FDA’s accelerated approval guidance gets pushback from industry

The pharmaceutical industry has some questions regarding the US Food and Drug Administration’s (FDA) recent guidance on its accelerated approval program for drugs and biologics. Industry groups also asked for greater clarity about when the agency will provide feedback on confirmatory trials and how the guidance would align with the agency’s other policies on accelerated approval.

In addition, the Pharmaceutical Research and Manufacturers of America (PhRMA) questioned the need of confirmatory studies for certain treatments granted accelerated approval, especially for programs that address unmet medical needs. The group argued that Congress did not intend to mandate confirmatory trials for all drugs that receive accelerated approval.

In December 2024, FDA issued guidance to provide information on its policies for accelerated approvals to accommodate the revisions made to the program under the 2023 Consolidated Appropriations Act (CAA). The guidance sets new procedures for withdrawing products if they fail to demonstrate clinical benefit. It also expands on existing FDA policies by describing considerations for evaluating surrogate endpoints. (RELATED: Accelerated approval: FDA revises guidance to reflect revised withdrawal procedures, Regulatory Focus 5 December 2024)

Under CAA, Congress aimed to strengthen the accelerated approvals programs by granting FDA greater authority to require that conformity trials be underway at the time of approvals.

The FDA received 42 comments on the guidance, showing significant interest in the topic.

A key criticism of FDA’s accelerated approval program is that confirmatory trials are often completed late or, in some instances, not at all. This leaves significant questions about the efficacy of products unanswered while the studies remain pending. (RELATED: Study: Half of confirmatory studies for accelerated approvals are late, Regulatory Focus 4 April 2023; Study: 'Little incentive’ for drugmakers to complete confirmatory trials for accelerated approvals, Regulatory Focus 29 August 2022)

PhRMA and BIO want more clarity on FDA’s timeline for feedback

Both PhRMA and the Biotechnology Innovation Organization (BIO) want more clarity on when FDA will provide feedback on confirmatory studies. The guidance said that sponsors intending to seek accelerated approvals should consult with FDA early on about their confirmatory trials but does not have a timeframe for the agency to respond to requests.

PhRMA stated that “we strongly recommend that FDA revise the Draft Guidance to provide clear timelines for FDA feedback on confirmatory study requirements. The Draft Guidance places significant emphasis on early initiation and prompt completion of confirmatory studies. To advance this objective, it is important that sponsors receive timely Agency feedback on their proposed postmarketing requirements, protocols, and milestones—and in particular, that the timelines for FDA feedback enable confirmatory studies to be underway at the time of accelerated approval.”

The group recommended that FDA provide feedback on confirmatory study protocols within 60 days.

BIO agreed on the need for a clear timeline for FDA to respond to requests. The group said it “recommends that FDA establish target timelines for providing feedback and alignment on protocols for confirmatory studies. This will be important for ensuring they can be initiated in a timely manner.”

PhRMA says law did not explicitly require confirmatory studies

PhRMA also asserted in its comments that it was not the intent of Congress to require confirmatory studies for certain accelerated approval programs.

The group said that the statute, “expressly recognizes that FDA may—not must—require postapproval confirmatory studies, and Congress required FDA to publish a rationale when it determines that such a trial is not required. PhRMA believes Congress specifically left open the possibility that there may be situations where confirmatory studies are either impractical or infeasible, and we recommend revising the Draft Guidance to clarify that the accelerated approval pathway is not always foreclosed in these circumstances.”

PhRMA indicated that there are “significant challenges” in conducting confirmatory clinical studies for specific rare diseases and vulnerable populations.

The group said that “confirmatory studies may be infeasible in some situations with high unmet need where it is unlikely that a single agent, much less multiple agents with different mechanisms of action, can be studied in a long-term clinical outcome study.”

PhRMA and BIO: Retain the 2014 guidance

PhRMA and BIO also asked FDA to incorporate the principles of the guidance with an earlier guidance issued in 2014 on expedited programs for serious conditions.

FDA indicated that it planned to keep some concepts from its 2014 guidance even after the final guidance is published. However, the final version of the draft guidance would replace the sections related to accelerated approval from the 2014 guidance.

PhRMA said that “to avoid confusion, we encourage FDA to issue one guidance document covering all accelerated approval questions incorporating information from the 2014 Guidance, the Underway Draft Guidance, and therapeutic area-specific guidance on accelerated approval.”

BIO concurred. It said that “it is important that FDA provides a clear and consistent policy around the accelerated approval pathway and other expedited programs and across the Centers and programs. The final guidance Expedited Program for Serious Conditions – Drugs and Biologics (May 2014) provided a resource that could be utilized across the expedited programs for many years, especially the definitions and the table comparing the different expedited programs.”

The group added that “as FDA is finalizing this guidance it is important that the ease of use and clarity of that original guidance is not eroded.”

Accelerated approval guidance should be in one document

The Association for Accessible Medicines (AAM) urged FDA to consolidate its January guidance on deciding whether a confirmatory trial is underway with the guidance. (RELATED: Accelerated approval: FDA explains when it considers confirmatory trial underway, Regulatory focus 10 January 2025)

The group said that “as we observed previously, FDA issued a separate draft guidance, Accelerated Approval and Considerations for Determining Whether a Confirmatory Trial is Underway, just one month after it published the Draft Guidance that is the subject of these comments, and comments on that draft guidance are due to a separate docket just four days after these are due.”

It further noted that “when FDA publishes multiple separate guidances on the same subject and replaces some sections with new thinking but not others, it is confusing for stakeholders who have to piece together FDA’s thinking as it evolves over time. When FDA finalizes the guidance on accelerated approval, it should incorporate in a single guidance all of the related topics that are relevant for stakeholders.”

Clarity on generics

AAM asked for more detail on how the withdrawal procedures would affect generic drugs.

“Any withdrawal proceeding affecting the drug or biologic on which an ANDA or 351(k) BLA relies must provide sufficient process to adequately safeguard the follow-on applicants’ rights and interests,” said the group.

Furthermore, it said that “FDA should provide adequate notice of proposed withdrawals to follow-on applicants, including providing a copy of the proposed notice of withdrawal not only to the sponsor of the drug approved under accelerated approval but also to applicants with approved or pending ANDAs or 351(k) applications that reference the drug proposed for withdrawal.”

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FDA’s accelerated approval guidance gets pushback from industry

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