New Accelerated Approval Guidance Underscores Need for Accountability | Sheppard Mullin Richter & Hampton LLP

[co-author: Julian Klein*]

On December 5, 2024, just in time for the holidays, the U.S. Food and Drug Administration (“FDA” or the “Agency”) released a draft guidance titled “Expedited Program for Serious Conditions: Accelerated Approval of Drugs and Biologics Guidance for Industry” (the “Draft Guidance”).[1] FDA’s so-called “accelerated approval” program is designed to expedite the development and review of new drugs and/or biologics that fulfill unmet medical needs for serious or life-threatening conditions by granting market approval to therapeutics that show promise by meeting a surrogate endpoint (so long as the drug and/or biologic sponsor promises to conduct post-market, confirmatory trials to verify safety and efficacy). The Draft Guidance updates FDA’s policies and procedures for accelerated approval, including heightened requirements for confirmatory trials and a new process for expedited withdrawal of approval, based on mandates from the 2023 Consolidated Appropriations Act, which was penned to address concerns over the lag time between initial approvals under the accelerated approval program and final approval following the successful completion of confirmatory trials.[2] FDA is inviting comments to the Draft Guidance, with a deadline set for February 2, 2025.

A. The Accelerated Approval Program

The accelerated approval program was established by FDA in 1992 and later codified by Congress in 1997 through the Food and Drug Administration Modernization Act. Under the accelerated approval program, sponsors of accelerated approval drugs and/or biologics may receive premarket approval for drugs intended to treat serious or life-threatening conditions that fulfill unmet needs based on the identification of a surrogate or intermediate clinical endpoint. However, as a way to balance the urgent need for treatment of certain conditions with an assurance of patient safety, these sponsors are required to conduct confirmatory trials after approval to verify the anticipated clinical benefits. These trials help ensure that the initial approval based on surrogate endpoints translates into tangible clinical benefits for patients, and are used to support a complete finding of safety and efficacy that meets FDA’s standard for full market approval. Of course, FDA retains the authority to withdraw accelerated approval if confirmatory trials fail to verify clinical benefits or if sponsors fail to meet other conditions of accelerated approval (e.g., if the sponsor disseminated misleading promotional materials).

B. Evolving Guidance

The codified accelerated approval pathway has undergone several amendments; most recently, with the 2023 Consolidated Appropriations Act of 2023. The Act revised Section 506(c) of the Federal Food, Drug, and Cosmetic Act (the “FDCA”) to grant FDA several new authorities and responsibilities in administering the accelerated approval program. Specifically, the Act requires FDA to specify heightened requirements for confirmatory studies (which may include enrollment targets, study protocols, and completion milestones) at the time of product approval and introduces new procedures for expedited withdrawal of approval.[3]

Prior to the new Draft Guidance, FDA’s most recent guidance on the accelerated approval pathway was published in 2014, but differs considerably in scope, focus, and procedure from this year’s iteration.[4] For example, the 2014 Guidance provides a broader view of all expedited programs – including fast track designation, breakthrough therapy designation, priority review designation, as well as the accelerated approval, while the recent Draft Guidance is solely focused on the accelerated approval pathway. Furthermore, the Draft Guidance includes comprehensive procedures – established by the 2023 Consolidated Appropriations Act – for expedited withdrawal of drugs approved under the accelerated approval pathway. Although the 2014 Guidance includes some criteria for withdrawal, they are no longer current in light of this newer legislation.

Another key difference relates to confirmatory trials (i.e. post-market trials to verify the anticipated effect on irreversible morbidity or mortality (“IMM”) or other clinical benefit). While the 2014 guidance set forth the general requirement that sponsors of accelerated approval therapies conduct confirmatory trials – including the notion that confirmatory trials require due diligence from sponsors – the Draft Guidance mirrors the heightened requirement established by the 2023 Consolidated Appropriations Act. Notably, confirmatory trials must now be underway at the time of approval and sponsors must update FDA on confirmatory trial progress every six months. Finally, while both guidance iterations underscore the need for ongoing communication between sponsors and FDA, the recent Draft Guidance specifically notes the importance of ongoing consultation regarding novel endpoints and confirmatory trial design.

The key differences included in the new legislation and recent Draft Guidance highlight an increasing need to hold sponsors accountable for exercising the due diligence required in return for receiving early market access by confirming safety and efficacy through Phase 3 confirmatory trials and, if this doesn’t happen, to pull lingering – and ineffective – accelerated approval drugs and/or biologics from the market.

The Draft Guidance incorporates these changes and, once finalized, will encompass FDA’s most up-to-date approach and recommendations for accelerated approval, providing a framework for sponsors to follow in developing, marketing, and monitoring drugs and biologics under this expedited program. The Draft Guidance highlights the importance of early communication between sponsors and FDA, particularly regarding novel endpoints and confirmatory trial design, and reasserts the Agency’s ultimate goal of balancing the expedited availability of promising therapies for serious and/or rare conditions with an assurance safety and efficacy through adequate regulatory oversight.

C. The Tea Leaves

The 2023 Consolidated Appropriations Act, and FDA’s accompanying Draft Guidance, make certain changes to the way that manufacturers will approach development for accelerated approval drugs and biologics – for example, by bumping up the timeline for initiating confirmatory trials, heightening the periodic reporting requirement, and reeling in the slack on lingering, unconfirmed accelerated approval therapeutics – but it’s important to consider why these changes are being made, and why now. So, why did Congress opt to make these changes to the accelerated approval program? The short answer is that the stats were not headed in a good direction. As raised by stakeholders in favor of the Act’s accelerated approval program reforms, program use has increased and – along with it – so have lag times between accelerated approval (i.e., proven surrogate endpoint) and subsequent full approval (i.e., proven safety and efficacy). For example, only half of the oncology drugs granted accelerated approval between 1992 and 2019 completed confirmatory trials within five years.[5] This means that drugs/biologics for which safety and efficacy have not been fully proven are lingering on the market for years, and all that time are fully available to patients with serious and rare conditions. Although Congress and other industry participants recognize the value in accelerating access to promising therapies for serious and/or rare disease patients who would otherwise not have access to any treatment, the Act serves as a clear signal to FDA that it’s time to tighten the reins on these drugs and do what it takes to decrease the lag time between accelerated approval and full approval for products that are already, or are about to be, on the market and in the hands of patients.

And, in the new Draft Guidance, FDA indicates that it’s listening. As explained above, the new Draft Guidance differs considerably to the 2014 guidance by honing in on the accelerated approval program, specifically, suggesting a clear focus by FDA on this particular expedited approval pathway. And, within this focus on the accelerated approval pathway, a primary point of emphasis is enhancing accountability for confirmatory trials. As outlined in the Draft Guidance, FDA plans to achieve this enhanced accountability by coupling new confirmatory trial requirements[6] with bolstered withdrawal authority, creating a much more robust sense of FDA oversight that simply has not been present with the accelerated approval program to date. Here, the enhanced guidelines for confirmatory trials represents somewhat of a “shield” – a means for FDA to guard against drugs being granted accelerated approval only to linger on the market without the any movement on the required post-market trials – the bolstered withdrawal process represents a sort of “sword” for FDA to combat these lingering drugs. This means that sponsors cannot take their feet off the gas once accelerated approval is granted.

Although the incoming Trump administration leans heavily on its platform of deregulation, which could handicap FDA’s ability to administer the accelerated approval program to its full potential, the previous Trump administration did pass significant “Right to Try” legislation aimed at increasing terminally ill patients’ access to treatments that have not yet been proven safe and effective[7] – a similar goal as the accelerated approval program, although designed in a way that nearly cuts out FDA altogether. So – as with most all areas of FDA regulation – it’s a bit of a “wait and see” situation when it comes to the future of the accelerated approval program. But, in the meantime, the Agency has a tangible goal to work toward as it aims to reduce the lag time between accelerated approval and full approval for currently marketed or soon-to-be marketed drugs and biologics by implementing the provisions of the Act, as reflected in its new Draft Guidance, and accelerated approval sponsors should prioritize efficient confirmatory trial completion to ensure that their drugs and/or biologics remain on the market.

*Julian Klein is a summer associate in the firm’s New York office.

FOOTNOTES

[1] Draft Guidance available here: Accelerated Approval – Expedited Program for Serious Conditions | FDA.

[2] Public Law 117-328 available here: PUBL328.PS.

[3] The Act also granted FDA authority to require that confirmatory trials be underway prior to or shortly after accelerated approval, but FDA plans to address this update in separate guidance.

[4] 2014 Draft Guidance available here: Expedited Programs for Serious Conditions – Drugs and Biologics.

[5] See Richard G. Frank, Mahnum Shahzad & Ezekiel J. Emanuel, Accelerated Approval of Cancer Drugs: No Economic Reward for Drug Makers That Conduct Confirmatory Trials, 41 Health Affs. 1273 (2022).

[6] In terms of timing, FDA keys in on developing and submitting a protocol as early as possible, initiating confirmatory trials before accelerated approval is granted, and early and frequent consultation with FDA (including status reports every six months). In terms of design, the Agency focuses on clinical endpoints, and, when needed, the evaluation of the same surrogate endpoints used for accelerated approval.

[7] See President Donald J. Trump to Sign Right to Try Legislation Fulfilling the Promise He Made to Expand Healthcare Options for Terminal Americans, Trump White House Archives (May 30, 2018).