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.

August 15, 2025

Re: Proposed Data Collection Submitted for Public Comment and Recommendations; Docket No. CDC–2024–0106

The National Center for Health Research (NCHR) appreciates the opportunity to submit these comments in strong support of the continued implementation of the National Youth Tobacco Survey (NYTS) for the 2026-2028 cycle. 

NCHR is a nonprofit think tank committed to advancing evidence-based policies that improve the health of adults and children. We focus on evaluating medical products, prevention strategies, and public health surveillance systems to ensure they are safe and effective. We are very concerned about the health risks associated with youth tobacco and nicotine use.

We strongly support the continued implementation of the National Youth Tobacco Survey (NYTS) for the 2026-2028 cycle. NYTS is the cornerstone of public health surveillance in this field. Discontinuing or significantly weakening it would create an irreversible gap in the nation’s health data infrastructure. The sustained operation of NYTS is an essential prerequisite for the effective implementation of public health strategies, and an essential component of the MAHA movement.

NCHR Recommendations

We respectfully urge CDC and FDA to jointly support and implement the National Youth Tobacco Survey for the 2026–2028 cycle, including the following priorities:

1. Retain core trend measures to ensure continuity in time-series analysis, while expanding items that address emerging products (e.g., nicotine pouches, synthetic nicotine);
2. Ensure oversampling of key populations, including but not limited to under-represented age groups, racial/ethnic minorities, and adolescents with mental health risks;
3. Release the full public use dataset for each wave promptly and restore datasets from 2020–2023 which were recently removed from public websites; and
4. Preserve CDC’s scientific leadership in survey design and analysis, while supporting strong interagency collaboration with FDA to ensure funding and continuity.

NYTS Is Irreplaceable for National Youth Tobacco Surveillance

Since its annual implementation beginning in 2004, the NYTS has remained the sole nationally representative source on tobacco and nicotine use among middle school students (grades 6–8) and the most comprehensive dataset for high school students (grades 9–12) [1]. NYTS captures a full spectrum of tobacco and nicotine products. These include traditional cigarettes, cigars, e‑cigarettes, heated tobacco, nicotine pouches, and newer synthetic products [2]. This dataset allows for the tracking of both established and emerging patterns of use. NYTS also measures behavioral variables, such as exposure to pro‑ and anti‑tobacco messaging, social norms, perceived harms, peer influence, pathways of access, dependence indicators, and cessation behaviors, along with contextual factors like mental health and school connectedness [1]. 

The NYTS is the only national survey that provides this level of detail on an annual basis. Surveys such as the Population Assessment of Tobacco and Health (PATH), which focuses on longitudinal regulatory research; the Youth Risk Behavior Surveillance System (YRBSS), which is limited to high schoolers and conducted biennially; and the National Survey on Drug Use and Health (NSDUH), which covers broader substance use across age groups, offer valuable data. However, none of them match the NYTS in comprehensive youth-specific tobacco surveillance [3]. The rapid release cycles of NYTS support timely and responsive policy action. For example, when JUUL’s popularity surged among youth between 2017-2019, NYTS was the only system capturing the magnitude and speed of adoption, a responsiveness that remains unmatched in national surveillance [4] [5].

NYTS Has a Proven Track Record and Will Contribute to MAHA Goals

NYTS data have driven some of the most consequential youth tobacco policies. For example, between 2017 and 2019, NYTS data showed that current e-cigarette use among high school students more than doubled, rising from 11.7% to 27.5%, prompting the FDA to declare youth vaping an “epidemic” and initiate enforcement actions restricting flavored products [6] [7]. These findings also informed the federal Tobacco 21 law, raising the minimum purchase age to 21, which is a milestone policy supported by evidence showing youth nicotine use trends [1] [8]. Furthermore, NYTS data underpinned evaluation of FDA’s “The Real Cost” campaign by tracking shifts in youth perceptions and behavior over time [1] [9] [10]. NYTS has also provided evidence that some youth are more at risk than others, which provides state and local governments with the information they need to develop policies to improve the health of all their children [1]. Taken together, NYTS has served as the early warning system that benefits federal and state health strategies.

NYTS provides the empirical foundation the FDA needs to fulfill its statutory mandate under the Family Smoking Prevention and Tobacco Control Act of 2009 to prioritize youth protection in tobacco regulation [4] [11]. Without it, the agency lacks a reliable means to monitor youth use trends, assess product-specific risk, or measure regulatory impact. Additionally, NYTS informs at least seven Healthy People 2030 objectives [2]. These include tracking adolescent use of e‑cigarettes, cigarettes, flavored products, and other nicotine-containing products [2]. In addition, state Youth Tobacco Surveys can be compared with NYTS data to better evaluate local progress.

In conclusion, youth nicotine and tobacco use are serious and constantly changing public health concerns. NYTS is the most reliable national system for identifying emerging trends and guiding effective prevention strategies. Discontinuing or weakening this survey would severely undermine efforts to reduce youth exposure to nicotine and tobacco products and to prevent long-term addiction.

We strongly support the full approval and continued implementation of this essential survey. For questions or further discussion, we can be reached at info@center4research.org

References

1. Gentzke AS, Wang TW, Cornelius M, et al. Tobacco product use and associated factors among middle and high school students — National Youth Tobacco Survey, United States, 2021. MMWR Surveill Summ. 2022;71(5):1-29. doi:10.15585/mmwr.ss7105a1
2. Centers for Disease Control and Prevention. About National Youth Tobacco Survey (NYTS). CDC Smoking and Tobacco Use. Updated May 15, 2024. Accessed Aug 11, 2025. https://www.cdc.gov/tobacco/about-data/surveys/national-youth-tobacco-survey.html
3. Boakye E, Erhabor J, Obisesan O, et al. Comprehensive review of the national surveys that assess E-cigarette use domains among youth and adults in the United States. Lancet Reg Health Am. 2023;23:100528. doi:10.1016/j.lana.2023.100528
4. Wang TW, Gentzke AS, Creamer MR, et al. Tobacco product use and associated factors among middle and high school students — United States, 2019. MMWR Surveill Summ. 2019;68(12):1-22. doi:10.15585/mmwr.ss6812a1
5. Cullen KA, Gentzke AS, Sawdey MD, et al. e-Cigarette use among youth in the United States, 2019. JAMA. 2019;322(21):2095-2103. doi:10.1001/jama.2019.18387
6. Creamer MR, Jones SE, Gentzke AS, Jamal A, King BA. Tobacco product use among high school students — Youth Risk Behavior Survey, United States, 2019. MMWR Suppl. 2020;69(1):56-63. doi:10.15585/mmwr.su6901a7
7. US Food and Drug Administration. Spotlight on Science – Winter 2020. Updated January 9, 2020. Accessed Aug 11, 2025. https://www.fda.gov/tobacco-products/ctp-newsroom/spotlight-science-winter-2020
8. Agaku IT, Nkosi L, Agaku QD, Gwar J, Tsafa T. A rapid evaluation of the US Federal Tobacco 21 (T21) law and lessons from statewide T21 policies: findings from population-level surveys. Prev Chronic Dis. 2022;19:210430. doi:10.5888/pcd19.210430
9. The ASCO Post Staff. The Real Cost campaign may have prevented thousands of youths from initiating e-cigarette use. The ASCO Post. March 18, 2025. Accessed Aug 11, 2025. https://ascopost.com/news/march-2025/the-real-cost-campaign-may-have-prevented-thousands-of-youths-from-initiating-e-cigarette-use/ 
10. Kowitt SD, Sheldon JM, Vereen RN, et al. The impact of The Real Cost vaping and smoking ads across tobacco products. Nicotine Tob Res. 2023;25(3):430-437. doi:10.1093/ntr/ntac206
11. US Food and Drug Administration. Family Smoking Prevention and Tobacco Control Act – An Overview. Updated August 29, 2024. Accessed Aug 11, 2025. https://www.fda.gov/tobacco-products/rules-regulations-and-guidance-related-tobacco-products/family-smoking-prevention-and-tobacco-control-act-overview

August 4th, 2025

I’m Dr. Diana Zuckerman, president of the National Center for Health Research, a patient-centered, evidence-based public health think tank. Our Center is very involved in FDA issues pertaining to the safety and effectiveness of medical products, and I appreciate the opportunity to share my views today. My perspective is as a scientist trained in epidemiology and public health, and also as a patient with three implants in my body.

MDUFA performance measures have focused on speed, but they should also evaluate whether patients are protected from ineffective or unsafe products. All FDA user fees have performance goals that emphasize speedy reviews and FDA staff being available for meetings with companies to help them understand what they need to do to obtain approval or clearance. That makes sense –industry is paying for something that they want.

However, PDUFA uses a much greater percentage of its user fees for post- market surveillance and safety analysis, compared to MDUFA. All user fee negotiations are behind closed doors and patient, consumers, and health professionals are not allowed to be there or even to observe. We should be part of the process. Instead, we’ve been told that in past MDUFA negotiations, CDRH asked that user fees help support these kinds of safety and quality issues but that industry refused. Equally discouraging, CDRH complied with industry’s refusal.

The MDUFA V Commitment letter shows what happens when patients, consumers, and health professionals are excluded. The letter sounds like parents telling their children what they need to do to earn their allowance. Statements starting with “FDA will do x or “FDA’s response letter will include y” were made “200 times in the Commitment Letter. There were just a few statements starting with FDA and industry will ___” and even fewer saying
what industry needs to do. This raises the question: Is Industry being regulated by FDA or do MDUFA agreements reverse that balance?

Why are performance goals all about what FDA has to do? Performance goals
should also be based on the types of accomplishments most important to patients, pre- and post-market.

Before FDA determines if a product can go on the market, CDRH lead reviewers are supposed to be like project managers who can rely on subject matter experts. But there aren’t enough subject matter experts. So, lead reviewers have to review the software, cybersecurity, electrical safety, biocompatibility etc. even if they don’t have that expertise. So, to meet their deadlines and keep their managers happy, many reviewers will assume criteria are met that they were not able to evaluate.

Those inferior reviews are common when a Commitment letter focuses on speed
of review, with no metrics for quality.

Let’s compare MDUFA commitments to user fees for other federal agencies, using the same analogy Congress used when it first passed FDA user fees. When we visit a National Park such as the Grand Canyon, we pay user fees (called entrance fees) to get in and those fees help pay for staff that keep the parks running. That’s in addition to the appropriations that all taxpayers pay. But those of us paying for admission don’t get to boss the Park Service
employees around. We don’t tell them what to do. We pay extra fees for food and lodging – shouldn’t the device industry pay extra for necessary inspections and post-market activities that help to make CDRH effective?

Bottom line: Entrance fees help ensure that parks function well, and MDUFA should help make sure CDRH functions well – by helping improve the quality of FDA reviews and the outcome for patients using devices.

Thanks to an analysis by Device Events, a company founded by a former FDA staffer, I can tell you that the number of adverse events more than tripled from 65,000 per month in 2015 to 225,000 per month this year (equivalent to 2.7 million/yr). Was that because of MDUFA pressure for speedy reviews? Some of these adverse events are very serious. In fact, this year so far, there have been 6,754 death reports to the FDA for medical devices. Let me give one example of a very common medical device, dental implants. There are 2.9 million adverse event reports for dental implants in MAUDE, and another 2.1 million that were included in summary reports, for a total of 5 million adverse event reports. But FDA has not held a public meeting for dental implants, nor has FDA provided public information about what those adverse events are or whether some types of dental implants may be safer or more effective than others. Everyone should have access to that information, and FDA should consider those specifics when it reviews new dental implants as well as those already on the market.

Since fewer than 5% of devices that FDA regulates provide clinical trials of safety or effectiveness before going on the market, it is essential that user fees should help pay for timely post-market reviews. That is especially important when FDA is being forced to speed up reviews and when staffing cuts have made reviews less thorough than they should be, and in-person inspections less frequent.

What kind of performance goals make sense for MDUFA?

CDRH lacks sufficient staff to review DTC ads, detailing activities, or ads to
doctors that directly or indirectly promote inappropriate off label use. User fees
should help pay for those activities.

User fees should also support FDA staff to create Patient Booklets, Informed Consent Checklists, and other materials that CDRH has used to help ensure that patients can make informed decisions. This is especially important when the device labels are intended for doctors, not for patients. User fees should also support Dear Doctor” letters, warnings to patients, and recall campaigns. PMA reviews should be rated on whether clinical studies are too small or too short-term. Safety and effectiveness data should be analyzed for male and female patients of different ages. Performance goals should also specify how many approvals were based on at least one randomized, controlled trial demonstrating robust evidence of a favorable benefit-risk profile. Post-market surveillance should sometimes result in FDA warnings, recalls, or withdrawals. Performance data should specify how often the FDA uses these mechanisms and the reasons for those actions.

What about the money?

MDUFA user fees are a fraction of PDUFA user fees, even for the largest device companies. The 510k user fees are too small to pay for a thorough speedy review, so either the review times need to be longer or the fees need to be greater. Given the cuts in FDA staffing this year, and the importance of speedy reviews to industry, it’s inevitable that improving quality requires increasing the fees. If those increases are adequate, it will still be possible for the FDA to waive fees for the smallest device companies, as they’ve done in the past.

A final word: User fees should be based on the average cost of each review. Past commitment letters have said the fees will be reduced if the number of applications exceeds expectations. That makes no sense at all – each review requires time and attention. FDA should reject industry demands that fees be reduced if more applications are received.

July 17, 2025

I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Thank you for the opportunity to share my views today.

The National Center for Health Research is a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on the safety and effectiveness of medical products. We do not accept funding from companies that make products that are the subject of our work and therefore have no conflicts of interest.

My perspective is as a cancer survivor who in trained in epidemiology and public health and held research positions at Yale and Harvard before coming to DC to work in the US Congress, HHS, White House, and as the president of a research center. On a personal and professional level, I understand the importance of the FDA and this Committee and I thank you for your service.

In order to consider whether the benefits outweigh the risks of Blenrep, it’s important to ask who was studied in the research you’re considering today.

• Fewer than 5% were U.S. patients (and why so few?) Thank you to Dr. Pazdur
  for his comments on that issue today.
• 5% were Black in one study, and none in the other. More important than the
  percentage, there were only 12 Black patients, and that is much too few to
  generalize whether the drug is safe or effective for them. The number of Asian
  and Hispanic patients were also too small to conduct subgroup analyses or to
  generalize.
• Patients over 75 were also under-represented: 15% & 12% in the two studies.
  That is fewer than half of the percentage that is typical for this disease.

Under these circumstances, would the treatment be approved for Whites only, or not
approved for Blacks? Nobody would want to do that.

There are other flaws in the studies

• The Comparator arm in DREAMM-8 is not an approved regimen in the U.S.
• We agree with the FDA that there are other, better treatment options for
  multiple myeloma. And half the patients had only one previous treatment, and
  those were not the most popular treatments available, which again indicates
  that these patients are not generalizable to patients in the U.S.
• Many patients lowered dosage due to poor tolerability of selected dosages – so
  how can FDA approve an indication based on those dosages?

I’ve attended hundreds of FDA Advisory Committee meetings and I’ve never seen such
a serious side effect as ocular toxicity that affects most patients. As the FDA pointed
out, even blurred vision can be debilitating and risky. Unfortunately, we did not hear
from patients who were harmed by that adverse event.

• Ocular Toxicity is unique and serious
• May be asymptomatic at first, which means it can be more harmful because when it is finally diagnosed, it may not be reversible
• In real world, toxicity monitoring will not be as careful as in a clinical trial. And the rural patients who might most benefit from this treatment option would be the ones least likely to have access to careful monitoring by an ophthalmologist.

In conclusion, Blenrep has benefits, but are they enough to outweigh risks?

• The primary endpoint of progression free survival was met – but that is compared
  to an unapproved treatment in DREAMM-8 and not compared to optimal
  treatments in DREAMM-7. Since the unapproved treatment is not available,
  we’re left with basically just one study indicating a benefit, not two.
• Given the very clear risks, the small number of U.S. patients, the under-
  representation of Blacks and older patients, and the availability of other effective
  treatment options, what should patients be told of this drug? Can Black patients
  or patients over 75 be adequately informed of the benefits and risks of this
  treatment for them if this treatment is approved?

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.

March 10, 2025 — (Docket No. FDA-2024-D-3334)

The National Center for Health Research (NCHR) [and the Cancer Prevention and Treatment Fund] appreciate[s] the opportunity to comment on the FDA’s draft guidance on Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway. We strongly support the FDA’s efforts to ensure timely completion of confirmatory trials; however, we have concerns regarding the vagueness of key criteria to be used to determine when a trial is considered “underway.” FDA’s clearly defined and specified regulatory expectations are needed to improve corporate achievements and public trust in the Accelerated Approval process.

Concerns About Imprecise Language & Lack of Specificity

As currently written, the guidance relies heavily on important terms such as “diligent and timely,” which are very vague and leave room for inconsistent interpretation by sponsors. Unfortunately, some companies’ definitions of diligent and timely will not be considered timely or diligent by regulators or public health experts and will not reduce the frequent delays in the completion of confirmatory trials. The lack of specific enrollment and timeline benchmarks will result in delays that expose patients to drugs without verified clinical benefit for many years.This is exactly the situation that the guidance is intended to correct. For that reason, we strongly recommend that the FDA replace ambiguous terms with clear, measurable criteria, including concrete benchmarks and milestones and clearly defined interim analyses to avoid delays.

Timeline for confirmatory trials. The draft guidance states that a confirmatory trial’s target completion date should be “consistent with diligent and timely conduct.” This language is too broad and subjective, resulting in a wide range of timelines for target completion dates, many of which will be lengthier than necessary. Since these are just the target completion dates, the actual completion dates are likely to be even later, and there are no specific warnings or penalties in the guidance of how the FDA plans to strengthen accountability. Instead of this vague wording, the FDA should specify that confirmatory trials should be completed within 1-3 years of accelerated approval, depending on how rare the disease is and how large and longitudinal the study is.That is consistent with a review of oncology drugs granted accelerated approval from December 11, 1992, to May 31, 2017.[1] Although 40% of the 93 indications had not yet completed confirmatory trials or verified benefit when the study was published in 2018,  those with confirmatory trials underway at the time of approval were verified after a median of 3.1 years. For the 9 indications without ongoing trials at the time of approval, those that were verified later were verified after a median of 5.5 years, ranging from 0.5 to 12.6 years. Additionally, 8 indications had remained on the market for more than 5 years without verifying their benefit, and 5 indications (5%) were withdrawn from the market. These findings confirm that a substantial percentage of confirmatory studies experience delays or remain incomplete for extended periods, highlighting the need for stronger regulatory oversight to ensure timely completion and protect patient safety.

Patient Enrollment Prior to Approval. The current guidance states that “enrollment of the confirmatory trial has been initiated.” This needs to be clarified. Does “enrollment has been initiated” mean that:

• one or more patients were enrolled
• or some number or percentage of patients have been identified as suitable but have not yet agreed to participate
• or some number or percentage have started providing baseline data
• or some number or percentage of patients have started treatment
• or some number or percentage of patients have almost completed treatment?

A 2015 study found that 19% of clinical trials failed to meet accrual goals or were terminated early due to insufficient enrollment, with recruitment challenges cited as a major barrier to trial completion.[2] That is why it is essential that “enrollment has been initiated” be defined as a substantial number of patients (such as 25 patients or 25% of patients, whichever is larger) already have been in treatment long enough to determine if adverse events or other missing data are likely to be a problem.That would better ensure that the trial is feasible as designed.

We agree with the guidance that completion of a confirmatory trial will be compromised when a drug granted accelerated approval becomes available on the market. This is especially a concern when the trial is a randomized, blinded trial, but it is also important to ensure an appropriate comparison sample for any confirmatory study. For that reason, it is essential that all patients be enrolled for most of the planned length of the trial prior to granting accelerated approval or at least prior to making the newly approved drug available on the market. FDA should not permit researchers to break the blinding of an ongoing study or switch to open label as soon as a product has been approved, because it undermines the integrity of the study and makes any results inconclusive or potentially inaccurate. That is unfair to all the patients who enrolled in the study, whether in the experimental or control group, because the study becomes useless in terms of determining the safety and efficacy of the treatment compared to a control group.

We agree with the guidance that “to ensure the confirmatory trial enrolls and retains sufficient U.S. participants, the sponsor’s enrollment strategy should prioritize early U.S. recruitment.” Because of demographic differences, differences in health habits, and differences in medical care and medical systems, U.S. study participants should be considered the most important study population for confirmatory trials submitted to the FDA. However, we disagree with the guidance that implies it is sufficient for the U.S. recruitment “be closer to completion at the time of accelerated approval.” Instead, recruitment in the U.S. should be completed and the treatment of those U.S. study participants should be near completion.

Progress Reports. The 180-day progress reports need to be improved by requiring them to include recruitment rates, patient retention, adverse events and other safety concerns, and additional metrics that will help identify barriers to the timely completion of the study. FDA guidance should clarify what is acceptable and not acceptable if enrollment targets are not met or drop out rates or missing data undermine the integrity of the study.These reporting requirements will improve transparency and accountability and help ensure a level playing field among companies conducting confirmatory trials.

Concerns Regarding Rare Disease Trials. The FDA acknowledges the unique challenges of conducting randomized post-marketing confirmatory trials for certain rare diseases, particularly those with very small populations and high unmet need. As a result, the proposed guidance permits non-randomized post-marketing studies and, in some cases, does not require that a confirmatory trial be underway before granting accelerated approval—provided there is appropriate justification.

While we recognize the difficulties in patient recruitment and trial feasibility in rare disease settings, this plan is overly flexible and will inevitably result in patients, CMS,  and other healthcare entities spending millions of dollars on treatments that have not been proven to provide meaningful clinical benefits. An example of this is the case with Sarepta accelerated approval drugs for Duchenne Muscular Dystrophy.[3] Without a clear requirement that studies be underway, patients will not have the information they need to make informed treatment decisions for many years, and meanwhile other companies will have less incentive to develop new treatments and conduct their studies in a timely manner. Furthermore, the FDA guidance allowing confirmatory trials to be a continuation of the accelerated approval’s trial evaluating the same surrogate endpoint should not be considered to be a confirmatory trial, since many surrogates do not accurately predict a clinically meaningful outcome. However, continuing the initial study for a confirmatory trial that follows the study participants for a longer period of time to evaluate a meaningful clinical endpoint should be encouraged. We previously raised our objection to confirmatory trials that use unproven biomarkers and surrogate endpoints that are not clinically meaningful in our comment for the guidance entitled “Expedited Program for Serious Conditions—Accelerated Approval of Drugs and Biologics” [Docket No. FDA-2024-D-2033], which highlighted the need for stronger evidence.[4]

Patients with rare diseases are desperate for treatments, but deserve better efficacy evidence than has often been provided by the many expensive treatments approved by the FDA. Patients will not get the evidence they need unless the FDA requires specific enrollment milestones pre-approval and a clearly defined timeline for confirmatory trials, with FDA providing incentives to comply and penalties or disincentives for non-compliance. If studies take longer than promised, the FDA should require companies to allow patients to have free access to the drugs under the FDA’s expanded access program until the confirmatory trial is completed. This would balance the need for patient access with scientific rigor and patient safety.

Conclusions

We support the FDA’s efforts to improve the accelerated approval process, but the vague wording of this guidance is very unlikely to achieve that goal. The FDA needs to be more specific and less “flexible” to ensure that confirmatory trials are completed within a few years of accelerated approval and that the trials provide the clinically meaningful information that patients need to make informed decisions.

References

[1] Beaver, J. A., Howie, L. J., Pelosof, L., Kim, T., Liu, J., Goldberg, K. B., Sridhara, R., Blumenthal, G. M., Farrell, A. T., Keegan, P., Pazdur, R., & Kluetz, P. G. (2018). A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: A review. JAMA Oncology, 4(6), 849–856. https://doi.org/10.1001/jamaoncol.2017.5618

[2] Bull, J., Uhlenbrauck, G., Mahon, E., Furlong, P., & Roberts, J. (2015, September 3). Barriers to clinical trial recruitment and possible solutions: A stakeholder survey. Applied Clinical Trials. https://www.appliedclinicaltrialsonline.com/view/barriers-clinical-trial-recruitment-and-possible-solutions-stakeholder-survey

[3] Bendicksen, L., Zuckerman, D. M., Avorn, J., Phillips, S., & Kesselheim, A. S. (2023). The Regulatory Repercussions of Approving Muscular Dystrophy Medications on the Basis of Limited Evidence. Annals of internal medicine, 176(9), 1251–1256. https://doi.org/10.7326/M23-1073

[4] National Center for Health Research. (2025, February 4). Public comment on FDA draft guidance: Expedited program for serious conditions—Accelerated approval of drugs and biologics (Docket No. FDA-2024-D-2033). National Center for Health Research. https://www.center4research.org/nchr-comment-accelerated-approval-draft-guidance

November 7, 2024

I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Our center is a nonprofit public health research center that scrutinizes the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products so we have no conflicts of interest.

We thank FDA and this Committee for your important work. My expertise is in clinical trial design and data analysis and as a breast cancer survivor. Prior to my current position, I was a post-doc in epidemiology and public health at Yale Med School, and was a faculty member and PI at Yale and Harvard.  I also investigated FDA approval standards while working in the US Congress, HHS, and the White House. I’m on the Board of the nonprofit Alliance for a Stronger FDA, which educates Congress about the need to financially support the essential work of the FDA.

As a survivor of T1 breast cancer, I appreciate the desire for less invasive treatment. But I am concerned that this cryoablation system was studied in a small, one-arm trial instead of a larger randomized clinical trial. We also share FDA concerns about serious data irregularities– including missing data that weren’t analyzed correctly — and lack of racial diversity of the patients in the study.

A breast cancer diagnosis is a traumatic experience and our research center has talked to hundreds of patients who tell us how overwhelming it is to consider all their treatment options. What matters most is overall survival, but recurrence also matters. Quality of life is very important but requires validated tests to be meaningful, and that was not done here. Most important, since 5-year recurrence is low for these kinds of early-stage breast cancers regardless of treatment, we can’t know the long-term success without a larger, longer term, randomized trial.

On a personal note, I went into my surgery with a diagnosis of DCIS. The tiny invasive cancer was found only as a result of the surgical specimen. Very small tumors can be difficult to find, and a randomized trial with post-market follow-up for a longer period of time would make it possible for patients to make better informed decisions, choosing the treatment that’s best for them.

Breast cancer treatment teams try to give patients the best possible information, but many patients tell us they are confused by the treatment options. They’re confused by the implications of terms like recurrence, disease-free survival, overall survival, primary and secondary cancer.

In addition, we also need to be concerned about how a new treatment that does not require surgery might be inappropriately promoted and used for larger or higher-risk tumors than those in the indication, and an indication that includes women who are younger than those studied. That use might be off label or included in the label, so if this product is approved the label should clearly specify what the data indicate and the indication should be consistent with that. We also urge FDA to require a short, simple patient checklist to maximize informed consent.

After her presentation, Advisory Panel members asked Dr. Zuckerman two questions as part of the panel discussion. Her answers are included below.

A: Thank you for asking about the patient checklist. FDA has sometimes used checklists to help provide understandable information about a medical device. Checklists should include facts that are short, simple, and easy to understand. For example, a checklist for this Cryoablation System could include facts such as:

1. “Research shows that _% of women using this product have a recurrence of breast
cancer within 5 years, compared to _% for women undergoing lumpectomy surgery.

2. There are no studies indicating how often recurrence of breast cancer occurs within 10 years of using this product.

The patient would initial each statement to show that she read it, and the physician should also sign it to show their explanations were consistent with the checklist. Keep in mind that informed consent is a process, not just a document, and it is important that the physician not make statements inconsistent with the checklist.

A: Thank you for asking why I said randomized controlled clinical trials were needed to help women make informed choices. We all know that randomized controlled trials are the gold standard and there is no reason why that wasn’t done with this product, since the alternative is clear: the standard of care is lumpectomy. You’ve heard that women wouldn’t want to participate in a randomized trial if they could choose cryoablation instead, but that is not true if they were accurately told that this is a clinical trial, and we are conducting it to find out whether or not Cryoablation is as effective as surgery. Patients need to know that it is study being done to find out if the product is effective; they should not be told that it is as effective as surgery when that is not known.

October 30, 2024

Hello, my name is Tess Robertson-Neel, and I am the manager of the Patient, Consumer, & Public Health Coalition, which is an informal coalition of more than 2 dozen nonprofit organizations that focuses on ensuring safe, effective, and affordable medical and consumer products. The coalition does not accept funding from entities with financial ties to the products that we deal with.

Our coalition appreciates the FDA’s efforts to improve informed consent in clinical trials of medical devices and all the suggestions made in this mornings’ presentations. We support the suggestions made in the draft guidances on informed consent, but we encourage the agency to either make these recommendations enforceable or create incentives to maximize compliance.

My experiences in public health research and study design have highlighted the complexities of getting true informed consent from participants. True informed consent is a process that should meet participants where they are, it is not just information on a piece of paper. We agree with the FDA that there is a need for improvement. We’ve worked with thousands of patients, and they tell us that informed consent documents are often too long, technical, and/or confusing for most patients to understand. As we all know, the longer the informed consent documents are, the less likely they are to be read. CDRH has attempted to improve the process for devices that have been cleared or approved by using patient information checklists, which we support in the post-market environment and think would also be helpful to improve informed consent during clinical trials when there are many unknowns about risks and benefits.

The checklist format could include numerous facts, and the patient must initial each fact separately to show that they have read it. The healthcare provider or study representative must also sign the checklist to indicate that they provided the same information orally. However, checklists can also be too long, including information that is either self-evident or not obviously relevant to a patient who is trying to decide whether to sign it or not. Moreover, when CDRH provides a sample checklist but allows a company to revise it however they choose, that may not protect patients from misleading or confusing information. For that reason, a patient information checklist must include certain information in a specific format to ensure that the patient has all the key information about the trial and what is known and not known about the device.  Most important, the information that the health professional provides orally to the patient should be virtually identical to the information provided in writing.

The average reading level in the U.S. is 7th-8th grade and that means that half of all Americans read below that level.  This checklist or any other information provided to ensure informed consent must therefore be simple, to the point, and easy to understand.

Thank you for the opportunity to share our views today.

October 30, 2024

Hello, my name is Laura Lytle. I am the Health Policy Director for the National Center for Health Research (NCHR), a nonprofit think tank that conducts, analyzes, and scrutinizes research on a range of health issues, with a particular focus on which prevention strategies, treatments and products are most effective for which patients and consumers. We do not accept funding from companies that make products that are the subject of our work, so we have no conflicts of interest.

I am grateful for the time today to share NCHR insights and to underscore the importance of strengthening patient informed consent. We applaud the FDA’s efforts to provide a framework to improve patient informed consent and transparency.  We support the suggestions made in the FDA’s draft guidance on Key Information and Facilitating Understanding in Informed Consent.  We wish to provide insight today on ways to codify the FDA’s guidance to provide meaningful and impactful improvements to the consent process.  

1. Checklist.  True informed consent requires a typical patient to easily understand the medical device they are considering. We support FDA’s previous use of patient information checklists to ensure informed consent for products already on the market and urge that this model be used in clinical trials to ensure that all key information is easily conveyed and understood by the patient. Short checklists consisting of a sentence or two for each key fact allows for the patient to pause and digest information and sign their initials before moving on to the next checklist item. 
2. Process.  Informed consent is supposed to be a process, not a presentation of long, complicated documents filled with legal and technical terms that the patient must sign without having the time and/or ability to fully understand and consent.  The process should include both oral and written components. Patients rarely read lengthy informed consent documents and are more likely to ask questions during an oral discussion of the risks, benefits, rights and responsibilities of a clinical trial.
3. Key Information. Key information should inform patients of details they likely would not know and inform patients of what is known and not known about the potential benefits and risks of participation.  
4. Patient privacy and access to their information, especially how the data is stored, who has access and what the patient will be provided with their information during and after the conclusion of the study.  This is especially true for post market research in medical devices. 

Thank you for the opportunity to speak with you today, we thank the FDA for their efforts to provide guidance in order to improve and standardize the informed consent process.

July 25, 2024

Thank you for the opportunity to speak today. My name is Grace Drew. I am a medical student at the University of Texas Health Science Center at Houston, and today I’m speaking on behalf of the National Center for Health Research. Our nonprofit research center analyzes scientific and medical data and provides objective health information to patients, providers, and policymakers. We do not accept funding from pharmaceutical companies or any companies with financial ties to our work, and therefore we have no conflicts of interest.

We appreciate the chance to participate in FDA Advisory Committee meetings like this one, which bring together experts to examine data based on complex treatment regimens. We agree with the questions raised by FDA scientists about whether the trials conducted on durvalumab adequately address the possible benefits of perioperative treatment compared to neoadjuvant or adjuvant treatment.

We all understand the need for improved treatments for non-small cell lung cancer. Patients deserve the best possible treatments based on the best possible evidence. Obviously, overtreatment can be as problematic as undertreatment, because excessive drug dosing can cause unpleasant or dangerous adverse effects, toxicity, as well as significant financial burden to patients.

We agree that the AEGEAN trial met its primary endpoint by demonstrating a statistically significant and clinically meaningful improvement in event-free survival. However, we agree with FDA scientists that the design of the AEGEAN study does not allow for a within-trial assessment of the individual contributions of durvalumab given concurrently with chemotherapy in the neoadjuvant phase compared to durvalumab given in the adjuvant phase. This is especially important because emerging data from completed trials of neoadjuvant only, adjuvant only, and perioperative immune checkpoint inhibitor regimens across other drugs in the class raise questions about the need for immune checkpoint inhibitors in both perioperative phases of therapy.

Even more important, we agree with the FDA’s concern that the AEGEAN trial indicated a nonsignificant reduction in disease-free survival in the patients that received durvalumab both before and after surgery. Since it is not statistically significant, this could have occurred by chance or could be a lasting effect of the durvalumab and platinum chemotherapy treatment before surgery. This nonsignificant finding contributes to the uncertainty about whether it is beneficial for patients to receive durvalumab both before and after surgery, rather than one or the other.

We agree with the FDA scientists that it is not appropriate to conclude that durvalumab improves disease-free or overall survival, although we also agree that the data suggest that durvalumab probably doesn’t reduce disease-free or overall survival. While the overall survival rate exceeded expectation, it was not significantly greater than the overall survival of the placebo patients, and therefore could have occurred by chance. In addition, the results may be biased because the patients in the modified resected set may have differed from the placebo group in ways that affected disease-free survival. Thus, we cannot conclude that durvalumab given both before and after surgery improved overall survival.

In conclusion, the one statistically significant benefit — event-free survival — could have been due to durvalumab given either concurrently with chemotherapy in the neoadjuvant phase or in the adjuvant phase. The other results show no statistically significant benefit in terms of disease-free or overall survival. The FDA is responsible for making a decision based on studies that are adequately designed to address the benefit of perioperative treatment as compared to neoadjuvant or adjuvant treatments.  Unfortunately, better designed trials are necessary to determine the safest, most effective regimen for durvalumab therapy. Thank you.

The Oncologic Drug Advisory Committee voted unanimously (11-0) that the FDA should require clinical trials that determine the individual contributions of treatment given before and after surgery before approving drugs to be given during both periods. They did not vote on whether Imfinzi should be approved for use before and after surgery despite the lack of evidence that both times are more beneficial than one or the other.