FDA officials look outward to improve the expedited drug approval process

Regulatory NewsRegulatory News | 31 January 2022 |  By 

International regulators take a variety of approaches to expedited drug approvals, according to a new opinion piece from leading US Food and Drug Administration (FDA) officials. Many health authorities take a time-limited approach to granting expedited approvals, while others limit these programs to new molecular entities, according to Gautam Mehta of FDA’s Center for Drug Evaluation and Research (CDER) and FDA coauthors.
“The expiry periods for conditional and provision approval programs place the onus of timely completion of confirmatory trials and verification of benefit on the applicant” in several of the regions studied, including the EU, the UK, Switzerland and Australia. Metha and colleagues note that in other regions including the US, the health authority has the burden of initiating “a resource-intensive withdrawal process.”
Some flexibility probably should be baked into a time-limited expedited approval system to account for unforeseen and indication-specific issues with confirmatory trials, according to the authors. “Overall, these time-limited approaches may limit public exposure to stale claims of effectiveness that cannot be expeditiously substantiated.”
Mehta, a clinical reviewer at CDER, authored the Viewpoint in JAMA Oncology together with Richard Pazdur, director of FDA Oncology Center of Excellence, and R. Angelo de Claro, the center’s associate director for global clinical sciences.
Pazdur has previously written about FDA’s accelerated approval process. In a 2021 NEJM Perspective, Pazdur and Julia Beaver, chief medical officer at the oncology center of excellence, highlighted an FDA review of accelerated approvals for 35 oncology indications for anti-programmed death ligand 1 antibodies. The agency’s review found that for 10 of these indications, “the required trials did not end up confirming benefit and yet their marketing authorization continued.” (RELATED: Pazdur: Oncology accelerated approvals under review by ODAC, Regulatory Focus 26 April 2021.)
In a 3-day hearing in April 2021, the FDA Oncologic Drugs Advisory Committee (ODAC) reviewed six of these indications that remained after sponsors voluntarily withdrew four. The committee recommended that two indications be withdrawn, but not before Pazdur joined the committee’s discussion as an active participant, pressing an industry representative and offering clarifications to the committee on how to factor postmarketing study results into their recommendations on accelerated approvals (RELATED: ODAC recommends pulling 2 of 6 accelerated approvals, Regulatory Focus 30 April 2021).
Mehta and coauthors also laid out in a table the similarities and differences of the seven expedited approval pathways they examined, showing which applications are eligible and whether approvals sunset without sponsor reapplication.
Health authorities also differ in postmarketing requirements, with the US requiring a confirmatory trial that “verifies the clinical benefit in the same or a related population,” according to the chart. By contrast, EMA requires that “specific obligations” are met in order to confirm a positive benefit-risk balance, with MHRA following EMA. Health authorities in Japan and Australia each also require confirmatory trials that show efficacy and safety; Health Canada requires confirmatory trials, but also requires annual progress reports and specified postmarket surveillance.
The US requires that postmarketing studies to confirm clinical benefit for a drug marketed under an accelerated approval based on a surrogate endpoint. However, this requirement and subsequent actions don’t always happen expeditiously, note Mehta and coauthors. “In a recent analysis, the median time to verification of benefit was 3.4 years, whereas withdrawal took 8.8 years.” When a confirmatory trial was already underway at the time of accelerated approval, verification of benefit took place over two years earlier than when no such trial was underway (3.1 vs 5.5 years).
The FDA officials call for more harmonization between the US and global regulators, as is occurring in coordination around Project Orbis. “Future discussions of the accelerated approval program in the US can continue to build harmony between these agencies and strengthen this approval pathway” through examining differences and sharing innovations, they wrote.
JAMA Oncology Viewpoint


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