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Posted 26 April 2021 | By Kari Oakes 

Pazdur: Oncology accelerated approvals under review by ODAC

3179 On 27 April, the US Food and Drug Administration’s Oncology Drugs Advisory Committee (ODAC) meets to consider the fate of a half-dozen oncology immunotherapy indications granted accelerated approval. The confirmatory trials of these drugs have not verified their clinical benefit in the indications for which they received approval.
The virtual meeting will take stock of the indications individually; committee members will engage in a “general discussion focused on next steps for each product including whether the indications should remain on the market while additional trial(s) are conducted,” according to FDA’s meeting announcement.
The head of FDA’s Oncology Center of Excellence (OCE), Richard Pazdur, MD, together with OCE colleague Julia A. Beaver, MD, provided perspective in advance of the advisory committee meeting.
Writing in the New England Journal of Medicine, Beaver and Pazdur made the point that nearly half of the first 76 approvals for antibodies against programmed death 1 (PD-1) or programmed death ligand-1 (PD-L1) were made under the accelerated pathway. Required post-approval trials of these six checkpoint inhibitors did not confirm benefit for ten of the indications for which they received accelerated approval, but marketing authorizations were not withdrawn.
Pazdur and Beaver noted that these “dangling” approvals have been the subject on ongoing discussions between sponsors and OCE. Four indications were recently withdrawn voluntarily by sponsors, while the remaining six make up the slate of agenda items for the upcoming ODAC meeting. (RELATED: FDA calls in adcomm to review six more oncology accelerated approvals, Regulatory Focus 11 March 2021)
“The FDA sees these discussions as an essential step, since the fact that a clinical trial did not meet its end points does not necessarily mean that the drug is ineffective,” wrote the officials. A number of factors -- statistical testing and power problems, biomarker or participation issues, trial design and others – can affect whether a trial meets its primary endpoints.
If an endpoint is not met but there is still unmet medical need, “FDA works with sponsors to identify subsequent clinical trials that could satisfy the accelerated approval requirement,” wrote Beaver and Pazdur. However, the treatment landscape has changed since the first raft of accelerated approvals, meaning that the degree of unmet clinical need for some of the drugs and indications will be considered against a different yardstick than when their first marketing authorizations were issued.
Many of the original approvals under evaluation were granted on the strength of non-randomized, single-arm trials using surrogate endpoints. Though some other oncology drug classes have seen positive early trials results confirmed by benefits in such robust endpoints as overall survival, this has not always been the case for checkpoint inhibitors, noted the FDA officials.
Previously withdrawn were Genentech’s Tecentriq (atezolizumab) and AstraZeneca’s Imfinzi (durvalumab) for certain patients with locally advanced or metastatic urothelial carcinoma; Bristol-Myers Squibb’s Opdivo (nivolumab) and MSD’s Keytruda (pembrolizumab) were also voluntarily withdrawn for some patients with metastatic small-cell lung cancer.
Later this week ODAC members will consider atezolizumab for a slightly different population of patients with metastatic urothelial carcinoma and for those with unresectable or metastatic triple-negative breast cancer if their tumors express PD-L1. Nivolumab is up for review for hepatocellular carcinoma in patients previously treated with sorafenib; pembrolizumab is being considered by ODAC for that same indication, and for specific urothelial carcinoma and gastric/gastroesophageal junction adenocarcinoma indications.
Setting the ODAC agenda in context, Pazdur and Beaver made clear that they do not expect the meeting to be a tribunal on the merits of accelerated approval: “The small percentage of drugs whose clinical benefit is ultimately not confirmed should be viewed not as a failure of accelerated approval but rather as an expected trade-off in expediting drug development that benefits patients with sever or life-threatening diseases,” they wrote.
New England Journal of Medicine


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