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Avastin saga reveals debate over clinical trial endpoints.

Bevacizumab (Avastin), once the world’s best-selling cancer drug, could also be the most controversial in breast cancer history. The controversy surrounding its fast-track approval for metastatic breast cancer and later removal from the market sparked much debate among medical communities, patient advocates, and regulators. The debate exposed deep rifts in the global oncology comm unity about the appropriate endpoints for a drug to stay on the market. Avastin is a monoclonal antibody against circulating vascular endothelial growth factor. U.S. Food and Drug Administration approval of the drug was based on E2100 trial results showing a 5.5-month increase in progression-free survival (PFS) in metastatic breast cancer patients taking either paclitaxel with Avastin or paclitaxel alone. The Avastin group showed no overall survival (OS) benefit. The FDA’s move relied on PFS instead of OS. However, two additional trials submitted to the FDA in July 2010—AVADO and RIBBON-1—failed to live up to E2100’s results and showed a high incidence of side effects, which prompted the FDA to rescind Avastin’s approval for metastatic disease. On Dec. 16, 2010—the same day the FDA decided to revoke Avastin’s approval for metastatic breast cancer—the European Medical Agency reaffirmed its approval of the drug for the same indication. The agency concluded that Avastin with paclitaxel remained a valuable treatment option for metastatic disease, deeming improvement in PFS clinically meaningful. The rift highlights the contention to which usage of surrogate endpoints—rather than the standard health outcome OS— has given rise. According to Simone Mathoulin-Pélissier, M.D., head of the cancer trial unit from Bordeaux University in France, “Clinical trials are such globalized endeavors that the use of endpoints does not vary across continents. However, how research is interpreted and the impact that it has differs from one country to another based on health care organization and political and economic priorities.” To harmonize the discussion, coordinators developed an international project based in Europe, called DATECAN, to define endpoints in clinical trials. Mathoulin-Pélissier is one of the investigators. “DATECAN will be the first to provide standardized definitions of appropriate endpoints for several localizations in each setting (in particular for breast and pancreatic cancer and sarcoma), using a method of explicit consensus,” she explained.