ODAC Advises Changes to Clinical Study Designs for First-Line Hormonal Treatments of Metastatic Breast Cancer

BETHESDA, Maryland—Members of the Oncologic Drugs Advisory Committee (ODAC) have recommended a change in the endpoint the Food and Drug Administration (FDA) uses to evaluate hormonal agents as first-line therapy for metastatic breast cancer. The panel considered the issue of revising the design of hormonal therapy clinical trials at the agency’s request.

A key ODAC recommendation, made by a 10-to-3 vote, was that in making drug-approval decisions, FDA should replace response rate, its long-time endpoint for anticancer hormonal agents in the first-line setting, with time to tumor progression.

FDA has accepted response rate as an endpoint since 1976, when it approved the first hormonal anticancer agent, megestrol acetate (Megace), as a palliative treatment for advanced breast cancer. One year later, FDA cleared tamoxifen (Nolvadex) for marketing, again relying on response rate findings.

For more than 2 decades, FDA has evaluated breast cancer hormonal agents on whether they were noninferior (no worse than) or superior to an approved drug, usually tamoxifen, used as a comparison.

Generally, FDA has interpreted non-inferiority to mean ruling out that a new drug has a response rate that is 10% lower than the comparison agent. Since 1995, FDA has approved toremifene (Fareston), anastrozole (Arimidex), and letrozole (Femara) using this standard for evaluation. The agency has required sponsors to submit data on survival and time to progression as secondary endpoints.

During a half day of deliberations, ODAC members also:

• Voted 12 to 1 that non-inferiority to tamoxifen no longer be considered an acceptable basis for approval. If tamoxifen is the comparator, demonstration of superiority should be required.

• Voted 10 to 3 against designation of a single approved drug as the only acceptable comparator in future clinical trials. FDA noted that choice of a comparator will determine whether superiority or non-inferiority is an appropriate trial design and analysis.

• Advised FDA 9 to 4 that data do not suggest that one class of hormonal agents is clearly superior to another.

In urging a switch from response rate to a time-to-progression endpoint in trials of hormonal agents, ODAC members noted that large numbers of patients would be needed to adequately measure noninferiority using the new standard, but that patients with bone-only disease could be included. Also, the endpoint of time to progression could reflect the potential benefit of prolonged stable disease, the panel said.

"Clinical trials of hormonal agents in breast cancer should restrict patient eligibility only to those patients with demonstrated hormone-receptor-positive status rather than also including those with hormone-receptor-unknown status," stated Richard Pazdur, MD, director of the FDA’s Division of Oncology Drug Products, Center for Drug Evaluation and Research. "This more uniform patient population reflects patients who will receive hormonal therapy in the United States."

Dr. Pazdur noted that this discussion confirmed a prior ODAC discussion in December 2000 regarding patient eligibility.