In response to continued criticism of FDA’s initiative to make promising new therapies available to seriously ill patients based on early clinical results, the agency’s leading cancer expert lashed out at the alarmists and urged continued support for this early access process. A comprehensive review of FDA’s accelerated approval program reveals that it has brought many important treatments to patients years before the completion of confirmatory studies, and that relatively few such products have been removed from the market post approval, asserted Richard Pazdur, director of FDA’s Oncology Center of Excellence (OCE). The current attack on accelerated approvals misses “the broader gains of the program,” he stated in a discussion sponsored by Friends of Cancer Research (FOCR), an advocate for the program early on.1
Instead of attacking the program, we need to address “what’s going right” with it, Pazdur said. “We need to look at the big picture of what this initiative has provided for us.” He cited 165 accelerated approvals over the last ten years, with only about 10 therapies removed from the market.2 “If you just look at the problems, you miss the broad gains” of the process, he commented, which is apparent in early patient access to multiple new drugs for deadly cancers, many addressing serious unmet medical needs.
Ned Sharpless, director of the National Cancer Institute (NCI) and former FDA acting commissioner, agreed that the accelerated approval program “has been transformative” in bringing new cancer therapies to patients that previously were blocked by regulatory hurdles. He attributed reductions in cancer deaths to expedited reviews, particularly of new treatments for lung cancer.
Pazdur further explained that a failed postapproval trial for an innovative product “does not necessarily mean a failed drug.” More likely is that the study suffered from poor trial design, selection of the wrong patient population, or inappropriate study endpoints. Some drugs fail in confirmatory studies, he added, which also often is due to how the trial is designed. He noted that many critics of the program consider overall survival the only valid endpoint, but cited alternatives such as tumor reduction or delay in disease progression as appropriate.
While an initial approval of a new cancer drug may not be based on optimal results, the aim, Pazdur explained, is to get the drugs out to see how to use them in new combinations and for different procedures. The risk of ignoring the program’s benefits, he added, is the creation of a more orthodox regulatory approach that ignores the needs of patients.
These experts participating in the FOCR program were responding to a growing attack on FDA’s accelerated approval program, which has heated up since FDA utilized the process to authorize marketing of Biogen’s Alzheimer’s treatment, Aduhelm. The drug was rejected for approval by an FDA advisory committee in November 2020, and the agency’s decision to grant conditional approval in June 2021 prompted many experts on that committee to challenge the agency’s action.3
“Sure we can improve the program,” Pazdur said. He noted difficulties in removing a drug from market when it doesn’t meet primary endpoints, but added that such issues can be best addressed in early discussions with sponsors on the goals of accelerated studies and plans for conducting confirmatory trials.
At the same time, FDA has increased scrutiny of immunotherapies and other drugs awarded accelerated approval based on preliminary data, but that fail to document initial results in confirmatory studies. Last April (2021) FDA’s Oncology Drugs Advisory Committee spent three days examining the merits of six indications for three leading immunotherapies where postapproval studies had failed to support initial authorization. The panel voted to reject two approvals, prompting Bristol Myers Squibb to withdraw the use of Opdivo to treat liver cancer4 and Merck has said it will pull the gastric cancer indication for its leading drug Keytruda.5