Delays in sponsors providing post-approval evidence of effectiveness for therapies benefitting from streamlined FDA regulatory pathways, along with high launch prices on many of these quasi-experimental medicines, is generating pressure for further review and reform of the agency’s accelerated approval (AA) process. FDA reports that only about half of AA products have completed research to confirm benefits, including many leading oncology treatments carrying “dangling” indications. The agency’s approval of Biogen’s Aduhelm Alzheimer’s treatment last year based on questionable surrogate endpoint data, moreover, has heightened calls among legislators and researchers for tightening study timeframes and clarifying program requirements.
Deliberations by FDA’s Oncologic Drugs Advisory Committee (ODAC) accelerated the debate with its April 2021 meeting to assess the lack of confirmatory evidence for added uses of several leading cancer therapies. Since then, members of Congress, officials at FDA and other federal health agencies, sponsors and research organizations have weighed in on both the benefits in facilitating early patient access to effective treatments, along with the need to reform the process and timeframes for fully evaluating early evidence of effectiveness. Since then, several biopharma companies have withdrawn certain uses for therapies unable to provide that confirmatory data. Most recently, Gilead Sciences pulled two indications for the cancer drug Zydelig, acknowledging difficulties in providing evidence to support those uses since approval in 2014.1
Now AA revision tops FDA policy reform lists. While sponsors often experience difficulties enrolling patients in clinical trials once a therapy is available on the market, weak FDA penalties for delay, as well as incentives for a firm to provide an approved therapy for as long as possible, contribute to perennial delays in submitting follow-on results. The need for better systems to generate reliable information on medical product safety and effectiveness was cited as a top priority by Robert Califf at his Senate confirmation hearingin December, and he is expected to tap his expertise on providing timely and valid clinical research data in addressing these issues. The discussion is slated to involve appropriate use of real-world data (RWD) to support post-approval studies, as well as requirements for sponsors to design and launch confirmatory trials at the time of application approval, an approach that has become a regular discussion point in FDA-sponsor preapproval meetings.
Also up for debate are proposals to penalize sponsors for excessive delay in launching and conducting these studies and for the Centers for Medicare and Medicaid Services (CMS) to limit Medicare reimbursement of a drug until the manufacturer confirms early indications. While such requirements raise concerns about discouraging investment in innovative R&D, additional public-private collaborations could expand the infrastructure and lower the cost of conducting post-approval studies. And wider acceptance of RWD in confirmatory studies would be particularly helpful for small biotech companies that lack resources to prepare for or conduct post-approval studies before gaining initial market approval. These and other issues were discussed by Califf at others at a January conference organized by the UCSF-Stanford Center of Excellence in Regulatory Science and Innovation (CERSI).2
The current debate builds on considerable discussion of the AA program in recent years. Richard Pazdur, director of FDA’s Oncology Center of Excellence (OCE), has provided strong support for breakthrough and other accelerated development and review programs for cancer drugs, along with proposals for improvement: OCE’s Project Confirm seeks better compliance with post marketing requirements for oncology therapies benefitting from accelerated program.3 A white paper from the Institute for Clinical and Economic Review (ICER) in April 2021 presents proposals for revising and strengthening the AA process.4 And a broader reform proposal prepared in 2020 by the Friends of Cancer Research (FOCR) set the stage for identifying ways to maintain early access by addressing AA concerns.5
Additional information on FDA’s accelerated approval process is available6, as well asa useful summary of the agency’s four similar, but different, programs to facilitate patient access to new medicines.7