October 10, 2025

Re: National Coverage Analysis (CAG-00440R)
Request for Public Comment on Coverage of Colorectal Cancer Non-Invasive Biomarker Screening Tests

The National Center for Health Research (NCHR) appreciates the opportunity to provide comments in response to the Centers for Medicare & Medicaid Services (CMS) request for input on the coverage of colorectal cancer (CRC) non-invasive biomarker screening tests, including multi-target stool RNA (mt-sRNA) assays, and on the review of sensitivity and specificity cut points.

NCHR is a nonprofit think tank committed to bridging the gap between scientific evidence and public policy with the goal of improving the health and safety of patients and consumers. Our mission is to ensure that medical products and technologies are not sold in the U.S. unless they are proven safe and effective based on rigorous, independent evidence, with particular attention to how benefits and risks differ across diverse patient populations, including older adults who make up the majority of Medicare beneficiaries.

We recognize the need for more convenient CRC screening. However, FDA approval of the multi-target stool RNA (mt-sRNA) screening test ColoSense does not in itself establish clinical effectiveness in Medicare populations. The FDA’s Summary of Safety and Effectiveness Data (P230001) for ColoSense noted uncertainty regarding the test’s sensitivity, requiring a post-market study of 12,500 participants to confirm accuracy. We agree on the need for such a study, but it should be completed and analyzed prior to Medicare making a coverage decision. We describe the research evidence and shortcomings below.

Background and Context

ColoSense, the multi-target stool RNA (mt-sRNA) test, was assessed in the pivotal CRC-PREVENT trial (Barnell et al., 2023) of 8,289 participants, demonstrating analytical validity and 94% sensitivity for colorectal cancer (CRC). However, the FDA’s Summary of Safety and Effectiveness Data (SSED; PMA P230001) identified several limitations in the study design and performance interpretation. According to the SSED, “there is a chance that as many as 24.3% of patients with colorectal cancer may be missed by this test” based on the lower bound of the 95% confidence interval. The FDA therefore required Geneoscopy to conduct a post-approval study of 12,500 participants to confirm real-world sensitivity and specificity. The protocol for this post-market study was originally accepted on May 3, 2024, and the current protocol was accepted on September 9, 2024, but the study appears to have not begun according to fda.gov and there is no NCT registration number for the post-market study posted to ClinicalTrials.gov. 

This lack of an active or publicly registered required post-approval study raises substantial concerns about transparency, regulatory compliance, and readiness for coverage in the Medicare population. A study of 12,500 patients followed for 2 years will take years to complete, and yet the company hasn’t even started the research yet. Without post-market validation data, CMS cannot reasonably determine whether ColoSense performs as well as existing CMS-covered tests such as Colorguard, the multi-target stool DNA test.

Furthermore, ColoSense’s existing data reported a specificity of 85.6%, which is substantially lower than that of Cologuard Plus (91%), suggesting it would result in an increased false-positive burden and downstream colonoscopy demand (Exact Sciences, 2025). These unresolved issues reinforce the need for the FDA’s required post-market study to be appropriately completed before any national coverage determination is made.

The Role of Stool-Based RNA Colorectal Cancer Screening Tests

Stool-based RNA colorectal cancer screening tests expand early-detection options beyond colonoscopy and traditional fecal tests. These assays analyze RNA biomarkers shed by cancer cells into stool, identifying colorectal cancers and precancerous lesions through simple at-home sample collection (Barnell et al., 2023; Barnell et al., 2025).

Unlike other stool-based tests, the mt-sRNA test, ColoSense, eliminates the need for patients to swab or scrape their stool. Instead, the patient deposits a sample into a container and mails it to a lab for technician-handled analysis (Barnell 2025). This could potentially increase adherence among patients who are uncomfortable with other stool-based tests and unwilling or unable to undergo colonoscopy. 

However, the potential for increased adherence is valuable only if verified with real-world data.

Sensitivity and Specificity of Current Non-Invasive CRC Screening Tests

There are several FDA-approved stool-based CRC screening tests that are covered by Medicare.  The goal of stool-based CRC screening tests is to be non-invasive and more convenient than colonoscopies, with the understanding that positive results will require additional testing with a colonoscopy.  They therefore must balance high sensitivity to detect early cancers and advanced adenomas, as well as adequate specificity to prevent unnecessary colonoscopies and associated risks.

The fecal immunochemical test (FIT) is the most widely used stool-based screening tool. It detects hidden (occult) blood in stool by identifying human hemoglobin proteins using specific antibodies. FIT is simple, inexpensive, and can be done annually at home. However, while it is highly specific (~94%), its sensitivity for early cancers (~74%) and advanced adenomas (~23%) is lower than that of multi-target molecular stool tests, leading to more missed precancerous lesions (Imperiale et al., 2014; Lin et al., 2016; Knudsen et al., 2021; US Preventive Services Task Force (JAMA 2021).

The currently approved multi-target stool DNA (mt-sDNA) test, marketed as Cologuard, combines molecular DNA markers with a fecal immunochemical test (FIT) to detect occult blood and DNA mutations associated with colorectal cancer (CRC) and advanced adenomas. In the DeeP-C trial (Imperiale et al., 2014), Cologuard achieved 92.3% sensitivity for CRC, 42.4% for advanced adenomas, and 86.6–89.8% specificity, outperforming FIT alone (73.8% CRC sensitivity, 23.8% advanced adenoma sensitivity, 94% specificity) (Eckmann et al., 2020).

In contrast, ColoSense, a multi-target stool RNA (mt-sRNA) test, uses RNA rather than DNA biomarkers. However, the ColoSense test is not based solely on RNA biomarkers; it combines three components, which are a fecal immunochemical test (FIT) that detects hidden blood in stool, a panel of RNA transcripts shed by tumor or precancerous cells, and a patient factor (smoking status) to generate an overall test score. This means that the mt-sRNA assay, ColoSense, builds upon, rather than replaces, the traditional FIT methodology. However, the FDA’s performance audit identified several limitations in the CRC-PREVENT trial of ColoSense, so the agency required a post-market study to provide real-world accuracy and safety (FDA, 2023; P230001C). 

It is important to note that when the RNA portion of the ColoSense test was analyzed separately, it performed only slightly better than random chance with an Area Under the Receiver Operating Characteristic (AUROC) value of 0.58–0.62 (An AUROC of 0.5 indicates no diagnostic value, while 1.0 indicates perfect accuracy.). This indicates that most of the test’s diagnostic power likely comes from the FIT component rather than the RNA markers themselves. This raises clear questions about the added clinical value of the RNA component and reinforces the importance of continued evidence development before granting full Medicare coverage (Barnell et al., JAMA 2023; Supplement 3, eFigure 3). 

Taken together, these data indicate that while ColoSense is promising, it has not demonstrated that it as effective or superior to the existing CMS-covered mt-sDNA (Cologuard) or FIT tests. 

Patient-Centered Considerations

Expanding coverage for non-invasive colorectal cancer screening options has been found to improve participation among older adults and those with comorbidities who face challenges with colonoscopy preparation, sedation, or access to endoscopy facilities (Cooper et al., 2013; Lin, 2014; Kwok et al., 2023). These at-home stool tests, including the fecal immunochemical test (FIT), multi-target stool DNA (mt-sDNA; Cologuard), and multi-target stool RNA (mt-sRNA; ColoSense) can reduce logistical and procedural barriers to screening. For rural, minority, and socioeconomically disadvantaged populations, mail-based stool tests may help overcome transportation and access barriers (Sepassi et al., 2024; CDC, 2025; Redwood et al., 2023). However, these tests complement, rather than replace colonoscopy, which remains the diagnostic gold standard for detecting and removing precancerous lesions.

Risks, Limitations, Concerns, and Data Gaps

1. Disproportionate inclusion of smokers may bias the results.
   The ColoSense CRC-PREVENT trial incorporated smoking status as a variable in its composite scoring algorithm, alongside the fecal immunochemical test (FIT) and RNA biomarkers. The FDA’s Summary of Safety and Effectiveness Data (PMA P230001, 2024) reported that 34.3% of participants were classified as current or former smokers, a prevalence nearly three times higher than the U.S. adult current smoking rate average of approximately 12% (CDC, 2024). Because smoking is a known risk factor for colorectal neoplasia, this overrepresentation may have artificially inflated test sensitivity in a high-risk cohort. Moreover, the company does not explain why their study sample included so many smokers, and whether the study participants may not be representative of the general population or of the Medicare population in other ways as well. In addition, since smoking behavior was self-reported and some participants declined to disclose their status, the accuracy of this variable is uncertain and the proportion of smokers may have been even higher. 
2. False positives increase the downstream burden of colonoscopy.
   While stool-based screening tests aim to reduce unnecessary colonoscopies, their value depends on whether they perform at least as well as existing noninvasive options. ColoSense (mt-sRNA) demonstrated a specificity of 85.6% in the CRC-PREVENT trial, lower than the FDA-approved and CMS-covered Cologuard (mt-sDNA) test, which achieved about 91% specificity and 92% sensitivity for colorectal cancer in the DeeP-C study (Imperiale et al., 2014). Since ColoSense (mt-sRNA) data do not indicate that this RNA-based approach is at least as accurate or that it meaningfully improves real-world adherence, it may not be as beneficial as the ColoGuard test. Moreover, higher false positives increase downstream colonoscopy burden, so any new stool test with more false positives must demonstrate substantial added value to justify coverage. 
3. Trial performance may not reflect real-world Medicare outcomes.
   Adherence and follow-up rates observed in clinical trials are likely to be substantially higher than those seen in community or Medicare populations. Consequently, real world evidence of ColoSense compared to Cologuard would provide important information that is currently lacking. Continuous monitoring providing real world evidence of adherence, false-positive rates, and follow-up colonoscopy completion is essential to validate test performance.

For all the reasons specified in #1-3, the composite model’s performance may not reflect the accuracy of the test for a representative sample of patients of any age or health status, and certainly not those in the Medicare population. CMS should therefore interpret ColoSense’s published accuracy metrics with caution and require independent validation of the model without the smoking variable before considering coverage.

1. FDA-Mandated post-approval study is pending; CMS should wait.
   The FDA mandated a post-approval study to confirm the safety and effectiveness of ColoSense, enrolling 12,500 participants to assess performance across diverse populations (FDA PMA P230001C, 2024). Although the protocol was accepted on September 9, 2024, the FDA database currently lists the study as “Study pending” with no posted study information and no NCT number assigned on clinicaltrials.gov. The reporting schedule on the FDA website notes that progress reports have been submitted on time, but no links or public summaries of these reports are available. At present, the only registered clinical trial related to ColoSense is the pivotal CRC-PREVENT study (NCT04739722).

This FDA requirement of a post-approval study for ColoSense and the lack of evidence that the company has started recruited patients adds to the concerns about ColoSense’s trial findings and limits CMS’s ability to assess its performance in Medicare-age populations to make an evidence-based coverage determination. Given ColoSense’s commercial availability, the timely initiation and completion of the required post-approval study may not be a high priority. A NCD could inadvertently reduce the incentive to generate the evidence necessary for regulatory and clinical validation. We strongly encourage CMS to refrain from granting coverage until the required post-market data are available and reviewed by the FDA and/or CMS.

Recommendations

1. Deferred Coverage Decision Pending Completion of FDA-Mandated Post-Approval Study

Based on results and concerns about the current research and the lack of any useful information about the required post-market study, CMS should not grant coverage for ColoSense, the only multi-target stool RNA (mt-sRNA) test on the market, at this time. As noted above, the FDA mandated a post-approval study enrolling 12,500 participants to confirm the accuracy, safety, and effectiveness of ColoSense (FDA PMA P230001C, 2024). Although the protocol was accepted on September 9, 2024, the FDA database currently lists the study as “pending,” with no NCT registration number and no publicly available results or progress reports. Without completion and publication of this required post-market study, there is insufficient evidence to determine whether ColoSense is as beneficial to Medicare patients as currently covered non-invasive screening options. CMS should therefore withhold national coverage until the FDA-mandated study has been completed on a representative sample and its findings peer-reviewed. This cautious approach ensures scientific integrity, regulatory consistency, and prudence before providing a national Medicare NCD “seal of approval” to a test whose effectiveness and specificity remain unproven outside a potentially biased pivotal trial due to its very large proportion of smokers.

2. Performance Standards: Evidence-Based Benchmarks

Given that CMS already provides coverage for several convenient non-invasive stool-based tests, CMA should determine if future coverage for these or other stool-based CRC screening tests meet clear, evidence-based performance thresholds validated in Medicare-relevant populations. 

These thresholds should include:

• CRC sensitivity: ≥ 90% preferred, ≥ 70% minimum (Imperiale et al., 2014; 2024; Barnell et al., 2023).
• Advanced adenoma sensitivity: ≥ 40% minimum, ≥ 50–55% preferred.
• Specificity: ≥ 85% minimum; ≥ 90% preferred.

However, analytical accuracy alone should not justify coverage. CMS should require demonstration of adherence, follow-up completion, and cancer detection stage shifts prior to any future coverage determination.

3. Transparency and Post-Market Accountability

Prior to making a coverage determination, CMS should require Geneoscopy and other mt-sRNA screening test companies to make all FDA post-approval study protocols, enrollment progress, and data publicly available. Public dashboards or FDA-linked updates should include adherence rates, positivity rates, specificity, and follow-up colonoscopy completion, stratified by demographics. Such transparency will prevent premature coverage of unproven technologies and support equitable, evidence-based policy.

Conclusions 

While multi-target stool RNA (mt sRNA) testing represents a potentially useful approach to colorectal cancer screening, the current evidence is insufficient to support Medicare coverage at this time. The CRC PREVENT trial demonstrates analytical validity but lacks direct comparison with existing stool-based tests such as FIT or mt-sDNA, shows only marginal incremental value of RNA biomarkers beyond FIT, and includes population and methodological biases. Moreover, the FDA’s Summary of Safety and Effectiveness Data (P230001) acknowledges that the test (ColoSense) can miss up to 24 percent of colorectal cancers and mandated a post-approval study of 12,500 participants to confirm real world accuracy and safety. As of October 2025, this study has not been initiated, assigned a ClinicalTrials.gov (NCT) number, or publicly reported.

For Medicare coverage, new tests are reasonable and necessary if they either demonstrate significantly higher sensitivity, specificity, or adherence, or show that they are equally effective and more accessible than existing options. The current data for ColoSense show that the test may be less accurate, especially in a representative Medicare population, and there is no evidence that it meaningfully improves screening uptake.

Given these substantial evidence gaps, CMS should defer national coverage until the FDA mandated post-approval study is completed, independently verified, and vetted by FDA or CMS. Only when it is demonstrated to be at least as beneficial as the mt-sDNA test should CMS reconsider coverage. Taking this cautious, evidence driven approach will uphold CMS’s mission to ensure that coverage determinations are scientifically justified and protective of patient safety and public resources.

Respectfully submitted,
National Center for Health Research

Citations:

1. Barnell EK, Kruse K, Wurtzler EM, Scott MC, Barnell AR, Duncavage EJ. Analytical validation of a scrape-free multitarget stool RNA test for colorectal cancer screening. Pract Lab Med. 2025 Sep 3;47:e00502. doi: 10.1016/j.plabm.2025.e00502. PMID: 40994831; PMCID: PMC12454295.
2. PMA P230001: FDA Summary of Safety and Effectiveness Data. Accessed October 2025: https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001B.pdf
3. FDA, 2023; P230001C Summary of Safety and Effectiveness Data. Accessed October 2025 : https://www.accessdata.fda.gov/cdrh_docs/pdf23/P230001C.pdf
4. Post-Approval Studies (PAS) Database. Accessed October 2025: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma_pas.cfm?t_id=783383&c_id=7964
5. Exact Sciences. (2025). Cologuard HCP FAQ. Accessed October 2025. https://www.cologuardhcp.com/resources/faq
6. Santos DAR, Eiras M, Gonzalez-Santos M, Santos M, Pereira C, Santos LL, Dinis-Ribeiro M, Lima L. A preliminary assessment of a stool-based microRNA profile for early colorectal cancer screening. Sci Rep. 2025 Aug 5;15(1):28597. doi: 10.1038/s41598-025-14485-z. PMID: 40764826; PMCID: PMC12325799.
7. Liu H, Hansen L, Song C, Lin H, Chen D, Chen Z, Zhou H, Yang X, Pan W, Du J. Bioinformatic screen with clinical validation for the identification of novel stool based mRNA biomarkers for the detection of colorectal lesions including advanced adenoma. Sci Rep. 2025 Aug 11;15(1):29397. doi: 10.1038/s41598-025-13074-4. PMID: 40789879; PMCID: PMC12339692.
8. Barnell EK, Wurtzler EM, La Rocca J, et al. Multitarget Stool RNA Test for Colorectal Cancer Screening. JAMA. 2023;330(18):1760–1768. doi:10.1001/jama.2023.22231
9. Lin JS, Perdue LA, Henrikson NB, Bean SI, Blasi PR. Screening for Colorectal Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2021;325(19):1978–1998. doi:10.1001/jama.2021.4417
10. Le, Q. A., Greene, M., Gohil, S., Ozbay, A. B., Dore, M., Fendrick, A. M., & Limburg, P. (2025). Adherence to multi-target stool DNA testing for colorectal cancer screening in the United States. International journal of colorectal disease, 40(1), 16. https://doi.org/10.1007/s00384-025-04805-0
11. Cooper GS, Kou TD, Rex DK. Complications Following Colonoscopy With Anesthesia Assistance: A Population-Based Analysis. JAMA Intern Med. 2013;173(7):551–556. doi:10.1001/jamainternmed.2013.2908
12. Lin O. S. (2014). Performing colonoscopy in elderly and very elderly patients: Risks, costs and benefits. World journal of gastrointestinal endoscopy, 6(6), 220–226. https://doi.org/10.4253/wjge.v6.i6.220
13. Kwok, K., Levin, T. R., Dominitz, J. A., Panganamamula, K., Feld, A. D., Bardall, B., … & Day, L. W. (2023). Transportation barriers and endoscopic procedures: barriers, legal challenges, and strategies for GI endoscopy units. Gastrointestinal Endoscopy, 98(4), 475-481.
14.  Eckmann, J. D., Ebner, D. W., & Kisiel, J. B. (2020). Multi-target stool DNA testing for colorectal cancer screening: emerging learning on real-world performance. Current treatment options in gastroenterology, 18(1), 109-119.
15. Imperiale, T. F., Ransohoff, D. F., Itzkowitz, S. H., Levin, T. R., Lavin, P., Lidgard, G. P., … & Berger, B. M. (2014). Multitarget stool DNA testing for colorectal-cancer screening. New England Journal of Medicine, 370(14), 1287-1297.
16. Imperiale, T. F., Porter, K., Zella, J., Gagrat, Z. D., Olson, M. C., Statz, S., … & Limburg, P. J. (2024). Next-generation multitarget stool DNA test for colorectal cancer screening. New England Journal of Medicine, 390(11), 984-993.
17. https://www.cms.gov/medicare/coverage/evidence 
18. Sepassi, A., Li, M., Zell, J. A., Chan, A., Saunders, I. M., & Mukamel, D. B. (2024). Rural-Urban Disparities in Colorectal Cancer Screening, Diagnosis, Treatment, and Survivorship Care: A Systematic Review and Meta-Analysis. The oncologist, 29(4), e431–e446. https://doi.org/10.1093/oncolo/oyad347
19. https://www.cdc.gov/pcd/issues/2025/25_0025.htm
20. Redwood D, Toffolon M, Flanagan C, Kisiel J, Kaur JS, Jeffries L, Zenku M, Lent J, Bachtold J. Provider- and System-Level Barriers and Facilitators to Colonoscopy and Multi-Target Stool DNA for Colorectal Cancer Screening in Rural/Remote Alaska Native Communities. International Journal of Environmental Research and Public Health. 2023; 20(22):7030. https://doi.org/10.3390/ijerph20227030
21. https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=281 

October 7, 2025

I’m Dr. Diana Zuckerman, president of the National Center for Health Research.  Our non-profit think tank does not accept funding from any entities that have a financial interest in our work, so we have no conflicts of interest.

Research showing low IQOS (i-cos) use when they were very briefly on the market during the COVID pandemic in 2021 is not relevant to future use. There is new research and a new understanding of the impact of these products on quitting smoking, on potentially harmful exposures, and on health.  We also know more about the marketing of these products and about consumers’ understanding of the risks. I will briefly summarize these issues.

1.  These products have the potential to help people quit smoking, but the most recent research shows they usually don’t.  In a study published this year in the Journal of Epidemiology, which was based on all published studies since 2022, 68% of users of heated tobacco products also smoked cigarettes. 
2. Although the short-term biomarker data says that traditionally identified toxic exposures are lower for IQOS than cigarettes, there are no long-term data that would be needed to show that IQOS are a healthier alternative to cigarettes in the long-run.  Meanwhile, FDA has identified many other potential toxic exposures that we heard today are higher for IQOS than for cigarettes.
3. Consistent with those findings, rodent studies indicate respiratory, cardiovascular, and reproductive harm that is equal to or greater than the harms of cigarettes.  I don’t like to rely on rodent studies, but we can’t ignore those important findings.  Especially because in research based on 55 studies of humans or human cells that was published this year in the journal Healthcare, heated tobacco devices increased respiratory disease, hypertension, heart rates, and other predictors of serious disease.   

These products have been on the market for 10 years, and the company should have provided longer term data to support their claim of reduced risk rather than telling you that their short-term exposure data shows that lower risk is reasonably likely.

4. The Campaign for Tobacco Free Kids has described some of the marketing techniques that PMI uses to reach young consumers.  These include ads in fashion magazines and sponsoring concerts that appeal to teens and young adults.  Even more harmful, 2 of the heat sticks you’re considering today are menthol products.  We all know that menthol appeals to nonsmokers and those just starting to use tobacco. Why encourage the use of a product that will encourage young people to become dependent on nicotine?

5. I’ve worked with thousands of consumers to evaluate their understanding of health warnings.  While many consumers may understand a statement that they have just read that they would need to switch completely from cigarettes to IQOS to reduce risks, that doesn’t mean they will remember that message exactly later in the day or later in the week. After all, health professionals always tell us that moderation is the key – we can eat fried foods or ice cream or hot dogs, or anything else in moderation, so smokers will assume that using IQOS and smoking less is a good way to lower risk. And, the message about lower exposure to chemicals is inevitably going to be misunderstood as meaning less harmful.

July 11, 2025

I’m Dr. Diana Zuckerman, president of the National Center for Health Research.  I appreciate the opportunity to speak today.

My perspective is based on my 35 years of working on issues pertaining to the safety and effectiveness of medical products. I have post-doctoral training in epidemiology and public health, and was a faculty member and researcher at Vassar, Yale, and Harvard before moving to Washington to work as a
Congressional investigator on FDA issues in the U.S. Congress. Prior to my current position, I also worked at HHS and the White House. Our research center is a nonprofit think tank that scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products or have any financial interest in our work.

I am one of the FDA’s biggest fans, because I fully appreciate the agency’s importance.  As a founding Board member of the Alliance for a Stronger FDA, I work with nonprofits and industry to increase appropriations for the FDA. We all know that our healthcare system relies on generic drugs and frankly
would collapse without them. I wish appropriations would be sufficient to support all of FDA’s essential work, but we know that the FDA needs user fees to ensure getting safe and effective medical products to market in a timely manner. However, speed is not the most important part of that equation.

There have been many inspiring statements in the FDA this year about transparency and about the need for the FDA to regulate industry, rather than be influenced by unduly cozy relationships with industry. An important first step would be for user fee negotiations to include patient, consumer, and
public health advocates, instead of only industry and the FDA negotiating behind closed doors. Unfortunately, all user fee negotiations have focused on what industry wants and needs and what they are willing to pay for, and not on what patients and consumers want and need.

On a personal note, my life has depended on generic drugs, which I’ve taken for cancer treatment and for high blood pressure. Like most patients, we trust that generic medications work but we don’t always know for sure. We all depend on generic drugs and understand their importance, so all of us in this room are in this together, and we need to work together.

Trust in generic drugs is essential to help to make healthcare more affordable. Trust in the FDA and in generic drugs has eroded in recent years, and that’s why GDUFA needs to explicitly show that user fees will focus on ensuring that generic drugs are truly equivalent to brand name treatments in all the ways
that matter to patients. Speed should be secondary, because when patients realize that some generic drugs are ineffective or unsafe, it harms patients but also harms companies whose products are safe and effective.

Let’s talk about Performance Goals in GDUFA. Up until now, too few have been focused on safety or effectiveness. We are glad that metrics have included the number of inspections and timeliness of inspections and follow-up warning letters, import alerts, and regulatory meetings, and those metrics
should included. However, they are not sufficient.

Last summer, the FDA determined that Synapse (a company in India) “faked and forged” data submitted to the FDA. FDA withdrew the bioequivalency rating of 400 of their drugs, but they are still on the market. Neither patients nor pharmacists have access to the names of those drugs. Why is that? That
is terribly unfair to patients, but it is also unfair to companies whose safe and effective generic medications are competing with those 400 drugs. And it is also unfair to generic companies that make excellent medications when patients don’t know which generic drugs they can trust.

Valisure has also conducted research showing a sizable number of generic drugs are substandard, with doses that are too high, too low, or drugs that are contaminated or have other problems.

These are just some examples of why post-market surveillance, inspections, and re-inspections are so important and why GDUFA should include funding for those purposes and include those types of metrics in the Commitment Letter.

GDUFA should include metrics showing that these problems are being addressed and generic drugs are truly safe and equivalent to brand name drugs. That’s the promise that GDUFA and the FDA have made to patients and it needs to be kept.

Here is an important list of the kinds of metrics that are missing from previous GDUFA Commitment Letters and should be included in FDA monitoring under GDUFA IV. They are the exact same list that the FDA states are criteria for all generic drugs. They must be:

• Pharmaceutically equivalent
• Capable of making the drug correctly
• Capable of making the drug consistently
• The active ingredient is the same as the name brand and the
same amount gets in the body
• Inactive ingredients are safe
• Drug does not break down over time

We’ve heard about the progress that has been made at the FDA thanks to GDUFA. That progress is wonderful, but to regain trust, improvements should be measurable and included as metrics in GDUFA IV.

Thank you for the opportunity to share my views with you today.

July 14, 2025

Good morning. I’m Dr. Amanda Berhaupt, Health Policy Director at the National Center for Health Research. I appreciate the opportunity to speak on behalf of our nonprofit think tank. We scrutinize the safety and effectiveness of medical products and do not accept funding from companies that make those products or entities with a financial interest in our work.

Prior to my current position, I worked at the FDA and for the United States Senate. 

The appropriated funds for FDA are not sufficient to support all of its critical work, so the agency needs user fees to get safe and effective medical products to market in a timely manner. User fees are vital to ensure that reviewers have subject matter expertise, institutional knowledge, adequate time and uninterrupted access to the FDA library with peer-reviewed research, among other scientific resources. 

User fees have mainly supported faster reviews and more frequent meetings between the FDA and sponsors to address concerns about their applications. I want to emphasize that this is not what’s most important for most patients. Their greatest concern is to have access to safe and effective medical products to treat, maintain, and promote their health. 

With a renewed focus on transparency at FDA, will patients and healthcare professionals be represented at user fee negotiations? At minimum, they deserve to watch the negotiations virtually, and in real-time, if they are not participating. In the past, summaries of negotiations have been too vague, which has prevented key stakeholders from providing input. 

To date, the performance goals in the Commitment letters have outlined metrics for meetings and timelines in premarket reviews. These goals benefit industry, and may indirectly benefit patients, but are not patient-centered and do not focus on safety or efficacy. 

We urge the agency to include performance goals with metrics on quality post-market surveillance including confirmatory studies with clinically meaningful outcomes. This is especially important when drugs are approved based on data from short-term studies with a small sample size, or based on surrogate endpoints instead of measures for how a patient feels, functions, or their overall survival. 

Patient advocates, public health researchers and professionals without industry ties need representation during negotiations to ensure there are performance goals that directly benefit patients and consumers.  

The public’s trust in the FDA has eroded. PDUFA needs to show that user fees will do more to ensure that drugs are safe and effective in ways that matter to patients. Speed should be secondary, because when drugs are ineffective or unsafe, patients lose confidence in their doctors and the FDA, and look for advice from other sources like social media where they may find erroneous and harmful advice.

Food and Drug Administration Dockets Management Staff (HFA-305)

5630 Fishers Lane, Rm. 1061

Rockville, MD 20852

August 13, 2025

National Center for Health Research Comments on the Reauthorization of

The Prescription Drug User Fee Act [Docket No. FDA-2025-N-0816]

The National Center for Health Research appreciates the opportunity to share our views on needed improvements to the PDUFA negotiation process and policies for PDUFA VIII.  We are a nonprofit think tank that scrutinizes the safety and effectiveness of medical products and the policies that affect the U.S. healthcare system.  We do not accept funding from companies that make those products or entities with a financial interest in our work.

We wish that Congress provided sufficient appropriations for FDA’s essential work, and our president is a founding board member of the Alliance for a Stronger FDA, which includes industry and nonprofit leaders who work tirelessly to improve those appropriations.  However, we know that the agency needs user fees to get safe and effective medical products to market in a timely manner. User fees are vital to ensure that reviewers have subject matter expertise, institutional knowledge, adequate time, and uninterrupted access to the FDA library with peer-reviewed research, among other scientific resources. The agency also needs the staff and resources to revise indications and labeling as needed and to remove products from the market that are not proven to be safe or effective.

Unfortunately, user fees have mainly supported faster reviews and more frequent meetings between the FDA and sponsors to address concerns about their applications. That is not what’s most important for most patients. Most patients’ greatest concern is to have access to safe and effective medical products to treat, maintain, and promote their health.  Our own research shows, for example, that many years after FDA approved cancer drugs on the basis of surrogate endpoints, only one of the 18 drugs was proven to save lives or improve patients’ quality of life.[1]  It is important to note that our research confirmed and provided several years of follow-up data to a study of now-CBER director Dr. Vinay Prasad.

As a way of showing the FDA’s renewed commitment to transparency, we strongly urge that patients and healthcare professionals will be represented at PDUFA user fee negotiations. At a minimum, they deserve to watch the negotiations virtually if they are not permitted to actively participate. In the past, minutes of the negotiation meetings have been too vague to be informative, which has prevented key stakeholders from providing effective input.

Previous PDUFA Commitment letters have focused on performance goals for meetings and timelines for premarket reviews. These goals benefit industry, and may indirectly benefit patients, but are not patient-centered, and not focused on the public health mission of the FDA or the quality of drugs or biologics, because they do not focus on safety or efficacy.

We strongly urge the agency to include performance goals with metrics on quality post-market surveillance including confirmatory studies with clinically meaningful outcomes. This is especially important when drugs are approved based on data from short-term studies with a small sample size or based on surrogate endpoints instead of measures of how a patient feels, functions, or how long they live.

For example, user fees should be used to support for FDA staff and resources needed for essential work other than reviews of new drugs and biologics, especially for work that benefits companies as well as patients.  These include:

• Confirmatory trials required for products granted accelerated approval
• Post-market studies required for products approved based on surrogate endpoints or short-term preliminary data, or to follow-up on worrisome adverse event reports or unexpected findings from independently funded studies or testing
• Inspections of manufacturing facilities and related work caused by problematic findings or failed inspections, since those are also required to ensure that companies can sell their products and that the products being manufactured are safe and effective.

To ensure that PDUFA makes CDER and CBER function more effectively, patient advocates, public health researchers, and professionals without industry ties need representation during negotiations to ensure there are performance goals that directly benefit patients and consumers as well as the overall functioning of these important Centers.

To regain the public trust in the FDA, PDUFA needs to show that user fees will focus more on ensuring that drugs are safe and effective in ways that matter to patients. Speed should be secondary, because when drugs are ineffective or unsafe, patients lose confidence in their doctors and the FDA.  That is not good for our country and will not help achieve our mutual goal of healthier adults and children.

PDUFA Commitment Letter

We’ve reviewed the 71-page PDUFA VII Commitment letter and were very disappointed at how infrequently any mention was made of the importance of FDA’s role ensuring that the drugs the agency is newly approving or previously approved are safe or effective.  There was more mention of “regulatory flexibility” aimed at making the regulatory process less stringent for the companies it regulates, than there was to ensuring that the benefits of newly approved drugs or previously approved drugs outweigh the risks for the American public.

Section K: Enhancing Regulatory Science and Expediting Drug Development 

As an example of how safety and efficacy were rarely mentioned, we will briefly examine Section K of the PDUFA VII Commitment Letter.  This section describes what FDA should do “to advance the use of biomarkers and pharmacogenomics, enhancing communications between FDA and sponsors during drug development, and advancing the development of drugs for rare diseases” to ensure that “new and innovative products are developed and available to patients in a timely manner.“

This section of the Commitment Letter describes numerous steps required of the FDA to facilitate approvals, with no mention of ensuring solid scientific evidence of safety or efficacy.  In PDUFA VIII, any such programs should include clear instructions that evidence from two well-designed studies is still the cornerstone of FDA approval, as well as the importance of clinically meaningful outcomes and statistical significance.

The Commitment Letter for PDUFA VIII should specify ways to increase safety and efficacy information that is publicly available and easy-to-understand, to reduce the burden on patients and providers that need to make potentially life-saving or life-threatening decisions regarding medical treatments.

For example, in #2 of Section K of the PDUFA VII Commitment Letter, entitled “Ensuring Sustained Success of Breakthrough Therapy Program,” the following addition in blue to the existing wording (in black) would have made it clear in PDUFA VII (and for information about the Breakthrough Program in a PDUFA VIII Commitment Letter) that, in addition to speedy review, the benefits of each approved Breakthrough drug should outweigh the risks:

Both FDA and the regulated industry are committed to ensuring the expedited development and review of innovative therapies for serious or life-threatening diseases or conditions by investing additional resources into the breakthrough therapy program to ensure that the therapies are proven to have benefits that outweigh the risks.

Another example is #3 in that same section in the PDUFA VII Commitment Letter, entitled “Early Consultation on the Use of New Surrogate Endpoints.”   The description should have made it clear that the FDA must agree to the use of a surrogate endpoint in order to use it as a primary endpoint.  This could have been clear (for PDUFA VII and in future descriptions of surrogate endpoints in PDUFA VIII) with the edits to the current wording (in black) which is in blue below:

Requests to engage with FDA on this topic will be considered a Type C meeting request. The purpose of this meeting is to discuss the feasibility of the surrogate as a primary endpoint and identify any gaps in knowledge and how they might be addressed. The outcome of this meeting may require further investigation by the sponsor and discussion and will require agreement with the agency before the surrogate endpoint could be used as the primary basis for product approval.

Our next example is #4, entitled “Advancing Development of Drugs for Rare Diseases.“ This current wording (in black) for PDUFA VII requires additional wording (in blue) to make it clear that evidence is important for treatment for rare diseases. This wording would have improved this section in the PDUFA VII Commitment Letter and in future information about regulating treatments for rare diseases in a PDUFA VIII Commitment Letter.

“FDA will continue to include information on rare disease approvals in its annual reports on innovative drug approvals, including utilization of expedited programs and regulatory flexibility and including metrics that indicate that approvals are based on convincing evidence that the drug or biologic has clinically meaningful benefits that outweigh the risks, and appropriate comparative metrics to non-rare disease approvals.

To support the advancement of rare disease treatments, FDA will establish a pilot program for supporting efficacy endpoint development for drugs that treat rare diseases by offering additional engagement opportunities with the Agency to sponsors of development programs that meet specific criteria. This pilot program will be strengthened to provide greater assurance that the endpoints indicate clinically meaningful benefits.

Section L.  Enhancing Regulatory Decision Tools to Support Drug Development and Review

The first item in this section is entitled “Enhancing the Incorporation of the Patient’s Voice in Drug Development and Decision-Making.”  We appreciate the FDA’s ongoing efforts to be more patient-centered, but we agree with the numerous patient groups who report that the FDA rarely shows interest in patients who ask the agency to help reduce harm to patients caused by taking drugs for approved or off-label indications. Many patients involved in these FDA efforts were recruited by industry and trained to support industry priorities, particularly getting drugs to market as quickly as possible.  Too often these patients focus on anecdotal evidence based on their own experience, without understanding scientific standards or the benefits of controlled clinical trials or clinical endpoints rather than surrogate endpoints.  Their views are important but need to be balanced by including patients with different priorities and the perspectives that comes from being harmed by FDA-approved prescribed drugs.

Section M. Enhancement and Modernization of the FDA Drug Safety System

This section is especially important to patients’ health and safety.  Unfortunately, “modernization” in PDUFA VII included the goal of reducing or eliminating REMS and on maintaining Sentinel, rather than improving either of these programs.

We agree that PDUFA VIII fees should support REMS and Sentinel again, but specific improvements are needed to make REMS more effective, rather than to eliminate ones that were designed to safeguard patients.

REMS

For example, FDA required a REMS program to train physicians who prescribe opioids, with the goal of reducing the opioid epidemic by reducing inappropriate prescribing.  That REMS underwent several changes after it was initiated in 2012.  As early as 2017, there was clear evidence that most physicians did not undergo the brief online REMS training that was required to be offered, and that many of those who started the training did not complete it or answer all key questions correctly.[2]  Despite those shortcomings, in 2020, the FDA announced that “the central component” of the REMS was still a voluntary continuing education (CE) program “for all health care providers, including nurses and pharmacists, who are involved in the management of patients with pain (in addition to doctors and others who prescribe these products).” The companies were required to offer the training through accredited CE providers, but the REMS does not require health professionals to take the training. Although Congress passed a law in 2023 that requires that physicians registered with the DEA take an 8 hour training on opioids, the physicians do need to get a passing grade on a test based on the training.[3]  PDUFA VIII should be used to strengthen the REMS to either require health professionals to pass a test to show knowledge of key information needed to safely prescribe opioids, or FDA should work with medical societies or other entities who have the authority to do so.  We also point out the conflict of interest of the FDA having the companies that sell opioids to be responsible for the training and for evaluating the effectiveness of the training.

Sentinel System

The Sentinel System was launched in 2008, with the goal of being an early warning system that could identify risks years earlier than would otherwise occur, by analyzing information from health records of millions of patients. Sentinel has resulted in several changes in risk information included in drug labeling, but the impact seems relatively modest considering the cost and scope of the program.

PDUFA VIII should include performance goals that quantify and specify how Sentinel should be used to provide additional information about risks on labels and to what extent it has resulted in changes to indications as more information becomes available about the risks of specific drugs and biologics. The enormous Sentinel “real world” datasets can be used to evaluate various adverse events on popular and less widely used drugs and to compare the safety of drugs used by similar patients for the same indication.  Sentinel can provide evidence of benefits when different treatments for the same indication are compared, but since it is based on real world evidence, the benefits of drugs cannot be compared to a placebo.  Sentinel has the data to make such comparisons possible, but it is not known how often that has been used.  PDUFA VIII should require metrics on how user fees help Sentinel meet these types of important performance goals.

Other PDUFA Issues

We have provided just a few examples of the specific ways that the PDUFA VIII Commitment letter should specify the types of performance goals and program expectations that will help patients, consumers, and health professionals make better informed decisions about FDA-approved drugs and biologics. PDUFA VII was too focused on making it easier to get drugs and biologics to market quickly and not focused enough on making sure “innovative” treatments were more beneficial to patients than previously approved treatments, or compared to no treatments at all.

We also want to express our concerns about the “non-user fee” spending trigger. The PDUFA statute outlines that if spending of appropriated funds for FDA reviewer salaries and expenses falls below inflation-adjusted 1997 levels, the agency must refund user fees. The intent of this clause was to ensure that user fees are used to supplement congressional funding but not replace it. However, given the dramatic downsizing of FDA staff this year, there is a risk that these “trigger” levels of non-user fee spending will not be met and could result in the agency refunding user fees regardless of how well the performance goals stipulated by industry. This would have a catastrophic impact on the agency’s ability to review prescription drugs effectively and ensure that they are safe and effective.

We are also concerned that whenever the Congress is unable to agree on appropriations levels and the government shuts down as a result, staff paid by user fees are the only ones who are allowed to work.  That is just one of many reasons that user fees should support safeguards as well as reviews of new drugs and biologics.

We also ask that the FDA to be transparent about the cost of artificial intelligence (AI) in the review of drug applications. FDA expects that AI can reduce review time, but since AI sometimes makes up information or citations, human reviewers will still need to review any information that AI provides.  It is not clear whether AI is funded by non-user fee appropriated funds as a reviewer salary or an expense. Historically, AI models at the agency have been designed and managed by third-party consultants. It is likely that review queries would come at a cost to the agency, and we ask that FDA be transparent about that. This funding distinction is important because an increased use of AI in the review process, in tandem to fewer FDA staff, could lead to a spending gap that influences user fees.

In conclusion, there are many ways that PDUFA VIII can provide great benefits to patients and our healthcare system, in addition to benefits to industry.  The U.S. taxpayers deserve to have their needs met with the help of user fees, since they are the ones who purchase the drugs and biologics that are approved by the FDA.

We would be glad to discuss our concerns or answer any questions and can be reached at info@center4research.org.

References

[1] Rupp, T., & Zuckerman, D. (2017). Quality of Life, Overall Survival, and Costs of Cancer Drugs Approved Based on Surrogate Endpoints. JAMA internal medicine, 177(2), 276–277. https://doi.org/10.1001/jamainternmed.2016.7761

[2] Cepeda, M.S., Coplan P.M., Kopper N.W. et al .ER/LA Opioid Analgesics REMD: Overview of Ongoing Assessments of Its Progress and Its Impact on Health Outcomes, Pain Medicine, 18:1, 78–85. https://doi.org/10.1093/pm/pnw129

[3] U.S. FDA, Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) https://www.fda.gov/drugs/information-drug-class/opioid-analgesic-risk-evaluation-and-mitigation-strategy-rems

August 13, 2025

I’m Dr. Diana Zuckerman, president of the National Center for Health Research, a nonprofit think tank. We do not accept funding from entities that have a financial interest in our work, so I have no conflicts of interest.

Thank you for the chance to share my perspective as a scientist who has looked at the data on dermal fillers for many years.

Dermal fillers are very popular despite numerous well-known risks. As PMA products, those risks should be quantified with meaningful statistical data on the short-term and long-term risks, rather than merely listing adverse events as either “common” or “rare.” Unfortunately, statistics on risks aren’t available.

As FDA considers whether these same dermal fillers, or new versions of them, should be approved for use in the dé cole taje area, I urge the FDA to improve the information available to patients about dermal fillers. FDA should require well-designed, controlled clinical trials so that patients have the information they need to make informed decisions. That should require data describing clearly defined short-term and long-term risks, because when the benefit is cosmetic, even short-term, mild or moderate adverse events such as weeks-long or months-long pain, swelling, rash, or bruising matter to patients. Specific information about the frequency and impact of migration also needs to be specified.

We agree with the FDA that use of dermal fillers injected in the de cole tage area has additional risks, such as potential interference with imaging and screening methods for cancer, which could result in false negative or false positive cancer diagnoses. The agency gives several good examples to back up that concern, based on post-approval studies and clinical experiences. How much better it would be to provide and quantify that type of risk information prior to approval.

As the FDA points out, potential harm to the vascular and/or lymphatic systems is of great concern for dermal fillers used in the de cole taje area. It has come to our attention that some major manufacturers of dermal fillers have stopped reporting vascular system impairment and instead categorizing those AEs as obstruction/occlusion. This is clearly intended to make their products seem safer than they are and is the kind of misleading reporting that makes it difficult to trust the data that some major companies are providing. As a result of manipulated data, patients are unable to compare which products are safer, or to make informed decisions about what risks they are willing to take for these cosmetic improvements.

I appreciate that the FDA is talking about studies to evaluate which risks are most important to patients. Unfortunately, merely listing possible risks on a label or a patient booklet is not enough. We’ve talked to thousands of patients who have told us they never saw the label, or the patient booklet that was supposedly required to be given to them. Not all physicians are as transparent as the experts on this panel. But even if patients read and understood the information, there are 2 problems: #1: What physicians tell patients is much more influential than anything provided in writing. Some physicians and their staff are unrealistically reassuring in person. The written informed consent protects them from legal liability if they make any overly optimistic assurances when talking to patients. And #2, research and clinical experience both tell us that patients tend to underestimate risk when they want something. Vague statements about cosmetic complications that are “short-term” may be misunderstood and those complications may last much longer than expected. Most patients assume that any risks that are referred to as “uncommon’ or “rare” won’t happen to them. They are willing to take the risk – but if they experience rare complications, they feel betrayed and devastated, especially for serious complications – but also for cosmetic problems. And for these PMA products, patients do not have the legal recourse for compensation that they would have with an unsafe prescription drug or 510k device.

We strongly agree with the FDA that we have little information about the impact of repeated use dermal fillers over the years. Since some fillers are already being used off label for the de cole tage area, FDA should analyze de-identified data from a registry. However, the FDA needs access to registry data to analyze it, but most registries in the U.S. are owned by medical societies that do not currently make all safety data available to the FDA or the public.

FDA notes that subpopulations of patients may be at higher risks for some potential adverse events, but research is lacking so informed consent isn’t possible for those patients.

The FDA states that “nearly every filler type has been associated with a severe complication” leading to stroke.

There are unique risks to the de cole tage area in addition to the skin necrosis, anaphalaxis, abscesses, migration, granulomas, and risk of intravascular injection which FDA describes as inherent to treatment with dermal filler
anywhere in the body. In addition to breast cancer misdiagnosis and interference with diagnostic imaging, the FDA lists unique risks of complications affecting breast feeding.

The FDA noted a newly recognized adverse event, bone resorption, which was identified on imaging that was conducted for reasons unrelated to the dermal injections.

Although the total number of MDR serious injury reports were less than 18,000 as of last Fall, we all know this is a voluntary reporting system and we know that few health professionals or technicians want to spend their valuable time reporting AEs. And they do not have an incentive to report problems experienced by their patients, especially if they might be considered responsible for them. Bottom line: MDR data are not helpful for quantifying risks.

In conclusion, PMA devices deserve good research for patients understand the risks. When the benefits cosmetic, the risks should not conflict with those benefits. When benefits are not life-saving, the risks should not be life-threatening. That’s why it is so important to require scientific evidence that the benefits outweigh the risks, so women can make informed decisions.