FDA Draft Guidance Supports Randomized Trials for Accelerated Approvals

The FDA released a draft guidance for drug sponsors of clinical trials in oncology, outlining its move toward requiring randomized controlled trials to grant accelerated approvals for most oncology therapeutics.

The FDA issued a draft guidance concerning trial design for studies whose purpose is to support accelerated approval of oncology therapeutics, stating its preference for randomized controlled trials (RCTs) over single-arm trials.1

The draft discusses the FDA’s reasons for supporting RCT design which compares new therapeutics with a currently available therapy as opposed to single-arm trials. It also details key challenges and considerations for design and analysis of such trials to justify accelerated approval of new agents.

“The FDA’s accelerated approval program has provided patients with cancer earlier access to novel treatments that can be practice changing,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence, in a press release.1 “Today’s draft guidance provides recommendations to sponsors for designing clinical trials to support accelerated approval.

The FDA’s accelerated approval pathway is used frequently for oncology therapeutics due to the need to provide new options to patients with life-threatening cancers. The FDA has considered the clinical end points such as response rate and duration of response in single-arm trials sufficient to predict clinical benefit for patients outside these trials, though they require a confirmatory trial for approval to continue.

The draft guidance identifies several limitations on the ability of single-arm trials to provide supporting evidence for accelerated approval.2

Toxicity: Due to smaller numbers of enrolled patients, these trials may not identify all serious adverse events and they can’t be distinguished as treatment related.

Combination Therapy: Combination regimens are difficult to assess without comparing with individual components.

Data: Comparing results from single-arm trials to past trials is unreliable because of differences in patient population and trial design, and time-to-event outcomes such as progression-free survival (PFS) and overall survival (OS) are not meaningful without a comparator.

The FDA suggests that RCTs would improve safety and efficacy assessments due to direct comparison to patients receiving approved therapy rather than historical trials of other therapies. The draft also states that RCTs could be performed in an earlier treatment setting whereas single-arm trials would more likely enroll patients who lacked other treatment options.

The draft discusses the benefits of a “one-trial” approach where a single RCT could lead to accelerated approval and long-term follow-up would provide confirmatory evidence of clinical benefit post-marketing.

The FDA acknowledges that single-arm trials may be appropriate in some situations when developing a RCT to evaluate a therapeutic is not feasible but recommends discussion with the FDA before and during a single-arm trial whose goal is accelerated approval.

If drug sponsors conduct 2 separate RCTs to support accelerated approval and to verify clinical benefit, the first trial should have an early primary end point such as response rate whereas the confirmatory trial could target longer-term end points such as PFS and OS. The “one-trial” approach should use a single clinical trial powered to evaluate both short-term and long-term end points.

In the case of separate trials, the FDA recommends that the confirmatory trial be underway by the time the accelerated approval action is taken, since enrollment will be more challenging if the drug is already commercially available, and timely completion is needed to verify that the drug is safe and effective. The FDA also notes that the confirmatory trial could be performed in an earlier line of therapy than the trial that led to accelerated approval.

For the “one-trial” approach, the FDA states that the trial will need to be designed carefully based on preliminary data to ensure that the selected end points can be assessed to show clinical benefit in both stages. Sponsors should consider factors such as “the anticipated impact of crossover (if permitted), the preliminary data on the drug’s effects, including the toxicity profile, the treatment landscape, and the treatment used in the control arm,” to prevent bias from the approval or other regulatory action from impacting the ongoing trial. They should also discuss with the FDA whether to submit for accelerated approval if the treatment landscape changes, such as when the trial’s comparator arm is no longer standard of care.

Additionally, the FDA draft stated the agency may request a summary of survival data when considering accelerated approval to assess the impact of the treatment’s toxicities on survival, and they may request additional updates as the application is reviewed.

Single-arm trials would be reserved for “that drugs that are expected to provide a meaningful advantage (including an efficacy advantage) over available treatment.” Historical trials of available therapies should be prespecified in consideration of how they align with the trial’s design and patient selection. The FDA recognizes that this may be challenging in molecularly defined patient populations, and states that it may be appropriate to demonstrate that the treatment will have a greater magnitude of efficacy versus the wider historical trial population.

For the analysis of single-arm trials, the draft recommends a minimum follow-up of 6 months to assess durability of response in most cases, as well as the use of blinded independent central review to prevent bias in assessing response. It also states that

The FDA also called attention to the role of Project Confirm, an initiative by the FDA Oncology Center of Excellence to promote the transparency of outcomes related to accelerated approvals, including a database tracking the status of all oncology accelerated approvals.1

These steps are aimed at continuing the use of accelerated approval while maintaining the quality of clinical trials investigating new therapeutics for patients with cancer.

“Building quality and efficiency into the design of oncology clinical trials is a crucial component in providing maximum benefit to those living with cancer,” stated Pazdur in the press release.


1. FDA issues draft guidance aimed at improving oncology clinical trials for accelerated approval. News release. FDA. March 24, 2023. Accessed March 27, 2023. https://bit.ly/3FXh6JM

2. Clinical trial considerations to support accelerated approval of oncology therapeutics guidance for industry. Draft guidance. FDA. March 2023. Accessed March 27, 2023. https://bit.ly/3JWsSW6

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