Overview of FDA’s New Draft Guidance DocumentsKey updates under...

Overview of FDA’s New Draft Guidance Documents

Key updates under the Accelerated Approval Guidance and the Confirmatory Trial Guidance include:

a. Confirmatory Trials. The FDA now has authority to require that a confirmatory study already be underway before granting approval under the Accelerated Approval pathway. The Confirmatory Trial Guidance states: “If FDA determines that a confirmatory trial must be underway prior to Accelerated Approval and the trial is not underway, FDA does not intend to grant Accelerated Approval until this deficiency is addressed.” In some cases, the FDA may even require that trial enrollment be complete at the time of approval.[15]

The Accelerated Approval Guidance states that confirmatory trials must begin early, often by the time of approval, with clearly defined milestones to ensure completion.[16] Trials should efficiently verify clinical benefits and align with the drug’s intended use. Delays or lack of due diligence could result in disciplinary action, including withdrawal of approval.

The FDA acknowledges that in certain cases — such as in the development of drugs for rare diseases for which patient enrollment is challenging — it may not require the confirmatory trial to be “underway” at the time of approval. This will be evaluated on a case-by-case basis. The FDA will generally consider a confirmatory trial to be “underway” if three criteria are met:

• The trial has a target completion date that is consistent with diligent and timely conduct of the trial, considering the nature of the trial’s design and objectives.
• The sponsor’s progress and plans for post-approval conduct of the trial provide sufficient assurance to expect timely completion of the trial.
• Enrollment of the confirmatory trial has been initiated.

The FDA may consider other factors, including patient enrollment accrual rates, the number of actively recruiting sites, projected dates of site activation and relevant benchmarks. The FDA may also consider protocol designs that include, for example, pre-planned assessment of surrogate or intermediate endpoints from an ongoing trial that will continue after the approval date.

b. Endpoint standards. The Accelerated Approval Guidance clarifies the meanings of two types of endpoints that can be used as bases for Accelerated Approval, a surrogate endpoint that is considered reasonably likely to predict clinical benefit and/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.

Determining whether an endpoint is reasonably likely to predict clinical benefit involves biological plausibility and empirical evidence.[17] The FDA stresses that while these endpoints do not need to fully prove clinical benefit at the time of approval, they must demonstrate sufficient potential to predict positive patient outcomes. In making the judgment as to whether a drug’s effect on a given endpoint is reasonably likely to predict clinical benefit, the FDA considers all relevant evidence and may consult external experts.

The FDA also recommends early consultation between sponsors and reviewing agencies for surrogate and clinical endpoints and stresses the importance of developing novel endpoints for more efficient drug development.

c. Withdrawal procedures. The Accelerated Approval Guidance clarifies the FDA’s authority to withdraw approvals if confirmatory trials fail to demonstrate benefit or are not conducted diligently. The FDA can withdraw approval if sponsors fail to conduct confirmatory trials on time, trials fail to confirm clinical benefits, safety concerns arise or promotional materials misrepresent the drug.[18] Sponsors receive formal notice and can appeal, request advisory committee reviews or meet with FDA officials. The guidance emphasizes public transparency, with announcements and responses published.

d. Promotional oversight. The FDA heightened oversight of promotional materials for drugs granted Accelerated Approval. Sponsors must align promotional claims with verified benefits, with materials subject to FDA review before dissemination. Claims must be accurate, balanced and consistent with the evidence available at the time of approval. The FDA also highlighted its authority to address misleading or unsubstantiated promotional materials.