New Draft Guidance From FDA Explains When an Accelerated Approval Trial Is “Underway”

On January 6, with increased attention and scrutiny from patients, providers, developers, and payors on the accelerated approval pathway for drugs, the Food and Drug Administration (FDA) released new draft guidance for industry on what it means for a drug’s confirmatory trial to be “underway” under section 506(c) of the Federal Food, Drug, and Cosmetic Act.

Background

Under the accelerated approval pathway, FDA may approve drugs, including biologic drugs, for serious or life-threatening diseases based on a surrogate or intermediate endpoint, such as a laboratory measurement, a radiographic image, or other measure that is reasonably likely to predict clinical benefit, but is not itself proof of clinical benefit. This can shorten clinical trials and lead to products being approved earlier, allowing increased patient access to novel products. However, drugs approved through accelerated approval also carry some risk in that the clinical benefit of the drug has not yet been confirmed. To mitigate that risk, sponsors of drugs approved via accelerated approval are generally required to complete postapproval confirmatory studies verifying the drug’s clinical benefit. If the confirmatory study fails to show clinical benefit or if the sponsor fails to conduct a required postapproval study with due diligence, the product may be withdrawn.

In 2022, citing concerns with delays in postapproval study initiation and completion—some confirmatory studies for drugs approved under accelerated approval had not finalized a protocol or enrolled any patients more than a year after approval—Congress enacted reforms to the accelerated approval pathway in the Food and Drug Omnibus Reform Act (FDORA). These reforms included granting FDA the explicit authority to specify conditions on the studies and requiring postapproval studies to be “underway” before approving the drug or within a specified period after a drug’s approval. The draft guidance explains FDA’s general policy for determining whether a trial needs to be underway prior to approval, and how it will determine whether a trial is underway.

FDA Generally Requires Confirmatory Trials to be Underway Before Granting Accelerated Approval, but Outlines “Limited Exceptions”

FDORA granted FDA the authority to require sponsors to have confirmatory trials underway before approving the product, but the law does not explicitly require it of all sponsors. In the draft guidance, FDA clarified its intent that for most drugs, the agency will generally require confirmatory trials to be underway before a drug is approved via the accelerated approval pathway.

FDA also describes “limited exceptions” where the agency may not require a confirmatory trial to be underway prior to granting accelerated approval. These include trials that are dependent on an event that hasn’t taken place, for example, an infectious disease outbreak that has not yet occurred. FDA may also grant accelerated approval to drugs treating certain rare diseases if there are unique challenges that are appropriately justified for FDA, or if a rare disease’s clinically relevant endpoints and natural history enable a postmarketing study that does not require randomization.

In addition to concerns about ensuring confirmatory trials are completed in a timely manner, FDA notes that randomized controlled trials may be difficult to conduct if the trial is not underway when the drug is approved. (After approval, patients who otherwise may be enrolled in a trial may be less inclined to enroll in a trial and potentially receive a placebo, rather than the approved drug.) To that end, if FDA determines that enrollment or retention in a confirmatory trial will be especially challenging after a drug is approved, the agency may require a study to be fully enrolled before granting the accelerated approval.

Assuming that a trial will need to be underway prior to approval, FDA encourages sponsors to have early discussions with FDA on their postapproval study plans, including the study design, timing for initiating the study, and an appropriate justification for that plan and timeline. This will allow FDA and the sponsor to come to agreement on a plan before a decision is required.

What Does “Underway” Mean?

The draft guidance explains that trials will generally be considered “underway” prior to approval if the following criteria are met:

1. Target Completion Date: The confirmatory trial should have “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.”

   Although FDORA authorized FDA to set a target completion date as a condition of a required postapproval study, the draft guidance suggests that the agency will rely on sponsors to provide much of the basis for determining that target date. The draft guidance, recognizing concerns about delays in timely completion of confirmatory trials, says that sponsors providing a proposed target date, should factor in diligent conduct of the trial “in a manner that limits the amount of time the drug will remain approved without verification of clinical benefit.” FDA also notes that appropriate target completion dates may be informed by the natural history of the disease/rate of disease progression; the availability of alternative treatments; the anticipated recruitment timeline; and the timeline for efficacy analysis, factoring in event rates for a particular disease, or the minimum follow-up required to show efficacy. In all cases, the agency says, sponsors should provide FDA with a “clear and sound justification” for the proposed target completion date.
   
   

2. Assurance of Timely Completion: Another factor for considering whether a trial is “underway” will be whether “the sponsor’s progress and plans for postapproval conduct of the trial provide sufficient assurance to expect timely completion of the trial.”

   In analyzing the sufficiency of the sponsor’s assurances of timely completion, FDA will consider how many participants the sponsor has accrued to date, the rate of accrual, and, if full enrollment is not expected prior to approval, the anticipated timeline for when enrollment will be complete after the drug is approved. FDA will also consider how many trial sites are active to date, and the projected rate of additional site activation.

   FDA also expects sponsors to propose benchmarks to help the agency assess whether the trial is underway to FDA’s satisfaction at the time of approval. These benchmarks should include, at a minimum, the participant recruitment goal, how many sites are expected to be activated, and a proportion of primary endpoints that will have accrued at the time of approval. Failure to meet one or more of these benchmarks will affect FDA’s consideration of approval, but FDA will also consider a sponsor’s justification for any delayed progress and a plan to address that delay.
   
   

3. Enrollment Initiated: FDA generally will only consider a confirmatory trial underway if enrollment .

   FDA specifies in the draft guidance that enrollment in the trial, specifically in the trial period that is intended to provide confirmation of benefit, will generally need to have started for the agency to consider a trial underway. The draft guidance does not specify a number or percentage of patients that must have enrolled, but as described above, FDA will consider progress in enrollment as evidence of assurance of timely completion of the study.

Other Considerations

Sequence of Communication and Trial Design

In addition to providing guidance on when a confirmatory trial is underway, the draft guidance recommends that sponsors should request a meeting to discuss a comprehensive drug development program, including plans for confirmatory trials, soon after reaching understanding with the agency that accelerated approval may be viable. FDA and the sponsor should come to agreement on the design of any required confirmatory trials as soon as practicable, generally soon after the end-of-phase 2 meeting. The draft guidance says the trial “must be feasible to conduct and appropriately designed to verify and describe clinical benefit.”

Mitigating Post-approval Enrollment Challenges

FDA repeatedly emphasizes that sponsors consider potential challenges that accelerated approval may pose in enrolling patients in a confirmatory trial. However, the agency notes that adverse effects of accelerated approval on enrollment may be avoided by conducting a confirmatory trial in a population not being studied for treatment of the approved indication, for example, in a population with an earlier disease stage or in a different treatment setting. Even when studied in the same population as the approved indication, FDA advises that adverse effects may be mitigated by completing all or a significant portion of enrollment before the drug is approved.

U.S. Participant Recruitment

To ensure the confirmatory trial enrolls and retains a sufficient number of U.S. participants, FDA has repeatedly said that participants in clinical trials should be representative of patients who will use the drugs after they are approved. In emphasizing early enrollment of U.S. participants here, FDA appears to be suggesting that it wants sponsors to be able to show that participation of U.S. patients in a trial will not be impeded by an accelerated approval.

Conclusion

While FDA has long expressed an expectation that accelerated approval confirmatory trials will be underway by the time a drug is approved, the draft guidance clarifies FDA’s general policy and explains its considerations for what “underway” means. If a sponsor is considering pursuing accelerated approval for a product,  plans regarding confirmatory trials should be incorporated early in the clinical trial design.