Comments Regarding the FDA’s Draft Guidance for Accelerated Approval of Drugs and Biologics
February 4, 2025
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
Oncology Center of Excellence (OCE)
Submitted electronically
Comments on Draft Guidance for Industry: Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics
Public Citizen, a national nonprofit consumer advocacy organization with more than 500,000 members and supporters nationwide, submits the below comments on the Food and Drug Administration’s (FDA’s) draft guidance for industry issued in December 2024 regarding the expedited program for serious conditions — accelerated approval of drugs and biologics.[1]
Our comments describe certain aspects of the draft guidance that can be improved in the final guidance to ensure the appropriate use of the accelerated approval pathway for introducing effective and safe drugs and biologics intended to treat serious or life-threatening diseases or conditions for which there is an unmet medical need in the U.S. market.
I. Evidentiary criteria for accelerated approval
The guidance states that accelerated approval of drugs and biologics can be based on two types of endpoints: “a surrogate endpoint that is considered reasonably likely to predict clinical benefits” or “a clinical endpoint that can be measured earlier than [irreversible morbidity or mortality] IMM that is reasonably likely to predict an effect on IMM or other clinical benefit.” Hereafter, we refer to those as surrogate endpoints.
Although the guidance provides examples of important factors for identifying and assessing surrogate endpoints, it acknowledges that determining the extent to which such endpoints are reasonably likely to predict clinical benefit is “context-dependent” and is a “matter of judgment that will depend on the biological plausibility of the relationship between the disease, the endpoint, and the desired effect, and the empirical evidence to support that relationship.” In making these determinations, the guidance indicates that the FDA may consult advisory committees, which are permitted by law, as needed.
Public Citizen urges the FDA to revise the guidance to indicate that an advisory committee whose members have been fully vetted for conflicts of interest should be convened for all plausible applications for new drugs or biologics that are considered under the accelerated approval pathway. Vetted advisory committees are the optimal way to secure unbiased expert consensus regarding the appropriateness of surrogate endpoints for the effectiveness of new drugs and biologics.
As stated in the guidance, one of the key concerns with the accelerated approval pathway is that patients “may be exposed to safety risks from a drug that ultimately does not demonstrate clinical benefit.” We therefore urge the FDA to make it clear in the guidance that any surrogate endpoint used in a clinical trial supporting an accelerated approval should be validated and that the evidence supporting this validation should be published in a peer-reviewed medical journal. Overall, there should be a strong, evidence-based agreement in the research community that an effect on such surrogate endpoints is reasonably likely to predict meaningful clinical benefit and that this benefit would be readily apparent to patients, family members, or clinicians. Similarly, what would be considered a meaningful clinical benefit of any drug or biologic for a given indication or patient population should be clearly identified through unbiased expert consensus.
The above changes are critical because they will minimize the use of inappropriate surrogate endpoints, as exemplified by the FDA’s infamous 2021 approval of the subsequently withdrawn Alzheimer’s disease drug aducanumab (Aduhelm) under this pathway based on an unvalidated surrogate endpoint (reduction of amyloid-beta plaques in the brain).[2] Even at the time of the FDA’s accelerated approval of aducanumab, there was sufficient evidence — including findings from the clinical trials of this drug — supporting the lack of a compelling, meaningful correlation between the surrogate endpoint and clinical measures of cognitive function.[3]
Another area in which the use of vetted advisory committees at the premarketing stage can be useful is to ensure that drugs and biologics considered under this pathway provide meaningful added therapeutic benefits over existing treatments. This issue is critical due to findings that high therapeutic value was only demonstrated for 39% of 90 indications for all drugs that received accelerated approval between 2007 and 2021 in the United States.[4] This study also found that demonstrated therapeutic value was even lower for cancer drugs that received accelerated approval.
II. Procedures for confirmatory trials
The accelerated approval pathway relies in part on confirmatory trials, also called post-marketing or post-approval studies, for verification of drug or biologic benefits. The guidance notes that such trials “are intended to verify and describe the anticipated effect on [IMM] or other clinical benefit” and that they “must be completed with due diligence.”
We urge the FDA to revise the guidance to ensure that for any drug to be granted accelerated approval, post-approval studies already be underway (i.e., enrolling subjects) at the time approval is granted. Importantly, the FDA should require that all these studies have clearly defined timetables for progress reports, study milestones, and planned study completion dates, and that this information is available to the public at the time accelerated approval is granted.
The above revisions are critical given that a cohort study demonstrates that 41% of 46 cancer drugs granted accelerated approval from 2013 to 2017 in the United States did not improve overall survival or quality of life in their confirmatory trials after more than five years of such approval, with results not yet available for another 15% of these drugs.[5] Moreover, 60% of the cancer drugs whose accelerated approval had been converted to regular approval during the study period continued to be supported only by surrogate endpoints.
All progress reports and findings of confirmatory studies should be made available to the public in a timely fashion. We also recommend that information on the proposed completion dates of these studies and where to access their progress reports should be made publicly available on FDA web pages that are updated regularly. Such information can be included in the prescribing information of drugs and biologics granted accelerated approval, like the “succinct description of the limitations of usefulness of the drug and any uncertainty about anticipated clinical benefits” information that is included in the guidance.
III. Procedures for expedited withdrawals
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. This approach means that withdrawals may be delayed until many patients have been harmed. In fact, a BMJ investigation demonstrated that 21% of 112 drugs without confirmed clinical benefit since their approval under the accelerated pathway through 2020 had been on the market for more than five years and some for more than twenty years.[6]
Therefore, we urge the FDA to revise the guidance to make it clear that the agency will initiate withdrawal procedures for unproven drugs or biologics approved under the accelerated pathway at its discretion without waiting for applicants to request voluntary withdrawal. We especially recommend that the final guidance indicate that the FDA will withdraw drugs or biologics whose post-approval studies have not been completed in a timely manner and all drugs and biologics without verified clinical benefit within no more than five years after approval.
Ensuring the ability of the FDA to initiate withdrawals of unproven drugs and biologics granted accelerated approval is of utmost importance because applicants generally have financial incentives against voluntary withdrawals of their drugs and biologics. Therefore the FDA typically may have to expend considerable resources to ensure that unverified drugs or biologics are no longer marketed.[7] For example, in the case of hydroxyprogesterone caproate (Makena), the drug was not removed from the U.S. market until April 2023 although the drug’s confirmatory trial failed to verify its clinical benefit in 2019 and an October 2022 FDA advisory committee had near unanimously recommended its withdrawal.[8],[9] It also is concerning that the data from the confirmatory trial of hydroxyprogesterone caproate became available eight years after the drug was approved. Overall, countless women and their fetuses were exposed to the known and potential serious risks of this ineffective drug in the 12 years between its accelerated approval and eventual withdrawal.
Obeticholic acid (Ocaliva) is another recent example of the problem with relying on voluntary withdrawal of unproven drugs and biologics approved under the accelerated approval pathway. In 2024 an FDA advisory committee voted nearly unanimously that post-marketing evidence did not verify the benefit of obeticholic acid on clinical outcomes in the indicated population and that the drug also had an unfavorable benefit-risk profile.[10] Instead of promptly withdrawing obeticholic acid from the market, the FDA issued a drug safety communication about the post-marketing evidence to alert clinicians and patients about the drug’s risks. Inexplicably, although the FDA declined to convert the accelerated approval of obeticholic acid to traditional approval, the drug remains on the market as of early February 2025.
IV. Documentation of all preapproval consultations and communication between applicants and the FDA
The guidance states that the FDA has established processes for early consultation between FDA review teams and applicants to discuss various study endpoints. As recommended by a recent Office of Inspector General report, it is important for the FDA to ensure appropriate documentation of such meetings.[11] As described by a 2022 report by the House Committees on Oversight and Reform and on Energy, FDA staff did not properly document all FDA-Biogen working group meetings (in addition to numerous calls and email exchanges of the working group) in relation to the agency’s review of aducanumab.[12] Moreover, the FDA should never involve applicants in the preparation of FDA briefing documents for an FDA advisory committee meeting, which was another violation of FDA rules in the aducanumab case.
Likewise, the FDA should document all the instances in which applicants chose to deviate from the FDA guidance with respect to the optimal use of surrogate endpoints and design of supportive trials. Such documentation can be critical for FDA scientists when they review evidence for a drug or a biologic and prepare briefing materials for advisory committees.
V. Other changes
The approval of a drug or biologic through the accelerated approval pathway can limit the ability of applicants to successfully conduct post-marketing studies. For example, the confirmatory trial for hydroxyprogesterone caproate faced difficulties enrolling subjects because they did not want to risk receiving treatment with placebo when the drug was already available through accelerated approval.[13] We therefore encourage the FDA to provide instructions in the final guidance on how applicants can best address challenges with recruiting subjects for mandated post-marketing studies, especially when considering proposed enrollment targets and study completion dates.
We also suggest that the FDA clarify in the final guidance that withdrawal of accelerated approval for a drug or a biologic occurs should simultaneously trigger the regulatory process to remove the product from the list of drug products that were withdrawn or removed from the market for reasons of safety or effectiveness.[14] This will ensure that withdrawn products are not compounded under the exemptions provided by section 503A(a) or section 503B(a) of the Federal Food, Drug, and Cosmetic Act.
VI. Conclusions
Patients rely on the FDA to ensure that all approved drugs, including those approved through the accelerated approval pathway, are safe and effective, and do not remain on the market if their clinical benefit has not been clearly demonstrated.
The FDA guidance for accelerated approval represents an opportunity for the agency to enhance the appropriate use of the accelerated approval pathway for drugs and biologics.
Thank you for considering our recommendations as you finalize this guidance to address lapses in the current system and effectively protect the public from risky and ineffective new drugs and biologics considered under the accelerated approval pathway.
Sincerely,
Nina Zeldes, MSc., Ph.D.
Health Researcher
Public Citizen’s Health Research Group
Azza AbuDagga, M.H.A., Ph.D.
Health Services Researcher
Public Citizen’s Health Research Group
[1] Food and Drug Administration. Expedited program for serious conditions — Accelerated approval of drugs and biologics. Guidance for industry. December 2024. https://www.fda.gov/media/184120/download. Accessed February 4, 2025.
[2] Office of Inspector General. How FDA used its accelerated approval pathway raised concerns in 3 of 24 drugs reviewed. January 2025. https://oig.hhs.gov/documents/evaluation/10160/OEI-01-21-00400.pdf. Accessed February 4, 2025.
[3] Public Citizen. Comments Regarding H.R. 6996, the Accelerating Access for Patients Act of 2022, and H.R. 6963, the Accelerated Approval Integrity Act of 2022. March 16, 2022. https://www.citizen.org/wp-content/uploads/2622.pdf. Accessed February 4, 2025.
[4] Vokinger KN, Kesselheim AS, Glaus CEG, et al. Therapeutic value of drugs granted accelerated approval or conditional marketing authorization in the US and Europe from 2007 to 2021. JAMA Health Forum. 2022;3(8):e222685.
[5] Liu ITT, Kesselheim AS, Cliff ERS. Clinical benefit and regulatory outcomes of cancer drugs receiving accelerated approval. JAMA. 2024;331(17):1471-1479.
[6] Mahase E. FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway. BMJ. 2021;374(July 30):n1898.
[7] Aaron DG, Cohen IG, Adashi EY. The FDA struggle to withdraw Makena: problems with the accelerated approval process. JAMA. 2022;328(24):2394-2395.
[8] Office of Inspector General. How FDA used its accelerated approval pathway raised concerns in 3 of 24 drugs reviewed. January 2025. https://oig.hhs.gov/documents/evaluation/10160/OEI-01-21-00400.pdf. Accessed February 4, 2025.
[9] Public Citizen. Ineffective medication for prevention of preterm birth should have been withdrawn years ago. March 3, 2023. https://www.citizen.org/news/ineffective-medication-for-prevention-of-preterm-birth-should-have-been-withdrawn-years-ago/. Accessed February 4, 2025.
[10] Food and Drug Administration. Final summary minutes of the Gastrointestinal Drugs Advisory Committee meeting regarding obeticholic acid (NDA# 207999). October 10, 2024. https://www.fda.gov/media/182630/download. Accessed February 4, 2025.
[11] Office of Inspector General. How FDA used its accelerated approval pathway raised concerns in 3 of 24 drugs reviewed. January 2025. https://oig.hhs.gov/documents/evaluation/10160/OEI-01-21-00400.pdf. Accessed February 4, 2025.
[12] Committee on Oversight and Reform and Committee on Energy and Commerce. Aduhelm investigation. Biogen selected investigation documents. December 2022. https://oversightdemocrats.house.gov/sites/evo-subsites/democrats-oversight.house.gov/files/Final_Document_Packet-Biogen_UPDATED_Redacted.pdf. Accessed February 4, 2025.
[13] Aaron DG, Cohen IG, Adashi EY. The FDA struggle to withdraw Makena: problems with the accelerated approval process. JAMA. 2022;328(24):2394-2395.
[14] Public Citizen. Petition: FDA should promptly add banned medications to list of withdrawn drugs to prevent pharmacy compounding. April 27, 2023. https://www.citizen.org/news/petition-fda-should-promptly-add-banned-medication-to-list-of-withdrawn-drugs-to-prevent-pharmacy-compounding/. Accessed February 4, 2025.