However, the FDA is not so much a “dinosaur” as a political football. In contrast to patient advocates such as yourself, there are many others (e.g., politicians, medical-journal editors, health care policy experts, and yes, citizen activists) who are pushing the FDA toward greater caution. Combine that with the frequent changes in FDA Commissioners (and for long periods, no FDA Commissioner at all), low budgets for research by the FDA, changes in Presidential Administrations and in control of Congress, and safety failures of marketed drugs making the headlines, all of which either paralyze the FDA or move it toward greater caution. This is despite the efforts of many in the FDA (such as those who developed the Critical Path Initiative) to improve and accelerate drug development. It’s tough to be an FDA regulator in the early 21st century.

Moreover, the personalized medicine biology-driven clinical trial strategy is rather new. Not all clinical trial practitioners (let alone regulators) fully accept it, pending further demonstration of its value. As we stated in our article, only a few years ago, many industry commentators were of the opinion that the development of imatinib to treat CML was a unique case, and development of other personalized biology-driven drug discovery-based cancer medicines would not be successful. However, the examples discussed in the de Bono and Ashworth article–and in our blog post–show that that is not true. Nevertheless, this breakthrough drug development strategy is still limited in its application, because of the lack of biomarkers. Biomarker identification and qualification/validation is an early-stage area of science and technology.

As for PLX4032, although it is a breakthrough drug, and a basis for truly effective treatments for metastatic melanoma, all patients who initially experience partial or complete responses, and dramatically better progression-free survival (over 7 months on the average) than dacarbazine eventually relapse and die of their disease. Dr. Flaherty and his colleagues are hard at work determining the mechanism of resistance, and developing combination therapies and other means to overcome resistance to PLX4032.

There you have it–a pretty difficult and complex situation. You all need to keep working with all the stakeholders who support innovation and patient access, and even with the FDA and the pharmaceutical and biotechnology companies. All the best to you.

PLX4032 is a repeat of the imatinib story. We have known since June 2009 that PLX4032 is a far superior option to any other treatment option now available to metastatic melanoma patients. that knowledge has since been confirmed by the extension cohort results, and a completed Phase II trial, yet patients are still waiting for this drug, and dying while they wait. the reason? FDA requires results from a randomized clinical trial these days before they will consider granting Accelerated Approval, even for a proven breakthrough drug like PLX4032. The Phase III trial is a randomized controlled trial comparing overall survival between 340 patients getting PLX4032 and 340 patients getting a 35 year old, toxic, barely effective chemo drug called dacarbazine. Based on the data in hand for both drugs, there is virtually no chance that dacarbazine will prove to be equivalent, or even close to equivalent, with PLX4032. Because it is an overall survival trial, there is no cross over to PLX4032 allowed for patients who progress on dacarbazine. They are denied access to PLX4032 per the protocol to ensure that they die on the schedule of a patient given only dacarbazine, an obsolete dug that even the FDA thinks is little more than a toxic placebo. It is the control, however, because it is the only FDA-approved drug for metastatic melanoma.

The result here will be another two year delay, and thousands of patients denied access to a drug that would have improved and extended the lives of most of them. The sponsors have announced they will be starting an expanded access program sometime early next year; however, that program will incorporate eligibility restrictions, and some patients – maybe many – will continue to be denied access to progress already made because of a stagnant and failing set of regulatory policies.

I applaud your focus on better, first-principal, science-directed drug development, but without broad recognition that our FDA is not only not ready for it, but is an enormously powerful barrier to it, the emergence of better drug development methods and personalized cancer treatments (which is where the science is telling us we must go) will struggle to become the new mainstream of progress against disease. Statistically-driven, randomized controlled trials are compatible with the kinds of small, fast, unblinded, adaptive (in real time) scientific trials we now need to be running. PLX4032 is the perfect example of the learning process for treating metastatic melanoma being held up by a simplistic, scientifically and medically meaningless, and grossly unethical Phase III overall survival trial being run to provide a p-value (and little else) to the FDA’s Office of Oncology Drug Products. Along with the recognition that FDA is a barrier, must come pressure from enlightened researchers to cause the FDA to accept and pursue the rapid and dramatic institutional change it needs, or just get out of the way.

Patients really can’t wait for a extended struggle between the dinosaurs at FDA and the expanding groups of researchers who think the process needs to change, and they shouldn’t have to. As for Accelerated Approval being an active pathway for approval at FDA for cancer drugs, that hasn’t been true since 2003, and it isn’t true now. they may be calling some approvals Accelerated, but the requirements for obtaining it from the FDA are nearly identical to those required for full approval, and these days it is very hard to tell what those approval standards are. FDA is delaying and/or denying approval for almost every new cancer drug.

Progress certainly requires better science, but it also requires better (much better) regulation, and so far, the FDA isn’t headed in that direction. They are doing exactly the same thing today that they were doing in 1999 when they failed to move as fast as they should have with imatinib. in fact, what they are doing with PLX4032 is a near exact copy of how they handled imatinib. They just don’t learn over there.

See our August 4 blog post:

http://biopharmconsortium.com/blog/2010/08/04/its-still-tough-to-get-an-antiobesity-drug-through-the-fda/