Do the FDA Avastin hearings mark the end of an era?

The Avastin public hearings, which were organized by the FDA, began yesterday as part of Genentech's appeal to reverse the FDA's plan to withdraw the drug's accelerated approval. This temporary approval, which was pending more data, was granted back in 2008.

The approval came despite a recommendation for disapproval by the Oncologic Drugs Advisory Committee, which cited a lack of survival benefit. Although there was nearly a doubling of progression-free survival, it came with significant, albeit infrequent, serious toxicities and even excess treatment-related deaths. We have previously covered the background and controversies surrounding this topic in Hurdles on the Faster Track.

Now as two more trials have been analyzed -- neither showing a survival benefit -- the FDA stated that in the balance, the benefit did not outweigh the harm. The public hearing has taken on a circus-like atmosphere despite the seriousness of the topic and the emotional testimonies of patients whose disease has improved or been stable on Avastin. On the other hand, several patients and advocacy groups have lobbied against approval, saying that giving this drug the nod despite the lack of scientific evidence of benefit is counterproductive to the whole field -- attention must be focused on developing survival-enhancing therapies. How can such divergence in opinions exist?

Actually, both sides of the argument have some merit. There probably are individuals who are clearly benefitting from Avastin. However, we do not know how to identify them, so the impact from the small number of "super-responders" is diluted. The average effects in large trials then look rather small or nonexistent. This is probably true of many drugs we use today. We could probably get more dramatic effects, but only if we treat that fraction of patients who would benefit--if only we had tests to guide these decisions. Avastin affects a complicated process -- angiogenesis, which involves tumor blood vessel formation that includes numerous receptors, enzymes and biological pathways.

So called "predictive biomarkers" have been particularly elusive for Avastin.There is no right answer to this wrenching issue that has dominated the headlines this week. Many patients and doctors want "freedom to operate" and the ability to do what they believe is best for their patients. Others don't want health care dollars (and in some cases, patient safety) expended for the kind of benefit seen in the trials so far.The process of testing new cancer agents has forever changed because of this. It is now necessary to define predictive factors at the same time a drug is initially being developed. Not only is FDA approval in jeopardy, but drug companies can no longer afford the cost of huge trials to show a tiny difference in outcomes. The FDA hearings mark a milestone in this turn - the end the old era of cancer drug development.