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The FDA will conduct an unprecedented public review of accelerated approval for oncology-drug indications left "dangling" for lack of confirmatory evidence to support benefits observed in earlier studies.

Beginning at 1 p.m. ET on Tuesday and continuing through Thursday, the FDA Oncologic Drugs Advisory Committee (ODAC) will hear evidence supporting a total of six indications for three different immune checkpoint inhibitors: nivolumab (Opdivo), pembrolizumab (Keytruda), and atezolizumab (Tecentriq). The three-day review pertains to indications in breast, urothelial, gastric, and hepatocellular cancers.

After hearing presentations from FDA staff and the sponsors for the three drugs, the panel will vote whether to recommend for or against continued approval of each indication and whether additional studies should be conducted. Other approved indications for the drugs will not be affected by the ODAC recommendations nor will pending applications for other indications. The FDA is not bound by advisory committee decisions but follows the committees' advice in most cases.

The last time the FDA revoked an accelerated approval was almost 10 years ago, when the agency withdrew approval of bevacizumab (Avastin) for breast cancer. In 2019, Eli Lilly from the market after the drug failed a confirmatory trial in soft-tissue sarcoma.

The FDA grants accelerated approval with a requirement for additional studies to confirm a drug's safety and efficacy for a specific indication. If the additional data fail to confirm a drug's benefit, the FDA has the authority to revoke approval for the indication, said Richard Pazdur, MD, of the FDA's Oncology Center of Excellence (OCE), in an of the ODAC meeting.

"We are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible," said Pazdur. "The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies. However, when confirmatory trials do not confirm clinical benefit, a reevaluation must be performed to determine if the approval should be withdrawn."

On Tuesday ODAC will consider atezolizumab's accelerated approval for use in combination with nab-paclitaxel (Abraxane) to treat advanced triple-negative breast cancer. Wednesday the panel will hear evidence for separate approvals in urothelial cancer for atezolizumab and pembrolizumab. Thursday ODAC will consider accelerated approvals in hepatocellular cancer for pembrolizumab and nivolumab and in advanced gastric/gastroesophageal junction cancer for pembrolizumab.

The six indications were among 10 "dangling" approvals that maintained market approval despite follow-up clinical trials' failure to confirm the drugs' benefits for the indications, said Pazdur and Julia A. Beaver, MD, also of the OCE, in a perspective article published last week in the . The status of the other four accelerated approvals was resolved when the drug sponsors voluntarily withdrew the indications: nivolumab and pembrolizumab for metastatic small cell lung cancer, durvalumab (Imfinzi) for advanced urothelial cancer, and atezolizumab for a separate indication in advanced urothelial cancer.

Originally created in 1992 to speed up availability of drugs for HIV, the accelerated approval program has been dominated by oncology in recent years, Pazdur and Beaver noted. In the past 10 years, 85% of accelerated approvals involved cancer drugs. The program helped make anti-PD-1/L1 checkpoint inhibitors the most rapidly developed therapeutic class in history, as almost half of the first 76 approvals for the drugs were accelerated. Overall, more than 150 accelerated approvals have been granted to oncology drugs.

Since the accelerated approval program's inception, 6% of accelerated approvals in oncology have been withdrawn.

"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 severe or life-threatening diseases," Pazdur and Beaver concluded.

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