Is Cancer's "Pencillin Moment" FDA's Moment of Doubt?
In late August, the New England Journal of Medicine featured something remarkable: Results of a phase 1 study on a drug called PLX4032.
Usually, a phase 1 study isn't worth getting too excited about, but this was different. In a study of patients with metastatic melanoma--a late stage cancer in which survival is measured in weeks and current therapies do very little--nearly all treated patients experienced tumor reduction, with 81% having shrinkage of 30% or more. The drug targets patients with a specific mutation to the B-raf kinase, a new strategy made possible by relatively cheap and rapid sequencing and genotyping. Hailed by the BBC as "cancer's penicillin moment," enthusiasm is running high about this molecule, which was discovered by a private company called Plexxikon and partnered with Roche.
But the drug's remarkable success in the clinic is raising ethical issues about how clinical trials are structured and conducted. A recent article in the New York Times frames the debate and shows the sharp divisions among even the physicians who participate in these studies. The issues are not unique to PLX4032, but are thrown into sharp relief by the drug's high level of efficacy--doctors participating in the study are convinced that the drug works, but the protocol for the ongoing phase 3 study calls for a largely ineffective control arm to continue, in order to see if tumor reduction translates to a survival benefit. It is theoretically possible, after all, the tumors could shrink but then rebound in a more severe form, meaning little or no overall survival advantage.
Possible, but given what we've seen thus far, not likely. And physicians are understandably upset that, as one put it, "we can’t let patients on the control arm cross over because we need them to die earlier to prove this point."
What's interesting is that these issues about the inflexibility of FDA's data requirements hearken back to the days of the first AIDS drugs and the beginning of the accelerated approval process in 1992. Activists pushed through accelerated approval because at the time, the only alternative to drugs that appeared to work was...nothing at all. Accelerated approval was, over time, and with some controversy, extended to cancer drugs. And drug companies were generally enthusiastic about it--it allowed them to run shorter, cheaper trials and get some drugs on the market that might not have been feasible to push through trials otherwise.
The apparent irony is that in this case, it is Roche that is against measures to get the drug on the market more quickly. The company understandably feels that it has a high chance of success in a formal survival study and that enrolling patients in any kind of controlled study will be next to impossible after the drug is approved. And yet that means that the company is pushing to spend significant amounts of extra time and money when it knows patients will be clamoring for its drug over standard therapy.
The Times implies this is because Roche is looking toward potential competitive drugs in the same class and wants an FDA-sanctioned survival benefit to tout in its marketing. That's possible, but it should be noted that FDA has been clamping down on accelerated approval lately--and has long questioned whether shrinking tumors is really a predictive surrogate endpoint for survival. It may well be that Roche is doing what it thinks it must to secure approval.
Read the BioPharm Executive online newsletter September 2010.
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More By Karl Thiel