FDA Reviews Gains and Risks of Accelerated Approval Process

Is FDA approving too many new drugs and added indications too quickly based on surrogate endpoints that fail to pan out? While patient advocates and the research community have been strong backers of early access to treatments that demonstrate potential effectiveness for serious and life-threatening conditions that lack effective treatment, some consumer advocates and research experts believe that FDA has been lax in approving medicines with insufficient supporting data.

Now the agency is reviewing the record of its accelerated approval (AA) program following the recent withdrawals of certain key indications for several leading cancer therapies based on the failure of postapproval studies to document extended benefits of treatment. That development has raised questions about the broader FDA policy, including frequent difficulties in conducting postapproval clinical trails and the relatively few therapies that have had approvals withdrawn by the agency.

These issues will be reviewed by FDA’s Oncologic Drugs Advisory Committee (ODAC) at a three-day meeting on April 27–29, 2021, a notably long session to discuss several supplemental biologics license applications (sBLAs) where confirmatory trials failed to verify clinical benefit. The experts will assess advanced cancer indications for Roche/Genentech’s TECENTRIQ (atezolizumab), Merck’s KEYTRUDA (pembrolizumab), and Bristol Myers Squibb’s (BMS) OPDIVO (nivolumab). Since December 2020, these sponsors voluntarily withdraw these immunotherapies for certain indications based on failure to meet primary endpoints in confirmatory trials, as did AstraZeneca for use of IMFINZI (durvalumab) to treat advanced bladder cancer.

These monoclonal antibodies target PD-1/PD-L1 proteins to boost immune response against cancer, raising questions about the broader efficacy of such treatment. The confirmatory studies aimed to document overall improved survival compared to standard-of-care chemotherapy, after gaining accelerated approval based on tumor response in early studies. The ODAC meeting will examine the status of efforts by Genentech, Merck, and BMS to confirm additional indications for their therapies, and, in the process, will scrutinize the AA program more publicly for a range of cancer types.

The meeting is part of a broad, ongoing effort by FDA’s Oncology Center of Excellence (OCE) to review AA policies and the role of surrogate endpoints in evaluating new therapies. Sponsors are anxious to know whether the agency is focusing on this small subset of treatments or on the use of surrogate endpoints and other accelerated research strategies more broadly. Over its 30-year history, FDA’s AA program has led to speedy approvals of dozens of products, primarily for oncology and hematology in recent years. Although FDA may withdraw an accelerated approval for a product, the manufacturers did so voluntarily in the above cases, and for some dozen other therapies in previous years. There are only two cases where the agency initiated a withdrawal, following a complex and time-consuming process.

OCE’s review is expected to tap a white paper issued by the Friends of Cancer Research (FOCR) at its annual meeting in November 2020 that outlines ways to update the AA policy to provide FDA with greater flexibility in both approving and in withdrawing approvals of innovative drugs. Prepared by a multi-stakeholder working group, the report emphasizes the importance to patients of early access to new treatments, the benefits and risks of utilizing surrogate endpoints to streamline research, and challenges in conducting post-approval studies to confirm early evidence. There is discussion of differences and similarities between FDA’s policy and the European Medicines Agency’s conditional marketing authorization policy, particularly related to market withdrawal actions. The panel recommends added flexibility in policies governing AA approval decisions, including the role and design of confirmatory trials and expanded use of real-world evidence to better confirm benefits and risks with broader use of a medicine. Such approaches aim to assist FDA in understanding factors that contribute to failed confirmatory studies and the need for a more efficient process for making withdrawal decisions.

The ODAC meeting will provide an opportunity for sponsors to provide updates on ongoing studies for their therapies and to examine whether further testing could revise the withdrawal actions. A long-debated issue is industry’s poor record in conducting and reporting results from postapproval studies, and FDA appears to be taking a harder line on requiring confirmatory trials to support clinical benefit.