The US Food and Drug Administration released a draft guidance this week outlining recommendations for companies designing trials intended to support accelerated approval for oncology drugs.
The draft guidance provides nonbinding recommendations for the design of randomized controlled trials and single-arm trials for accelerated approval, along with recommendations for confirmatory trials post-approval. The public can comment on the guidance through May 26, 2023.
The guidance notes that a randomized controlled trial is the preferred approach for accelerated approval data. However, the FDA also laid out how a single-arm trial could still meet these requirements. The agency also said sponsors could consider a “one-trial” approach to both support accelerated approval and meet confirmatory study requirements by measuring long-term clinical benefit in the same trial.
While the guidance on trial designs is “not a major shift in policy,” according to Jeff Allen, CEO of advocacy group Friends of Cancer Research, the recommendations provide potential flexibility in how drugmakers design their studies.
“The guidance is showing that there continues to be a need for flexibility for developing the evidence around these drugs,” Allen said. “The one-trial approach is a bit of a newer thought, in terms of how to generate this evidence in an efficient manner, and it could help in certain circumstances versus having to set up an entirely new trial for confirmatory evidence.”
For randomized trials, the FDA suggested two approaches: separate trials for short- and long-term endpoints or one trial powered for both short- and long-term endpoints. The one-trial approach would have multiple endpoints, such as response rate to support the accelerated approval and progression-free survival or overall survival to verify clinical benefit.
If taking the one-trial approach, the FDA recommended that drugmakers take steps to preserve the integrity of the trial and its data. The guidance recommends that trial sponsors consider factors that may introduce bias into the results, such as the anticipated impact of crossover, the drug’s toxicity profile, the treatment landscape, and the treatment used in the control arm, among other factors. The agency also suggested blinding of data related to the long-term endpoint until a pre-specified time point.
For single-arm studies, the FDA suggested that response rate — or similar measures such as complete remission rate or major molecular response — remains an appropriate endpoint to measure early clinical benefit. If sponsors choose to use response rate as the primary endpoint for accelerated approval, the agency also recommended measuring the magnitude and duration of response, typically a minimum follow-up of six months. The FDA also suggests a blinded independent central review of response to reduce potential bias and that the analysis should be on the entire trial population, considering many single-arm studies enroll a small number of patients.
Single-arm studies should also have a pre-specified historical trial for comparison to the investigational treatment. However, the FDA recognized that historical trials may be difficult to find for treatments in molecularly defined patient populations, and suggested the sponsor provide data showing that the magnitude of the treatment effect in the molecularly defined subgroup is better than in the historical trial.
Allen noted that the one-trial approach could be an option for drugmakers developing treatments for biomarker-defined patient populations that struggle to enroll enough patients for multiple studies.
“[Enrollment] has been a continued challenge in the targeted therapy space, along with identifying sites that have the necessary testing in place to identify patients,” he said. “If you already have a trial that’s up and running, there could be certain clinical scenarios where it would be a good option to keep the trial running until you get the longer-term evidence on a larger group of patients.”
The agency also provided guidance for the trial design of required confirmatory studies after accelerated approval. If drugmakers take the one-trial approach, they should have the pre-specified endpoint for long-term clinical benefit in that study.
If sponsors are conducting a separate randomized trial as a confirmatory study, the FDA recommended they begin confirmatory trials before the marketing application is submitted due to challenges enrolling patients after approval.
“Waiting to initiate a randomized controlled confirmatory trial until after an accelerated approval has been granted can create challenges in enrolling participants due to the availability of the drug in clinical practice,” the guidance reads. “Therefore, to help ensure the feasibility and timely completion of the trial intended to verify clinical benefit, FDA strongly recommends that this trial be well underway, if not fully enrolled, by the time of the accelerated approval action.”
Allen noted that the guidance to begin confirmatory studies earlier is important to getting these post-marketing trials completed and reducing uncertainty around accelerated approvals.
“When the confirmatory studies are underway at the time of the accelerated approval, they have a higher likelihood of being completed and being completed sooner,” he said. “A message throughout this guidance document is that managing the uncertainty that comes with any accelerated approval is an ongoing process and that includes the confirmatory studies in order to try and reduce that uncertainty over time as there’s more experience and more data about new drugs.”
Last year, the Food and Drug Omnibus Reform Act included in the 2022 year-end omnibus spending bill gave the FDA new powers to require confirmatory studies after accelerated approval. Specifically, it gave the FDA powers to specify the conditions for any post-approval studies by the date of the accelerated approval, to require that post-marketing studies be underway within a certain time frame of approval, and to create a formal expedited withdrawal process for drugs granted accelerated approval.
Several precision oncology treatments have been withdrawn after accelerated approval due to confirmatory studies showing a lack of long-term benefit. In 2021, Merck voluntarily withdrew its accelerated approval indication for Keytruda (pembrolizumab) as a third-line treatment for patients with advanced, PD-L1-expressing gastric or gastroesophageal junction cancer. Last year, Genentech withdrew accelerated approval for its immunotherapy Tecentriq (atezolizumab) as a first-line treatment for bladder cancer patients, including those with PD-L1 expression in at least 5 percent of tumor-infiltrating immune cells.
The latest guidance reiterates that confirmatory studies are required and “must be carried out with due diligence,” it reads. The guidance recommends that sponsors have early discussions to provide the FDA with confirmatory study information such as enrollment targets, the study protocol, and expected milestones, including the target date of study completion. The randomized one-trial approach may not require a separate study, according to the guidance, but drugmakers conducting single-arm studies for accelerated approval may need to conduct a separate, randomized confirmatory trial.
“I hope that it helps drug developers identify which situation fits their product best, but the FDA is signaling continued flexibility and the desire for early interactions with developers in order to help them chart a way forward,” Allen said.