the right biologic for each individual patient. I am often left prescribing based on what is dictated by the patient's insurance instead of what is best for the patient's RA. Without precision medicine, the majority of my patients do not reach the treat-to-target goal of low disease activity or remission.

Rheumatologists are wasting valuable time for their patients when there is currently an available tool that predicts tumor necrosis factor-alpha inhibitor (TNFi) non-response prior to initiating therapy.

I have directly witnessed the benefits of PrismRA to my patients with RA. In my practice, this test has significantly advanced upon the trial-and-error therapy selection approach and finally brought precision medicine to the rheumatology space. Beyond my firsthand experience with PrismRA, its clinical utility has been well-documented in a number of clinical trials and publications. As published, the PrismRA test can accurately predict non-response to the TNFi class of medications as a whole. In 174 RA patient samples from the prospective NETWORK004 study (Jones A, 2021; Cohen S, 2021), where patients were treated with TNFi therapies and the treating rheumatologists were blinded to the PrismRA result, PrismRA demonstrated the following test characteristics:

• Positive Predictive Value: 87.7% - This describes the percentage of patients with a prediction of non-response to TNFi therapies who DID NOT reach ACR50 on a TNFi.
• Sensitivity: 60.2% - This describes the percentage of true TNFi non-responders (those who do NOT respond, defined as an ACR50 response at 6 months) identified by PrismRA testing as having a molecular signature of non-response. This is a dramatic improvement in our ability to identify TNFi non-responders compared to the current trial-and-error approach.
• Specificity: 77.3% - This describes the percent of true TNFi responders (those who respond based on ACR50) who did NOT have a molecular signature of non-response.

PrismRA helps me steer patients away from medications that will not work with a high level of accuracy based on their biology while greatly improving disease management and reducing patient/health system costs. I strongly support overturning the NCO to a positive LCD so that my elderly patients with RA can get on the right medication sooner after they fail methotrexate or first­ line TNFi therapy. I have adopted PrismRA into my standard practices and have encouraged other rheumatologists and providers to do the same. I have firsthand experience seeing how PrismRA can improve patient outcomes, and I vehemently support its coverage.

Thank you to MolDX for taking my comments into your consideration.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

Thank you for allowing providers to be heard on this important topic in Rheumatology. As you probably know, there are limited resources to guide our decision-making in treating our patients. This test has been a great asset to our practice in making the best medication options specific to each individual patient. As a Nurse Practitioner in Rheumatology, I ask that you overturn your “non-coverage” determination for PrismRA Molecular Signature Test. I have found PrismRA to be extremely useful and insightful. I have used it to help guide the care that I provide for my Rheumatoid Arthritis patients. PrismRA provides information that is clinically actionable. This is shown to accomplish low disease activity levels more quickly than the trial-and-fail method of finding a targeted synthetic biologic. The information provided by PrismRA cannot be ascertained by any other method that I am aware of and for this reason, I would ask that you make it available for all my patients with a positive coverage decision.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 10 years of experience in treating Rheumatoid Arthritis patients.

Rheumatoid Arthritis is a devastating autoimmune disease. Treating patients with this potentially deadly and debilitating disease early is important, as joint damage caused by RA generally occurs within the first two years of diagnosis. Up to 70% of patients with RA that are inadequately treated become disabled within 10 years (Burton W, 2006). As a Rheumatologist, we do not have a precision medicine tool available to determine which targeted biologic therapies will work best for our patient’s disease, and without a predictive test, I am left with a trial-and-learn/error approach.

The data that I have read/seen on PrismRA has been documented in several peer reviewed studies and publications. The positive predictive value of the test is close to 90% in patients who have a molecular signature of non-response who will not reach ACR50 with treatment with an anti-TNF. Rheumatologists like myself, have no way of predicting whether our patients will respond to this class of drugs in advance of prescribing anti-TNF therapies without the use of PrismRA. Without a predictive test like PrismRA, I must use a trial-and-error approach to treat this disease. PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs.

I have used PrismRA to help inform my treatment decision and I feel it has helped me get my patients on the most effective therapy sooner and into low disease activity. I strongly support the coverage of PrismRA for my patients, and I believe there is strong evidence and clinical need to overturn this NCD to an LCD so that we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis.

Thank you for your consideration of my comments.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a Board-Certified Rheumatologist with over 16 years of experience.

I am advocating for approval and coverage of a lab test called PRISM-RA that I feel is essential in helping rheumatologists like myself make treatment decisions for our Rheumatoid Arthritis patients. As you know, this test predicts with very good accuracy, which patients are likely or unlikely to respond to anti-tnf therapy, a biologic class of medication we commonly prescribe.

Prior to the availability of PrismRA, we were choosing a first-line biologic therapy and doing a trial-and-error approach, hoping that the first biologic we choose helped a patient. We did not have the appropriate tools to help us match therapy to a patient’s unique disease biology.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. PrismRA was specifically developed for use by physicians to guide medical management decisions in RA adult patients (18 years or older) with moderate to high disease activity who have not reached significant improvement on conventional DMARDs and are considering starting a biologic medication.

At present, we have no real good way of predicting whether a patient will respond to this commonly prescribed class of medication without the use of the PrismRA test. Moreover, because RA is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to move to the next mechanism of action. PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient. Getting a biologic right the first time will save a lot of health care dollars rather than cycling through different meds until the right one is found. We now have a test that can steer us in the right direction from the beginning, leading to better patient outcomes and less burden to healthcare. It is also a test that only needs to be ordered once a lifetime of a RA patient and provides valuable insight into responsiveness to a commonly prescribed therapy.

I consider the PrismRA test to be an excellent tool that is essential to rheumatologists in helping to predict response or lack of response to a commonly prescribed class of medications (anti-tnf blockers). I believe there is strong evidence and clinical need for PrismRA so that we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner.

Thank you for your time and attention to this critical matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing today in support of a positive LCD for the PrismRA Biomarker Test. I would like my formal comments on the Draft LCD: Molecular Biomarker Testing to Guide Targeted Therapy Selection in RA to be taken into consideration. To highlight my credentials, I am a practicing rheumatologist with over 10 years of experience. I specialize in Rheumatoid Arthritis, Lupus, Antiphospholipid Syndrome, Giant Cell Arteritis, amongst other rheumatic diseases.

Currently, there is no test or clinical tool to inform or guide me to the right biologic for my patients.

With how I currently practice, the majority of my patients do not reach the treat-to-target goal of low disease activity and I am left with prescribing based on what is dictated by the patient’s insurance. We are wasting critical time in my patients' lives, instead of utilizing a tool that helps inform TNF inhibitor (TNFi) non-response.

PrismRA has dramatically improved how I treat my patients and how I select which biologic is the best start. Having PrismRA in our armamentarium allows for more efficient decision-making in that it eliminates many question marks in our selection process. As demonstrated in the PrismRA analytical validation (Jones A, 2021), PrismRA has a positive predictive value of 87.7% (95% CI 78-94%).

Knowing with nearly 90% certainty that a patient will not respond to a class of biologics before initiating therapy, provides information that we as rheumatologists have never had before. With PrismRA, we do not lose valuable time for our patients and can slow their disease progress in a timely fashion. Thus, optimizing QOL more frequently than ever before.

As an example, I have provided the case details from a current patient of mine where PrismRA was incredibly beneficial. I have a male patient who was on Humira for over 10 years and still had residual 1- hour-long morning stiffness. He was content being able to play his favorite sport a few days a week, but I could tell he had aspirations of playing more frequently and waking up with less of a need for a “good oiling” for his morning stiffness. I ordered a PrismRA, and the result identified him to be a non-responder to TNFi therapy. So, what was thought to be efficacious in TNFi therapy was more of a slight improvement over his debilitation that he was ecstatic about years ago. He never even considered that there was a possibility to feel better. We switched him to IL6i Actemra and within 2 weeks of the switch, he felt immensely better. He now golfs almost every day with nonexistent morning stiffness.

I strongly support implementing PrismRA into a rheumatology practice and have firsthand experience seeing improved therapy selection and outcomes for patients struggling with RA by utilizing PrismRA. There is significant evidence and a clinical need to overturn this NCD so that we can stop the trial-and-error approach for targeted therapy selection for patients with RA. Please post a positive LCD so patients starting their first biologic or targeted synthetic DMARD or considering a second TNFi after TNFi exposure can get on the right medication sooner with PrismRA.

Thank you for your consideration.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing Rheumatologist and I would like to provide you with this letter of support for the Molecular Signature Response Classifier, PrismRA. Rheumatologists, like myself, have been waiting for a precision medicine tool like PrismRA to enter our specialty. Currently, I am limited in my ability to choose the most appropriate biologic for my Rheumatoid Arthritis patients and often insurance dictates which therapy I must choose. I find myself using a trial-and-error approach to determine what to prescribe next versus using a tool that helps predict therapy response to biologics.

Since learning about PrismRA through the clinical validation and clinical utility studies, I have started implementing the test into my practice. Most recently I used PrismRA for a patient that was not doing well on methotrexate, and I was considering which biologic to start her on. With the result from PrismRA, I found out that her disease biology was appropriate for TNFi therapy. This information helped her get on the right drug much more quickly.

I fully support the coverage of PrismRA and believe this test can help end the trial-and-error methods currently being used.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I submit this letter as a comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I offer my perspective based upon my 22 years in private practice as a rheumatologist, where nearly 25-30% of my patients are covered by Medicare. About a quarter to a third of my patients carry a diagnosis of rheumatoid arthritis.

Since the early days of my career when biologic disease modifying antirheumatic drugs had their advent for the treatment of rheumatoid arthritis, and particularly since biologic and targeted synthetic disease modifying antirheumatic drugs with mechanisms of action that did not target tumor necrosis factor became therapeutic options, I, along with almost the entirety of the global rheumatology community, have wondered how to choose the most appropriate therapy for an individual patient. The therapeutic choice has often been no more than an educated guess, shaped by experience, habit or external administrative, non-clinical factors. Fortunately, for the majority of patients with rheumatoid arthritis prescribed anti-tumor necrosis factor inhibitors, beneficial clinical outcomes are achieved, with states of low disease activity and remission attained in fewer numbers. Patients without favorable outcomes face further guesswork with subsequent therapeutic choices, an impediment in controlling this chronic disease where delays lead to both short- and long-term adverse consequences.

The Prism RA test has allowed the patient's unique biomarker profile to take some of this guesswork out of decision-making and direct avoidance of medications that are unlikely to have clinical benefit in patients deemed unlikely to respond by its results. I have had at least a dozen patients over the past year who have been prescribed alternative (non-tumor necrosis factor inhibitor) therapies because their Prism RA results revealed high probability of non-response to tumor necrosis factor inhibitors, thereby saving them from ineffective therapy, prolonged symptoms, and unnecessary potential adverse events. A particular example of the test's utility was realized about six months ago, when a patient covered by Medicare with longstanding rheumatoid arthritis and uveitis chronically treated with the tumor necrosis factor inhibitor adalimumab had two unusual successive flares of her disease brought into question the safety and efficacy of continued adalimumab versus a potential change to a less-desirable therapy. With the results of her Prism RA test showing no signal, where a molecular signal of non-response was not detected, I felt confident recommending continued adalimumab to treat her conditions, with continued success since then. Perhaps a better example of the test's utility is another patient covered by Medicare who was prescribed a Janus-kinase inhibitor as first line therapy in 2021 for his moderate rheumatoid arthritis, based upon his Prism RA result of very high likelihood of non-response to tumor necrosis factor inhibitor. Upon achieving remission on his therapy, he moved out of the area, followed up with a rheumatologist unfamiliar with the data or value of the Prism RA test who then changed his effective treatment to a tumor necrosis factor inhibitor based upon potential safety concerns, which effectively drove the patient back to our practice because his rheumatoid arthritis lost control and became highly symptomatic. He happily regained remission upon reinitiation of his janus kinase inhibitor therapy.

Please consider favorably coverage of the PrismRA test for patients with rheumatoid arthritis for whom tumor necrosis factor inhibitor therapy is being considered either as a second line therapy after failing conventional synthetic disease modifying antirheumatic drugs or failing a tumor necrosis factor inhibitor therapy. A no coverage determination will constitute a move backwards from precision medicine and result in continued guesswork of appropriate therapy. Molecular signal response classifiers have revolutionized the field of oncology; please help in bringing this necessary tool to the field of rheumatology to promote the progressive advance of applying the right specialty medicine to the right patient.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I have been a practicing rheumatologist for 20 years I would like to comment on the draft coverage decision regarding PrismRA. When treating my RA patients I am limited in my ability to start a patient on the correct drug based on their unique disease biology due to the currently available resources and clinical assessments. I am forced to use a trial-and-error approach. I do not have a test or clinical assessment to inform me of the right biologic for these patients. With the availability of PrismRA I do not have to use the trial-and-error approach to treat my RA patients. Rheumatoid Arthritis is a devasting disease where up to 70% of these patients that are inadequately treated become disabled within 10 years. Therefore, my goal is to get my RA patients in remission/low disease activity as soon as possible. PrismRA can help me do this. PrismRA is the first and only available Molecular Signature Response Classifier (MSRC) that predicts inadequate response to all TNFi therapies in RA. The data that I have seen on PrismRA has been documented in several peer reviewed studies and publications. One of the many data points I have seen is that the Positive Predictive Value (PPV) of the test is about 90%. This is the percentage of patients with a molecular signature of non-response who will NOT reach an ACR50 on a TNFi. ACR50 is our goal for the patient to be in low disease activity. Precision medicine tools, like a MSRC/PrismRA provides insight that helps with informed therapy selection. I feel there is strong evidence and a clinical need to overturn this NCD to an LCD so we can stop the trial-and-error approach to treating RA patients.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 15 years of experience.

Currently (in the absence of PrismRA), I must choose a first-line biologic therapy without the appropriate tools that will help me match therapy to a patient’s unique disease biology. Without a predictive test, I am left with a trial-and-learn/error approach. PrismRA is the only test of its kind that is commercially available to prevent a trial-and-learn/error approach to treating patients with a biologic and informing me of the best therapy option.

At present, rheumatologists like me have no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies without the use of the PrismRA test. Moreover, because RA is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to move to the next mechanism of action (MOA). PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs. I support utilizing and implementing the PrismRA test into my practice and have firsthand experience in seeing how a therapy selection test like PrismRA can improve outcomes for patients struggling with RA.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatology physician assistant with 7 years of experience.

When it is time for me to put an RA patient on a biologic therapy, without a predictive test, a lot of time can pass in finding the right therapy because I don't know if the drug will work or not. It is a trial-and-error approach because I don’t have a test or a clinical assessment that lets me know the most appropriate biologic for my patients. The PrismRA test informs which biologic class is the best for my patients. My goal is to get my patients into low disease activity and utilizing PrismRA has helped me get more of my patients’ disease under control.

PrismRA is the 1st and only Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. The clinical validity has been documented in several peer-reviewed studies and publications.

Before I started using PrismRA, I had no way of predicting whether a patient will respond to this class of drugs in advance of using a TNFi therapy. I believe it has helped me get a higher percentage of my RA patients into low disease activity. PrismRA helps me steer my patients away from medications that will not work based on their unique biology. It has improved my disease state management and patient outcomes as well as reducing patient and healthcare system costs.

I support utilizing PrismRA in my practice and have first-hand experience in seeing how a therapy selection test like this can improve outcomes for RA patients. I support the coverage of PrismRA for my RA patients and hope that you do too so that we can stop the trial-and-error approach for RA patients.

Thank you for considering my comments on this subject.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

In response to the Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis, I am inclined to comment on the most recent coverage decision. I am a practicing rheumatologist with twenty-six years of experience. In this time, I have had the privilege of treating thousands of patients with biologics, including TNF-inhibitors. Unfortunately, I have also witnessed thousands of patients suffer from pain, irreversible loss of joint function, depression and a myriad of other symptoms as a direct result of the trial and error of choosing the most effective rheumatoid arthritis (RA) therapy; largely influenced by the discretion of insurance companies.

PrismRA has proved to be a pivotal component when determining the most effective course of action with targeted biologic therapy since its introduction into my practice. While it is the first and only commercially available Molecular Signature Response Classifier (MSRC) test with the ability to predict an inadequate response to TNF-inhibitor therapy in RA, it has allowed me to bypass the use of unnecessary and inadequate treatment options in an effort to consider alternate therapies that have true potential to alter the patient’s RA disease course in hopes of achieving remission and/or low disease activity in a shorter time span.

PrsimRA is an invaluable tool that many of my patients have had the advantage of benefiting from. With the advancements in knowledge and technology in the RA arena, it would be unwise to decline support for this test which would, in turn inhibit the ability of practitioners such as myself to use evidence-based practices to prevent detriment to our patients.

Our first duty is to do no harm; the declination of coverage for the use of PrismRA will in turn bring harm to our patients. I therefore strongly support the utilization and implementation of the PrismRA test for both my practice and other rheumatology practices alike.

Thank you for considering my opinion in this matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a Rheumatologist practicing with forty-six years of experience in treating patients with Rheumatoid Arthritis. I am confronted daily with the need to choose the correct first line biologic therapy for appropriate patients. Until recently this has been a matter of trial and error without any regard for a patients biology which may be uniquely responsible for their response to a particular agent.

Prism RA is the only commercially available test which can avoid the trial-and-error approach to therapy and provide me with information that allows me to choose the best treatment option for the patient. Without this I am often forced to prescribe whatever is best covered by their insurance. Since approximately half of my patients fail to reach a state of low disease activity, several months may be wasted with an agent which has produced an unsatisfactory outcome. The next step is often another trial-and-error choice which has a 60 % chance of efficacy.

With access to information predicting TNF inhibitor non-response, precious time and money can be saved and the patient may return to a normal productive state much sooner.

Rheumatoid Arthritis is a serious multisystem autoimmune disease. Early diagnosis and aggressive treatment is critical to prevent permanent joint damage. Choosing the correct agent can prevent this damage which can occur within months of disease onset. Prism RA is the only currently available test that can guide physicians' medical management decisions in adults with RA who have not reached low disease activity goals on cs DMARDS and are candidates to start a biologic DMARD. It can also help with patients who are not adequately responding to TNFi therapy in deciding whether to escalate or cycle to another TNFi or an agent with a different mechanism of action. As published in clinical validation studies, the Prism RA test can accurately predict non response to all TNFi therapies with a positive predictive value of 87. 7%. This is the percentage of patients with a molecular signature of non response who will not reach ACR 50 on a TNFi.

As an example, one of my patients had inadequate responses to multiple DMARDs and biologics. She had also tried one TNFi early in her treatment course which was entirely ineffective. Since she was running out of alternatives, I entertained another TNFi trial. I ordered a Prism RA test the result of which was that she was highly unlikely to respond. A different agent was chosen and she subsequently did extremely well.

Patients who are treated with TNFi as first line biologic therapy and fail, lose valuable time and risk potential disability before they can move to another class of drugs. Precise medical tools like a molecular signature response test have helped me choose the best first line therapy without a frustrating trial and error approach. Therefore, I strongly support the coverage of Prism RA for my patients.

Thank you for your kind consideration in this matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing physician assistant in rheumatology for 7 years.

Up until we had access to PRISM RA, our only option was to choose a first-line biologic therapy without any tools to help us match a therapy to a patient’s unique disease biology. We had been limited in our ability to choose therapies for patients. I have had many patients with rheumatoid arthritis over the years that have tried and failed multiple TNF therapies before finally responding very well and rapidly to a non-TNF mechanism. This has led to higher healthcare costs for these patients due to persistent requirements for steroids, NSAIDs, and pain medications for a longer period of time while waiting to secure the correct therapy for them.

PRISM RA has significantly impacted my ability to choose the most successful therapies for my patients. It allows for more rapid management of disease activity for patients that are found to be TNF non-responders. For me, as a provider, it is extremely important to know who those patients are to manage their treatment quickly as RA can be quite a devastating disease and rapid control of the disease is crucial. PRISM RA allows me to identify them with 1 blood test.

There is no sense in wasting valuable time in my patients’ lives using a trial-and-error approach to determine treatment options when we have PRISM RA as a tool to help inform our decision.

I believe there is strong evidence and clinical need to overturn this NCD to an LCD so we can stop trial-and-error approach for targeted therapy selection for patients with rheumatoid arthritis and get them on the right therapy sooner.

I thank MolDX for considering my comments as a strong supporter of PRISM RA.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I’m writing this email to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 37 years of experience. I have treated over a thousand patients with rheumatoid arthritis during that time and began using anti TNF alpha medications when they first came out in the late 1990s.

Currently, with the lack of available resources and clinical assessments, I’m limited in the ability to start a patient on the drug that’s most appropriate to them based on their unique disease biology.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all the anti TNF alpha therapies for rheumatoid arthritis (RA). PrismRA is intended for use by physicians to guide medical management decisions in RA adult patients with moderate to high disease activity who have either not reached treatment disease activity objectives 1) on csDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change. (This includes dose escalation or cycling to another TNFi).

At present, or at least prior to the availability of PrismRA, rheumatologists such as myself had no way of predicting whether a patient would respond to this class of drug in advance of prescribing TNFi therapies. Furthermore, because RA is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to move to the next mechanism of action (MOA). One of my patients had an inadequate response to one anti TNF alpha. Before switching to another biologic, a PRISM test was performed. The test revealed that she was a nonresponder. The usual next step would be to try a different anti TNF alpha for several months. Often a third one would then be tried before switching to a drug with a different MOA. Without the PRISM test 6 months or more or time and great expense would have been wasted. Instead, I was able to switch her to a medication with a different MOA and she had good results. As this patient’s history illustrates, PrismRA helps me to steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes. This kind of precision medicine also reduces patient out-of-pocket cost and reduces the overall healthcare system burden.

Precision medicine tools, like a molecular signature response classifier (MSRC), provide insight that informs therapy selection. A molecular signature response classifier (MSRC) has helped me guide first-line therapy selection without a trial-and-error approach. I strongly support the coverage of PrismRA for my patients.

Thank you for your consideration to this matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to make a comment in support of PrismRA being covered by Medicare. I am a Physician Assistant. Throughout my career I have chosen a first-line biologic based on trial-and-error or based on what is dictated by the patient's insurance. This leaves the patient at risk for further disease progression and ultimately, joint damage.

I was excited when I first learned about PrismRA as the need for a precision medicine tool in rheumatology has been great. Being able to predict inadequate response to TNFi therapy in rheumatoid arthritis has been a game changer.

I most recently used PrismRA with a patient that had been treated with several biologics, but I needed insight into which one would be best for her disease biology. The PrismRA result helped guide her therapy away from medications that will not work and got her on the most appropriate therapy more quickly.

I will continue to utilize PrismRA, and I support the coverage of this test.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local coverage Decision. I am a practicing physician assistant rheumatology with 18 years of experience treating RA patients.

When it is time for me to put my RA patients on a biologic therapy- I have to make this choice without a predictive test because I do not know if the drug will work or not. It is a trial-and-error approach because I don’t have a test or a clinical assessment that lets me know the right biologic for my patients. The PrismRA test informs which biologic class is the best to start. My goal is getting these patients into low disease activity and utilizing prismRA has helped me get more of my patients into this.

PrismRA is the 1st and only Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNF therapies in RA. The Clinical validity (CV) has been documented in several peer reviewed studies and publications.

Before I started using PrismRA I had no way of predicting whether a patient will respond to this class of drugs in advance of using a TNF therapy without the use of the PrismRA test. I believe it has helped me get a higher percentage of my RA patients into Low disease activity. PrismRA helps me steer my patients away from medications that will not work based on their biology. It has improved my disease state management and patient outcomes as well as reducing patient and health care system costs.

I support utilizing PrismRA into my practice and have 1st hand experience in seeing how a therapy selection test like this can improve outcomes for RA patients. I support the coverage of PrismRA for my RA patients and hope that you overturn this NCD to an LCD so that we can stop this trial-and-error approach for RA patients.

Thank you considering my comments on this subject.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing to provide comments around Prism/RA, the first and only Molecular Signature Response Classifier (MSRC) test. I've been practicing rheumatology for over 30 years. Recently, I started incorporating PrismRA into my treatment paradigm for my RA patients. This test helps inform therapy decisions as it identifies patients that will likely have an inadequate response to TNFi therapies.

With joint damage typically occurring within the first two years of diagnosis, early treatment is crucial. The first treatment I choose is so important because if it's ineffective, the efficacy of subsequent medications is reduced. PrismRA gives me the opportunity to avoid the typical trial­ and-error approach in favor of treating my patients based on their individual biology. This test is also helpful when a patient has failed a TNFi and I have to decide whether to try another one or move to another mechanism of action.

I've seen the data that shows how PrismRA can improve outcomes and am excited that we now have a precision medicine tool available that will lead to better care and treatment of all rheumatoid arthritis patients.

Please grant coverage of PrismRA, so that rheumatoid arthritis patients have the best chance of preventing irreversible joint damage by getting on the right therapy as quickly as possible.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing Rheumatologist with over 15 years experience treating patients. Besides my private practice work, I am involved with many studies in many of the diseases that patients suffer. The purpose of this letter is to show support for PrismRA, the Molecular Signature Response Classifier for Rheumatoid Arthritis.

Since the introduction of the TNFis, there has been a dramatic positive change in treating RA patients. Still though, many patients still do not reach remission of this debilitating disease, and will progress with more joint damage and disability. Without a predictive test, I am left with a trial-and-error approach, which often has unsatisfactory outcomes for patients, causing the further progression of RA. PrismRA is the only test of its kind that is commercially available to prevent the trial-and-error approach.

Since the introduction of PrismRA, I have utilized the test on a number of patients. I have been impressed with the results of the test. Sometimes, the results have shown that TNF inhibition is the correct choice. Sometimes, the results have shown that another mechanism of action would be a better choice. I have used the results and have seen better patient care, which is most important.

Thank you for your consideration of my feedback, as I strongly support your adoption of coverage for the PrismRA test.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing to provide comments around Prism/RA, the first and only Molecular Signature Response Classifier (MSRC) test. As a practicing rheumatologist, I’ve found PrismRA to help inform my treatment decision when choosing a biologic for my rheumatoid arthritis patients. It does so by appropriately predicting inadequate response to all TNFi therapies in RA.

When treating patients, my goal is to get them into low or no disease activity in the shortest time-frame possible, especially since joint damage generally occurs within the first two years of diagnosis. Without PrismRA, I must choose a first-line biologic therapy based on a trial-and-error approach as opposed to considering a patient’s individual biology. I face the same challenge when switching a patient’s biologic. This method wastes time and money and increases the chance that subsequent therapies will be less effective once a patient has failed a given therapy. With PrismRA, we can improve outcomes and finally treat based on individual genetic make-up.

Peer-reviewed studies have supported PrismRA’s clinical validity and utility. As such, I’ve begun incorporating this valuable precision medicine tool into my clinical practice. I respectively request that you grant coverage of PrismRA, so that all rheumatoid arthritis patients have the best chance of preventing irreversible joint damage by getting on the right therapy as quickly as possible.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I'm a practicing rheumatologist with four years of experience. I work in a busy practice and treat multiple complicated auto immune diseases.

At present and in the absence of PrismRA, when treating my RA patients, I must choose a first­line biologic therapy without the appropriate tools that will help me match therapy to a patient's unique disease biology. It is a trial-and-error approach that more often than desired, wastes valuable time.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to TNFi therapies for patients with RA. It is intended for use by physicians to guide treatment decisions in RA adult patients with moderate to high disease activity who have not reached treatment disease activity objectives. The clinical validity of PrismRA has been documented in several peer reviewed studies and publications. In their latest clinical utility data, those patients who were identified as having an inadequate response to TNFi who were redirected to another mechanism of action experienced a near two-fold improvement in disease activity. Simply put, using the test to guide therapy selection for RA patients failing csDMARDs with get more patients to lower disease activity.

At present and without the availability of PrismRA, rheumatologists have no way of predicting whether a patient will respond to this class of drugs before they prescribe a TNFi therapy. A trial-and-error treatment approach does not tailor therapy to a patient's individual disease biology and can lead to poor outcomes. These poor outcomes include:

• response rates decline up to 35% after failing first line therapy
• there is a higher likelihood of irreversible joint damage and chronic pain which leads to increased surgeries
• increased use of pain meds and steroids
• time and money wasted on ineffective treatment

Both myself and my colleagues have been using PrismRA in our practice. We have firsthand experience in seeing how a precision medicine test can improve outcomes for patients struggling with RA. For instance, a seropositive RA patient who failed methotrexate. PrismRA allowed me to confidently use another biologic other than a TNF inhibitor after methotrexate failure. My patient is now in low disease activity.

I believe there is considerable evidence and clinical need for this kind of precision medicine test so that we can end the trial-and-error approach of treating RA patients and get their disease under control sooner. I strongly encourage you to approve coverage of PrismRA.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 18 years of experience in my own private practice.

Without a predictive test, I am left with a trial-and-learn/error approach. Prism RA is the only test of its kind that is commercially available to prevent a trial-and-error approach to treating patients with a biologic and informing me of the best therapy option. Using PrismRA allows me to individualize my treatment selections and gives me confidence in choosing either a TNF or an alternative therapy for my patients.

As published in clinical validation (CV) studies, the PrismRA test can accurately predict non-response to all TNFi therapies. In 174 samples from the prospective observational in the NETWORK-004 study of patients treated with TNFi therapies, the PrismRA test demonstrated (Jones A, 2021):

• Positive Predictive Value (PPV): 87.7% (95% Cl 78-94%). This describes the percent of patients with a molecular signature of non-response who will NOT reach ACR50 on a TNFi.
• Sensitivity (true positive rate): 60.2% (95% Cl 50-69%). This describes the percentage of true TNFi non-responders (those who do not respond, defend as having a 50% improvement/ACRS0 within 6 months on ACRS0) who are identified by PrismRA testing having a molecular signature of non-response.
• Specificity (true negative rate): 77.3% (95% Cl 65-87%) This describes the percent of true TNFi responders (those who respond based on ARS0) who did NOT have a molecular signature of non-response.

At present, rheumatologists like me have no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies without the use of the PrismRA test. Moreover, because RA is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to move to the next mechanism of action (MOA). PrismRA has helped me to individualize treatment. Some patients will not respond to TNFi therapies. By using PrismRA, I am confident in going to an alternative treatment. PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs.

Patients who are being treated with TNFi as first-line biologic therapy and fail will have increased ineffectiveness by the time they are able to move to the next drug class. Precision medicine tools, like a molecular signature response classifier (MSRC), provide insight that informs therapy selection. A molecular signature response classifier (MSRC) has helped me guide first-line therapy selection without a trial-and­ error approach.

Thank you very much for considering my comments in your decision.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

Rheumatoid Arthritis is a debilitating and devastating autoimmune disease. Getting patients on the right course of therapy early in this disease is of utmost importance. The joint damage caused by RA usually occurs within the first two years of diagnosis. Without a predictive test, we physicians are forced to use a trial-and-error approach to treat this disease.

PrismRA is the only test of its kind that I can use to prevent this approach. Like many oncologists have done for years, it allows us rheumatologists the ability to exercise precision medicine to predict therapy response to biologics for patients with RA. It saves my patients from unnecessary disease progression and medication costs for therapy that might not work for them.

The data that I have seen on PrismRA has been documented in several peer-reviewed studies and publications. The positive predictive value of the test is 90% in patients who have a molecular signature of non-response who will not reach ACR 50 on a TNFi, which is our goal of low disease activity. Rheumatologists like myself, have no way of predicting whether our patients will respond to this class of drugs in advance of prescribing TNF therapies without the use of PrismRA. I have used PrismRA on my patients and I feel it has helped me get more patients on the right MOA and into low disease activity.

Precision medicine tools, like a molecular signature response classifier, provide insight that helps informs therapy selection. I feel there is strong evidence and a clinical need to cover PrismRA so we can stop the trial-and-error approach to treating RA patients.

Thank you for considering my comments.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to formally comment on the Draft LCD: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis in support of the PrismRA test. I am a practicing rheumatologist with over 25 years of experience treating patients with rheumatic diseases. I have utilized PrismRA with hundreds of my patients, and the test has objectively allowed me to select biologics better suited for my patients. I firmly believe a positive LCD should be posted so patients starting their first biologic or targeted synthetic DMARD or considering a second TNFi after first-line TNFi failure can get on the right medication sooner with PrismRA.

With the resources and clinical assessments currently available to me and my patients, I am limited in my ability to start a patient on the correct therapy based on their disease biology. Without a predictive test, I am left with a trial-and-error approach to biologic DMARD selection. PrismRA is the only available test or clinical tool to prevent this approach to treating patients by informing me of the best therapy option. It has been critical in helping find the agent that will work for my patients, thus decreasing the chance of ongoing pain, swelling, stiffness, and irreversible joint damage. PrismRA also helps save the patient and the healthcare system time and cost from inefficient and ineffective treatments.

In addition to my firsthand experience with PrismRA and its impact on therapy selection in hundreds of my patients, the test's clinical validity is demonstrated in numerous peer-reviewed publications. In a clinical validation study, the PrismRA test identified TNFi non-responders with almost 90% accuracy (Per Jones et al., positive predictive value of 87.7%, sensitivity of 60.2%, and specificity of 77.3%). In four additional clinical validation cohorts, PrismRA predicted non-response to TNFi therapies with statistical significance across multiple outcome measures, including ACR50, ACR70, CDAI LDA, DAS28-CRP LDA, and EULAR good response (Cohen S, 2021; Zhang L, 2021; Strand V, 2022 (CU1); Strand V, 2022 (CU2)). This further demonstrates the robustness of its predictive capabilities.

I have implemented the PrismRA test into my practice and have seen firsthand how a predictive therapy selection test like PrismRA can dramatically improve outcomes for patients struggling with RA. I fully support and encourage other rheumatology clinics to do the same and provide PrismRA to their patients. There is strong evidence and clinical need to overturn this NCD to an LCD to stop the trial-and-error approach for targeted therapy selection and get our patients with RA on the right therapy sooner.

I appreciate your consideration.

References were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA, CGS, WPS and Noridian:

Scipher Medicine is pleased to provide the following comments in response to the Draft LCD MolDX: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. We appreciate your review of our application and consideration of our formal comments in support of LCD for PrismRA^®. Our data supports that PrismRA^® is a significant step forward for precision medicine in rheumatology impacting the outcomes of patients suffering with RA.

Scipher Medicine has continued to strengthen the depth of the clinical evidence package for PrismRA^® since our application. In our largest interim analysis of our clinical utility study, significant improvements in patient outcomes were seen when 489 patients (both TNFi naïve and exposed) using PrismRA^® were compared to an externally controlled standard of care arm (n=761, EHR-derived cohort). When PrismRA^® was used, 1.5-2.9 greater improvements in clinical outcomes at 6 months were observed compared with an external-EMR derived control group receiving standard-of-care (SOC) when PrismRA^® was not used.21 The clinical validity results of this study are consistent with prior studies and support the clinical utility of the test, demonstrating superiority in patient outcomes when treatment selection is guided by PrismRA^®.

As we heard on the public meeting, PrismRA^® has overwhelming support from practicing rheumatologists who have already incorporated PrismRA^® into their medical practice with decision impact resulting in meaningful value in patient care. PrismRA^® has demonstrated accurate prediction of non-responses to TNFi therapies with precision, reproducibility, and marked improvement in clinical outcomes in real-world settings. Our test has been retrospectively and prospectively analytically and clinically validated in over 800 patient samples and prospectively evaluated for provider treatment selection and clinical utility in over 900 patient samples, solidifying the value proposition of this innovative test. Over 45% of processed PrismRA^® tests year to date included Medicare-eligible patients.

This test is critical for providers and patients to have access to as it brings precision medicine to Medicare patients. We demonstrate meaningful impact to patient care by improving clinical outcomes in a six- month period after initiation of b/tsDMARD therapy or change in b/tsDMARD therapy.

We are requesting that you consider our application and formal comments to support an LCD for PrismRA^® for Medicare eligible patients. Addressing the critical unmet need: “A test that can accurately predict response would help inform therapeutic decision-making, lessen unnecessary trial-and-error approaches, eliminate or reduce the time to effective therapy, and improve patient outcomes.”

Medical Necessity for PrismRA^®

PrismRA^® provides critical value for patients and addresses an unmet medical need for precision medicine in RA, saving patients from unnecessary active disease, progressive, irreversible joint damage, increased risk of cardiovascular disease, cancer & death.

Prior to PrismRA^®, the treat-to-target approach for the management of patients with RA was accompanied by a trial-and-error approach when selecting therapies. Since this approach often fails to efficiently identify the most effective therapy, RA patients suffer prolonged, poorly controlled disease, irreversible joint damage, and an increased risk of cardiovascular disease, cancer, and death.^1-8 If the patient fails their first targeted therapy, they are less likely to respond to their next targeted therapy while increasing their risk of poor disease outcomes.^9,10 As it is critical for patients to be on the right therapy sooner, PrismRA provides needed value for physicians and patients, and addresses an unmet medical need for precision medicine in RA by informing the selection of a b/tsDMARD early during care, thereby leading to improved clinical outcomes.^16-21

Rheumatoid arthritis (RA) is a chronic, systemic, progressive inflammatory autoimmune disease. Inadequate control of RA, even in its early stages, results in chronic inflammation which can lead to joint damage, permanent disability and poor health outcomes, including shortened life expectancy.¹ Up to 70% of RA patients who are inadequately treated become disabled within 10 years.² Early and effective treatment for RA can slow disease progression, thereby preventing debilitating, irreversible long-term joint damage, reducing pain and disability.^3-7 The critical value for patients to begin appropriate and effective therapy early in care can be highlighted by the decline of therapeutic response rates up to 35% after failing first-line TNFi therapy along with increased rates of inpatient hospitalizations, emergency department visits, and risk of infections.^8-11 The 2019 European League Against Rheumatism (EULAR)¹² and 2021 American College of Rheumatology (ACR)13 guidelines recommend a treat-to-target (TTT) approach, emphasizing the need for rapid diagnosis and early appropriate treatment of RA patients with the goal of reaching LDA or remission.

Neither the 2019 EULAR¹² or 2021 ACR¹³ clinical guidelines provide guidance or recommendations on the preference between classes of biologic or targeted synthetic disease- modifying antirheumatic drugs (b/tsDMARDs) following the failure of a conventional synthetic DMARDs (csDMARDs). Physicians are presented with six different classes of therapies to select from as second treatment option and additional lines of RA treatment including tumor necrosis factor-alpha inhibitors (TNFi), Janus kinase inhibitors (JAKi), IL-6 inhibitors, a T-cell inhibitor, a B-cell inhibitor and IL-1 inhibitors. Despite this armamentarium of b/tsDMARDs for treatment of RA, meaningful response rates with TNFi therapies defined by ACR50 clinical responses at 6 months range between 27-38%.^14,15 Individualized precision medicine is needed to help guide physicians initiate therapies specific to each one of their patients, especially in RA when therapeutic responses vary depending on the selection of the b/tsDMARD and one particular therapy may have conflicting outcomes in different patients.

PrismRA^® is the only available precision medicine tool for physicians to predict if a patient will inadequately respond to TNFi therapy. In the absence of PrismRA^® to inform treatment selection, approximately two-thirds of RA patients could fail to achieve ACR50 responses, regardless of prescribed b/tsDMARD and therefore unlikely to reach treat-to-target goals.^14,15 Moreover, because RA is a progressive disease, patients that ultimately fail b/tsDMARDs may have incurred irreversible damage and disability by the time they are able to switch to an effective medication with a different mechanism of action (MOA). PrismRA^® helps patients avoid medications that will not provide the desired responses based on their unique biology;^16-21 thereby improving disease management and patient reported outcomes while reducing patient and health system costs.^24,25 PrismRA provides critical value for patients, addressing an unmet medical need for precision medicine in RA, leading to earlier control of disease and avoiding irreversible joint damage, increased risk of cardiovascular disease, cancer and death.^1,4-8

Scipher Medicine’s Data Package and references were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing Rheumatologist and a Professor of Clinical Medicine with over 25 years' experience treating patients. Besides my private practice work, I am heavily involved in the teaching of fellows the craft of treating patients with rheumatologic diseases. The purpose of this letter is to show support for PrismRA, the Molecular Signature Response Classifier for Rheumatoid Arthritis.

Rheumatoid Arthritis is a devastating autoimmune disease. Treating patients with this potentially deadly and debilitating disease early is important, as joint damage caused by RA generally occurs within the first two years of diagnosis. Up to 70% of patients with RA that are inadequately treated become disabled within 10 years. These poor outcomes are partially due to lack of precision medicine tools to determine which targeted biologic therapy would work best for the individual patient's disease. This fact is critical as there are different mechanisms that drive RA, so no 2 patients will be treated the same.

Since the introduction of PrismRA, I have utilized the test on a number of patients. I have been impressed with the results of the test. Sometimes, the results have shown that TNF inhibition is the correct choice. Sometimes, the results have shown that another mechanism of action would be a better choice. I have used the results and have seen better patient care, which is most important.

Thank you for your consideration of my feedback, as I strongly support your adoption of coverage for the PrismRA test.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing Rheumatologist over 25 years experience treating patients. The purpose of this letter is to show support for PrismRA, the Molecular Signature Response Classifier for Rheumatoid Arthritis.

Rheumatoid Arthritis is a devastating autoimmune disease. Treating patients with this potentially deadly and debilitating disease early is important, as joint damage caused by RA generally occurs within the first two years of diagnosis. Up to 70% of patients with RA that are inadequately treated become disabled within 10 years. These poor outcomes are partially due to lack of precision medicine tools to determine which targeted biologic therapy would work best for the individual patient's disease. This fact is critical as there are different mechanisms that drive RA, so no 2 patients will be treated the same.

PrismRA is the first and only commercially available Molecular Signature Response Classifier test that predicts inadequate response to all TNFi therapies in RA. PrismRA is intended for use by physicians to guide medical management decisions in RA adult patients with moderate to high disease activity who have not reached treatment disease activity objectives 1) on csDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change (including dose escalation or cycling to another TNFi).

Thank you for your consideration of my feedback, as I strongly support your adoption of coverage for the PrismRA test.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing with 40 years of experience in treating Rheumatoid Arthritis patients.

Rheumatoid Arthritis is a devastating autoimmune disease. Treating patients with this potentially deadly and debilitating disease early is important, as joint damage caused by RA generally occurs within the first two years of diagnosis. Up to 70% of patients with RA that are inadequately treated become disabled within 10 years (Burton W, 2006). As a Rheumatologist, we do not have a precision medicine tool available to determine which targeted biologic therapies will work best for our patient's disease, and without a predictive test, I am left with a trial-and-learn/error approach.

The data that I have read/see on PrismRA has been documented in several peer reviewed studies and publications. The positive predictive value of the test is close to 90% in patients who have a molecular signature of non-response who will not reach ACRS0 on a aTNF, which is our goal of low disease activity. Rheumatologists like myself, have no way of predicting whether our patients will respond to this class of drugs in advance of prescribing aTNF therapies without the use of PrismRA. Without a predictive test like PrismRA, I must use a trail-and-error approach to treat this disease. PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs.

I have used PrismRA to help inform my treatment decision and I feel it has helped me get my patients on the most effective therapy sooner and into low disease activity. I strongly support the coverage of PrismRA for my patients, and I believe there is strong evidence and clinical need to overturn this NCD to an LCD so that we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis.

Thank you for your consideration of my comments.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 38 years of academic and clinical experience and am one of the directors of a group of 14 clinical rheumatologists.

As I am sure you have heard from many others, the treatment of rheumatoid arthritis has evolved dramatically in the past 20 years, with an abundance of very effective, very expensive biologic medications that have altered the course of the disease. However, the decision making behind the choice of agents is for the most part arbitrary. Without a predictive test, we are left with a trial-and­ learn/error approach.

That situation had fortunately changed in the last year with the availability of PrismRA, the only commercially available test of its kind, to direct the choice of biologic therapy and inform the best therapy option. Using a precision medicine test, like PrismRA, to predict therapy response to biologics saves patients from suffering the consequences of unnecessarily active disease, and resultant progressive damage to joints, and expensive medication costs-to say nothing of unnecessary toxicity (Johnson KJ, Sanchez HN, Schoenbrunner N. Defining response to TNF-inhibitors in rheumatoid arthritis: the negative impact of anti-TNF cycling and the need for a personalized medicine approach to identify primary non­ responders. Clin Rheumatol. 2019 Nov;38(11):2967-2976. doi: 10.1007/s10067-019-04684-1.)

The consensus among our entire group is that PrismRA is an indispensable tool that should be used whenever considering biologic therapy to supplement methotrexate in treating patients with rheumatoid arthritis.

Thank you for your kind consideration.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

The Coalition of State Rheumatology Organizations (CSRO) is comprised of over 40 state and regional professional rheumatology societies whose mission is to advocate for excellence in the field of rheumatology, ensuring access to the highest quality of care for the management of rheumatologic and musculoskeletal disease. Our coalition serves the practicing rheumatologist.

Today, we write in response to proposed local coverage determination (LCD) under the Molecular Diagnostic Services (MolDX) Program titled, Molecular Biomarker Testing to Guide Targeted Therapy in Rheumatoid Arthritis. As the scope of the MolDX program covers several Medicare Administrative Contractor (MAC) jurisdictionsⁱ, LCDs established by the MolDX Program are of interest to most of the states and regions under the CSRO umbrella.

Proposed Non-Coverage Decision for Molecular Biomarker Testing to Guide Targeted Therapy in Rheumatoid Arthritis (RA)

In the proposed LCD, MolDX has concluded that “clinical validity has not yet been established for molecular biomarker tests that guide targeted therapy selection in RA.” On that basis, MolDX proposes non-coverage for emerging technologies in this space. This is disappointing considering that MolDX’s “[Contractor Advisory Committee] subject matter expert (SME) panelists noted that physicians would welcome predictive tests to guide targeted therapy in RA patients and find them useful if they could help minimize the trial-and-error approach of current therapy.”

Even with adherence to the American College of Rheumatology (ACR) Guideline for the Treatment of Rheumatoid Arthritis, identifying the most effective therapy involves a “try- and-fail” approach. After a patient fails conventional disease-modifying antirheumatic drugs (DMARDs), the current clinical evidence does not support initiating treatment with one biologic or targeted synthetic DMARD over another. Nevertheless, tumor necrosis factor inhibitors (TNFis) are the most frequent first-line biologic DMARD prescribed. This is despite the fact that approximately 30-40% of patients do not achieve a meaningful clinical improvement with this drug class. Unfortunately, because of insurer requirements (e.g., dose escalation, in-class cycling, etc.), moving to another mechanism of action is often challenging, meaning patients may spend an extended period of time on a therapy that will not work for them. The consequence to the patient is increased disease severity, disability, and pain, not to mention diminished quality of life and difficulty with activities of daily living.

It should be noted that sustained high level of disease activity is associated with increased costs now and in the future. Those patients with uncontrolled disease often require increasing doses of steroids leading to diabetes, infections, osteoporosis and a myriad of other well-known side effects. Looking to the future, RA patients with active disease can incur more joint replacements, heart attacks and even some malignancies which will lead to long term increases in costs.

Rheumatologists and our patients are desperate for solutions to this “fail first” or “fail harder” paradigm. Molecular biomarker tests are the first tool offering an objective, science-based approach to identifying appropriate medication therapies for RA treatment and management. Recent studies support the clinical validity and utility, and most rheumatologists and patients are eager to gain access to these precision medicine tools in clinical practice to improve outcomes in RA. The proposed LCD seems to suggest that such precision tools may never be available for RA patients, but that, in any event, the current approach is good enough. On behalf of our patients, we reject that assertion. Our colleagues in oncology have experienced remarkable growth in the field of genetically-driven precision diagnostics and therapies, which has greatly improved not only the survival rates but also the management of certain cancers. Our patients deserve no less in terms of proactive, data-driven disease management, but we are concerned that the proposed LCD sends the message that investment in this field is simply not worth it.

Given the aforementioned, our coalition urges you establish a local coverage policy and associated payment for the use of molecular biomarker testing to guide targeted therapy in RA with the following caveats:

• The ordering and interpretation of molecular biomarker testing in rheumatoid arthritis should be at the sole discretion of the treating rheumatologist.

• Patients who are stable on their medication should not be switched to a different drug or denied coverage of their current medication by the Medicare program, including Medicare Advantage, based on the results of molecular biomarker testing.

Thank you for considering the feedback of practicing rheumatologists.

References were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

This letter is in support of coverage for the PrismRA test. I have been a practicing rheumatologist for over 15 years.

Rheumatoid Arthritis is a devasting autoimmune disease. Getting patients on the right course of therapy early in the disease is so important. The joint damage caused by RA usually occurs within the first 2 years of diagnosis. Without a predictive test, I must use a trial-and-error approach to treat this disease. The prismRA test is the only test of its kind that I can use to prevent this approach. Using precision medicine, like PrismRA, to predict therapy response to biologics for patients with RA saves my patients from unnecessary disease progression, and expensive medication costs.

The data that I have read/seen on prismRA has been documented in several peer reviewed studies and publications. The positive predictive value of the test is close to 90% in patients who have a molecular signature of non-response who will not reach ACR 50 on a tNF, which is our goal of low disease activity. Rheumatologists like myself, have no way of predicting whether our patients will respond to this class of drugs in advance of prescribing TNF therapies without the use of PrismRA. I have used PrismRA on my patients and I feel it has helped me get more patients on the right MOA and into low disease activity.

Precision medicine tools, like a molecular signature response classifier provide insight that helps informs therapy selections. I fell there is strong evidence and a clinical need to overturn this NCD to an LCD so we can stop the trail-and-error approach to treating RA patients.

Thank you for considering my comments.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am providing comments today on behalf of the North Carolina Rheumatology Association (NCRA). I am an independent community-based rheumatologist and I have worked in the field of rheumatology for over 15 years.

The North Carolina Rheumatology Association mission is to promote the science and practice of rheumatology and advocate access to the highest quality health care and management of patients with rheumatic diseases.

With regards to predictive biomarker tests, NCRA fully supports the future use of these precision medicine tools as important tools to optimize the care of our patients with rheumatic diseases.

NCRA feels that the clinical data presented to demonstrate the clinical utility of the tests is sufficient to allow the use of these tests in clinical practice and further delay is not warranted or necessary.

Hopefully, these tools will continue to improve with time, but they are desperately needed now to improve quality of care and the clinical evidence presented to support this is more than sufficient.

Each trial of a TNF inhibitor in a patient who is unlikely to respond, is going to delay bringing the disease activity down and increase the risk of negative outcomes, let alone the potential risks or side effects to these medications, so it would be beneficial if a test can give a clinically validated prediction of response to this class of drugs. Even if this test changes the treatment algorithm for some, not all, of the patients, there are huge advantages both in terms of clinical outcomes and cost savings.

The fail-first methodology is the current imposed method of finding the appropriate treatment of RA. Where time vs. costs is a significant issue in controlling disease activity, predictive tests, based on available data, provide rheumatologists with an option to bypass this fail-first approach.

Furthermore, based on the review described in the Contractor Advisory Committee (CAC) meeting, the subject matter expert (SME) panelists commented; “insurance companies often require a trial of 1-2 TNFis before covering other targeted therapies. There was consensus that the requirement by insurance companies for patients to fail multiple TNFis prior to paying for an alternate targeted therapy is unreasonable.” This policy has nothing to do with the efficacy of these medications and more to do with driving patients to drugs with higher rebates.

Although this is not completely related to today’s discussion which we all agree should focus on the value of the tests themselves, it is important to recognize the positive impact that these tests will have for patient access and outcome, and cost reduction.

In conclusion, the North Carolina Rheumatology Association fully supports to use of predictive biomarker tests and urges MolDX to generate an LCD policy and allow coverage for the tests.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing to give my perspective of Prism/RA, the first, and only, Molecular Signature Response Classifier (MSRC) test that is commercially available to me and my patients and can appropriately predict inadequate response to all TNFi therapies in RA. This is a much-needed tool in the field of Rheumatology and, as I have grown more familiar with it, it has become more and more valuable to me and my practice.

In the absence of Prism/RA, I must choose a first-line biologic therapy without the appropriate tools that will help me match therapy to a patient’s unique disease biology. It is the same treatment dilemma when switching a patient’s biologic. Our goal is constant, to achieve low/no disease activity in the shortest time-frame. With the help of Prism/RA, informing our treatment decisions, this goal is much more readily achieved. We are finally able to treat based on each patients’ individual biology.

It is my sincere request that you reverse your decision to grant coverage of this invaluable tool. So many patients will benefit from this technology as it continues to develop and more of my colleagues become aware of the value it provides their patients. I am in strong support of using Prism/RA to guide treatment in my RA patients.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I have been in practice for many years.

I am writing in support of coverage of Prism RA molecular signature response classifier test which predicts which patients with rheumatoid arthritis are unlikely to respond to tumor necrosis factor inhibitor therapy.

As you know, TNF inhibitor therapy is considered first line treatment by most insurance companies for rheumatoid arthritis. This is a devastating disease which responds best to early treatment. Delay in appropriate treatment can have severe consequences for these patients. Joint damage occurs within the first 2 years of diagnosis. We have no other tools which predict which patient will respond to any particular treatment.

Prism RA is the only test of which I am aware which predicts an adequate response to all TNF inhibitor therapies and rheumatoid arthritis. This company developed a molecular signature of nonresponders to TNF inhibitor therapy with a strong predictive value and specificity as well.

Given the unnecessary cost involved in treating patients with inappropriate medication as well as potential side effects from drugs that they should not be on in the first place, this test appears to be an important tool in trying to determine which drugs should be given to which patients. It will save time which is to the patient's benefit, eliminate the use of drugs which may cause unnecessary side effects and hasten their response to appropriate medication which they would otherwise not have. Time is critical in treating these patients.

I strongly urge that PrismRA be an insurance covered test because of its predictive value for the reasons which I have cited above. We do not need to use a trial-and-error approach for targeted therapy when we have better tools available.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing physician with 37 years in the field of Rheumatology. I have seen the progress in my field with the use of biologic medications but at the same time have witnessed the inefficient choosing of some meds on a TRIAL AND ERROR BASIS. With the use of PRECISION PERSONALIZED MEDICINE, the PRISM RA test, and its future iterations for other rheumatic drugs, offers the physician and patient efficiency, speed and eliminates wasting time, money, suffering and expanded downstream costs of inadequate disease control. These include unnecessary complications of RHEUMATOID ARTHRITIS such as MACE EVENTS (heart attack and stroke) with their expensive care, hospitalizations morbidity, disability and potential death. Additionally, by employing AI assisted technology, the right drug for the right patient at the right time and a race to remission philosophy action plan can be implemented in alignment with VALUE BASED CARE AND RESULTS ON AN AT RISK POPULATION. Spending a bit up front saves a great deal both financially and in terms of adequate remission like or low disease activity patients with RHEUMATOID ARTHRITIS down the road.

These are just some of the reasons why the LCD FOR MOLECUAR TESTING FOR RA AND OTHER MOLECULAR SIGNATURE TESTING AND TECHOLOGY IN RHEUMATOLOGY should be covered. As a physician, I don’t want to be guessing if a drug is likely to work or not. My patients deserve this best in class technology just like the ONCOLOGY field currently employs in clinical practice to predict drug responses to different types of cancer RHEUMATOLOGY IS A FIRST COUSIN OF ONCOLOGY AND WE HAVE AN EXPANDING RHEUMATIC AND AUTOIMMUNE POPULATION that CMS will be insuring. The cost and outcomes efficiency must be in the direction of rapid results with respect to population health dynamics in achieving LOW DISEASE ACTIVITY AND NEAR REMISSION STATES AS FAST AS POSSIBLE TO REIGN IN BIOLOGIC COSTS AND ADD MORE PREDICATBILITY TO BIOLOGIC EXPENSES FOR RA AND PATIENT COHORTS. Spending a little up front will save a lot downstream in RA CARE IN THIS BURDEONING BIOLOGIC ERA WITH EXPANDING BABY BOOMER POPULATIONS.

MY ASK IS FOR THE LCD TO COVER MOLECULAR SIGNATURE TESTING AS A VITAL TESTING METHOD TO CHOOSE THE CORRECT DRUG BIOLOGIC OR bsDMARD DRUG FOR THE MODERATE TO HIGH DISEASE ACTIVITY RA PATIENT

I have included some references below confirming or speaking to the clinical validity and ongoing expansion of knowledge using this testing method for RA drug therapy choice selection.

References were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

Thank you for the opportunity to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis.

I have been practicing rheumatology for over 25 years with a special interest in lupus, osteoporosis, arthropathy, and rheumatoid arthritis.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. It is meant to guide rheumatologists in our medical management decisions as we treat our adult RA patients (18 years or older) with moderate to high disease activity. It is appropriate, not only for patients who have never been on a biologic, but also for those who are on a biologic and may need to switch to another.

I have seen first-hand how patients have benefited from this important test. Simply put, PrismRA, saves patients time and money by avoiding therapies they may never respond to. Additionally, it helps prevent unnecessary joint damage that can occur while patients are cycling through these medications. PrismRA lets me do what is best for my patient earlier in the course of their disease.

Thankfully, I have had access to PrismRA for two years. In that time, I’ve been able to choose a more precise treatment pathway for my patients. The result is that they have reached a goal of low disease/no disease activity much faster.

I kindly ask that you provide coverage for PrismRA. It is a valuable tool that every RA patient should have access to, and every rheumatologist should be encouraged to use.

Thank you for your consideration.

References were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to weigh in on the Draft Local coverage decision. I am a practicing Rheumatologist with 30 years of experience treating RA patients.

When it is time for me to start my RA patients on a biologic therapy I have to make this choice without a predictive test or clinical assessment that lets me know the right biologic for my patient. It is a trial-and-error approach. The PrismRA test informs which biologic class is the best to start. My goal is getting these patients into low disease activity and utilizing PrismRA has helped me get my patients there.

PrismRA is the first and only Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. The Clinical Validity (CV) has been documented in several peer reviewed studies and publications. I have seen the data.

Without the use of PrismRA I have no way of predicting whether a patient will respond to this class of drugs in advance of using a TNFi therapy. PrismRA helps me steer my patients away from medications that will not work based on their biology. It has improved my disease state management and patient outcomes as well as reducing patient and health care system costs.

I support utilizing PrismRA in my practice and have firsthand experience in seeing how a therapy selection test like this can improve outcomes for RA patients. I support the coverage of PrismRA for my RA patients and hope that you overturn this NCD to an LCD so that we can stop the trial-and-error approach for RA patients.

Thank you for your consideration of my comments on this subject.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I wish to comment regarding the proposed LCD to not allow coverage for PrismRA, a blood test that predicts certain patients with rheumatoid arthritis who may not respond well to medications that block TNF. I am a practicing rheumatologist over 20 years of clinical practice and 20 years of involvement in clinical trials, largely involving the treatment of RA. We have made great strides in the treatment of our RA patients, with the goal of getting patients on DMARD therapy such as MTX within several months of symptom onset and following the ACR recommended treat to target decision making tree, with the goal of low disease activity or remission. The results of this approach have been remarkable, as we are able to reach this goal in approximately 60% of our patients, greatly improving daily activities and productivity, lowering overall healthcare costs of RA patients, and drastically decreasing long-term complications of RA including chronic, irreversible lung disease, cardiovascular complications, strokes, and lymphoma. While we have made great strides, our ongoing challenge is deciding upon which biologic treatment to choose in the patient population not meeting target treatment goals on traditional DMARD therapy. This is crucial, as data shows that patients who do not achieve low disease activity or remission within the first 6-12 months of treatment are much less likely to ever reach this goal. Consequently, these patients that do not achieve treatment targets early in their course are more likely to suffer from unnecessary and preventable complications of rheumatoid arthritis as mentioned above, and their healthcare costs greatly increase, including the need for joint replacement related to long-term disease activity, not to mention cost to society from loss of productivity. Part of our current challenge is making the correct initial treatment choice of biologic, which to date is essentially trial and error. Although we know that the specific inflammatory cytokine that is driving our rheumatoid patients’ disease differs from patient to patient, our ability to choose treatment based upon objective markers is minimal. Once the decision is made to start a biologic, it typically takes approximately 3 months to assess efficacy; it may take 6 months to achieve maximum benefit. If a TNF blocker is the preferred biologic agent based upon a patient’s insurance plan, and in many cases a trial with a 2^nd TNF blocker is required before changing mechanisms of action, then that patient is nearing the end of the window when low disease activity or remission is a feasible goal by the time they have the opportunity to start a therapy more precise for their genetic signature.

PrismRA is not a perfect test (no test in rheumatology is,) but data shows that proper usage in patients that have failed traditional DMARD therapy could greatly shorten the time period to treatment target. Although one may question whether the test is medically necessary, it is a medical necessity to avoid unnecessary exposures to side effects of medicines, especially if there is foreknowledge that therapeutic benefit of a specific medicine may be suspect. Cost of the test, which should only be performed once in the life of the patient, is much less than the cost to the medical system of a moderate to high disease activity RA patient, which this test could help prevent. Thank you for your reconsideration regarding the payment for this test, and potentially helping a greater percentage of our patients achieve life-changing control of their disease.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing to you of the great utility of PrismRA testing in my solo practice of rheumatology. Rheumatoid Arthritis is a devastating chronic deforming polyarthritis that affects 1 % of the US population. Most of the patients i see have moderate to severe rheumatoid arthritis. Although Methotrexate and biologics have revolutionized the treatment of rheumatoid disease, there is still considerable trial and error in selecting the best first biologic to treat rheumatoid arthritis. The PrismRA test is the first precision medicine test to eliminate anti-TNF therapy if patients are genetic non-responders. i have utilized this test in 50 patients and found it useful in my decision making in choosing the right biologic for mechanism of action. It has saved patients from 3-9 months of wasted time and expense when anti-TNF therapy is not going to work. I would strongly urge coverage for this molecular signature test to avoid inappropriate prescribing of anti-TNFs which tend to be chosen first.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing this letter in support of the Prism/RA test. I have been in practice for over 33 years.

As a rheumatologist, I have always had to use a trial-and-error approach with my patients to see which drug would work best. Ever since Prism/RA, I am able to make an educated decision on a treatment plan for my patients based on their individual molecular signature. By following the results of this test, I am able to get my patients on the right drug faster, which means they can hopefully achieve remission even sooner.

I have personally seen how well this test has helped my patients. I had a patient that had been doing well for a while on Humira, after a short period of time, she did not seem like she was improving or getting down to a low disease activity. The insurance company wanted me to use another TNF and I thought maybe she would do well, since she did mildly responded to the first one. I ran the Prism/RA test, and when the result returned High Non-Respondent, I quickly switched to a different MOA and prescribed Rinvoq. She is doing extremely well now. If it wasn’t for the Prism RA test, that patient would probably still be on a TNF, still in pain, and with bone and joint deterioration still occurring.

For the first time, we as doctors have some hard evidence to help us fight the insurance companies to advocate for the best plan of treatment for our patients, which in turn can help lower overall healthcare costs. If this test can get our patients to a low disease state in 6 months, I consider that a huge win for RA patients. There is nothing else out there that compared to this test, and for that reason, I hope this test gets covered, sooner than later.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 7 years of experience. Currently working there are a plethora of medications that I start to think about starting a patient on but have no way of knowing if they will respond to the medicine until I receive the results of the test.

Currently (in the absence of PrismRA), I must choose a first-line biologic therapy without the appropriate tools that will help me match therapy to a patient’s unique disease biology. Without a predictive test, I am left with a trial-and-learn/error approach. PrismRA is the only test of its kind that is commercially available to prevent a trial-and-learn/error approach to treating patients with a biologic and informing me of the best therapy option.

At present, rheumatologists like me have no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies without the use of the PrismRA test. Moreover, because RA is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to move to the next mechanism of action (MOA). PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs. I support utilizing and implementing the PrismRA test into my practice and have firsthand experience in seeing how a therapy selection test like PrismRA can improve outcomes for patients struggling with RA. I believe there is strong evidence and clinical need to overturn this NCD to an LCD so that we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

We request that the decision of non-coverage for PrismRA be overturned.

PrismRA is the first tool of its kind, delivering previously unattainable insight into a patient's biology. These insights help guide the care we deliver to patients. Our practice, very early on, entered patients into the Accelerate Information of Molecular Signatures (AIMS) research registry. When PrismRA was launched as a commercial product, we were excited to use it for patients who were not appropriate for clinical research because we feel the information provided by the test is actionable and needed to guide our first-line targeted therapy decisions. Our providers and our practice support the use of PrismRA and feel that it is a unique, insightful tool that should be available for all our patients.

Included below is a summary of some of the recent data we have found to be impactful in our decision to support PrismRA.

The AIMS study reported clinical outcomes of patients at 12 weeks (n=470) and 24 weeks (n=274) during an interim analysis. Absolute changes in clinical disease activity index (CDAI)scores from baseline were reported at both time points and stratified by test result and treatment received. CDAI is endorsed by the American College of Rheumatology as a disease activity measure to be used in the ongoing monitoring of rheumatoid arthritis patients.

• Patients with a prediction of non-response to TNFi who received a b/tsDMARD with an alternative mechanism of action experienced 1.8-fold greater improvements in CDAI scores than those treated with a TNFi
• In patients with a molecular signature of non-response to TNFi in high disease activity at baseline, this corresponded to 43.2% relative improvement in achieving a lower CDAI level when likely TNFi non-responders were treated with a non-TNFi therapy (38.9% vs. 55.7%)

In summary, we have found PrismRA to be a reliable and efficacious addition to our practice. We support its use and ask that it be available to all patients. It delivers insights that are not attainable through any other method and as such we believe it to be uniquely positioned to help guide our care for patients with RA and improve patient outcomes.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I’m writing this email to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist over 15 years of experience.

Currently, with the lack of available resources and clinical assessments, I’m limited in the ability to start a patient on the drug that’s most appropriate to them based on their unique disease biology.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. PrismRA is intended for use by physicians to guide medical management decisions in RA adult patients with moderate to high disease activity who have either not reached treatment disease activity objectives 1) on csDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change. (This includes dose escalation or cycling to another TNFi).

At present, or at least prior to the availability of PrismRA, rheumatologists like me had no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies without the use of the test. Furthermore, because RA is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to move to the next mechanism of action (MOA). PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs.

Patients who are being treated with TNFi as first-line biologic therapy and fail will have increased ineffectiveness by the time they are able to move to the next drug class. Precision medicine tools, like a molecular signature response classifier (MSRC), provide insight that informs therapy selection. A molecular signature response classifier (MSRC) has helped me guide first-line therapy selection without a trial-and-error approach.

I strongly support the coverage of PrismRA for my patients.

Thank you for your consideration of this matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I’m writing to you today on behalf of the American Arthritis and Rheumatology Associates (AARA) powered by Bendcare to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. Bendcare is a leader in the rheumatology market by delivering real-world technology, specialty practice management and research solutions that return control to physicians and patients, improving quality and outcomes resulting in cost-effective care.

AARA is the largest rheumatology group in America with over 350 health care providers across the nation currently practicing in 25 states. On average, we treat 55,000 patients with rheumatoid arthritis (RA) per year. AARA physicians and our affiliates are empowered to optimize the delivery of Rheumatologic care. We never stop searching for and providing personalized and innovative therapies to heal the whole person and improve quality of life for our patients.

We are innovative in our approach to treating patients with RA and have been involved in the clinical development of PrismRA. We have 93 care centers and 143 providers currently utilizing PrismRA to inform treatment selections for patients with Rheumatoid Arthritis either initiating their first biologic therapy or are failing a TNFi and need to change therapy. We have over 3,700 patients that have been tested as part of clinical research. Therefore, the decision of non-coverage from MolDX regarding PrismRA came as a surprise. Currently rheumatologists do not have a test or clinical assessment that can inform them of the right biologic for their patients. Without a predictive test we are left with a trial-and-error approach when making medical management decisions. Uncontrolled RA causes more than joint damage, it can damage organs such as the heart and lungs and many patients with RA who aren’t adequately treated become disabled within 10 years. We waste valuable time with a trial-and-error approach.

Currently AARA providers have ordered over 1,100 PrismRA tests to inform treatment selection for patients. When PrismRA is followed we experience better clinical outcomes. The Clinical Validity (CV) of PrismRA has been documented in several peer reviewed studies and publications. In a CV study, the PrismRA test identified a molecular signature of non-response to TNFi therapies with a positive predictive value (PPV) of 87.7% (95% confidence interval [CI] 78-94%), sensitivity of 60.2% (95% CI 50-69%), and specificity of 77.3% (95% CI 65-87%) (Jones A, 2021). Furthermore, in four separate validation cohorts, the PrismRA test predicted non- response to TNFi therapies with statistically significant odds/ratios across multiple outcome measures commonly used in RA, including ACR50, ACR70, CDAI LDA, DAS28-CRP LDA, and EULAR good response (Cohen S, 2021; Zhang L, 2021; Strand V, 2022 (CU1); Strand V, 2022 (CU2)). Patients who are being treated with TNFi as first-line biologic therapy and fail will have increased ineffectiveness by the time they are able to move to the next drug class. Precision medicine tools, like the PrismRA test, provide insight that informs therapy selection.

We at Bendcare believe there is strong evidence and clinical need to overturn this NCD to a favorable LCD so that we can stop the trial-and-error approach to therapy selection for patients with RA and get them on the right therapy sooner.

We respectively request Medicare coverage for the PrismRA test. Thank you for your time and consideration.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

This letter is written to you to support hopefully Medicare's approval all of the prism blood test.

I have found this test to be very useful along with ordering a cytokine panel measuring my patient's tumor necrosis factor level.

Almost all patients who come to me on a TNF inhibitor and who complain of not doing well correlates with the prism test showing that they would be a poor responder.

I think this test would be very helpful in people with rheumatoid arthritis and other autoimmune diseases who are treated with TNF inhibitors.

I thank you in advance.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I’m emailing you to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 20 years of experience.

In the absence of PrismRA, I must choose a first-line biologic therapy without the appropriate tools that will help me match therapy to my patient's unique disease biology. Using a precision medicine test to predict therapy response to biologics for patients with rheumatoid arthritis saves patients from unnecessary active disease, progressive and possibly irreversible joint damage, and expensive medication costs.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. The test is intended for use by physicians to guide medical management decisions in RA adults with moderate to high disease activity who have either not reached treatment disease activity objectives 1) on csDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change.

At present, without the use of PrismRA, rheumatologists like me have no way of predicting whether a patient will respond to this class of drugs before prescribing TNFi therapies. And because RA is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to move to the next mechanism of action. PrismRA helps me guide patients away from medications that will not work based on their unique biology, improves disease management and patient outcomes, and reduces patient and overall healthcare system costs.

I support utilizing PrismRA and have firsthand experience in seeing how a therapy selection test like PrismRA can improve outcomes for patients struggling with RA. I believe there is undeniable evidence and a clinical need to cover this valuable test so that we can stop the trial-and-error approach for targeted therapy selection for patients with RA and get them on the right therapy sooner.

Thank you for your consideration of this matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

As a practicing rheumatologist with almost 30 yr. experience in TREATING patients with RA, a debilitating and chronic heterogeneous disease, I find the most challenging task to find the right treatment for each patient which unfortunately has been a trial-and-error approach since we have not been able to predict response to different treatment options.

We now have PrismRA a molecular signature response classifier to guide our treatment option and avoid wasting time which can cause more joint damage and disability for the patient and money spent by insurance/prescription coverage in prescribing therapies that might not work i.e. TNF inh. which are frequently requested as a first treatment (sometimes 2 drugs).

Be aware that approximately 60 % of patients with RA inadequately treated early can become disabled within a few years.

As a rheumatologist treating many patients with RA, I encourage you to establish coverage to Medicare patients for MSRC testing to ease guiding treatment with more precision.

I strongly believe along with my colleagues THAT THIS TYPE OF TEST WILL HELP IMPROVE PATIENT CARE AND PROBABLY BE MORE COST EFFECTIVE.

THANK YOU FOR YOUR CONSIDERATION.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the draft coverage decision. I have been in practice for over 10 years.

Rheumatoid Arthritis is a devastating autoimmune disease. Getting patients on the right course of therapy early in this disease is so important. Before the PrismRA test, I was limited in my ability to start a patient on the right biologic for my RA patients. I have now used the PrismRA test to guide me better on the treatment of my RA patients. I do not have to use the trial-and-error approach anymore. My goal is to get my RA patients in remission/low disease activity as soon as possible because this is a horrible disease where up to 70% of these patients that are inadequately treated become disable within 10 years.

The data that I have read on prismRA has been documented in several peer reviewed studies and publications. The positive predictive value of the test is close to 90% in patients who have a molecular signature of non-response who will not reach ACR 50 on a Anti Tumor Necrosis Factor. Precision medicine tools, like a molecular signature response classifier provide insight that helps informs therapy selection.

I support using prismRA in my practice and have firsthand experience in seeing how this test can improve outcome for my patients struggling with RA. I support the coverage of PrismRA for my RA patients and hope that you overturn this NCD to an LCD so that we can stop this trial-and-error approach for RA patients.

Thanks for considering my comments on this matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis.

I am a rheumatologist who has been practicing since 2002. Rheumatology is becoming an increasingly exciting field with advent of new medications in the last 20-25 years. The idea has been to diagnose rheumatoid arthritis early and the approach is to follow the principal of “Treat to Target ‘. Optimum treatment of rheumatoid arthritis is necessary to prevent serious systemic complications of this disease on the eyes, heart, skin, nerves, lungs etc. Impact of rheumatoid arthritis on employment status is well known as Rheumatoid Arthritis has become a major cause of limiting work productivity in employees. For this reason, controlling inflammation and thereby pain in rheumatoid arthritis is of immense national importance. It has become one of the major causes of disability in this country.

In the last 20 years the world of rheumatology has been revolutionized by the advent of biologics which target the cytokines that cause inflammation in rheumatoid arthritis. All of these are very costly drugs. TNFi therapies were the first biologics that came out and has been tried all over the world with variable success. Traditionally, rheumatologists have been using different biologics on patient in a blind manner, depending on what they are familiar with and depending on what the patient’s insurance mandates. PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. PrismRA is intended for use by physicians to guide medical management decisions in RA adult patients (18 years or older) with moderate to high disease activity whose treatment has not yet been optimized with conventional DMARDs and are considering starting a biologic DMARD or small molecule or are considering a targeted therapy change (including dose escalation or cycling to another TNFi).

Because this genetic molecular signal test predicts which patient will respond to which biologic, it has become of utmost importance to us in the field of rheumatology. In addition, millions of dollars will be saved if we can treat the patient with the targeted biologic, as guided by this test.

Currently, many health insurances are not paying for this test. For the above-mentioned reasons, I urge you to consider adding this to the armamentarium of blood tests use to monitor rheumatoid arthritis.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I like Prism RA. I feel it is a beneficial tool for the providers and the patients in selecting the best plan of care.

Prism RA is a tool Rheumatologist need and there is nothing comparable for us to determine if patients would be a non responder to the class of TNFi therapies.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I'm writing this email to vouch my support for the molecular signature test, PrismRA. I'm a practicing rheumatologist with 22 years’ experience. I have found Prism RA to be very helpful in my practices as it is the first precision medicine tool available to rheumatologists. have used this test to help me decide which biologic is most appropriate for my rheumatoid arthritis patients. I no longer am forced to use the trial-and-error approach.

I think Prism RA should be covered by Medicare as there is strong clinical evidence and a great need in rheumatology.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

This is a letter in support of Medicare coverage for the Molecular Signature Response Classifier, PrismRA. I'm a rheumatologist with 40 years of experience treating autoimmune disorders. With the current available clinical assessments, I don't have the appropriate tools that will help me match therapy to a patient's unique disease biology. The PrismRA test can predict inadequate response to all TNFi therapies for my rheumatoid arthritis patients.

Being that RA is a progressive disease, the current trial and error approach can often lead to increased joint damage and/or disability. I've used the PrismRA test to help combat that issue. The results I have received have provided guidance as to which targeted therapy is most appropriate for my RA patients. All this to say, I greatly support Medicare coverage for PrismRA.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I'm writing this letter to show my support for the PrismRA test. I'm a Nurse Practitioner in Rheumatology. Without PrismRA, I have been limited in my ability to properly choose the most appropriate drug for my RA patients. A lot of the time, I'm just trying each drug to see which one works best. Once I learned about PrismRA and the test's ability to predict whether a patient will respond to TNFi therapies or not, I have been able to implement precision medicine into my treatment plans.

In my experience with PrismRA, I have received both types of results- some indicating response to TNFi, and some indicating non-response to TNFi. Both types of results have been helpful in my decision of which targeted therapy to choose for my patients. Ultimately, PrismRA has enabled me to more efficiently treat my patients and more importantly, limit progressive joint damage.

This blood test helps me steer patients away from medications that will not work for them and helps me get them onto the right medication faster. I fully support the coverage of PrismRA.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing Rheumatologist and I would like to provide you a letter in support of PrismRA. Rheumatologist such as I have been waiting for a tool to help guide decisions when it comes to prescribing bDMARDs. At present, rheumatologists like me have no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies without the use of the PrismRA test. Moreover, because RA is a progressive disease, patients that ultimately fail bDMARDs may have increased disability by the time they are able to move to the next mechanism of action (MOA). PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs.

I support utilizing and implementing the PrismRA test into my practice and have firsthand experience in seeing how a therapy selection test like PrismRA can improve outcomes for patients struggling with RA. I believe there is strong evidence and clinical need to have PrismRA available to help guide decisions so we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner for better outcomes.

I fully support the coverage of PrismRA to help guide treatment decisions to help patients get better sooner to avoid disease progression and cost to the patient and health care system.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing physician assistant with 11 years of Rheumatology experience.

Prior to the availability of PrismRA, I was forced to choose a first-line biologic therapy without evidence-based medicine and did not have the appropriate tools to help me match therapy to a patient’s unique disease biology.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. PrismRA was specifically developed for physicians to use to guide medical management decisions in RA adult patients (18 years and older) with moderate to high disease activity who have either not reached treatment disease activity objectives 1) on csDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change (including dose escalation or cycling to another TNFi.

At present, all of us practicing rheumatology have no way of predicting whether a patient will respond to this class of drug in advance of prescribing TNFi therapies without the use of the PrismRA test. Moreover, because RA is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to move to the next mechanism of action. PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs. Otherwise we are left to trial and error with medications which frequently leads to increased morbidity and ultimately increased cost of treatment.

I encourage utilizing and implementing the PrismRA test into my practice and have firsthand experience in seeing how a therapy selection test like PrismRA can improve outcomes for patients struggling with RA. I believe there is strong evidence and clinical need for PrismRA so that we are able to stop the trail-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner.

Thank you for your time and attention to this critical matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on your decision to cover the PrismRA blood test and the importance of providers having access to such tests. I am a rheumatology Physician Assistant and have been practicing rheumatology for over 10 years.

When treating RA patients, we must choose a therapy with a trial-and-error approach. We do not have the tools that will help us match therapy to a patient’s unique disease biology. This leads to valuable time lost when treating this devastating disease. This can lead to disease progression, joint damage and increased morbidity for the patient.

Having a test like PrismRA can help me get my RA patients on the right course of therapy because it can inform me if my patient will not respond to a TNF inhibitor. Getting my RA patients on the right course of therapy earlier is likely to lead to better outcomes. This will save my patients from unnecessary active disease (which will lead to joint damage), and expensive medication costs.

I have seen the data on PrismRA in peer reviewed studies and publications. The validation studies show a positive predictive value (PPV) close to 90% for patients with a molecular signature of non-response who will not respond reach an ACR 50 on a TNFi. I have used PrismRA in my practice and I believe it has helped me get more of my patients into remission because I am getting them on the right class of drugs sooner in their disease.

I hope that your decision will be to cover PrismRA. We need precision medicine tools, like PrismRA because it gives us insights on our RA patients and helps us make better treatment decisions and better patient outcomes.

Thank you for your time and consideration.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing rheumatologist. I am writing in regard to the MolDX local coverage decision (LCD) draft and to express my support for use of the molecular signature response classifier (MSRC) PrismRA in the management of rheumatoid arthritis.

In the rheumatology world, personalized medicine that utilizes patient-specific factors including genomic data in order to match individual patients to best therapies has long been considered a "holy grail" in the management of rheumatoid arthritis. The need for a personalized medicine approach in RA management is clear: RA is a devastating autoimmune disease that causes significant morbidity and irreversible joint damage if not well-controlled, and yet only ~30% of RA patients will reach the goal of disease remission or low disease activity with methotrexate alone, thereby necessitating progression to biologic or targeted DMARD therapy (O'Dell, J.R., et al., 2013; PMID 23755969). Moreover, over 40% of RA patients placed on a b/tDMARD will fail to achieve or maintain the goal of remission/low disease activity with their first b/tDMARD, which leads to increased rates of disease morbidity, joint damage and healthcare costs (Youssef, P. et al., 2020; PMID 31787605). Given the above, a tool that could help rheumatologists identify (i.e. personalize) specific classes of b/tDMARDs that are best suited to an individual RA patient’s disease would be a tremendous boon to the management of RA, helping patients achieve better/more rapid disease control and thereby reducing disease morbidity, joint damage and healthcare costs.

Prior to PrismRA, there were no commercially available tests that could help rheumatologists select specific classes of b/tDMARDs that would be best suited to an individual RA patient. Consequently, selection of a specific b/tDMARD for RA patients has hitherto been a trial-and-error approach that is unguided by patient-specific genomic factors. Given the growing number of FDA-approved b/tDMARDs for RA-as well as the rise of numerous biosimilar agents—there is now more need than ever for a tool to help rheumatologists select the best DMARD option for an individual patient.

PrismRA is a one-time blood test that utilizes patient-specific information—including 10 single-nucleotide polymorphisms and 8 gene transcripts—to predict inadequate response to all TNF inhibitor (TNFi) agents in an individual RA patient. As such, PrismRA represents a paradigm shift in the management of rheumatoid arthritis that introduces a personalized medicine approach to this devastating disease. By accurately identifying individual RA patients that are unlikely to respond to TNFi agents, PrismRA enables rheumatologists to select b/tDMARDs with alternative mechanisms of action (MOA) that will more rapidly and effectively control an individual patient’s disease while bypassing ineffective—and often very expensive—therapies.

PrismRA has been well demonstrated to accurately predict TNFi inadequate response in RA patients in multiple peer-reviewed publications. In the Network-004 study, of the 78 b/tDMARD-naïve patients who had a signal of TNFi non-response on PrismRA and were then treated with a TNFi agent, only 4 patients (5.1%) successfully achieved CDAI remission by 6 months. In contrast, of the 68 b/tDMARD-naïve patients who did not have a signal of TNFi non-response on PrismRA and were then treated with a TNFi agent, 22 patients (32.4%) successfully achieved CDAI remission at 6 months (Cohen, S., et al., 2021; PMID 34148193). In published data from the ongoing AIMS prospective observational study, RA patients who had a signal of TNFi non-response on PrismRA and were then treated with a TNFi agent had significantly lower ACR50 response at 6 months compared to patients who did not have a TNFi non-response signal on PrismRA (10.3% v. 45.8%; p=0.005). Moreover, when patients who had a signal of TNFi non-response on PrismRA were treated with a b/tDMARD with an alternative MOA, their ACR50 response at 6 months was significantly superior (34.8% v. 10.3%; p=0.05) (Strand, V., et al., 2021; PMID 34937469). Together, these results demonstrate that PrismRA is capable of accurately identifying individual RA patients who are very unlikely to respond to TNFi agents, thereby allowing such patients to be directed to alternative b/tDMARD options with other MOAs.

The above study results closely align with my personal experience using PrismRA. To date, I have utilized PrismRA in more than 50 of my b/tDMARD-naïve RA patients, and I have found that a significantly higher percentage of such patients are able to achieve the goal of disease remission or low disease activity with their first b/tDMARD when I make treatment decisions informed by PrismRA. In my experience, patients are unwaveringly enthusiastic about the concept of using the personalized medicine approach employed by PrismRA to guide therapeutic decisions in their RA management. Patients recognize that personalized medicine already exists in other fields such as oncology and psychology, and they readily welcome the advent of personalized medicine demonstrated in PrismRA in the field of rheumatoid arthritis.

In conclusion, PrismRA represents an exciting and desperately needed tool for bringing personalized medicine to the management of rheumatoid arthritis. By leveraging patient-specific factors including genomic data to identify individual RA patients who are very unlikely to respond to TNFi agents, PrismRA helps rheumatologists direct such patients to b/tDMARDs with alternative MOAs, thereby achieving more rapid/effective disease control. This leads to RA patients who are happier and healthier, while also reducing healthcare costs by avoiding unsuccessful treatments.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing to provide comments around Prism/RA, the first and only Molecular Signature Response Classifier (MSRC) test. As a practicing rheumatologist for more than 50 years, I’ve seen how much the care and treatment landscape has evolved in that time for RA patients. PrismRA is the latest tool that helps me choose a biologic based on a patient’s unique biology. It does this by appropriately predicting inadequate response to all TNFi therapies in RA.

Prior to PrismRA, I was forced to choose a first-line treatment based on a trial-and-error approach, or worse, based on what insurance dictates. I always aim to get patients into low or no disease activity as quickly as possible. Unfortunately, due to ineffective treatments or insurance requirements, that result can be delayed. In the meantime, patients may have sustained additional joint damage. The same problem exists when I need to switch a patient’s biologic. This trial-and-error approach wastes valuable time and money, especially since patients lose efficacy with each subsequent medication.

Peer-reviewed studies support PrismRA’s clinical validity and utility. Using the test significantly improves clinical outcomes as measured by CDAI and ACR50. I’ve started using it and it’s already helped guide my therapy choices.

PrismRA is finally a step toward precision medicine where I can prescribe a biologic based on a patient’s individual biology. I respectively request that you reconsider coverage of PrismRA, so that all rheumatoid arthritis patients have the greatest chance of success as quickly as possible.

Thank you for your consideration.

References were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practitioner and I would like to send this letter to support complete coverage of the Molecular Signature Response Classifier, PrismRA. This is a unique and novel test with no similarity or overlap with any other available test. For many years, rheumatologists and practitioners within rheumatology have been waiting for a tool to provide patient specific results, unique to each patient, to direct therapy and reach low disease activity in a quicker and more efficient manner. In our industry, entrenched contracts within insurance typically dictate a "one size fits all" approach to choosing therapy. Before PrismRA, there was no other method to predict whether a patient would respond to our biggest class of biologic therapy utilized to treat RA.

PrismRA has the benefit of extensive clinical validity and utility studies which have empowered my usage of the test. When a patient is ready to begin a biologic, I use PrismRA to decide whether they are an appropriate candidate for a TNFi mechanism of action drug. I have used this to save patients time, money, and give them back their lives.

This test empowers practitioners and is fundamentally necessary for treating our patients. It should be widely available and completely covered. There is no other test currently available with the same utility.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I wish to comment regarding the proposed LCD to not allow coverage for PrismRA, a blood test that predicts certain patients with rheumatoid arthritis who may not respond well to medications that block TNF. I am a practicing rheumatologist. I have done clinical trials for essentially all my 38 years of practice and can confirm the amazing progress that has been made in the diagnosis and treatment of rheumatic diseases. One of my observations regarding this metamorphosis relates to the Informed Consent documents for clinical trials. At the beginning of my practice, the informed consent document (ICD) was a simple form that briefly describe the trial and asked written permission for participation. Now, many of the therapeutic trials have 3 separate ICFs; one to do the trial, the second concerns pharmacokinetics, and the third addresses pharmacogenomics. This expansion of the ICF process is a direct reflection of societal demands regarding medical interventions but also the tremendous interest in being able to predict an individual’s response to therapy and prognosis. I currently manage about 500 patients with rheumatoid arthritis and my group has about 2000 rheumatoid arthritis patients. When first diagnosed, patients are anxious and frightened. Initial therapy is fairly standard with initiation of traditional disease modifying agents (DMARDs) with symptomatic therapies co-administered. The problem arises when patients do not get an adequate response to this initial treatment(s). The next steps are much more expensive and potentially dangerous so that clinicians need something to guide therapy. Otherwise, it is truly trial and error. The use of this test would (and should) be limited to patients with suboptimal responses to traditional DMARDs who would feel anti-TNF meds may be appropriate. I think this branch point in the treatment algorithm occurs at a critical time in this patient’s care. Currently, most managed care organizations require a specific TNF drug to be used next and will sometimes require 2 agents with this same mechanism of action be used before agents that affect alternative immune responses may be prescribed. This can be a critical period in the treatment of RA patients. When the immune system loses tolerance and becomes activated, it is critical to rebalance the immune response as quickly as possible. There is no question that the longer a RA patient has high disease activity, the more joint damage will occur. There is also information that indicates the longer a patient has uncontrolled disease, the harder it can be to get that patient into remission. I agree that this test is not perfect. However, the data currently available does demonstrate it could potentially spare many patients from trying therapies that are not effective, exposing patients to unnecessary toxicities and higher disease activity. I can find no medical reason not to allow the utilization of this test under the proper conditions to guide therapeutic choices at the point of non-response to traditional DMARDs when a biologic agent is being considered. It is also possible that if the cost of the testing is not exorbitant, the proper use of this predictive test could be cost effective since there is good date to demonstrate RA patients with low disease activity are less expensive than patients with moderate or high disease activity.

Thank you for your reconsideration regarding the payment for this test. I really would want appropriate RA patients to have access to this information at a critical time in their care.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 10 years of experience.

Without a predictive test, I am left with a trial-and-error approach as we have been for 20+ years of biologic usage. PrismRA is the only test of its kind that is commercially available to prevent a trial-and-error approach to treating patients with a biologic and informing me of the best therapy option.

The Clinical Validity (CV) of PrismRA has been documented in several peer reviewed studies and publications. In a CV study, the PrismRA test identified a molecular signature of non-response to TNFi therapies with a positive predictive value (PPV) of 87.7% (95% confidence interval [CI] 78-94%), sensitivity of 60.2% (95% CI 50-69%), and specificity of 77.3% (95% CI 65-87%) (Jones A, 2021). Furthermore, in four separate validation cohorts, the PrismRA test predicted non-response to TNFi therapies with statistically significant odds/ratios across multiple outcome measures commonly used in RA, including ACR50, ACR70, CDAI LDA, DAS28-CRP LDA, and EULAR good response (Cohen S, 2021; Zhang L, 2021; Strand V, 2022 (CU1); Strand V, 2022 (CU2)).

At present, rheumatologists like me have no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies without the use of the PrismRA test. As you know, RA is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to move to the next mechanism of action (MOA).

As an example, I have a patient that was diagnosed with Rheumatoid Arthritis, that failed conventional DMARDs and had persistent disease activity with active synovitis on exam. The next step in his management was the addition of a biologic. The PrismRA test suggested he would have an inadequate response with a TNFi, so we started Orencia/Abatacept. 6 months later, he is in remission. Remission may have been delayed much longer, had we started with a TNFi. Had we started a TNFi, he may or may not have

PrismRA helps me avoid medications that will not work for my RA patients based on their unique biology. It greatly improves disease management and patient outcomes and reduces patient and healthcare system costs.

I strongly support the coverage of PrismRA for my patients.

Thank you for your consideration of my comments.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to submit this letter as my formal comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 35 years of experience. Throughout my career, I have treated patients with Rheumatoid Arthritis daily and have seen how quickly patients deteriorate when they are not put on the right biologic early on in their disease onset.

At this point in time, I’m forced to choose a first-line biologic therapy for my RA patients without the appropriate tools to help me match therapy to each patient’s unique disease biology. The trial-and-error approach does my patients a disservice and prevents the chances of patients reaching low disease activity or remission. As an experienced Rheumatologist, the PrismRA test has helped me steer patients away from medications that will not work based on their individual biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs.

Treating patients with this potentially deadly and debilitating disease early is important, as joint damage caused by RA generally occurs within the first two years of diagnosis. Up to 70% of patients with RA that are inadequately treated become disabled within 10 years (Burton W, 2006). This is because rheumatologists and patients do not have a precision medicine tool to determine which targeted biologic therapies a patient should initiate that will work best for their disease.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. PrismRA is intended for use by physicians to guide medical management decisions in RA adult patients (18 years or older) with moderate to high disease activity who have either not reached treatment disease activity objectives 1) on csDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change (including dose escalation or cycling to another TNFi).

I support utilizing and implementing the PrismRA test into my practice and have firsthand experience in seeing how a therapy selection test like PrismRA can improve outcomes for patients struggling with RA. I believe there is strong evidence and clinical need to overturn this NCD to an LCD so that we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner. I strongly support the coverage of PrismRA for my patients. Thank you for taking my firsthand experience with PrismRA into account and for considering favorable coverage.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing Rheumatologist with over 20 years’ experience treating patients. The purpose of this letter is to show support for PrismRA, the Molecular Signature Response Classifier for Rheumatoid Arthritis.

Since the introduction of the TNFis, there has been a dramatic positive change in treating RA patients. Still though, many patients still do not reach remission of this debilitating disease, and will progress with more joint damage and disability. Before tools such as PrismRA, I would choose a biologic therapy without the help of a diagnostic that helps me match therapy to a patient's unique disease.

Since the introduction of PrismRA, I have utilized the test on a number of patients. I have been impressed with the results of the test. Sometimes, the results have shown that TNF inhibition is the correct choice. Sometimes, the results have shown that another mechanism of action would be a better choice. I have used the results and have seen better patient care, which is most important.

Thank you for your consideration of my feedback, as I strongly support your adoption of coverage for the PrismRA test.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

Our practice would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. We are a practicing rheumatology clinic with more than 30 years of experience in Rheumatology.

Without a predictive test, we are left with a trial-and-learn/error approach. PrismRA is the only test of its kind that is commercially available to prevent a trial-and-learn/error approach to treating patients with a biologic and informing our team of the best therapy option.

Using a precision medicine test, like PrismRA, to predict therapy response to biologics for patients with rheumatoid arthritis saves patients from unnecessary active disease period, progressive damage to joints with time, and expensive medication costs.

We support utilizing and implementing the PrismRA test into our practices and have firsthand experience in seeing how a therapy selection test like PrismRA can improve outcomes for patients struggling with RA. We believe there is strong evidence and clinical need to overturn this NCD to an LCD so that we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner.

Thank you for considering PrismRA as a treatment modality for rheumatoid arthritis.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a rheumatology practitioner and I would like to send this letter to support complete coverage of the Molecular Signature Response Classifier, PrismRA. There is no other test currently available for predicting patient response using individual and clinically validated biomarkers.

For years, rheumatologists and practitioners within rheumatology have been waiting for a tool to provide patient specific results, unique to each patient, to direct therapy and reach low disease activity in a quicker and more efficient manner. In our industry, entrenched contracts within insurance typically dictate a "one size fits all" approach to choosing therapy. Before PrismRA, there was no other method to predict whether a patient would respond to our biggest class of biologic therapy utilized to treat RA.

PrismRA has the benefit of extensive clinical validity and utility studies which have empowered my usage of the test. When a patient is ready to begin a biologic, I use PrismRA to decide whether they are an appropriate candidate for a TNFi mechanism of action drug. I have used this to save patients time, money, and give them back their lives. This test empowers practitioners and is fundamentally necessary for treating our patients. It should be widely available and completely covered. There is no other test currently available with the same utility.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing you today regarding the recent draft non-coverage LCD for PrismRA. I have been a private practicing rheumatologist for over 30 years and have some level of expertise in treating hundreds of Rheumatoid Arthritis patients.

The PrismRA test is the first and only test that can predict non-response to the anti-TNF class of drug therapies used for treating rheumatoid arthritis patients. By doing so I can can skip this class of drugs when results are indicative of a nonresponder and move on to other more potential effective therapies. Thus my patients are more likely to reach their treatment goal of low disease activity or remission quicker. The wrong treatment option can often cause a delay in response for several months, which is detrimental to the overall health of my patient and also may be very costly.

Currently, there are no other tools or lab tests that can accurately predict which drug group mechanism of action (MOA) a rheumatoid arthritis patient would adequately respond to. Medicare patients can be prescribed any MOA class, but it is a trial-and-error approach. In summary the PrismRA test will reduce the cost and time wasted with RA patients being treated with a very expensive medication that does not match their disease genotype.

I have been using PrismRA for over a year in my practice and have seen the benefits first hand on my RA patient population. I strongly encourage you to give a positive LCD approval for this novel test that will greatly improve patient care. This test truly represents the future direction of personalized medicine in rheumatology.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I'm a practicing rheumatologist with over 40 years of experience.

At present and in the absence of PrismRA, when treating my RA patients, I must choose a first­ line biologic therapy without the appropriate tools that will help me match therapy to a patient's unique disease biology. It is a trial-and-error approach that more often than desired, wastes valuable time.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to TNFi therapies for patients with RA. It is intended for use by physicians to guide treatment decisions in RA adult patients with moderate to high disease activity who have not reached treatment disease activity objectives. The clinical validity of PrismRA has been documented in several peer reviewed studies and publications. In their latest clinical utility data, those patients who were identified as having an inadequate response to TNFi who were redirected to another mechanism of action experienced a near two-fold improvement in disease activity. Simply put, using the test to guide therapy selection for RA patients failing csDMARDs will get more patients to lower disease activity.

At present and without the availability of PrismRA, Rheumatologists like myself have no way of predicting whether a patient will respond to this class of drugs before they prescribe a TNFi therapy. A trial-and-error treatment approach does not tailor therapy to a patient's individual disease biology and can lead to poor outcomes. These poor outcomes include: a.) declining response rates up to 35% after failing first line therapy, b.) a higher likelihood of irreversible joint damage and chronic pain which leads to increased surgeries, c.) increased use of pain medication and steroids, d.) time and money wasted on ineffective treatment.

I have used PrismRA in my practice. I have firsthand experience in seeing how a precision medicine test can improve outcomes for patients struggling with RA. I believe there is considerable evidence and clinical need for this kind of precision medicine test. I strongly support the coverage of PrismRA for my patients, and I believe there is strong evidence and clinical need to overturn this NCD to an LCD so that we can stop the trial­ and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with 9 years of experience. I am a 3rd generation physician with 26 MD’s in my family and a second generation rheumatologist.

I do not have a clinical assessment to inform me of the right biologic for my patients. I need the PrismRA test to guide which biologic is best to start. Without this valuable tool, I am left with prescribing based on what is dictated by the patient’s insurance. More than 50% of my patients do not reach low disease activity with how I currently practice.
The Clinical Utility of PrismRA has been documented in several peer reviewed studies and publications. In an Analytical Validation (AV) study, the PrismRA test identified a molecular signature of non-response to TNFi therapies with a positive predictive value (PPV) of 87.7% (95% confidence interval [CI] 78-94%), sensitivity of 60.2% (95% CI 50-69%), and specificity of 77.3% (95% CI 65-87%)
(Jones A, 2021).

At present, rheumatologists, like me, have no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies without the use of the PrismRA test. I have a patient who was failing their medication therapy and worsening until I did a PrismRA test and identified them as a treatment switch. PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs.

I strongly support the coverage of PrismRA for my patients. Please post a positive LCD so patients starting their first biologic or targeted synthetic DMARD or considering a second TNFi after TNFi exposure can get on the right medication sooner with PrismRA. Thank MolDx for considering your comments and any other closing remarks.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with over 30 years of experience. With currently available resources and clinical assessments, I am limited in my ability to start a patient on the correct drug based on their disease biology. PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA adult patients (18 years or older) with moderate to high disease activity who have either not reached treatment disease objectives 1) on CSDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change (including dose escalation or cycling to another TNFi).

At present, rheumatologists like me have no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies without the use of the PrismRA test. Moreover, because RA is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to move to the next mechanism of action (MOA). PrismRA helps me steer many patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs.

I support utilizing and implementing the PrismRA test into my practice and have firsthand experience in seeing how a therapy selection tests like PrismRA can improve outcomes for patients struggling with RA. I believe there is strong evidence and clinical need to overturn this NCD to an LCD so that we can stop the trail-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatology nurse practitioner with 5 months of experience. Though my time in practice is short, I have seen many patients with rheumatoid arthritis (RA).

As a newer rheumatology practitioner, I like to use evidence-based resources to help guide my practice. This technique ensures that I provide high-quality care to each and every patient I encounter. Currently the guidelines for biologic selection in rheumatoid arthritis patients is essentially trial and error. This practice leads to delayed appropriate treatment if the wrong biologic is selected. Delayed treatment puts the patient at risk for disease progression and as we know, up to 70% of patients with RA that are inadequately treated become disabled within 10 years (Burton W, 2006).

This leads me to a new validated tool to help guide biologic medication selection for my rheumatoid arthritis patients. PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. PrismRA is intended for use by practitioners to guide medical management decisions in RA adult patients (18 years or older) with moderate to high disease activity who have either not reached treatment disease activity objectives 1) on csDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change (including dose escalation or cycling to another TNFi). Moreover, the Clinical Validity (CV) of PrismRA has been documented in several peer reviewed studies and publications.

To provide an example of real-world data, there have been numerous occasions in which I have done a PrismRA test and found that the patient has a high likely-hood of not responding to TNFi therapy, and chose an alternate mechanism of action for initial biologic selection.

Alternatively, I have also experienced an RA patient that is not doing well on TNFi therapy, decided to run a PrismRA test, and find out that they are biologically likely to respond to TNFi therapy and simply change to another TNFi medication. PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs.

I support utilizing and implementing the PrismRA test into my practice and have firsthand experience in seeing how a therapy selection test like PrismRA can improve outcomes for patients struggling with RA. I believe there is strong evidence and clinical need to overturn this NCD to an LCD so that we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner.

Reference was provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

Thank you for the opportunity to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist and have widely adopted PrismRA as a decision-making tool in my busy practice.

I have seen first-hand how this biomarker can guide evidence-based and personalized treatment for the patient. PrismRA prevents the trial-and-error approach, which is frankly outdated and detrimental to a patient’s health. A recent patient I cared for really emphasizes the importance and utility of PrismRA—A young female with seropositive, erosive RA who was initially placed on a TNF inhibitor in line with her insurance plan. She had no response, progressed rapidly and developed joint contractures of her elbows over the ensuing weeks. PrismRA test soon became available at our practice, and her results showed “only a 5% chance of responding to a TNFi.” With this information, I decided against a second TNF inhibitor, switched biologic MOA and she is now in low disease activity state based on RAPID3 assessment. PrismRA test predicts therapy response with such accuracy. If I had known this information from disease onset, I would have spared this young woman unnecessary active disease period, progressive damage to joints, and expensive medication costs.

I could provide numerous other case examples to support PrismRA, but its clinical validity has been well- documented in several peer reviewed studies and publications (1-5). I strongly support the coverage of PrismRA for my patients, and hope you will reconsider your previous decision and grant coverage for PrismRA.

References were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the draft coverage decision. Rheumatoid Arthritis is a devastating autoimmune disease. Getting patients on the right course of therapy early in this disease is so important. Before the PrismRA test, I was limited in my ability to start a patient on the right biologic for my RA patients. I have now used the PrismRA test to guide me better on the treatment of my RA patients. I do not have to use the trial-and-error approach anymore. My goal is to get my RA patients in remission/low disease activity as soon as possible because this is a horrible disease where up to 70% of these patients that are inadequately treated become disable within 10 years.

The data that I have read on prismRA has been documented in several peer reviewed studies and publications. The positive predictive value of the test is close to 90% in patients who have a molecular signature of non-response who will not reach ACR 50 on a Anti Tumor Necrosis Factor. Precision medicine tools, like a molecular signature response classifier provide insight that helps informs therapy selection.

I support using prismRA in my practice and have firsthand experience in seeing how this test can improve outcome for my patients struggling with RA. I support the coverage of PrismRA for my RA patients and hope that you overturn this NCD to an LCD so that we can stop this trial-and-error approach for RA patients.

Thanks for considering my comments on this matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

We have spent over a decade academically researching the ability to use the molecular network of human cells - the Human Interactome - and additional molecular data to drive novel insights into unique patient disease pathobiology.^1-5 Derived from network science, our research, also referred to as the newly defined field of Network Medicine, can capture the complexity of heterogeneous diseases and improve our understanding of the underlying pathobiology to better inform the selection of optimal therapies.

We founded Scipher Medicine with the vision of applying our research in Network Medicine to bringing precision medicine to heterogeneous and complex disease areas that for far too long have been underserved by tools and technologies that help physicians make more informed decisions about the selection of effective therapies. As such, PrismRA is the culmination of years of research in this domain. We, therefore, fully support Scipher Medicine's application to obtain coverage for this vital test the results of which we strongly believe will accrue to the benefit of the Medicare eligible population.

Thank you for your consideration.

References were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

This letter is to show my support for Scipher Medicine's PrismRA lab test in regards to the decision of Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am qualified to discuss this topic as a practicing rheumatologist. I am a board certified in both Internal Medicine and Rheumatology.

Our practice had started participating in the study in April 2021. I have enrolled 67 patients in the PrismRA study to see the potential benefits of having a product that can produce a way to predict a high or low response of a patient starting a TN Fi therapy. This test helped to support decisions and treatment plans as a way of seeing that a patient may or may not have a strong response to a certain TNFi therapy.

PrismRA has the potential to be a great product. It is a good aid to find out if a patient with Rheumatoid Arthritis has potential to have a response to starting a TNFi therapy and would be nice to see this product blossom into so much more.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Decision. I am practicing rheumatologist treating RA patients.

Rheumatoid Arthritis is a devastating autoimmune disease. Getting patients on the right course of therapy early in this disease is so important. The joint damage caused by RA usually occurs within the first 2 years of diagnosis. Without a predictive test, I must use a trial-and-error approach to treat this disease. The prismRA test is the only test of its kind that I can use to prevent this approach. Using precision medicine, like PrismRA, to predict therapy response to biologics for patients with RA saves my patients from unnecessary disease progression, and expensive medication costs.

PrismRA is the first and only Molecular Signature Response Classifier test that predicts inadequate response to all TNF therapies in RA. The clinical validity has been documented in several peer reviewed studies and publications.

Precision medicine tools, like a molecular signature response classifier provide insight that helps informs therapy selection. I feel there is strong evidence and a clinical need to overturn the NCD to an LCD so we can stop the trial-and-error approach to treating RA patients.

Thank you for considering my comments on this subject.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

United Rheumatology (UR), a Rheumatology care management organization, presents the following comment to MolDX in response to a draft LCD. UR is the pre-eminent Rheumatology care management organization empowering rheumatologists to advance the standard of care while leading in the development of value-based precision medicine. UR’s membership represents 25% of the country’s independent practice rheumatologists, with more than 665 members in hundreds of practices across nearly 40 states. UR’S value-based approach to rheumatology drives UR’s members to seek clinical methods that prioritize patient outcomes while controlling costs and minimizing waste. Thus, UR members, like specialists in other fields, prioritize the opportunity to provide comprehensive services to their patients, which includes precision-based laboratory tools. While I write this letter on behalf of UR’s Medical Policy Committee which I chair, I am also a practicing Rheumatologist and have 46 years of experience managing complex patients with rheumatoid arthritis and I seek precision-based medicine for those patients.

As I am sure you are aware, rheumatoid arthritis is a potentially devastating autoimmune disease. Treating patients early with this debilitating disease is extremely important, as joint damage typically occurs within the first two years of diagnosis. Up to 70% of patients with RA that are inadequately treated become disabled within 10 years¹. Compounding this problem, Rheumatologists have not had access to a precision medicine tool to determine which targeted biologic therapies a patient should initiate that will work best for their disease. Many patients cycle through multiple drugs before their disease is under control. Because response to treatment is not immediate, it may be several months or longer before the adequacy of a response to a particular treatment can be assessed. Since fewer than half of patients achieve even a 50% improvement with any of the currently available biologic or other novel therapeutics, a patient might not be in remission for a year or longer and thus exposed to incremental risk of tissue damage. Thus, the development of precision tools to help patients and physicians choose the right medicine first is a major priority.

With currently available resources, I have been limited in my ability to start a patient on the correct drug based on their disease biology. Despite extensive investigative efforts over the past 25 years, I still do not readily have a test or clinical assessment to inform me of the right biologic for each of my patients. The innovative test PRISM-RA is the first and only currently available biomarker panel which will help inform me which biologic is the best start and start the path to precision-based medicine in RA. Without this valuable tool, I am left with prescribing based on what is dictated by the patient’s insurance and specialty pharmacies. This is precious time for our patients, who will continue to have disease progression until the right treatment is implemented. It is also a major waste of physician time. As there is a well-documented shortage of rheumatologists, with multiple months wait times for new patient appointments in many communities, optimizing the efficacy of physician time clearly is critical as well. Using PRISM-RA to predict therapy response to biologics for patients with rheumatoid arthritis saves patients from unnecessary active disease period, progressive damage to joints with time, and expensive medication costs.^2,3,4

The UR Medical Policy Committee uses peer reviewed publications to help inform our decisions and clinical pathways. Quoting from the literature, the clinical validity of PRISM-RA test identified a molecular signature of non-response to anti-tumor necrosis factor (TNF) therapies with a positive predictive value (PPV) of 87.7% (95% confidence interval [CI] 78-94%), sensitivity of 60.2% (95% CI 50-69%), and specificity of 77.3% (95% CI 65-87%). In four separate validation cohorts, the PRISM-RA test predicted non-response to TNF therapies with statistically significant odds/ratios across multiple outcome measures commonly used in RA, including ACR50, ACR70, CDAI LDA, DAS28-CRP LDA, and EULAR good response.^5,6,7,8 In addition, the PRISM-RA test can accurately predict non-response to all TNF therapies. In 174 samples from the prospective observational NETWORK-004 study of patients treated with TNF therapies, the PRISM-RA test demonstrated⁵:

• Positive Predictive Value (PPV): 87.7% (95% CI 78-94%). This describes the percent of patients with a molecular signature of non-response who will NOT reach ACR50 on a TNF.
• Sensitivity (true positive rate): 60.2% (95% CI 50-69%). This describes the percentage of true TNF non-responders (those who do not respond, defend as having a 50% improvement/ACR50 within 6 months on ACR50) who are identified by PRISM-RA testing having a molecular signature of non-response.
• Specificity (true negative rate): 77.3% (95% CI 65-87%) This describes the percent of true TNF responders (those who respond based on AR50) who did not have a molecular signature of non-response

It should be noted that many United Rheumatology practices participated in the NETWORK-004 study.

My partners have had an opportunity to test PRISM-RA in the real-world management of patients, and the test has repeatedly provided invaluable insights into response and non-response to management choices.

I believe there is compelling evidence and clinical need to overturn this draft preliminary decision to not cover PRISM-RA so that we can stop the unproductive approach for biologic therapy selection for patients with RA and get them on the right therapy sooner. Precision medicine tools, like PRISM-RA, provide insight that informs therapy selection. I strongly support the coverage of PRISM-RA for my patients and for all patients suffering from rheumatoid arthritis. Thank you in advance for your consideration in this matter.

References were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

This letter is to recommend coverage for doing the prism RA testing for patients with rheumatoid arthritis who are about to start biologic therapy. This test has been an invaluable tool for deciding heart medication to use. Many times in the past I have started a patient on a TNF inhibitor and oftentimes used a second search drug when the first one failed. Often times this takes 6 to 12 months before it is obvious that the patient has not responded to these medications. If the prism RA test was available initially, I would not have started the patient on TNF inhibitors but used an alternative medication that might've brought pain relief and prevented joint damage.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I’m a practicing rheumatologist and would like to comment on the Draft Local Coverage Decision around PrismRA, a molecular biomarker test that helps guide therapy selection in rheumatoid arthritis.

I’ve recently begun incorporating PrismRA into my practice as part of my RA disease management. It helps me choose a biologic by predicting inadequate response to all TNF-inhibitor therapies and does so with a positive predictive value of 90%. The goal, of course, is for patients to get started on the right path from the beginning, and ultimately, achieve improved clinical outcomes. More data is coming forth with Prism to help predict response to other mechanisms of action as well.

PrismRA, is the first test we have available to steer therapy for rheumatoid arthritis away from a trial-and-error approach to select first-line biologic therapy. Trial-and-error does not take into consideration a patient’s unique disease biology. This approach wastes valuable time and money. If patients don’t respond to the chosen medication, subsequent options may be less effective. Add to that the fact that rheumatoid arthritis is a progressive, debilitating disease. By the time patients move to another mechanism of action, they may have additional joint damage and disability.

I’ve experienced first-hand how PrismRA reduces these risks and avoids costly, unnecessary cycling through therapies that may not work.

Based on strong evidence and a clinical need for this precision medicine tool, I ask that you grant coverage of PrismRA. Thank you for your consideration and commitment to advancing care for all rheumatoid arthritis patients.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

American Rheumatology Network (ARN) is comprised of approximately 300 rheumatology providers located in 30 states. ARN members have access to and are united in shared best business practices, value-based treatment pathways and innovative practice performance technology.

In early 2021, ARN partnered with Trio Health to launch a clinical research program within the ARN network to develop a real-time, bi-direction integrated platform that drives clinical research to gain insights into community-based physician practices and improve patient care.

In response to the local coverage determination (LCD) under the Molecular Diagnostic Services (MolDX) program: Molecular Biomarker Testing to Guide Targeted Therapy in Rheumatoid Arthritis, we would like to comment on a few points in the proposed LCD. Data supporting these comments are attached.

First, we reiterate the urgent unmet need for a test that predicts treatment response in rheumatoid arthritis, particularly to TNFi therapies. TNFi inhibitors are suboptimally used in clinical practice due to a lack of clinical assessments available to inform treatment selection. In our analysis of 13,994 patients and 19,925 distinct TNFi episodes, nearly 33% of patients cycled through more than one TNFi therapy. For patients treated with 2 or more TNFi, 2689/4245 (63%) had discontinued 1 or more prior TNFi drugs due to lack/loss of efficacy. For patients with 3 or more TNFi, 829/998 (83%) discontinued for lack/loss of efficacy. A test that predicts non- response to TNFi therapies could have reduced the time patients spent trying ineffective therapies.

Second, standard disease assessments (clinical, laboratory data, or combinations thereof) are insufficient in assessing care. As noted by MolDX, previous studies have demonstrated discordance between patient-based (e.g. RAPID3) and predominantly physician-based (e.g. CDAI, DAS28) disease assessments (DAS). At the decision point for initiating b/tsDMARDs, paired DAS28:RAPID3 and CDAI:RAPID3 scores are weak to moderately correlated, respectively, and clinical severity categories for CDAI:RAPID3 were discordant for 28% of evaluated patients. In patients cared for by ARN physicians, correlations between paired continuous DAS scores were strong for CDAI:DAS28 (n=1063, r=0.788), moderate for CDAI:RAPID3 (n=582, r=0.399), and weak for RAPID3:DAS28 (n=637, r=0.149). This is variability in disease assessments highlights the heterogeneity of rheumatoid arthritis, not a deficiency in patient care. To address disease heterogeneity, validation of PrismRA included prediction of non-response according to several clinical response outcome measures at 6 months, including ACR20/50/70, CDAI, and DAS28, demonstrating that is a robust predictor of TNFi non-response (Cohen et al. 2021).

Third, the heterogeneity of rheumatoid arthritis necessitates new approaches to treatment selection. Biologics, such as TNFi, have been approved for rheumatoid arthritis patient care for more than 20 years; however, no combination of current clinical, laboratory or demographic data has demonstrated to be a valid or reliable predictor of treatment response and a trial-and- error approach remains prevalent.

The draft non-coverage decision presents a roadblock to innovation of precision medicine tests in rheumatoid arthritis, as well as other autoimmune diseases where TNFi therapy use is prevalent. Our patients deserve a solution to the ineffective therapy selection approaches in rheumatoid arthritis, and this solution should have payment and coverage options. We urge development of a local coverage policy that establishes guidance the clinical validity, clinical utility, and analytical validity for a molecular biomarker test to guide targeted therapy in rheumatoid arthritis.

Thank you for considering this feedback from ARN physicians.

Figures were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

We are a large rheumatology practice and use the prism RA test for patients. It is a great tool at helping us identify our next move when patient may not have good control under their current treatment. Please consider covering it for RA patients. They suffer enough.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I’m emailing you regarding the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I’m a practicing rheumatologist with 9 years of experience.

The American College of Rheumatology’s criteria for ≥50% response (ACR50) at six months with biologic and targeted synthetic (b/ts) DMARDs in RA patients with inadequate responses to methotrexate range from 27-37%. If patients and providers are not allowed access to PrismRA to help inform treatment selection, two-thirds of RA patients may likely fail to achieve ACR50 responses regardless of prescribed b/tsDMARD. Furthermore, they are highly unlikely to reach the treat-to-target goal of remission.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. PrismRA is intended for use by healthcare providers to guide treatment decisions in RA adult patients with moderate to high disease activity who have not reached treatment disease activity objectives. These decisions pertain to a patient who is 1) being considered to start on a TNFi therapy or 2) not achieving low disease activity on their current TNFi therapy and in need of a change in their treatment.

Up until the introduction of PrismRA, rheumatologists like me have no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies. When considering what a progressive disease RA is, patients who ultimately fail DMARDs may have increased disability by the time they are able to switch to the next mechanism of action. PrismRA helps me avoid medications that will not work for my patients based on their individual disease biology. This valuable test greatly improves disease management and patient outcomes. By getting patients to respond quicker, it has substantial savings for both the patient and the healthcare system. A patient who is identified as having an inadequate response to TNFi therapy, who is redirected to another mechanism of action could save up to $77,000/year.

I have been using PrismRA in my practice for ten months and have firsthand experience in seeing how a precision medicine test can improve outcomes for patients struggling with RA. In three specific cases where I was planning to switch biologic agents due to persistently high disease state, it helped me make a shared decision with the patient to switch to a different mechanism of action. In each of these cases, the patient RA is now considered in a low disease state based on their latest respective DAS-28 ESR scores.

I believe there is robust evidence and clinical need for this test so that we can end the trial-and-error approach of treating RA patients and get them on the right therapy sooner. I strongly encourage you to approve coverage of PrismRA.

Thank you for taking the time to review my comments.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a Rheumatology NP and I have been practicing in our clinic for 1 year. Within the year 2022, I was introduced to a innovative and effective way of providing clinical treatment decisions early for the management of Rheumatoid Arthritis. This is very critical for our ways of practice to prevent further joint damage and erosion as well as risks of cardiac and respiratory events. My vision for PrimRA is for it to be globally used in all rheumatology to minimize disease progression and for better future outcomes for patients.

The autoimmune space needs a test like PrismRA to help determine which drug to put patients on. Without a predictive test, I am left with a trial-and-error approach, which is not fair to my patients. PrismRA is the only test of its kind that is commercially available to prevent a trial-and-fail approach to treating patients with a biologic and informing me of the best therapy option.

As published in clinical validation (CV) studies, the PrismRA test can accurately predict non-response to all TNFi therapies. In 174 samples from the prospective observational in the NETWORK-004 study of patients treated with TNFi therapies, the PrismRA test demonstrated (Jones A, 2021): Positive Predictive Value (PPV): 87.7% (95% Cl 78-94%). This describes the percent of patients with a molecular signature of non-response who will NOT reach ACRS0 on a TNFi.

It is very frustrating being forced to follow insurance formularies when I have a test like PrismRA to predict my patient's response to a TNFi. PrismRA not only helps me steer my patients away from drugs they will not respond to, but also saves patient and health system costs. Thank you for taking my comments into consideration.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I’m a practicing rheumatologist with over 10 years of experience.

At present and in the absence of PrismRA, when treating my RA patients, I must choose a first-line biologic therapy without the appropriate tools that will help me match therapy to a patient’s unique disease biology. It is a trial-and-error approach that more often than desired, wastes valuable time.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to TNFi therapies for patients with RA. It is intended for use by physicians to guide treatment decisions in RA adult patients with moderate to high disease activity who have not reached treatment disease activity objectives. The clinical validity of PrismRA has been documented in several peer reviewed studies and publications. In their latest clinical utility data, those patients who were identified as having an inadequate response to TNFi who were redirected to another mechanism of action experienced a near two-fold improvement in disease activity. Simply put, using the test to guide therapy selection for RA patients failing csDMARDs with get more patients to lower disease activity.

At present and without the availability of PrismRA, rheumatologists have no way of predicting whether a patient will respond to this class of drugs before they prescribe a TNFi therapy. A trial-and-error treatment approach does not tailor therapy to a patient’s individual disease biology and can lead to poor outcomes. These poor outcomes include:
1-response rates decline up to 35% after failing first line therapy
2-there is a higher likelihood of irreversible joint damage and chronic pain which leads to
increased surgeries
3-increased use of pain meds and steroids
4-time and money wasted on ineffective treatment

I have been using PrismRA in my practice. I have firsthand experience in seeing how a precision medicine test can improve outcomes for patients struggling with RA.

I believe there is considerable evidence and clinical need for this kind of precision medicine test so that we can end the trial-and-error approach of treating RA patients and get their disease under control sooner. I strongly encourage you to approve coverage of PrismRA.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am submitting the comments within this letter on behalf of the Florida Society of Rheumatology (FSR), which is in full support of providing precision medicine coverage and access for patients with RA.

FSR is a large member organization with the focus of supporting the practice of Rheumatology in the State of Florida and the protection of patient access to appropriate rheumatologic medical care.

As an organization representing over 200+ rheumatologists in the state of Florida, we strongly disagree with the conclusion provided in this LCD, which states that “clinical validity has not yet been established for molecular biomarker tests that guide targeted therapy selection in RA.” There have been numerous amounts of data and evidence provided that not only meets current standards but exceeds requirements to be consider clinically validated.

Our organization works tirelessly to support policies that positively impact our patients and practices. The try and fail approach for treating patients is not ideal, especially when rheumatologists are mandated by insurance companies to use this fail first method for non-clinical reasons. Having precision medicine testing available provides our practices with another safe treatment option that can quickly get our patients on the right drug at the right time.

The Florida Society of Rheumatology respectfully requests MolDX to review all the data and comments submitted during this period of analysis for a complete assessment. We believe you will find that clinical validity has been established and we strongly advise that a policy that provides reimbursement and access to precision medicine testing be included for RA patients.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I’m a Nurse Practitioner.

At present and in the absence of PrismRA, when treating my RA patients, I must choose a first-line biologic therapy without the appropriate tools that will help me match therapy to a patient’s unique disease biology. It is a trial-and-error approach that more often than desired, wastes valuable time.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to TNFi therapies for patients with RA. It is intended for use by physicians to guide treatment decisions in RA adult patients with moderate to high disease activity who have not reached treatment disease activity objectives. The clinical validity of PrismRA has been documented in several peer reviewed studies and publications. In their latest clinical utility data, those patients who were identified as having an inadequate response to TNFi who were redirected to another mechanism of action experienced a near two-fold improvement in disease activity. Simply put, using the test to guide therapy selection for RA patients failing csDMARDs with get more patients to lower disease activity.

At present and without the availability of PrismRA, I have no way of predicting whether a patient will respond to this class of drugs before they prescribe a TNFi therapy. A trial-and-error treatment approach does not tailor therapy to a patient’s individual disease biology and can lead to poor outcomes. These poor outcomes include:
· response rates decline up to 35% after failing first line therapy
· there is a higher likelihood of irreversible joint damage and chronic pain which leads to increased surgeries
· increased use of pain meds and steroids
· time and money wasted on ineffective treatment

I believe there is considerable evidence and clinical need for this kind of precision medicine test so that we can end the trial-and-error approach of treating RA patients and get their disease under control sooner. I strongly encourage you to approve coverage of PrismRA.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

Thank you for giving me the opportunity to comment on the recent proposed draft non coverage Local Coverage Determination entitled Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. Since its initiation, Prism/RA has become a valuable tool in my practice when I am treating a patient with RA, as I have used it to inform my treatment plan for patients with this condition in an attempt to have a more targeted approach/therapy that has not been available to us for the longest period.

I believe there is strong evidence and clinical need to overturn this draft LCD to a positive coverage statement so that we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner. I have firsthand experience in seeing how a therapy selection test like Prism/RA can improve outcomes for patients struggling with RA, achieve low disease activity/remission earlier in their treatment course, prevent irreversible joint damage and consequently improve their functional status.

I work in a large multi-specialty practice in the rheumatology department. We have all integrated the Prism/RA test into our treatment protocols and find it a very useful tool when deciding on treatment plans.

Please reconsider your previous decision and grant coverage for Prism/RA.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am submitting this communication commenting on the draft local coverage decision molecular biomarker testing to guide targeted therapy selection in rheumatoid arthritis. I am a practicing rheumatologist with 25 years of experience. I see the entire spectrum of adult rheumatic disease and a major component of my practice is treating moderate to severe rheumatoid arthritis.

Diagnosing and formulating a treatment plan for this devastating and debilitating autoimmune disease is challenging at best. Treating patients in getting the disease under control early is very important, as joint damage caused by rheumatoid arthritis generally occurs within the 1st 2 years of diagnosis. Up to 70 % of patients with rheumatoid arthritis are inadequately treated and become disabled within 10 years. This is because rheumatologists and patients do not have a precision medicine tool to determine which targeted biologic therapies a patient should initiate that will work best for their disease.

Use of these complex medications has to be judged with high caution given the potential for serious adverse and possibly life-threatening effects. Therefore, committing the patient to a complex treatment regimen requires accurate decision making as best as possible.

The clinical validity of PRISMRA has been documented in several peer reviewed studies and publications. In 1 of those validation studies, the prism Rheumatoid Arthritis test identified a molecular signature of non-response to TNF inhibitor therapies with a positive predictive value of 87.7%, sensitivity of 60.2%, and specificity of 77.3%. Furthermore, in 4 separate validation cohorts, the prism Rheumatoid Arthritis test predicted nonresponse to TNF inhibitor therapies with statistically significant Odds/ratios across multiple outcome measures commonly used in Rheumatoid Arthritis, including ACR 50, ACR 70, CDAI, LDA, DAS CRP, and EULAR good response.

At present, rheumatologists like me have no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNF inhibitor therapies without the use of the prism Rheumatoid Arthritis test. And because Rheumatoid Arthritis is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to switch to the next mechanism of action.

I support utilizing the prism Rheumatoid Arthritis test in my practice and have 1st hand experience in seeing how a therapy selection test like prism RA can improve outcomes for patients struggling with rheumatoid arthritis.

I have used this test to make a much more accurate decision in initiating anti TNF therapy versus an alternate mechanism of action which are available to treat rheumatoid arthritis. This tailor's the treatment plan much more accurately for the patient while avoiding the potential adverse effects or the exceedingly high cost of these drugs.

PrismRA helps me avoid using medications that will not work for my patients based on the unique biology. It improves patient outcomes and it reduces time and money wasted on ineffective treatment. I believe there is strong evidence and clinical need to get PRISMRA covered so that we can stop the trial-and-error approach for targeted therapy selection for patients with rheumatoid arthritis and get them on the right therapy sooner.

I appreciate your attention to this matter and I am hoping for a positive outcome in your decision-making process.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing rheumatologist and have been treating patients with rheumatic disease for nearly 20 years. Currently, I treat over 400 patients with rheumatoid arthritis and use a variety of therapies, from simple NSAIDS and Plaquenil (hydroxychloroquine) to methotrexate to the most advanced biologic DMARDs with varying mechanisms of action. When choosing biologics, I most often opt for Enbrel or Humira as these two TNF inhibitors (TNFi) have the best formulary coverage on prescription drug plans. It has been my experience that about half of my patients achieve a satisfactory response with my initial biologic choice. After about a 3-to-6-month trial, I am often forced to switch therapy due to patient dissatisfaction and frustration with their continued disease activity. A switch usually involves a trying a second TNF inhibitor in hopes that the nuanced differences in these molecules will make a clinical difference.

Rheumatologists have long awaited the “holy grail” test to allow us to pick a biologic agent with a mechanism of action tailored to each individual patient. With the introduction of the PrismRA blood test, I have had the opportunity to utilize this test and make more precise choices for my active RA patients.

Below I have provided two real-world examples of how PrismRA has benefited my patients:

Case 1

57-year old while female with long-standing RA had been on Embrel and methotrexate for the past 5 years and always stated she was doing well on the current regimen, though never at a optimal function. Physical exam showed progressive deformity in her feet and X-rays showed erosions in her feet. The PrismRA blood test was ordered and the results showed an “inadequate response to TNFi detected.” She was switched to Orencia and after 1 month of therapy, reported feeling significantly better. At follow-up, patient stated, “I have more energy overall and I’m feeling better than I have in a long time.”

Case 2

62-year-old female with long-standing RA, fatty liver disease, and coronary artery disease had been stable on methotrexate for almost 10 years. In the last year, she had more flares requiring frequent steroid packs or injections. A decision was made to advance her to biologic therapy. Typically, a TNFi would have been chosen. However, the PrismRA test showed a “very high likelihood of inadequate response to TNFi-Patient would have a 5% chance of responding to a TNFi”. Due to her comorbidities, a decision was made to start Orencia. However, her managed Medicaid plan would only approve this drug if Kineret or Xelijanz were tried first. She was started on Kineret and showed great response within the first month of therapy. The PrismRA test guides us away from TNFi use when therapeutic response is unlikely. Before the availability of this test, my patient often cycled through 2 TNFis over a 6-12-month period without achieving satisfactory results. Precision medicine allows us to see earlier improvements in disease activity and functional status than were previously possible.

Given that we have so many targeted therapy options from which to choose, a blood test with a positive predictive value of nearly 90% to predict TNFi non-response meets a critical unmet need in rheumatology.¹ Although this test was developed in the last few tears, the overwhelmingly positive and firsthand results seen in my patients make me a strong supporter of PrismRA. Medicare coverage of this test would allow my elderly RA patients a higher chance of achieving low disease activity and greater improvement in function than was previously feasible.

Please post a positive LCD so my patients starting their first-line biologic therapy or considering escalating or cycling TNFi after an initial TNFi failure can get on medication better suited for their biology with PrismRA.

Reference was provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing Nurse Practitioner. I would like to provide you a letter in support of PrismRA. Rheumatologist such as I have been waiting for a tool to help guide decisions when it comes to prescribing bDMARDs. At present, rheumatologists like me have no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies without the use of the PrismRA test. Moreover, because RA is a progressive disease, patients that ultimately fail bDMARDs may have increased disability by the time they are able to move to the next mechanism of action (MOA). PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs.

I support utilizing and implementing the PrismRA test into my practice and have firsthand experience in seeing how a therapy selection test like PrismRA can improve outcomes for patients struggling with RA. I believe there is strong evidence and clinical need to have PrismRA available to help guide decisions so we can stop the trial-and-error approach for targeted therapy selection for patients with Rheumatoid Arthritis and get them on the right therapy sooner for better outcomes.

I fully support the coverage of PrismRA to help guide treatment decisions to help patients get better sooner to avoid disease progression and cost to the patient and health care system.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

Throughout my career as a family physician, as well as my tenure as U.S. Surgeon General, and chair of the National Prevention, Health Promotion and Public Health Council, I have prioritized the role of preventive care and innovation to improve outcomes for patients suffering from debilitating diseases, and health equity.

A critical cornerstone in achieving improved patient outcomes is the availability of, and access to, precision medicine technologies and solutions for as many patients as possible, regardless of their gender, race, age or status. In many diseases, such as autoimmune diseases and specifically rheumatoid arthritis (RA), we are still putting our patients through a “trial and error” treatment pathway where patients cycle through multiple drugs before finding the right therapy, placing an unnecessary clinical burden on patients.

The clinical benefits that precision medicine can and has achieved in cancer cannot be overstated, and the time has now come to ensure that similar technologies are applied outside of cancer in areas such as RA. PrismRA represents one such opportunity and is already changing the healthcare delivery paradigm and improving health outcomes of countless RA patients across the country.

We have an opportunity to provide rheumatologists with the tools they are requesting and enable them to better help their patient communities. I encourage MolDX to consider the importance of health equity in your review of the PrismRA test and how we best ensure that best care is available to all Medicare eligible patients.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing today to formally comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist, division head of rheumatology, and diplomate of the ABIM in IM and Rheumatology.

As rheumatologists diagnosing and treating rheumatoid arthritis, we are currently forced to select a first-line biologic therapy without appropriate tools. Without a predictive test, this essentially leads us to a guessing or trial-and-error approach. It is clear from the literature that certain arthritis therapies work better than others for certain types of patients. PrismRA is the only commercially available test that helps avoid this approach to treating patients with a biologic. Although other tests are available that show biomarkers linked to disease activity and radiographic progression, like the Vectra test. There have been no tests that predict the response to specific types of therapy. PrismRA has been the only test that utilizes gene expression information, demographics, and other genetic factors to help predict response to certain therapies.

The clinical utility of therapy selection informed by predicted non-response to tumor necrosis factor-alpha inhibitors was demonstrated in recent studies (Stand V, 2022 CU1; Strand V, 2022 CU2). RA genetic and biomarker data alone are insufficient to predict individual treatment response. Therefore, RNA sequences combined with clinical factors are a more robust way to predict response. With PrismRA, this is the first time we have even come close to a personalized medicine approach in rheumatology. For decades now, our oncology colleagues have utilized a personalized approach to the treatment of certain types of cancer. Precision medicine has informed treatments down to the receptors seen on pathological specimens and flow cytometry. This has allowed oncology to advance their treatments much further than if they had used a standardized or trial-and-error approach. Scipher is trying to elevate the treatment of rheumatoid arthritis and make it more personalized. More work is required on these types of tests, but that is precisely what Scipher is doing at this time (Inform clinical trials). I have seen firsthand that knowing before initiating treatment whether a patient will have a high percentage of non-response saves time, reduces disability, improves quality of life, and reduces wasted healthcare dollar.

New technology standing up to scrutiny:

There is no perfect analogy, but when the hemoglobin A1c test was first on the scene in 1977, no knew what a game changer it would become. It is still being updated with new internationally standardized assays. We have no realized the cost-effectiveness of the test as it related to diabetes and metabolic syndrome. Knowledge of hemoglobin A1c improves almost every aspect of the care of diabetes and the prevention of comorbidities. If HbA1c is ≥7%, “a 1% reduction in HBA1c was associated with a 1.7% reduction in all-cause total healthcare costs and 6.9% reduction in diabetes-related healthcare costs (both p ≤ .0001), with associated annual cost savings of $545 and $555, respectively.”

Rheumatoid arthritis is also a devasting and costly autoimmune disease as joint damage caused by RA generally occurs within the first 2 years of diagnosis. 70% of patients with RA, even when adequately treated, become disabled within 10 years (Burton W, 2006). There is a window of opportunity early in the treatment of rheumatoid arthritis that is critical. More than 30% of my patients do not reach low disease activity with how I currently practice. We are wasting valuable time in my patients’ lives as we use trial-and-error approaches to determine what to prescribe next versus incorporating a tool that helps inform TNF inhibitor non-response. Most treatment paradigms allow for 3 to 4 (sometimes up to 6) months before considering a switch to a different agent. In this time, if you choose the wrong medicine, you could be increasing the risk of ongoing disability. Targeted biologic therapies have changed the course of the disease, but very few patients respond to their first treatment. And it is common for rheumatoid arthritis patient to switch therapy class early in the treatment course. Predicting which medications work for certain of patients is an unmet need that Scipher is trying to address.

The American College of Rheumatology’s criteria for ≥50% response (ACR50) at six months with biologic and targeted synthetic (b/ts) DMARDs in RA patients with inadequate responses to methotrexate range from 27-37% (Curtis JR, 2010; Incerti D, 2020). Therefore, in the absence of PrismRA to inform treatment selection, two-thirds of RA patients may fail to achieve ACR50 responses regardless of the prescribed b/tsDMARD and are unlikely to reach the treat-to-target goal of low disease activity or remission. Using a precision medicine test, like PrismRA, to predict therapy response to biologics for patients with rheumatoid arthritis saves patients from unnecessary active disease periods, progressive damage to joints with time, and expensive medication costs that are ineffective (Johnson KJ, 2019; Boystov N, 2016; Stand V, 2018).

Clinical Support for PrismRA:

When I started using PrismRA, there was one particular patient with whom I decided to use the test. By report to me, he was doing well with his arthritis therapy, but his DAS 28 scores and sedimentation rates were routinely elevated. He and I had become anchored on his current treatment, which included methotrexate and Humira (covered by TRICARE). When we ordered PrismRA, it showed that he had a high likelihood of non-response to the TNFi agents; thus, we changed his therapy to a JAK inhibitor (Xelijanz). On follow-up at 3 months, he was in a DAS-28 remission and showed a meaningful change in his health assessment questionnaire, RAPID3, and CDAI scores. This example showed me the validity and power of PrismRA to predict response to future arthritis treatments.

When I read the decision of the board not to cover PrismRA, I noticed resources and articles were utilized and reviewed that were quite outdated. When you consider what Scipher has recently accomplished, we need to start thinking about the future and how artificial intelligence (AI) systems can help us develop tests and best practices to better care for our patients. Without AI, it is impossible to interpret the human genome because of its size, breadth, and complexity. AI is the only option we have in finding testable and reproducible variables. Scipher has done this with their unique clinical validity of the PrismRA test.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. The clinical validity (CV) of PrismRA has been documented in numerous peer-reviewed studies and publication. In a validation study, the PrismRA test identified a molecular signature of non-response to TNFi therapies with a positive predictive value (PPV) of 87.7% (95% confidence interval [CI] 78-94%), a sensitivity of 60.2% (95% CI 50-69%), and a specificity of 77.3% (95% CI 65-87%) (Jones A, 2021). Furthermore, in four separate validation cohorts, the PrismRA test predicted non-response to TNFi therapies with statistically significant odds ratios across multiple outcome measures commonly used in RA, including ACR50, ACR70, CDAI LDA, DAS28-CRP LDA, and EULAR good response (Cohen S, 2021; Zhang L, 2021; Strand V, 2022 CU1; Strand V, 2022 CU2).

I support using PrismRA and firmly believe that it should be an option as we consider the complexity of the disease process. There is strong evidence and clinical need to overturn the LCD to stop the trial-and-error approach. Please post a positive LCD so patients starting their first biologic or targeted synthetic DMARD or considering a second TNFi after TNFi exposure can get on the right medication sooner. I strongly support the coverage of PrismRA for my patients.

Thank you, MolDX, for taking my formal comments into consideration.

References were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

Thank you for giving me the opportunity to comment on the recent proposed local coverage decision (LCD) entitled Molecular Biomarker Testing to Guide Targeted Therapy Selection in RA.

I am writing to express my medical opinion of Prism RA. As you are aware, rheumatoid arthritis is a complex disease, presenting itself in varied ways depending on the individual patient. Additionally, response to therapy is often patient specific and not all categories of medication demonstrate adequate response. This often forces a trial-and-error approach that can subject patients to sub-optimal outcomes. When initiating a biologic treatment for RA, TNFis are chosen 90% of the time. Prism RA identifies those patients likely to have an inadequate response to TNFis, ensuring optimized treatment that reduces pain, inflammation and irreparable joint damage.

I have been using Prism RA for over a year in my medical practice and have found it invaluable and have incorporated Prism RA into my treatment protocol.

I urge you to provide coverage for Prism RA and reverse the current LCD/non-coverage decision.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing Rheumatologist with over 20 years' experience treating patients. Besides my private practice work, I am extensively involved in the Rheumatology community, currently a Clinical Associate Professor of Rheumatology, the President of the California Rheumatology Alliance (CRA) and have been very active with the Southern California Rheumatology Society and Arthritis Foundation. The purpose of this letter is to show support for PrismRA, the Molecular Signature Response Classifier for Rheumatoid Arthritis.

Since Rheumatoid Arthritis is a complex disease, there are many challenges in treating patients. Having a test that can prevent the current "trial and error" process treating patients, and will enable better patient outcomes.

Since the introduction of PrismRA, I have utilized the test on several patients. I have been impressed with the results of the test. Sometimes, the results have shown that TNF inhibition is the correct choice. Sometimes, the results have shown that another mechanism of action would be a better choice. I have used the results and have seen better patient care, which is most important.

Thank you for your consideration of my feedback, as I strongly support your adoption of coverage for the PrismRA test.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I’m writing this email to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with over 8 years of experience.

Currently, with the lack of available resources and clinical assessments, I’m limited in the ability to start a patient on the drug that’s most appropriate to them based on their unique disease biology.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. PrismRA is intended for use by physicians to guide medical management decisions in RA adult patients with moderate to high disease activity who have either not reached treatment disease activity objectives 1) on csDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change. (This includes dose escalation or cycling to another TNFi).

At present, or at least prior to the availability of PrismRA, rheumatologists like me had no way of predicting whether a patient will respond to this class of drugs in advance of prescribing TNFi therapies without the use of the test. Furthermore, because RA is a progressive disease, patients that ultimately fail DMARDs may have increased disability by the time they are able to move to the next mechanism of action (MOA). PrismRA helps me steer patients away from medications that will not work based on their biology while greatly improving disease management and patient outcomes as well as reducing patient and health system costs. Patients who are being treated with TNFi as first-line biologic therapy and fail will have increased ineffectiveness by the time they are able to move to the next drug class. Precision medicine tools, like a molecular signature response classifier (MSRC), provide insight that informs therapy selection. A molecular signature response classifier (MSRC) has helped me guide first-line therapy selection without a trial-and-error approach.

I strongly support the coverage of PrismRA for my patients and I hoping for a change in your previous decision.

Thank you for your consideration of this matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing rheumatologist with over twenty years of experience.

When it comes to treating my RA patients, with the currently available resources and clinical assessments, my ability is limited to start a patient on the correct drug based on their unique disease biology. I do not have a test or clinical assessment to inform me of the right biologic for my RA patients. I have used the PrismRA test to inform me which biologic is the most appropriate to start. This type of precision medicine allows me to eliminate a trial-and-error approach to treating my RA patients. My goal is to get my RA patients in remission/low disease activity as soon as possible. RA is a devastatingly horrible disease where up to 70% of patients that are inadequately treated become disabled within 10 years.

PrismRA is the 1st and only available Molecular Signature Response Classifier that predicts inadequate response to all TNF therapies in RA. I have used PrismRA in patients that failed methotrexate and need to start a biologic therapy. I have also used in patients that are failing on biologic therapy and in need of a change in therapy. The clinical validity of PrismRA has been in peer-reviewed studies and publications. This test has helped me get more of my RA patients into low disease activity which is the goal of every rheumatologist.

I support using prismRA in my practice and have firsthand experience in seeing how this test can improve outcomes for my patients struggling with RA. Precision medicine tools, like PrismRA provide insight on my RA patients that I currently do not have. It has helped me guide therapy without a trial-and-error approach.

Thank you for considering my comments on this matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I’m a practicing rheumatologist with 35 years of experience.

At present and in the absence of PrismRA, when treating my RA patients, I must choose a first-line biologic therapy without the appropriate tools that will help me match therapy to a patient’s unique disease biology. It is a trial-and-error approach that more often than desired, wastes valuable time.

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to TNFi therapies for patients with RA. It is intended for use by physicians to guide treatment decisions in RA adult patients with moderate to high disease activity who have not reached treatment disease activity objectives. The clinical validity of PrismRA has been documented in several peer reviewed studies and publications. In their latest clinical utility data, those patients who were identified as having an inadequate response to TNFi who were redirected to another mechanism of action experienced a near two-fold improvement in disease activity. Simply put, using the test to guide therapy selection for RA patients failing csDMARDs with get more patients to lower disease activity.

At present and without the availability of PrismRA, rheumatologists have no way of predicting whether a patient will respond to this class of drugs before they prescribe a TNFi therapy. A trial-and-error treatment approach does not tailor therapy to a patient’s individual disease biology and can lead to poor outcomes. These poor outcomes include:

• response rates decline up to 35% after failing first line therapy
• there is a higher likelihood of irreversible joint damage and chronic pain which leads to increased surgeries
• increased use of pain meds and steroids
• time and money wasted on ineffective treatment

Both myself and my colleague have been using PrismRA in our practice. We have firsthand experience in seeing how a precision medicine test can improve outcomes for patients struggling with RA.

I believe there is considerable evidence and clinical need for this kind of precision medicine test so that we can end the trial-and-error approach of treating RA patients and get their disease under control sooner. I strongly encourage you to approve coverage of PrismRA.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

This is a letter to address the proposed limited coverage decision/non-coverage decision (LCD/NCD) entitled Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. This preliminary coverage document impacts the accessibility of PrismRA and other precision medicine tests.

I am a rheumatologist with 31 years’ experience taking care of Rheumatoid Arthritis patients.

It is most important that policy makers become familiar with the diseases, treatments, and options related to items for which they make big decisions. In the case of Rheumatoid Arthritis, the PrismRA test not only allows for better treatment of patients, but could save enormous amounts of money in medications that are destined to fail.

Rheumatoid Arthritis is a potentially crippling and disabling disease, with increased mortality and serious morbidity. It requires aggressive treatment, and many patients need biologic therapy that is very expensive.

Until PrismRA came out, there was no way to predict whether or not a biologic would work for a patient, and therefore we had to use guess work, going through trial and error. Unfortunately, that means that many patients take a medication for weeks on end (it may take 12-16 weeks for these medications to work), only to find out it does not work for them. In addition to the patient being in pain needlessly while waiting to find out if the medications will work, the cost of these medications makes their use in patients who are not going to be good responders a very expensive endeavor.

PrismRa identifies markers in the patients blood which can help predict whether or not they may be poor responders to TNF inhibitors (the class of medications most frequently used as first line biologic therapy for RA — including Humira/Adalimumab, Enbrel/Etanercept, Remicade/Infliximab, Cimzia/Certolizumab, Simponi and Simponi Aria/Golimumab).

This has been extremely helpful in clinical practice, and it is a one-time test, which does not need to be repeated. This test may save thousands of dollars for EACH individual patient who is found to be a poor responder, and for whom trial of a TNF inhibitor would be nothing but a waste of time and money, prolonging patient suffering and costing the system unnecessary expense.

Therefore I urge you to reconsider and cover this very useful test, for which there is no substitute, clinical or otherwise.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to weigh in on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a Nurse Practitioner who specializes in rheumatology with 2 years of experience. I completed American College of Rheumatology courses and was trained by a board-certified rheumatologist that I continue to work with. Together we see over 2,500 patients and many of those patients have rheumatoid arthritis.

At this time when treating a patient with rheumatoid arthritis we are faced with a trial/error approach to our therapies which is also dictated by insurance and required steps to progress their treatment. 1st line therapy when advancing a patient to biologics are Anti-TNFs which sadly not all or even most patients respond to. When we are treating to target goal it is recommended by the ACR that our patients have a 50% response to treatment at 6 months of treatment. When we are having to cycle through medications that our patient may or may not respond to we are left with the inability to meet these goals. Which increases time to move patients to remission or low disease activity which is our goal as we know if RA is not treated then up to 70% of these patients can become disabled within 10 years due to inadequate treatment (Burton W, 2006). If rheumatology specialists were able to utilize precision medicine tools it would be able to help these patients get to goal more rapidly as well as avoid complications and sequelae of RA.

I would like to present support to PrismRA as it is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFi therapies in RA. PrismRA is intended for use by providers to guide medical management decisions in RA adult patients (18 years or older) with moderate to high disease activity who have either not reached treatment disease activity objectives 1) on csDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change (including dose escalation or cycling to another TNFi). The Clinical Validity (CV) of PrismRA has been documented in several peer reviewed studies and publications. In a CV study, the PrismRA test identified a molecular signature of non-response to TNFi therapies with a positive predictive value (PPV) of 87.7% (95% confidence interval [CI] 78-94%), sensitivity of 60.2% (95% CI 50-69%), and specificity of 77.3% (95% CI 65-87%) (Jones A, 2021). Furthermore, in four separate validation cohorts, the PrismRA test predicted non-response to TNFi therapies with statistically significant odds/ratios across multiple outcome measures commonly used in RA, including ACR50, ACR70, CDAI LDA, DAS28-CRP LDA, and EULAR good response (Cohen S, 2021; Zhang L, 2021; Strand V, 2022 (CU1); Strand V, 2022 (CU2)).

• As published in clinical validation (CV) studies, the PrismRA test can accurately predict non-response to all TNFi therapies. In 174 samples from the prospective observational in the NETWORK-004 study of patients treated with TNFi therapies, the PrismRA test demonstrated (Jones A, 2021):
  Positive Predictive Value (PPV): 87.7% (95% CI 78-94%). This describes the percent of patients with a molecular signature of non-response who will NOT reach ACR50 on a TNFi.
  
  
• Sensitivity (true positive rate): 60.2% (95% CI 50-69%). This describes the percentage of true TNFi non-responders (those who do not respond, defend as having a 50% improvement/ACR50 within 6 months on ACR50) who are identified by PrismRA testing having a molecular signature of non-response.
  
  
• Specificity (true negative rate): 77.3% (95% CI 65-87%) This describes the percent of true TNFi responders (those who respond based on AR50) who did NOT have a molecular signature of non-response

At this time we have no way to predict if a patient will respond to TNFi therapies without the use of PrismRA tests other than utilizing trial and error or having to go through step edits in place by insurance companies. With this it can cause patients to have worsening disease activity for prolonged periods of time. I recently used PrismRA for a patient with sero-negative erosive rheumatoid arthritis. With the erosive status it was imperative that we get the patient established on an effective treatment regimen which included the use of biologics to slow/halt disease activity. She had tried TNFi therapy that was not effective for 3 months, at which point we opted to use PrismRA prior to switching therapy to see if using a different TNFi was worth utilizing or if progressing to a different class of therapy would be more successful. In her case she was a non-responder to TNFi therapy which prompted therapy to change and patient was subsequently changed to an IL-6 medication which has helped us to reach 50% response in 2 months.

I support utilizing and implementing the PrismRA test into my practice. I have seen in multiple situations how this test is applicable and can shorten treatment time as well as decrease healthcare burden for patients struggling with rheumatoid arthritis. It is a tool that is providing precision medicine in a field where targeted therapy can provide successful patient outcomes and prevent the complications that can arise with RA when it is not in low disease status/remission. I have seen many patients that do not respond to TNFi therapy with targeted therapy. Rheumatology providers have another tool which can be utilized to help manage a patients' disease more effectively.

Thank you for your time and consideration of this important matter.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I would like to comment on the Draft Local Coverage Decision Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis. I am a practicing with 35 years of experience and have extensive experience in treating rheumatoid arthritis with biologic therapies. We presently have no approved test to allow us to predict which biologics may be of value in a patient with RA. I have used the Prism RA test in hundreds of patients prior to selecting a biologic therapy.

I have found the results to be highly predictive of those patients who will or will not respond to anti-TNF agents. I have had several patients who were predicted by the test to be non-responsive to anti -TNF drugs. Due to insurance step-edits, they were required to try an anti-TNF agent first. After several months of a non-response and tens of thousands of dollars of wasted medicines, there were switched to an alternative agent with good response. If I had been allowed to follow the predictive response, we could have saved the system and patients months of wasted time, not to mention the added expense.

The PrismRA test has been validated with a positive predictive value of 87.7%, sensitivity of 60.2% and specificity of 77.3%. Given my experience on hundreds of patients, I find these values to be accurate.

Thank you for considering these comments.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing Rheumatologist with over 25 years’ experience treating patients. Besides my private practice work, I am extensively involved in the Rheumatology community. The purpose of this letter is to show support for PrismRA, the Molecular Signature Response Classifier for Rheumatoid Arthritis.

Since Rheumatoid Arthritis is a complex disease, there are many challenges in treating patients. Having a test that can prevent the current "trial and error" process treating patients, and will enable better patient outcomes.

Since the introduction of PrismRA, I have utilized the test on a number of patients. I have been impressed with the results of the test. Sometimes, the results have shown that TNF inhibition is the correct choice. Sometimes, the results have shown that another mechanism of action would be a better choice. I have used the results and have seen better patient care, which is most important.

Thank you for your consideration of my feedback, as I strongly support your adoption of coverage for the PrismRA test.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing about the draft coverage decision. I have been in practice as a Rheumatologist for over 30 years.

I have used the Prism RA test to inform me which biologic is the best to use with my RA patients. It is amazing how much the practice of Rheumatology has changed over the years. As physicians we have so many more options to help our patients and Prism RA is one of those options. Prism RA test is just a way to help one further way for me to help my patients.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I’m a practicing rheumatologist and would like to comment on the Draft Local Coverage Decision around PrismRA, a molecular biomarker test that helps guide therapy selection in rheumatoid arthritis.

The rheumatology community has anxiously awaited a precision medicine tool like PrismRA that allows physicians to target therapy based on a patient’s individual biology. The benefit is that patients get on the right therapy sooner, thereby improving their clinical outcomes.

I began using PrismRA a few months ago and it has become a valuable tool in my practice. It guides therapy by identifying inadequate response to all TNFi therapies. I’m finally able to avoid the current trial-and-approach when choosing a first-line biologic or when switching from one medication to the next. Furthermore, I’m basing my choices on patient biology versus what insurance dictates. The latter approach can often lead to higher costs in the end, not only financially, but in terms of additional joint damage as patients cycle through medications that don’t work for them.

Peer-reviewed studies show improved CDAI and ACR50 response rates when patients are predicted TNFi non-responders and go on an alternate mechanism of action. Those response rates are also improved for those patients who do not have a non-response signal and, therefore, go on a TNFi. This data provides strong evidence for making PrismRA a part of RA patient care.

Please reconsider your previous decision and grant coverage for Prism/RA, so we can stop the trial-and-error approach to targeted therapy selection for patients with rheumatoid arthritis.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a rheumatology practitioner, and I would like to send this letter to support complete coverage of the Molecular Signature Response Classifier, PrismRA. There is no other test currently available for predicting patient response using individual and clinically validated biomarkers. For years, rheumatologists and practitioners within rheumatology have been waiting for a tool to provide patient specific results, unique to each patient, to direct therapy and reach low disease activity in a quicker and more efficient manner. In our industry, entrenched contracts within insurance typically dictate a "one size fits all" approach to choosing therapy. Before PrismRA, there was no other method to predict whether a patient would respond to our biggest class of biologic therapy utilized to treat RA.

PrismRA has the benefit of extensive clinical validity and utility studies which have empowered my usage of the test. When a patient is ready to begin a biologic, I use PrismRA to decide whether they are an appropriate candidate for a TNFi mechanism of action drug. I have used this to save patients time, money, and give them back their lives. This test empowers practitioners and is fundamentally necessary for treating our patients. It should be widely available and completely covered. There is no other test currently available with the same utility.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am writing this letter (Rheumatologist) requesting coverage for PrismRA test as it is helpful to choose the right biologic treatment for difficult RA patients-both for the initial starters as well as after failure of 1st biologics. I have used this test in several patients and found it very useful. Multiple literature is available regarding this. Thanks in advance for considering this test for approval.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am a practicing Rheumatologist. I would like to comment on the Draft Local Coverage Decision: Molecular Biomarker Testing to Guide Targeted Therapy Selection in Rheumatoid Arthritis.

We see many RA patients every day and order dozens of blood tests to help determine the best treatment plan based on how the disease is affecting their unique biology. From there it becomes a guessing game on what medication will work best for my patients. This trial-and-error approach leads to irreversible joint damage when my patients aren't put on the proper medication. Delayed treatment puts the patient at risk for disease progression and as we know, up to 70% of patients with RA that are inadequately treated become disabled within 10 years (Burton W, 2006). Using a precision medicine test, like PrismRA, to predict therapy response to biologics for patients with rheumatoid arthritis saves patients from unnecessary active disease period, progressive damage to joints with time, and expensive medication costs (Johnson KJ, 2019; Boytsov N, 2016; Strand V, 2018).

PrismRA is the first and only commercially available Molecular Signature Response Classifier (MSRC) test that predicts inadequate response to all TNFitherapies in RA. PrismRA is intended for use by physicians to guide medical management decisions in RA adult patients (18 years or older) with moderate to high disease activity who have either not reached treatment disease activity objectives 1) on csDMARDs and are considering starting a b/tsDMARD or 2) TNFi therapies and are considering a targeted therapy change (including dose escalation or cycling to another TNFi). Because RA is a progressive disease, patients that ultimately fail DMAROs may have increased disability by the time they are able to move to the next mechanism of action (MOA).

Patients who are being treated with TNFi as first-line biologic therapy and fail will have increased ineffectiveness by the time they are able to move to the next drug class. Precision medicine tools, like a molecular signature response classifier (MSRC), provide insight that informs therapy selection. A molecular signature response classifier (MSRC) has helped me guide first-line therapy selection without a trial-and-error approach. I strongly support the coverage for PrismRA and my patients.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I am the laboratory medical director for Scipher Medicine and am responsible for the performance of analytical tests (diagnostic immunology and NGS) included in the algorithmic analysis for PrismRA. I am a board-certified (American Board of Pathology) pathologist with over 20 years’ experience in directing pathology laboratories, including anatomical, clinical and molecular/genomic pathology testing. The laboratory I am directing is CLIA, CAP and NYSDOH certified/accredited. I am writing to you in strong support of this test.

To select the best therapy for their patient, rheumatologists are currently forced to rely on a trial-and-error approach, frequently delaying the patient from receiving effective treatment by many months. The PrismRA molecular signature response classifier (MSRC) yields precise results and accurately predicts non-response to tumor necrosis factor-α inhibitors (TNFi), as demonstrated in published analytical and clinical validation studies, thus removing the need for a patient to initiate a likely-to-be ineffective treatment.^1,2 Published clinical utility studies³ have also shown that providers find the MSRC results to be helpful information when selecting therapy for their patients, and that use of the test in treatment decision-making leads to greater improvement in patient outcomes.

In analytical validation studies (Table 1), the MSRC test was shown to be reproducible, and repeatable in predicting non-response to TNFi therapies in rheumatoid arthritis (results below). PrismRA sets a high standard for analytical performance.

Clinical validation studies demonstrated that the MSRC accurately predicted non-response to TNFi therapies in both patients who had previously tried a TNFi and those who had not yet initiated a biologic therapy. In these studies (Table 2), 87.7% of patients with an MSRC prediction of non-response did not reach ACR50 by six months on a TNFi. Conversely, of those patients who did achieve ACR50, 77.3% did not have an MSRC result predicting non-response. Finally, 60.2% of patients (and 67.8% of TNFi naïve patients) who did not reach ACR50 by six months had an MSRC prediction of non-response. Importantly, the MSRC test’s performance held across multiple clinical measures, including ACR70, CDAI LDA, DAS28-CRP LDA, and EULAR good response.²

In summary, the study results highlighted in this letter support the MSRC’s suitability for routine clinical use. The current unreliable and costly trial-and-error approach can lead to a long and potentially harmful road to identifying the right drug for the patient. Using the MSRC to rule out drugs that are less likely to be effective helps patients get on an appropriate therapy sooner, which has the potential to save them from unnecessary and sometimes significant side effects and prevent wasted resources across the healthcare system.

Tables and references were provided for review.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

I have had the opportunity to use PRISM RA for clinical decision making with regards to seropositive rheumatoid arthritis and wanted to give my feedback. In this particular case, the patient had failed methotrexate, leflunomide, and hydroxychloroquine, in achieving remission for rheumatoid arthritis. In discussion we had decided to use a TNF inhibitor to see if we could get the Rheumatoid Arthritis under better control. We checked a PRISM RA and found that the patient did not have genetic signaling to warrant not using TNFi therapy for the treatment of her RA. This was good news, and we proceeded with approval of Humira for the patient, and to this date, she has done very well with the use of Humira. This tool/lab test provides insight as a clinician that can help with decision making, deciding which biologic therapy to use, what would be effective or not for the patient (with regards to TNF inhibitors), and also can save time, prevent irreversible joint damage, and help the patient achieve remission sooner and decrease the overall burden of health care costs. As noted in the TICORA study from 2007, it's wise to be aggressive and achieve remission as quickly as possible, and this tool does allow this, to improve the standards of healthcare that we can provide. I would recommend this tool for future use and allow its acceptance to all patient populations of rheumatoid arthritis.

Thank you for your comment. We have addressed your comment in Response #1.

The following comment was submitted to Palmetto GBA:

Prism RA has been used in our practice. I have seen it as a beneficial tool for our patients and helping guide provider decisions in selecting the best plan of care. We have performed this test on many patients that were not responding to TNFi medications like Humira for example and the test showed they are high non responders which provides evidence as to why they are not responding to the current treatment.

Many times, our practice uses this lab test on TNFi naïve patients to help us determine the next step in treatment. When the patients’ Prism RA comes back as a high non responder, we by-pass the TNFi drug class all together which saves the patient the 6 months we would have spent trialing a TNFi.

Adding: Prism RA is a tool Rheumatologist need and there is nothing comparable for us to determine if patients would be a non-responder to the class of TNFi therapies.

Thank you for your comment. We have addressed your comment in Response #1.