A Matter of Endpoint
Despite an advisory panel’s 5–4 recommendation against the drug, FDA conditionally approved Avastin for MBC, citing Genentech’s E2100 study. It showed a 5.5-month increase in progression free survival (PFS) from 5.8 to 11.3 months. Last December, however, FDA began efforts to withdraw the MBC indication in line with a CDER recommendation.
CDER cited four studies of Avastin for MBC. The most favorable study showed patients with MBC living just 2.9 additional months after using Avastin. The other studies showed 2.9 months of PFS with Avastin plus capecitabine (RIBBON1 trial), 1.2 months of PFS with Avastin plus taxane/anthracycline chemotherapy (RIBBON1 trial), and 0.9 months of PFS with docetaxel (AVADO trial).
“To confirm the benefit to patients required for an accelerated approval, CDER expected to see a magnitude of benefit similar to the 5.5 month improvement in progression-free survival seen in E2100 or other real clinical benefit, such as improvement in quality of life or overall survival benefit,” a CDER spokeswoman, Erica V. Jefferson, told GEN. “When the confirmatory studies failed to show a clinical benefit, CDER proposed that the breast cancer indication be withdrawn.”
Genentech has responded by noting that the initial 5.5-month benefit was the largest in median PFS observed in a first-line MBC trial; that the E2100 study had limited power to detect the sort of overall survival the agency seeks; and that the AVADO and RIBBON1 clinical trials verified the clinical benefit of Avastin in MBC because they met their primary endpoint of improved PFS with a high degree of statistical significance.
Genentech says that PFS should be a primary endpoint. It can be objectively measured, and the EU recognizes it as an endpoint in oncology clinical studies, the firm pointed out. FDA says the primary endpoint should instead be overall survival: “FDA has considered PFS as a surrogate endpoint of clinical benefit rather than a direct measure of clinical benefit,” according to a Dec. 15, 2010, memo from Richard Pazdur, M.D., director of FDA’s Office of Oncology Drug Products, to Janet Woodcock, M.D., director of CDER.
Genentech has also questioned the expertise of the FDA’s Oncology Drug Advisory Council (ODAC), which raised an early red flag about Avastin by recommending against the MBC indication in July 2010. Of the 13 ODAC members attending that meeting, two were breast cancer oncologists, Genentech noted.
The firm pointed to the exclusive breast cancer specialization of the National Comprehensive Cancer Network panel, which upheld the indication after reviewing the same postapproval clinical trial data that turned ODAC against the drug. As Genentech itself noted, though, ODAC’s purview includes a broader mix of oncology topics, not just breast cancer.
Additionally, CDER and Genentech have squabbled on procedural issues, notably the number of representatives who can speak for them at the hearing. Genentech has named six presenters and CDER five, but CDER also wants three professionals on hand to answer questions, though they won’t give presentations.
Genentech says that’s unfair, citing rules that anticipate speakers giving presentations, then answering questions. CDER says excluding the three would prevent it “from fully and fairly presenting its case and would impinge the purpose of this hearing to protect the public health.”