FDA calls in adcomm to review six more oncology accelerated approvals
Regulatory News | 11 March 2021 |
After drugmakers voluntarily withdrew four indications for their cancer drugs in recent months, the US Food and Drug Administration (FDA) on Thursday said it would convene an advisory committee to review six more oncology indications with accelerated approval after confirmatory trials failed to verify their clinical benefit.
Over the course of three days in April, FDA’s Oncology Drugs Advisory Committee (ODAC) will review six indications for Roche’s Tecentriq (atezolizumab), Merck’s Keytruda (pembrolizumab) and Bristol Myers Squibb’s Opdivo (nivolumab) in breast, urothelial, gastric and hepatocellular cancers. The committee will receive updates on the results of the confirmatory trials and the status of any ongoing or planned trials for each indication and will be tasked with making recommendations on whether the indications should remain approved while additional trials are conducted.
All three of the drugs were among the four that recently had indications voluntarily withdrawn by their manufacturers. The withdrawals and review of the six additional indications are part of an industry-wide review of oncology accelerated approvals that marks a shift in FDA’s oversight of accelerated approvals. (RELATED: Industry-wide accelerated approval review yields four withdrawals, Regulatory Focus 10 March 2021).
"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. 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trials do not confirm clinical benefit, a reevaluation must be performed to determine if the approval should be withdrawn,” said Richard Pazdur, MD, director of FDA’s Oncology Center of Excellence.
Pazdur added that the meeting will give outside experts and patients a chance to provide input to the agency on how it should proceed with each indication.
FDA said that including the four recent withdrawals, only 6% of accelerated approvals for oncology indications have been withdrawn. However, the agency has faced criticism in the past for allowing drugs with accelerated approval to remain on the market after failing to verify clinical benefit and for its lax oversight of postmarketing requirements.
“One of the major concerns about the implementation of the accelerated approval program over the last few years has been when accelerated approval drugs had so-called ‘confirmatory’ trials performed after approval and those studies were negative or showed no change in meaningful clinical endpoints, and no actions were taken on the drug,” said Aaron Kesselheim, director of Harvard Medical School and Brigham & Women’s Hospital’s Program on Regulation, Therapeutics and Law (PORTAL).
Kesselheim also pointed out that confirmatory trails for accelerated approvals often take several years to complete and many continue to use surrogate endpoints, in some cases the same surrogate endpoints that the accelerated approval was based on.
But Kesselheim said it is “reassuring to hear that the FDA and drug manufacturers are returning to the original intent of the accelerated approval program and taking these kinds of actions, because otherwise physicians and patients may be misled into using drugs that haven’t proven to work, pose risks for adverse events, and invariably cost a lot of money.”
Federal Register Notice
Over the course of three days in April, FDA’s Oncology Drugs Advisory Committee (ODAC) will review six indications for Roche’s Tecentriq (atezolizumab), Merck’s Keytruda (pembrolizumab) and Bristol Myers Squibb’s Opdivo (nivolumab) in breast, urothelial, gastric and hepatocellular cancers. The committee will receive updates on the results of the confirmatory trials and the status of any ongoing or planned trials for each indication and will be tasked with making recommendations on whether the indications should remain approved while additional trials are conducted.
All three of the drugs were among the four that recently had indications voluntarily withdrawn by their manufacturers. The withdrawals and review of the six additional indications are part of an industry-wide review of oncology accelerated approvals that marks a shift in FDA’s oversight of accelerated approvals. (RELATED: Industry-wide accelerated approval review yields four withdrawals, Regulatory Focus 10 March 2021).
"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. 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,” said Richard Pazdur, MD, director of FDA’s Oncology Center of Excellence.
Pazdur added that the meeting will give outside experts and patients a chance to provide input to the agency on how it should proceed with each indication.
FDA said that including the four recent withdrawals, only 6% of accelerated approvals for oncology indications have been withdrawn. However, the agency has faced criticism in the past for allowing drugs with accelerated approval to remain on the market after failing to verify clinical benefit and for its lax oversight of postmarketing requirements.
“One of the major concerns about the implementation of the accelerated approval program over the last few years has been when accelerated approval drugs had so-called ‘confirmatory’ trials performed after approval and those studies were negative or showed no change in meaningful clinical endpoints, and no actions were taken on the drug,” said Aaron Kesselheim, director of Harvard Medical School and Brigham & Women’s Hospital’s Program on Regulation, Therapeutics and Law (PORTAL).
Kesselheim also pointed out that confirmatory trails for accelerated approvals often take several years to complete and many continue to use surrogate endpoints, in some cases the same surrogate endpoints that the accelerated approval was based on.
But Kesselheim said it is “reassuring to hear that the FDA and drug manufacturers are returning to the original intent of the accelerated approval program and taking these kinds of actions, because otherwise physicians and patients may be misled into using drugs that haven’t proven to work, pose risks for adverse events, and invariably cost a lot of money.”
| Accelerated approval indications under review at the 27-29 April ODAC meeting | |||
| Company/product | Indication | Accelerated approval | Confirmatory trial(s) |
| Tecentriq (atezolizumab) | PD-L1 positive unresectable locally advanced or metastatic triple-negative breast cancer. | 8 March 2019 | IMpassion131 |
| Tecentriq (atezolizumab) |
Treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin chemotherapy. | 18 April 2017 | IMvigor211 IMvigor130 |
| Keytruda (pembrolizumab) | Treatment of patients with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy. | 18 May 2017 | KEYNOTE-361 |
| Keytruda (pembrolizumab) | Treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. | 22 September 2017 | Keynote-061 Keynote-062 |
| Keytruda (pembrolizumab) | Treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib. | 9 November 2018 | KEYNOTE-240 LEAP-002 |
| Opdivo (nivolumab) | Treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib. | 22 September 2017 | CheckMate -459 |
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