Critics of accelerated approval program offer early feedback on new FDA guidance

Though the deadline for comments on the FDA’s accelerated approval draft guidance has been pushed back a month to March, a handful of critical stakeholders have already submitted feedback. AgencyIQ discusses what the groups had to say to the FDA.

FDA’s accelerated approval pathway and recent changes

• The Accelerated Approval Program (AAP) is one mechanism by which the FDA may expedite the approval of new drugs and biological products. A unique characteristic of the AAP is that FDA may evaluate a product’s effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, known as an intermediate endpoint. According to FDA, “A surrogate endpoint used for accelerated approval is a marker – a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit.” The majority of accelerated approvals have been granted for oncology and hematology indications. As of 2012, FDA also has the authority to grant accelerated approval to products intended to treat serious or life-threatening diseases or conditions for which adequate therapies are lacking based on “adequate and well-controlled” clinical trials. FDA estimates the AAP is responsible for access to life-saving anti-cancer therapies a median of 3.1 years before they would have been available otherwise.
• Sponsors who obtain accelerated approval for a product are required to conduct confirmatory studies to verify its clinical benefit – at least in theory. These postmarketing requirements (PMRs) are usually agreed upon at the time of the marketing application’s review and approval, though execution of these requirements has been variable. Companies often face delays in running these studies because of enrollment challenges or other factors. Products for which the benefits of the drug have not been confirmed often linger on the market for years without full (or any) confirmation of the expected clinical benefit. These are so-called “dangling” accelerated approvals. A fiscal year 2018 annual report from the FDA showed only 69% of PMR status reports were submitted on time, but rate was 83% in fiscal year 2022, according to the most recent data the FDA provided. It should be noted that in 2020, the agency published draft guidance that aimed to help sponsors promptly complete their requirements.
• This is just one factor that has led to concerns about the AAP in recent years. Besides the failure of some sponsors to complete timely confirmatory studies, the FDA’s admitted lack of confidence in a few of the surrogate endpoints most frequently used as the basis for accelerated approval (i.e., Progression Free Survival and Objective Response Rate) and the underwhelming results of confirmatory trials for products that were considered game changers at the time they received accelerated approval have chipped away at some stakeholders’ confidence in the program. Also, products approved via the AAP are typically used to treat serious, often rare and rapidly progressing diseases – all factors that increase the costs of product development and, eventually, the price of these treatments.
• At the end of 2022, new legislation tightened the AAP, with implications for sponsors and the FDA alike. The Consolidated Appropriations Act of 2023 (parts of which are also known as the Food and Drug Omnibus Reform Act, or FDORA) included provisions that the FDA could now require, “as appropriate,” that a study or studies be underway before approval “or within a specified time period after the date of approval” for a product to be granted accelerated approval. The FDA had already begun to require this for certain products as a condition of approval. Next, the legislation required the FDA specify the conditions for a postapproval study (or studies), “which may include enrollment targets, the study protocol, and milestones, including the target date of study completion.” It also enabled the FDA to more easily withdraw products for which confirmatory trials had not confirmed safety or effectiveness, or both.
• Lastly, FDORA directed the FDA to develop guidance by the end of June 2024 to describe: 1) “How sponsor questions related to the identification of novel surrogate or intermediate clinical endpoints may be addressed in early-stage development meetings,” 2) the use of “novel clinical trial designs” to complete confirmatory studies, 3) the new procedures by which FDA can withdrawal accelerated approvals per FDORA, and 4) any further considerations in “evaluating the evidence” on the use of novel surrogate or intermediate clinical endpoints.

FDA’s recent draft guidance on accelerated approval

• On Dec. 6, 2024, the FDA published a new draft guidance on use of the AAP to expedite approval of products intended to treat serious conditions. In the Federal Register notice that accompanied the draft, the FDA requested all comments be submitted by Feb. 4, 2025. Within days of the guidance’s release, the Biotechnology Innovation Organization (BIO) submitted a request for a 30-day comment period extension.
• As AgencyIQ explained in December, the new guidance spans 25 pages and contains detailed background information on the legislative foundations for FDA’s authorities surrounding the accelerated approval pathway. The document hit the marks laid out in FDORA without venturing outside the bounds, with the bulk of its content focused on two topics: granting and withdrawal of accelerated approval. Prior to this new draft, recommendations for the AAP were mostly contained in a 2014 guidance on all of the FDA’s expedited programs for serious conditions, alongside those on fast-track designation, breakthrough therapy designation, and priority review designation. While many of the operational recommendations offered in the new draft were consistent with those issued in the previous version, there were several additions tied to FDORA. [Read AgencyIQ’s full breakdown of the draft here]
• On Jan. 17, the FDA announced that stakeholders would have an additional month to submit comments on the draft guidance, pushing the deadline back to March 6.

While the guidance remains open for comments, several groups are already calling for reforms to the program and FDA’s guidance

• As of Feb. 10, 19 comments have been submitted on the main AAP draft guidance, with most from non-industry organizations that have tended to be critical of FDA’s administration of the AAP in the past. These include Arnold Ventures, the Critical Path Institute (C-Path), the National Center for Health Research (NCHR) and Public Citizen. Several comments have also been submitted by individuals or organizations associated with Harvard Medical School and Brigham and Women’s Hospital, including one letter coauthored by Aaron S. Kesselheim, another submitted by the Program On Regulation, Therapeutics, And Law (PORTAL), and another from the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard (MRCT Center).
• A few interesting themes have emerged in the feedback submitted so far. First, several organizations remain concerned that the bar is too low for sponsors seeking accelerated approval. NCHR, a nonprofit think tank, called the guidance “a long-overdue step in the right direction” but indicated it doesn’t provide assurance that the products approved via the AAP will provide meaningful clinical benefit to patients. The organization cited several studies that found many of the products granted accelerated approval based on a surrogate endpoint do not meaningfully outperform existing treatment options when used in the clinic. Not only have studies later revealed shortcomings with numerous products granted accelerated approval, noted Public Citizen, but the FDA has failed to act when its outside expert panels (advisory committees) have evaluated the results of confirmatory trials and found them unpersuasive or problematic. Both Public Citizen and Arnold Ventures encouraged a more stringent process for advisory committee members; the latter went further, saying the FDA should “discourage the approval of waivers whenever possible.”
• Stakeholders remain uncertain about the FDA’s withdrawal procedures. As an example of what organizations don’t want to happen moving forward, Public Citizen recounted the case of hydroxyprogesterone caproate. Even though the product was granted accelerated approval in 2011 to reduce the risk of preterm birth, the letter states that the data from its confirmatory trial wasn’t available until eight years after its approval and that even though the confirmatory study failed to show clinical benefit, the product continued to remain on the market for years, exposing “countless women and their fetuses … to the known and potential serious risks of this ineffective drug in the 12 years between its accelerated approval and eventual withdrawal.” It wasn’t until several years after the confirmatory trial results were released that the FDA convened an advisory committee to evaluate the product, and even after its members “near unanimously recommended” its withdrawal, the agency took six more months to do so. In the final guidance, Public Citizen urged the agency to clarify that the withdrawal of an accelerated approval product would immediately trigger its inclusion on the FDA’s list of drug products withdrawn or removed from the market for reasons of safety or effectiveness.
• Clinical benefit is the bar for traditional product approval; it should also dictate the conversion of accelerated to traditional approval, commenters wrote. Confirmatory trials for products granted accelerated approval should be conducted in line with requirements for traditional approval. This means confirmatory trials must provide solid evidence that a product offers meaningful clinical benefit to patients, argued NCHR. To this end, the organization stated strong support for FDA’s new, clear-cut directive to sponsors in the draft that products should not be considered for accelerated approval “if the completion of an adequate and well controlled clinical trial to verify and describe clinical benefit will be infeasible.”
• However, the draft contains too many allowances for how confirmatory trials are completed, which could set back progress on strengthening the AAP, according to NCHR. The organization pointed out that the guidance indicates sponsors may be able to re-evaluate the same surrogate endpoint on which an accelerated approval was based for a longer duration in a confirmatory study rather than requiring the use of a definitive clinical outcome. The organization expanded on this point further, writing, “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,” and that such modifications “inevitably raise questions about the validity of the results of those trials.” PORTAL zeroed in on this language as well and wrote that the FDA needs to provide rationale for this recommendation, as the organization believes “single-arm trials should support accelerated approval only in exceptional cases, such as treatments that appear to have substantial effects in ultra-rare cancers with no alternatives.”
• The guidance also lacks sufficient direction on how surrogate endpoints should be selected and when they can be used, commenters wrote. Public Citizen urged the FDA to require the use of surrogate endpoints that have been validated with “evidence supporting this validation … published in a peer-reviewed medical journal” if intended to serve as the basis for accelerated approval. Arnold Ventures wrote that the FDA should also make it clear in the finalized guidance when it’s appropriate to use surrogate endpoints. For example, the organization said the final guidance should specify that surrogate endpoints should not be used “in cases where clinical endpoints are available” or “for drugs and biologics that treat an acute disease, where there is no advantage to using surrogate endpoints due to the rapid progression of the disease.”
• The withdrawal process is cumbersome and leaves patients open to risk based on the decisions of companies rather than the FDA, commenters argued. “We are concerned that the guidance suggests that the FDA will continue to rely primarily on applicants to voluntarily withdraw accelerated approvals of their unproven drugs and biologics when needed,” Public Citizen wrote. A problem with this approach is that “applicants generally have financial incentives against voluntary withdrawals of their drugs and biologics,” the organization explained. To mitigate concerns about the lengthy withdrawal process, Public Citizen urged the FDA to provide assurance in the final version of the guidance that it will remove products that have failed to demonstrate benefit from the market within five years. PORTAL also suggested that setting “More specific deadlines for each phase of the withdrawal process (e.g., decision publication or response to public comments) would ensure a more predictable and timely procedure.”
• While decisions about coverage and costs may not be in the FDA’s wheelhouse, they are front of mind for stakeholders. “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,” NCHR wrote. Arnold Ventures underscored the gravity of the situation, noting that etepilrsen was granted accelerated approval in 2016 to treat Duchenne muscular dystrophy, but as of January 2025, its confirmatory trial remained unfinished. Despite lack of confirmed benefit, “patients and payers in the U.S. spent in the U.S. spent $2.6 billion over 2017-2022 period” on it, the organization reported, with each one-time treatment potentially costing “more than $1 million per year.”
• Several comment letters referenced and quoted from an HHS Office of Inspector General (OIG) report about the FDA’s use of the AAP, published in January 2025. The OIG wrote that its independent evaluation was performed on just a small sample of the products that have been approved by the Center for Drug Evaluation and Research (CDER) via the accelerated approval pathway (24 out of 278) since its creation. Of the 24 approvals that were assessed, 10 (including aducanumab) were included because the approval processes raised concerns among stakeholders. While OIG found that the FDA took a consistent approach to the review and approval of 21 of the 24 products, it cited concerning deviations in the process to approve Biogen’s aducanumab, Sarepta Therapeutics’ eteplirsen, and hydroxyprogesterone caproate. These three cases demonstrate the need for additional guardrails, the report states.

What’s next

• While these comments aren’t representative of the views of all industry stakeholders, they’re interesting because they represent a concerted viewpoint that FDA needs to be a more shrewd steward of its authorities, especially after Congress just recently expressed its viewpoint that FDA’s program was in need of significant changes to promote accountability. This guidance is among the first opportunities for those stakeholders to see how FDA intends to flex those authorities in pursuit of reforms, and clearly some stakeholders find FDA’s efforts to date to be lacking in rigor. The comments are also notable because they’re among the first to be received by the FDA during the new Trump administration at a time when incoming leadership of HHS and FDA are likely to be less favorable to the pharmaceutical and biopharmaceutical industries.
• Some important stakeholders have yet to weigh in on the guidance. Only a few biopharmaceutical companies have posted comments, of which the rare disease company Chiesi is the most prominent. Likewise, only a few patient advocacy organizations, such as Breakthrough T1D (formerly JDRF) and the Leukemia & Lymphoma Society, have responded.
• One major limitation of the comments is due to a decision made by FDA to publish a second draft guidance on the AAP several weeks after it published this draft guidance. The second guidance is focused more narrowly on how the FDA defines the term “underway” for the purposes of ensuring that a trial has begun prior to making an approval decision. While that decision was likely done to keep public comments more focused on niche policy issues, it does mean that in-depth comments on this guidance are missing some key nuance. It will also make it more difficult to finalize the guidance documents during the Trump administration due to a new one-in, ten-out policy limiting the publication of new regulations and guidance.

Featuring previous research by Amanda Conti.
To contact the author of this item, please email Rachel Coe ( rcoe@agencyiq.com).
To contact the editor of this item, please email Jason Wermers ( jwermers@agencyiq.com)

Key documents

• FDA Draft Guidance: Accelerated Approval – Expedited Program for Serious Conditions (December 2024)