FDA encourages RCTs in accelerated approval guidance for oncology

The US Food and Drug Administration (FDA) issued draft guidance on the design of oncology trials for accelerated approval, calling randomized controlled trials (RCTs) – rather than single-arm studies -- the “preferred approach” to support accelerated approval.

Sponsors can conduct a single RCT to support accelerated approval and verify clinical benefit or run two trials, one that supports accelerated approval through the use of an early endpoint and one confirmatory trial that is powered to assess a longer-term clinical endpoint, according to the draft guidance, which was published in the Federal Register on 27 March.

“This ‘one-trial’ approach maintains efficiency in drug development and can provide early access to a drug using the accelerated approval pathway, while ensuring that a postmarketing trial is fully accrued and well underway to verify longer term benefit in a timely fashion,” the agency wrote in the draft guidance.

RCTs are preferred, but single-arm trials may be appropriate to support accelerated approval in some cases, such as when there are concerns about the feasibility of an RCT, according to the draft guidance.

Accelerated approval reform
One of the criticisms of the accelerated approval pathway is that some drugs have stayed on the market for years without demonstrating clinical benefit in a confirmatory trial (RELATED: Health policy experts call for stronger accelerated approval reforms, Regulatory Focus 06 July 2022). FDA officials floated the two RCT trial design options as a way to improve the program in a perspective published last year in the New England Journal of Medicine (RELATED: FDA officials urge ‘comprehensive’ approach to accelerated approval reforms, Regulatory Focus 22 September 2022).

Ravi Parikh, MD, associate director of the Penn Center for Cancer Care Innovation, who recently published a study about patients’ exposure to cancer drugs that were marketed under accelerated approval and later withdrawn, said better endpoints and trial designs are essential to prevent this type of exposure (RELATED: Study: Certain cancer drugs saw widespread use before accelerated approval withdrawal, Regulatory Focus 23 February 2023).

“The FDA’s effort to ensure that confirmatory trials are ongoing at the time of accelerated approval will speed public access to confirmatory trial results and ensure that ineffective drugs are on the market for shorter amounts of time,” Parikh said in an interview with Focus. “However, we have shown that the greatest use of ineffective drugs granted accelerated approval is immediately after approval. Thus, the best way to ensure that as few people as possible are exposed to accelerated approval drugs that will fail confirmatory trials is to ensure accelerated approval is based on better endpoints and trial designs, including randomized trials.”

Two RCT approach
For sponsors planning to conduct an RCT for accelerated approval and another to confirm results, FDA recommends that the confirmatory trial be “well underway, if not fully enrolled, by the time of the accelerated approval action.” Waiting to start the confirmatory trial until after accelerated approval can create problems in enrolling participants because the drug is already available in clinical practice, the agency noted in the draft guidance.

FDA said that it “may be acceptable” in a confirmatory trial for sponsors to evaluate the drug in the same cancer type but in another line of therapy, such as earlier-stage disease. “This approach has the potential to provide access to effective drugs to patients with earlier-stage disease in which benefit may be greater, and it facilitates patient accrual when a drug has already received accelerated approval for a later-stage indication,” the agency wrote.

One RCT approach
Before launching an RCT using the one-trial approach, FDA recommends that sponsors consult with them on whether the expected effect on response rate or another early endpoint is of a sufficient magnitude to be reasonably likely to predict clinical benefit. “Depending on the disease course, the intended population, and guidance from FDA, use of endpoints other than response rate could also be evaluated in a ‘one-trial’ approach together with subsequent evaluation of clinical benefit endpoints,” the agency wrote.

The trial size should be adequate to detect a “clinically meaningful and statistically significant improvement” in both the endpoints for accelerated approval and the verification of clinical benefit. The agency noted that the trial design can incorporate adaptive design elements, such as sample size re-estimation.

The draft guidance also notes that efficacy analyses in support of accelerated approval “should be avoided until the trial is close to or fully enrolled” to help mitigate potential issues with accrual if accelerated approval is granted.

Single-arm studies
The guidance recommends that sponsors who are considering single-arm studies first discuss with the FDA whether this trial approach would be appropriate to support accelerated approval. The agency also recommends that the trial sample size and analysis population for response be pre-specified.

“Given the small size of most single-arm trials, the analysis population is generally expected to be the entire trial population. Patients who have received at least one dose of the study drug would then be included in the analysis population regardless of whether they have had the opportunity to respond due to short follow-up time. Multiple increases to the study sample size with repeated looks at the data in the absence of a pre-specified plan may introduce bias in the assessment of efficacy and should be avoided,” the agency wrote.

For single-arm studies, stable disease should not be a component of response rate, according to the guidance. Clinical benefit rate, which is response rate plus stable disease for more than six months should also not be used. “Such measures can largely reflect the natural history of disease, whereas reduction in tumor size represents a direct therapeutic effect,” the FDA wrote.

Comments on the draft guidance can be submitted to regulations.gov and labeled as Docket No. FDA-2023-D-0110. The public comment period closes on 26 May 2023.

Draft guidance

FDA encourages RCTs in accelerated approval guidance for oncology

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