Earlier this month, the US Food and Drug Administration (FDA) issued new draft guidance regarding their accelerated approval pathway for new drugs and biologics, an expedited program designed to help address unmet medical needs for serious or life-threatening conditions. As usual, the FDA is soliciting comments to the new guidance, due by February 4, 2025.
2014 Guidance vs. New 2024 Draft Guidance
The new draft guidance applies to sponsors developing treatments for life-threatening conditions that are reasonably likely to predict effects on irreversible morbidity, mortality, or other clinical benefits. The new draft guidance expands on the FDA’s 2014 guidance on accelerated drug approval in three material aspects. Specifically, per the new guidance, the FDA intends to provide:
- New resources for sponsors using novel endpoints.
- Expanded guidance about post-marketing confirmatory trials.
- A more extensive framework for expedited withdrawal of accelerated approval.
New Processes and Recommendations for Sponsors Using Novel Endpoints
The FDA defines clinical endpoints as “measurable events or outcomes that can help determine whether a medical intervention, such as a therapy, is benefiting patients.” Both the previous 2014 guidance and new 2024 draft guidance iterate that sponsors must use endpoints to demonstrate that a treatment warrants accelerated approval because the treatment is reasonably likely to predict clinical benefit.
Moreover, the 2024 draft guidance highlights the importance of early consultation between sponsors and the FDA in developing novel surrogate or intermediate clinical endpoints for accelerated approval. The 2024 draft guidance recommends that sponsors:
- Seek consultations with FDA Review Teams early and frequently when sponsors intend to use a new clinical or surrogate endpoint.
- Request a Type C Meeting to discuss a novel biomarker or surrogate endpoint and “the feasibility of using that surrogate endpoint as a primary efficacy endpoint and to identify any gaps in knowledge and how they might be addressed.”
- Submit a Rare Disease Endpoint Advancement Pilot Program Proposal to collaborate with the FDA to develop new surrogate or intermediate clinical endpoints that facilitate accelerated approval for a rare disease treatment.
Expanded Guidance for Timely Conduct of Post-Marketing Confirmatory Trials
Post-marketing confirmatory trials are clinical trials that sponsors must conduct to verify and describe the clinical benefits of an accelerated drug. The 2014 guidance recommended that sponsors have mapped-out timelines for completing confirmatory trials when the sponsors file their applications for accelerated drug approval.
The 2024 draft guidance goes one step further, encouraging sponsors to (1) initiate confirmatory trials before submitting their marketing applications and (2) collaborate with the FDA to establish trial progress conditions, including enrollment targets and completion dates. Additionally, the 2024 draft guidance implores sponsors to have early consultations with FDA Review Teams to ensure that sponsors’ confirmatory trials yield “interpretable results.”
Expedited Withdrawal of Accelerated Approval
Under section 356(c)(3)(A) of the federal Food, Drug, and Cosmetics Act, the FDA has the authority to withdraw approval of an accelerated drug under the following circumstances:
- Confirmatory trials fail to verify the predicted clinical benefit.
- Other evidence reveals that the treatment is not safe or effective under the conditions of use.
- The sponsor does not conduct post-marketing confirmatory trials in a timely manner.
- The sponsor disseminates unapproved, false, or misleading promotional materials about the treatment.
Per the 2024 draft guidance, the FDA will provide the following information in a written notice of a proposal to withdraw accelerated approval:
- Whether an Advisory Committee has been convened to discuss withdrawal or if it is still necessary to convene an Advisory Committee.
- How the sponsor can submit an appeal or respond to the written notice.
- When the FDA will publish a proposal to withdraw accelerated approval in the Federal Register Notice seeking public comment on its proposal to withdraw approval.
- A reminder that if the sponsor does not request a hearing within the timeframe stipulated in the written notice, the sponsor will waive the right to a hearing.
Key Takeaways
Under the 2024 draft guidance, drug developers who sponsor accelerated approval of treatments for life-threatening illnesses should strongly consider:
- Meeting with the FDA early in the application process if sponsors plan to use a novel surrogate or intermediate clinical endpoint as the basis for accelerated approval.
- Having confirmatory trials underway when filing an application for accelerated approval.
- Communicating early and frequently with FDA Review Teams to ensure confirmatory trials yield interpretable data.
- Ensuring that promotional materials and labels of accelerated drugs or treatments are not false or misleading.
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