On December 6, 2024, the U.S. Food and Drug Administration (FDA) announced the availability of a new draft guidance document on accelerated approval of drug products. When finalized, this guidance will replace the accelerated approval-related content in FDA’s 2014 guidance Expedited Programs for Serious Conditions—Drugs and Biologics.

Brief Background on Accelerated Approval

FDA’s accelerated approval pathway is a critical regulatory mechanism that can expedite the availability of new drugs to treat life-threatening or otherwise serious diseases. FDA invented accelerated approval through rulemaking in 1992. Congress later codified this authority in section 506 of the Food, Drug, and Cosmetic Act (FD&C Act), initially rubber-stamping FDA’s accelerated approval regulations and then later introducing revisions.

When operating under accelerated approval, FDA will approve a drug based on clinical trial data showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. Such a surrogate endpoint is, in the words of the draft guidance, “a biomarker, such as a laboratory measurement, radiographic image, physical sign, or other measure, that is thought to predict clinical benefit but is not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.” Following accelerated approval, FDA requires drug sponsors to conduct post-approval studies intended to verify and describe the drug’s clinical benefit. For example, a drug might receive accelerated approval to treat a type of cancer based on a showing that it shrinks tumors. The drug’s sponsor would then conduct a post-approval study designed to show an effect on a clinical endpoint, such as an improvement in overall survival or other clinical benefit. When a post-approval study fails to verify clinical benefit or is not completed, FDA can withdraw the drug’s approval.

Technically, there are two types of endpoints that can support accelerated approval: surrogate endpoints that are reasonably likely to predict clinical benefit and intermediate clinical endpoints that are reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit. In practice, surrogate endpoints support accelerated approval much more often.

What Prompted FDA to Issue This Draft Guidance?

FDA’s new draft guidance comes in response to the Consolidated Appropriations Act of 2023 (Pub. L. 117-328), which revised the statutory framework governing accelerated approval and required FDA to issue guidance covering:

• How a drug sponsor’s questions related to the identification of novel surrogate or intermediate endpoints may be addressed in early-stage development meetings with FDA
• The use of novel clinical trial designs for post-approval confirmatory studies
• The new expedited procedures for withdrawal of approval
• Considerations related to the use of surrogate or intermediate clinical endpoints that may support accelerated approval, including considerations in evaluating the evidence related to such endpoints

New Procedures for Withdrawal of Approval

The statutory changes made by the Consolidated Appropriations Act include provisions aimed at promoting timely completion of post-approval confirmatory studies and providing FDA with a new, expedited procedure for withdrawal of approval when confirmatory studies are not done or fail to verify clinical benefit.

Historically, when confirmatory studies required under accelerated approval fail to verify a drug’s clinical benefit, sponsors have most often acquiesced to withdrawal of approval under 21 CFR 314.150(d). In some cases, however, sponsors have sought to maintain approval. Prior to the recent statutory changes, FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) needed to offer such sponsors an opportunity for a public hearing at which they could contest the Center’s proposal to withdraw approval. Since the inception of accelerated approval, two such public hearings have taken place. In both cases, the approvals were eventually withdrawn (Avastin’s breast cancer indication in 2011 and Makena’s approval to reduce the risk of preterm birth in 2023).

The FD&C Act now gives FDA a procedure for expedited withdrawal of approval that does not involve a public hearing and is intended to take less time. This new procedure gives sponsors an opportunity for a meeting with and written appeal to the Commissioner or the Commissioner’s designee. It also requires FDA to solicit public comment on the proposal to withdraw approval and publish a summary of public comments received. FDA’s new draft guidance elaborates on the new withdrawal procedure. FDA has already followed this procedure once, effectuating withdrawal of approval for PEPAXTO (melphalan flufenamide) in 2024.

Daylight Between the Statute, Regulations, and Guidance

With the most recent amendments to section 506 of the FD&C Act, the divergence between the statutory provisions and FDA’s regulations and guidance has grown. Since 1992, FDA’s regulations have stated that accelerated approval is available only for drugs that “provide meaningful therapeutic benefit to patients over existing treatments.” In the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, however, Congress revised the corresponding statutory language so that it merely directs FDA to “[take] into account” the availability or lack of alternative treatments when approving a drug under accelerated approval. FDA’s recent draft guidance acknowledges this difference (see lines 90-94 and footnote 23 in the draft guidance) but does not indicate that FDA plans to take advantage of the greater flexibility provided by the statute. More significantly, FDA’s accelerated approval regulations continue to outline the hearing procedures that formerly applied to withdrawal of approval, while the FD&C Act now describes the new process.

The Consolidated Appropriations Act of 2023 required FDA to issue this draft guidance within 18 months of its enactment and requires FDA to finalize the guidance one year after the public comment period closes. FDA is currently accepting comments through February 4, 2025.