Life in the Fast Lane: FDA Issues New Draft Guidance for Accelerated Approval of Drugs and Biologics

In 1976, the Eagles released the song, “Life in the Fast Lane,” as part of their iconic album, Hotel California. Approximately 16 years later, the Food and Drug Administration began offering pharmaceutical companies their own shot at life in the fast lane by establishing the Accelerated Approval Program.¹

Accelerated approval is one of FDA’s expedited review programs, which allows for approval of drugs that treat serious and life-threatening conditions in areas of unmet medical need.² The pathway provides an opportunity for sponsors to obtain new drug approvals more quickly than under the traditional approval process. For an accelerated approval to be granted, the sponsor must show FDA a surrogate or intermediate clinical endpoint from clinical trials that is reasonably likely to predict a clinical benefit (namely, an effect on irreversible morbidity or mortality).³ Receipt of accelerated approval does not guarantee FDA approval.

In December 2024, FDA released a draft guidance, “Expedited Programs for Serious Conditions — Accelerated Approval of Drugs and Biologics” (the “Draft Guidance”). The Draft Guidance, once finalized, will be the latest of several FDA guidances to discuss the agency’s expedited programs.⁴ The Draft Guidance is not legally binding on companies or FDA. However, it offers insight into FDA’s current thinking on eligibility for accelerated approval, postapproval requirements for sponsors, and withdrawal of accelerated approval. Interested parties may provide comments to the Draft Guidance by February 4, 2025.

Decision-Making Process for Accelerated Approval

• The Draft Guidance covers in detail FDA’s decision-making process regarding eligibility for accelerated approval. As a starting point, FDA acknowledges two forms of risk generally associated with the accelerated approval program that inform its decision-making: (1) patients may be exposed to a drug that ultimately does not demonstrate a clinical benefit; and (2) because the drug may have shorter or smaller clinical trials, there may be less information available at the time of approval regarding the occurrence of rare or delayed adverse effects.
• FDA also discusses key considerations for determining whether a surrogate or intermediate clinical endpoint reasonably predicts a clinical benefit, which is required for a grant of accelerated approval. FDA notes, “Data showing that, in studies of interventions that improve a clinical outcome, the extent of change in the proposed surrogate correlates with the extent of improvement typically provide the strongest support for a surrogate endpoint.”⁵ However, FDA acknowledges that such information often is not available in clinical trials. In those instances, it will weigh information from other sources, including preclinical animal models, epidemiological data, and relevant clinical data.
• The Draft Guidance notes that FDA may be open to the use of “novel surrogate or intermediate clinical endpoints,” but also states that “[t]he accelerated approval pathway will not be an option for every serious disease with unmet medical need, particularly when the evidence is insufficient to support use of a surrogate endpoint or intermediate clinical endpoint, or when an adequate and well-controlled confirmatory study would be infeasible.”
• According to the Draft Guidance, when assessing surrogate endpoints, FDA will consider the following factors:
  • The extent to which the pathophysiology of the disease and the role of the surrogate endpoint in that pathophysiology is understood.
  • Whether there is reliable and consistent epidemiologic evidence supporting correlation between the surrogate endpoint and clinical outcome of interest.
    • For example, the Draft Guidance notes that “more persuasive evidence may come from prospective, longitudinal studies showing strong correlation and precisely defining the relationship,” although such a relationship does not necessarily establish that the drug’s efficacy will be beneficial.
  • Whether there is evidence from clinical trial data supporting that the effect on the surrogate endpoint has been shown to predict a clinical benefit with another drug or drugs.
    • FDA notes that this factor generally is more persuasive if the drug is in the same or a closely related pharmacological class.

Postapproval Requirements

• If a company obtains accelerated approval, it must conduct confirmatory trials to verify and describe the effect of the drug on irreversible morbidity or mortality or other clinical benefits.⁶
  • The Draft Guidance advises that sponsors should diligently monitor trial progress and be prepared to make appropriate modifications when enrollment is below expected levels or when the trial is otherwise not progressing as intended. Modifications may include adding resources, adding sites, and other protocol changes.
• The drug labeling must include a succinct description of limitations of usefulness of the drug and any uncertainty about anticipated clinical benefits in the INDICATIONS AND USAGE Section.⁷
• If a company obtains approval, it must submit copies of all promotional materials to FDA’s Office of Prescription Drug Promotion prior to the intended date of dissemination or publication (after 120 days following marketing approval, unless told otherwise by FDA, at least 30 days prior to initial dissemination or publication).

Withdrawal of Accelerated Approval

• FDA may use expedited procedures to withdraw approval for a drug that has previously received accelerated approval if any of the following circumstances occur:
  • The sponsor fails to conduct any required postapproval study of the product with due diligence.
  • Postapproval studies fail to verify and describe the predicted clinical benefit.
  • Other evidence demonstrates the product is not shown to be safe or effective under the conditions of use.
  • The sponsor disseminates false or misleading promotional materials with respect to the product.⁸
• In such cases, FDA may issue a proposal to withdraw approval. Before the expedited withdrawal occurs, under the FD&C Act, the sponsor is entitled to: (1) “due notice;” (2) an explanation for the proposed withdrawal; (3) an opportunity to meet with the FDA Commissioner or Designee; (4) an opportunity for written appeal; and (5) an opportunity for an advisory committee meeting on the proposed withdrawal, if one has not already occurred.⁹
• The Draft Guidance indicates that, if the sponsor fails to exercise these statutory rights within the timeframe specified in FDA’s notice of proposed withdrawal, the agency may consider these rights to have been waived. That is, the sponsor could lose its statutory rights to challenge a proposal to withdraw the accelerated approval.

AGG Observations

• The Draft Guidance emphasizes that FDA’s determination of whether a surrogate endpoint satisfies the requirements for accelerated approval is highly context dependent. Although the Draft Guidance notes that FDA may be open to “novel surrogate or intermediate clinical endpoints,” it advises that these endpoints must be supported by additional preclinical or clinical data.
• The Draft Guidance signals that, although FDA’s review of accelerated approval applications is on a case-by-case basis, FDA will not relax the pathway’s evidentiary requirements merely to address an unmet medical need.
• FDA emphasizes the importance of early and frequent communication between sponsors and FDA, particularly on issues related to proposed surrogate and intermediate clinical endpoints, clinical trial designs, and confirmatory trials. Given that the agency’s assessment of these issues is case-specific, early communication will be particularly important for sponsors who plan to use a novel endpoint or who anticipate clinical or confirmatory trial issues (e.g., the drug is intended to treat a rare disease for which it will be difficult to find clinical trial participants).
• If a sponsor believes it will be difficult in clinical trials to show a surrogate endpoint that satisfies accelerated approval requirements, the sponsor should act early to find supporting data about the drug or pathology of the disease state to support its claim that the drug is reasonably likely to produce a clinical benefit. If a sponsor reviews and follows the Draft Guidance recommendations, and can satisfy the statutory requirements, it might, indeed, have a shot at life in FDA’s accelerated approval fast lane.

[1] 21 C.F.R. Part 314, Subpart H; 21 C.F.R. Part 601, Subpart E.

[2] Id.

[3] See our previous Bulletin for more information on the accelerated approval pathway generally, available here.

[4] See Guidance for Industry — Expedited Programs for Serious Conditions — Drugs and Biologics (May 2014); See also Guidance for Industry — Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (February 2019) and Guidance for Industry — Limited Population Pathway for Antibacterial and Antifungal Drugs (August 2020).

[5] “Expedited Program for Serious Conditions — Accelerated Approval of Drugs and Biologics.” HHS, FDA. December 2024.

[6] 21 U.S.C. § 356(c)(3) and 21 C.F.R. 314.510 and 601.41.

[7] See 21 C.F.R. 201.57(c)(2)(i)(B).

[8] 21 U.S.C. § 356(c)(3)(A).

[9] 21 U.S.C. § 356(c)(3)(B).