With no permanent commissioner, the U.S. Food and Drug Administration appears to be both cracking down on Accelerated Approvals while struggling with a backlog of inspections.
With no permanent commissioner, the U.S. Food and Drug Administration (FDA) appears to be both cracking down on Accelerated Approvals while struggling with a backlog of inspections. Here’s a look.
6 Former FDA Commissioners Urge Biden to Nominate Permanent Agency Head
The Biden Administration has yet to nominate a permanent commissioner to head the FDA. Currently the interim commissioner is Janet Woodcock, a 36-year-veteran of the agency, who many in the industry think should be made permanent commissioner.
Six former FDA commissioners, Scott Gottlieb, Robert Califf, Mark McClellan, Margaret Hamburg, Jane Henney and Andrew von Escehenbach, signed a joint letter urging the president to nominate someone soon.
“We urge you to prioritize securing its leadership team, including through seeking the formal nomination and confirmation of an FDA Commissioner,” they wrote. “The agency’s experienced staff and its science-based regulatory processes will play a critical role in helping the nation confront the evolving pandemic.”
Although not specifically endorsing a candidate, they did praise Woodcock, noting they have all worked with her and that she is “a highly effective advocate for advancing the FDA’s mission—a role she has continued from her first day as Acting Commissioner.”
GAO Expresses Concerns over FDA Inspection Backlog
The FDA’s inspection programs have long been of concern to the Government Accountability Office (GAO). Now, a year after the agency halted most of its foreign and domestic inspections because of the pandemic, the GAO expressed urgency over how long it will take to catch up. The GAO issued a new report and testified before the House Appropriations Subcommittee on Agriculture, Rural Development, Food and Drug Administration, and Related Agencies. They said the FDA needs to issue a plan to address the backlog and other longstanding issues.
Since the shutdown, the FDA has partially depended upon alternative tools, such as inspection reports from foreign regulators, records requests, and product sampling. Some of its inspections have been resumed on a limited basis.
“While these tools can provide useful information, most do not substitute for an inspection, and FDA will face a backlog as it was unable to complete more than 1,000 of its planned inspections for FY 2020,” said Mary Denigan-Macauley, GAO Health Care Director.
FDA Cracks Down on Accelerated Approvals
The FDA is running an industry-wide evaluation of its accelerated approvals with a focus on determining which have not met post-marketing requirements. For example, AstraZeneca recently announced it was withdrawing its checkpoint inhibitor Imfinzi in bladder cancer after failing to confirm earlier results.
The Imfinzi accelerated approval was for advanced bladder cancer with high PD-1 levels or in patients regardless of PD-1 status, and was to be confirmed by the DANUBE trial, but failed to meet the overall survival endpoints compared to standard of care.
For patients with extensive stage small cell lung cancer, Imfinzi is approved as a first line treatment, based on OS data from the Phase III CASPIAN clinical trial.
On March 1, Merck announced it had voluntarily withdrawn the U.S. indication for Keytruda for metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other previous line of therapy. The company notes that this decision has no effect on other indications for Keytruda.
The checkpoint inhibitor received accelerated approval for this indication in June 2019 based on tumor response rate and durability of response data from KEYNOTE-158 (cohort G) and KEYNOTE-028 (cohort C1). The deal with the FDA was that the approval was contingent on completing a post-marketing evaluation proving Keytruda was superior to other products in extending overall survival (OS).
On January 2020, KEYNOTE-604, the confirmatory Phase III trial, hit one of the dual primary endpoints, progression-free survival (PFS), but didn’t reach statistical significance for the other primary endpoint of OS.
“The accelerated pathways created by the FDA have been integral to the remarkable progress in oncology care over the past five years and have helped many cancer patients with advanced disease, including small cell lung cancer, access new treatments,” said Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “Keytruda remains a foundational treatment for certain patients with metastatic non-small cell lung cancer. We will continue to rigorously evaluate the benefits of Keytruda in small cell lung cancer and other types of cancer, in pursuit of Merck’s mission to save and improve lives.”
And on March 8, Roche pulled its checkpoint inhibitor Tecentriq (atezolizumab) for metastatic urothelial carcinoma (mUC) in patients previously treated with platinum-based therapies. The drug failed to meet endpoints in confirmatory trials. It was granted accelerated approval in 2016 based on data from a cohort in the IMvigor210 study.
