February 4, 2025 (Docket FDA-2024-D-2033)
The National Center for Health Research (NCHR) appreciates the opportunity to comment on the FDA’s draft guidance regarding the accelerated approval program. As a nonprofit think tank dedicated to bridging the gap between scientific evidence and health policies, we recognize the need to expedite access to safe and effective treatments for serious and life-threatening conditions. We urge the FDA to strengthen the guidance on the Accelerated Approval pathway to ensure rigorous evidentiary standards, enforceable post-market obligations, and meaningful regulatory action when drugs fail to demonstrate clinical benefit.
Strengthening the Evidentiary Standards for Accelerated Approval
The FDA draft guidance states that accelerated approval requires that a “surrogate or intermediate clinical endpoint is reasonably likely to predict clinical benefit” but also admits that the prediction may not be accurate and that as a result patients may be harmed and not helped by the drug. In fact, there is strong evidence that surrogate endpoints in cancer drugs does not correlate with overall survival (Prasad et al., 2015) or quality of life (Hwang & Gyawali, 2019). It is therefore very important that the guidance indicates that “confirmatory trials should evaluate meaningful clinical endpoints to verify and describe the anticipated effect on irreversible morbidity or mortality (IMM) or other clinical benefits.” Unfortunately, published research suggests that for many years, drugs granted accelerated approval have failed to provide evidence of meaningful benefits for patients.
A recent study by Liu et al. (2024) found that of 46 cancer drugs granted accelerated approval between 2013 and 2017, fewer than half (43%) demonstrated clinical benefit in confirmatory trials. Moreover, 60% (29/48) of the drugs that had converted to regular approval did so based on surrogate endpoints rather than improvements in overall survival or quality of life. Similarly, a study by Skydel et al. (2022) found that 57% of cancer drugs that received accelerated approval were later converted to regular approval without confirmatory trials evaluating meaningful clinical outcomes. Instead, most approvals relied on surrogate endpoints. Despite this lack of evidence, these drugs remained widely used, with substantial financial implications for both patients and public healthcare programs.
The lack of confirmation of the benefits of cancer drugs approved on the basis of surrogate endpoints is not unique to the accelerated approval pathway. For example, we conducted a follow-up study of 18 cancer drugs that had been approved based on surrogate endpoints between 2008 and 2012, but that Kim and Prasad (2015) had reported had not been proven to improve survival in the 3-5 years after approval. Two years later (5-7 years after FDA approval), we found that none had proven to have an overall survival benefit in post-market studies, and one had a lower overall survival rate (Rupp & Zuckerman, 2017). Of the few that evaluated quality of life, only one showed an improvement in quality of life, and several worsened it. Yet, all but one of these drugs had remained on the market, at substantial physical and financial cost. This study is an important reminder that the lack of meaningful clinical evidence is a long-standing problem for many drugs that FDA has approved on the basis of surrogate endpoints, and that the proposed guidance is a long-overdue step in the right direction.
Unfortunately, the guidance includes provisions that could weaken these efforts to strengthen the benefits of the accelerated approval pathway. For example, it states that confirmatory trials may, in some cases, re-evaluate the same surrogate endpoint with a longer duration rather than requiring a definitive clinical outcome.
We strongly support the statement in the guidance that “Accelerated approval should not be considered if the completion of an adequate and well controlled clinical trial to verify and describe clinical benefit will be infeasible. This is a major improvement over previous FDA statements that justified lack of confirmatory evidence as an inevitable result of patients being unwilling to participate in well-designed placebo-controlled confirmatory intended to evaluate the benefits of drugs that were on the market through accelerated approval because it is difficult to recruit patients willing to risk being in the control arm (Blumenthal et al, 2017) This may often be true, since many patients assume a newly approved drug is better than a placebo and probably better than a comparison drug, since they do not understand the uncertain benefits of accelerated approval drugs that were not studied on clinically meaningful endpoints. However, if well-controlled confirmatory trials are not feasible, and if the FDA continues to use that justification for inadequate or uncompleted confirmatory trials, then accelerated approval is based on a false promise of solid evidence based on confirmatory trials. The alternative is for the FDA and researchers to make it very clear to patients that a drug with accelerated approval is not proven to have clinically meaningful benefits compared to a placebo or alternative treatment.
Unfortunately, the guidance undercuts its strong statement requiring that well-controlled confirmatory trials be feasible by stating that feasibility concerns such as difficulty enrolling patients, may justify modifications to trial design. Such modifications inevitably raise questions about the validity of the results of those trials; published research has demonstrated that such exceptions can result in approvals that fail to confirm meaningful clinical benefits for patients.
Based on previous research findings, we strongly urge the FDA to strengthen its draft guidance to require that surrogate endpoints be rigorously validated through empirical evidence, and that confirmatory trials must provide statistically significant evidence of clinically meaningful benefits—such as overall survival or quality of life—rather than relying on the same surrogate endpoints or unvalidated biomarkers used for initial approval. The FDA must ensure that accelerated approval is based on overall survival or meaningful, objective Quality of life metrics that are validated and assessed in well-designed, controlled clinical trials. Progression-free survival often does not predict overall survival and subjective measures of quality of life can be biased by inadequate blinding or randomization/matching.
Ensuring Timely and Rigorous Post-Marketing Confirmatory Trials
The draft guidance rightly emphasizes the importance of timely confirmatory trials, pointing to the new statutory provision that gives the FDA the authority to require confirmatory trials be underway before approval. Unfortunately, the law does not require that confirmatory trials be underway, nor has the FDA defined what it means for a study to be underway. For example, how many patients need to have been enrolled or completed treatment to satisfy the definition that the confirmatory trial is “underway”?
A study by Shahzad et al. (2023) found that confirmatory trials initiated before approval were far more likely to be completed within five years and more likely to lead to either traditional approval or withdrawal, compared to those initiated post-approval. This strongly supports requiring confirmatory trials to be underway before accelerated approval is granted, which should be explicitly stated in the final guidance.
As of January 2025, the FDA’s track record indicates that many confirmatory trials are either significantly delayed, poorly designed, or never completed, remaining on the market for many years or indefinitely. For example, Liu et al. (2024) found that of the 46 cancer drugs granted accelerated approval, 41% (19/46) failed to demonstrate clinical benefit, and an additional 15% (7/46) lacked confirmatory data—leaving only 43% (20/46) that showed a clinical benefit in confirmatory trials. Despite this, many of these drugs remained on the market, with half staying available for more than 3.6 years after confirmatory trials were completed, and some for almost 10 years.
Much of the research on accelerated approval confirmatory trials have focused on oncology drugs, but concerns about insufficient evidence extend beyond cancer treatments. For instance, Bendicksen et al. (2023) analyzed the accelerated approval of Sarepta’s drugs for Duchenne muscular dystrophy (DMD), which were based on questionable surrogate markers. The FDA approved the company’s first drug, eteplirsen (Exondys 51), in 2016 based on a 12-patient one-armed study that showed only minimal increases in dystrophin—a surrogate endpoint that remains unproven as a predictor of clinical benefit. The post-market trial was due to be completed in 2020 but hadn’t been started until that year, and more than 8 years after accelerated approval the confirmatory trial has not been completed, and the drug remains on the market at an estimated cost exceeding $1 million per year per patient. Meanwhile, the FDA has granted accelerated approval to several other Sarepta drugs for Duchenne’s Muscular Dystrophy, and none of those confirmatory trials has been completed and no post-market data from any of those drugs has been made public.
Given the obvious weak incentive and poor track record of publicly available timely confirmatory studies for numerous drugs after accelerated approval, we strongly encourage the FDA to require that company studies start enrolling a substantial number of patients in a confirmatory trial prior to being granted accelerated approval. We also recommend that when the FDA requires that a confirmatory trial be underway that the agency clearly specify serious consequences for non-compliance, including automatic withdrawal of drugs if trials fail to meet prespecified deadlines for completing the promised enrollment goals or fail to achieve the primary endpoints.
Expedited Withdrawal of Ineffective or Unsafe Drugs
Despite having the authority to rescind approval, the FDA has often failed to act swiftly when drugs fail confirmatory trials. Beaver et al. (2018) reported that among 93 oncology drugs granted accelerated approval between 1992 and 2017, only five (5%) were withdrawn, despite 40% (37/93) having yet to complete confirmatory trials or verify clinical benefit at the time of analysis. Furthermore, the median time from accelerated approval to verification of clinical benefit was 3.4 years (range 0.5–12.6 years).
Even more dramatically, a study by Vokinger et al. (2022) found that none of the novel drugs granted accelerated approval from 2018-2019 were rated as having high therapeutic value, meaning that many patients using accelerated approval drugs experience little or no clinical benefit. While financial costs are not the FDA’s concern, the approval of ineffective drugs imposes a significant burden on healthcare systems and the patients and physicians attempting to make informed decisions about medical care, raising ethical questions that go beyond the financial ones.
Conclusion & Recommendations
The goal of the draft guidance should be to strengthen the accelerated approval program so that it benefits patients by requiring better evidence that the drug is safe and effective prior to granting accelerated approval. The FDA can restore trust in new drugs and biologics that initially got on the market through the accelerated approval pathway by requiring that confirmatory trials prove clinically meaningful benefits and requiring that well-designed confirmatory trials are well underway before granting accelerated approval. In addition, with few exceptions (such as a pandemic that interferes with study enrollment and completion), the FDA should enforce deadlines for completion of well-designed clinical trials. The agency should include stricter evidentiary standards for surrogate endpoints, such as rigorous validation of those surrogates; mandating real-time tracking and public disclosure of confirmatory trial progress, including enrollment and completion deadlines; and enforcing automatic withdrawals of drugs that fail confirmatory trials within the original agreed to timeframe. The proposed guidance requires important information about the known and unknown risks and benefits in the label; we strongly encourage short, easy-to-understand Patient Checklists that require patients to sign each statement to ensure that those who enroll in pre-market and post-market trials are clearly informed about what is known and what is unknown about the risks and benefits of accelerated approval drugs.
We appreciate the FDA’s efforts to improve the accelerated approval framework and look forward to meaningful reforms that prioritize public health and solid data about clinically meaningful outcomes so that patients and their healthcare providers can make informed decisions.
References:
Beaver JA, et al. (2018). A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol.
Bendicksen L, Zuckerman DM, et al. (2023). The Regulatory Repercussions of Approving Muscular Dystrophy Medications on the Basis of Limited Evidence. Ann Intern Med.
Blumenthal G et al (2017) Setting the Record Straight on FDA Approvals in Oncology. JAMA Internal Medicine.
Hwang TJ, Gyawali B. (2019). Association between progression-free survival and patients’ quality of life in cancer clinical trials. Int J Cancer.
Kim C, Prasad V (2015). Cancer Drugs Approved on the Basis of a Surrogate End Point and Subsequent Overall Survival: An Analysis of 5 Years of US Food and Drug Administration Approvals. JAMA Intern Med.
Liu, I. T. T., et al. (2024). Clinical benefit and regulatory outcomes of cancer drugs receiving accelerated approval. JAMA.
Prasad V, Kim C, Burotto M, Vandross A. (2015). The strength of association between surrogate end points and survival in oncology: a systematic review of trial-level meta-analyses. JAMA Internal Medicine. 175(8):1389-1398.
Rupp, T., & Zuckerman, D. (2016). Quality of life, overall survival, and costs of cancer drugs approved based on surrogate endpoints. JAMA Internal Medicine.
Shahzad, M., et al. (2023). Association between preapproval confirmatory trial initiation and conversion to traditional approval or withdrawal in the FDA accelerated approval pathway. JAMA.
Skydel, J. J., et al. (2022). CMS spending on drugs granted accelerated approval, 2012-2017. Health Affairs.
Vokinger, K. N., et al. (2022). Therapeutic Value Assessments of Novel Medicines in the US and Europe, 2018-2019. AMA Netw Open.