Rashomon effect

Avastin: FDA lags EMA decision in breast cancer; both lag physician practice

While FDA has been haggling with Genentech Inc. for a year - and counting - over whether to remove metastatic breast cancer from Avastin's label, the rest of the world is moving on. EMA has made a decision to keep bevacizumab and doctors in Europe and the U.S. have already started to adjust their prescribing habits by giving the drug to a narrower population of patients.

Last month, six members of FDA's Oncologic Drugs Advisory Committee confirmed a 2010 ODAC vote, voting unanimously on June 29 to back a proposal by the Center for Drug Evaluation and Research to withdraw accelerated approval for Avastin in first-line HER2-negative metastatic breast cancer.

The vote was the culmination of a two-day hearing in which both Genentech, a unit of Roche, and CDER made their cases for why the indication should remain on - or be removed - from the drug's label.

One day later, the European Commission approved Avastin in combination with capecitabine in first-line metastatic breast cancer patients for whom taxanes or anthracyclines are inappropriate. Indeed, Avastin plus paclitaxel for first-line metastatic breast cancer has been approved in Europe since 2007.

While both agencies looked at the same trials, they differed in their interpretation of progression-free survival data and how they conducted the final analyses.

Trials using PFS as a primary endpoint have had mixed success at FDA's Office of Oncologic Drug Products. Senior officials in OODP have expressed skepticism about the relevance of PFS and frequently assess its benefit on a case-by-case basis with no standard margin that must be met.

While EMA's guidelines on PFS allow for similar flexibility, the European agency stated unequivocally in its assessment report for Avastin that PFS is "an important and meaningful clinical benefit."

Perhaps more importantly, EMA based its decisions largely on subgroup analyses, recognizing that the particular chemotherapy used with Avastin made a difference in efficacy. CDER did not.

Regardless of what FDA does and what EMA has already decided, doctors already have started to focus treatment with Avastin on patients with the most aggressive disease.

The situation is reminiscent of how regulators and physicians dealt with data on K-Ras in 2008. In response to post hoc data showing the marker's relevance in predicting treatment response in metastatic colorectal cancer, European regulators added K-Ras status to the labels of Erbitux cetuximab and Vectibix panitumumab in 2007, and U.S. doctors quickly incorporated the testing into clinical

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