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FDA Panel Recommends Stricter Process for Accelerated Approval of Cancer Drugs

TOP - March/April 2011, VOL 4, NO 2 published on April 28, 2011 in In the News

The US Food and Drug Ad ministration (FDA) held a public meeting in February to assess whether stricter criteria are needed when considering oncology drugs for accelerated approval. Measures enacted in 1992 allow the FDA to grant accelerated approval for drugs targeted at unmet needs in cancer based solely on data from single-arm studies and relying on end points other than the standard metric of overall survival. At the meeting, experts with the FDA’s Oncologic Drugs Advisory Committee (ODAC) criticized the FDA, with Silvana Martino, DO, who directs the Breast Cancer Program at the Angeles Clinic and Research Institute in Santa Monica, California, calling its actions “ignorant.”

Gary Lyman, MD, MPH, professor of medicine and director of comparative effectiveness and outcomes research at Duke University School of Medicine and the Duke Comprehensive Cancer Center in Durham, North Carolina, sat on the ODAC panel and discussed the hearing with The Oncology Nurse- APN/PA. “The major concern of the ODAC is that accelerated approval has been granted on the basis of a single-arm study in more than half of instances, which limits a full comparative look at efficacy and safety,” he explained.

Lyman said relying on such limited evidence might be appropriate in exceptional cases, such as for drugs to treat rare tumors or when a drug has very strong, observable treatment effects, but “the default recommendation is that this conditional approval be based on at least one well-designed randomized, controlled trial [RCT] reporting significant improvement in an outcome measurement likely to convey clinically meaningful benefit.” In every case, approval should be “based on the robustness of the results in terms of a strong treatment effect and a very favorable risk-to-benefit ratio,” said Lyman.

On the rare occasions when accelerated approval is granted without data from an RCT, Lyman said ODAC recommends that the FDA require the drug’s maker to have an RCT under way or imminent. The FDA should review plans for the trial to ensure that its design allows for reliable results, suitable to support licensing approval.

The review of the accelerated approval process was prompted by the FDA’s controversial decision in December to withdraw approval of bevacizumab (Avastin) in breast cancer, which Lyman said was the first time the agency had rescinded an approved indication of a drug brought to market under this mechanism. “There are a number of others—including 6 that we reviewed yesterday—that have not fulfilled their postmarketing requirements and may be vulnerable,” he added. The drugs in question include Erbitux by Eli Lilly, Bexxar and Arranon by GlaxoSmithKline, Clolar by Genzyme, Vectibix by Amgen, and Gleevec by Novartis for its indication in gastrointestinal stromal tumors.

At the meeting, the panel questioned manufacturers about their failure to submit requisite follow-up data for these 6 drugs, but the FDA gave no indication that their approval status is in jeopardy. Most of the manufacturers cited difficulty recruiting enough patients for clinical trials to produce meaningful results as the primary reason for the delays. Amgen’s representative told the committee the company was confident it had complied with the FDA requirements.

Whereas most companies that receive accelerated approval for a drug show due diligence in complying with follow-up requirements, Lyman said a few have taken a decade or longer to submit the requested data. “The ODAC members [believe] that plans for more frequent updates—perhaps annually—of studies with outstanding validation or postmarketing requirements would help shorten the time interval to completion and consideration for full approval.”

Members of the ODAC panel also voiced concern that the FDA had occasionally granted full approval to a cancer drug without requiring solid data from an RCT. “The ODAC believes that, with few exceptions, such approval should be based on at least 2 well-done RCTs with consistent or robust results,” said Lyman.

Lyman acknowledged that patients with cancer and advocacy groups have complained in the past that strict standards delay access to lifesaving medications. “It will be important that no unnecessary delays occur,” he said. If drug companies are pushed to fulfill their postmarketing requirements more promptly, Lyman said he expects it to shorten the time to full approval and decrease how long an ineffective or unsafe drug remains on the market.

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Last modified: July 22, 2021