ODAC's decision on Avastin in breast cancer raises many questions

The story surrounding the FDA's process for the final approval of Avastin (bevacizumab) for advanced breast cancer raises many questions about the standards on drug approval in this changing era of targeted therapy and personalized medicine.

In early 2008, the FDA granted an "accelerated" approval on the basis of a trial that showed a significant delay in the time to progression, but no difference in survival time, when added to Taxol (paclitaxel) as first-line treatment. This meant that final approval would be dependent on subsequent trials showing similar degrees of benefit. When two additional trials were submitted for review, both showed significant improvements in time to progression, but again with no difference in survival. The advisory panel to the FDA voted on July 20 this year to NOT recommend full permanent approval.

Did the FDA and the advisory panel change the ground rules, now asking for a survival benefit when none of the trials were designed to enroll enough patients to do this? Or was it that the difference in progression time was not as large in the subsequent trials, even though statistically, one cannot compare these values across trials.

Either way, researchers and advocacy groups are both split on whether the FDA advisory panel made the right call and what the final FDA ruling should be, which is due by September 17. For other indications in advanced lung, colon, and refractory brain cancer, Avastin produces a survival advantage. However, does delay in progression in its own right represent a real benefit? The FDA has the charge of ensuring that new drugs have a favorable benefit/risk profile, but it does not specifically define what the rules are for measuring each of these. In some cancers, prolongation of progression is tightly linked to an improvement in survival, but this is not solidly the case in breast cancer. Also, progression delay might improve quality of life, but such evidence is hard to generate, and was not clearly shown in the two Avastin trials. The issue of the economic cost of small incremental benefits is also being raised, but the FDA is not supposed to take that into account--still, some wonder whether this factor somehow crept into the advisory board's decision.

The way the FDA thinks and decides on these issues still remains somewhat veiled. While FDA officials are very open about discussing their thoughts and regularly meet with companies ahead of time to review trial designs and strategies for approval, none of these discussions bind them to their ultimate decision. This leaves companies trying to figure out the quickest and surest path to approval, not necessarily representing the best scientific or societal plan, or even for that matter, the best thing for the company itself.

This sage may tell us that NOW is an opportune time for governmental agencies (both regulatory and Medicare/Medicaid), patient advocates, the pharmaceutical industry, and clinical researchers to all come to the table to discuss a framework, or "rules of the game," for moving forward in light of both health care reform and new discoveries in cancer biology personalized medicine.

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