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Research (NCHR) [and the Cancer Prevention and Treatment Fund] appreciate[s] the opportunity to comment on the FDA’s draft guidance on Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway.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 The draft guidance states that a confirmatory trial’s target completion date should be “consistent with diligent and timely conduct.”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.

June 26, 2024

I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Our center is a nonprofit public health think tank that scrutinizes the safety and effectiveness of medical and consumer products, and we don’t accept funding from companies that make those products. Our largest program focuses on cancer prevention and treatment.

Thank you for the opportunity to share my views today. My expertise is based on my current work as well as my post-doc training in epidemiology and public health, and as a former faculty member and researcher at Yale and Harvard.  I’ve also previously served as professional staff in the US House of Representatives and US Senate, at the Dept of Health and Human Services, and the White House.  I’m a founding Board member of the nonprofit Alliance for a Stronger FDA, which educates Congress about the need to financially support the essential work of the FDA.

The question today is whether General snus should continue to be labeled as safer than other tobacco products.  I will focus on the scientific evidence, which I personally found challenging due to lack of some key information. So, I will raise the questions that weren’t a focus of the FDA review, and I respectfully encourage you to try to get the answers to these questions today. Several panel members and previous speakers have already asked some of these questions.

1. We all know the risks of smoking, including cancer, lung disease, and cardiovascular diseases.
2. Equally important: Most smokers start smoking as children or teenagers and most of these diseases are diagnosed decades later – usually in the patients 50’s or 60’s or even later. That’s more than 30 years later—often 40 or 50 years later, or even later.

In contrast, the data being discussed today found:

1. A significant increase in several serious cardiovascular diseases, and these were diagnosed in studies that followed relatively young white men. For example the Araghi et al. study published in 2022 included 9 million person years of study, which sounds impressive, but averaged 22 years, including some men that were followed for only 5 years

• • Those results indicate some serious risks are evident apparently at a younger age than found with cigarettes.

2. There was no increase found in oral cancers, despite previous evidence that smokeless tobacco can cause oral cancers. However, oral cancers usually develop in people in their 50’s or older, and many of the individuals in these studies were younger.  My question is whether the follow-up for these individuals in any of these studies is long enough to draw conclusions about oral cancer.  In addition, information provided in previous research indicate that snus in Sweden differs from snus sold in the U.S. and therefore the data provided on Swedish consumers may differ from the impact on U.S. consumers.  I hope you will ask that question.

Bottom line:

1. How good is the evidence that using the General snus sold in the U.S. is safer than smoking cigarettes in either the shorter term (10 or 20 years) or longer term (30, 40, or 50 years)?
2. How often do General snus users also use other tobacco products or switch to other tobacco products? Apparently the answer is often, so does the nicotine in General snus make it more difficult to quit tobacco use and instead result in continued use of snus and other tobacco products?
3. Can the information available be understood by teenagers or adults who consider using snus if it has a modified risk claim – which will be perceived as a seal of approval by the FDA? If the lack of information makes it so difficult for me to make sense of the risks of snus, I have to assume they will too.

Thank you for the opportunity to share these views.  I encourage you to ask these questions and make sure the answers make sense.