Is FDA Killing Research?

It sounds crazy. But it’s what Wyeth’s R&D chief Bob Ruffolo fears if the unprecedented political storm currently engulfing FDA continues to force the agency to raise drug safety hurdles.

“Who is going to bring a new, improved version of Avandia to market,” asks Ruffolo, given the likely trial-size FDA is going to request? How will any company be able to prove that their drug doesn’t have the safety issues associated with Avandia, if these (whether or not they are real) only become apparent from Steve Nissen’s meta-analysis of trials involving 28,000 patients?

No drug is risk-free, and no company-sponsored clinical trial can feasibly replicate real-world drug usage over a number of years. Yet people [politicians, patient groups, Public Citizen, and now FDA] "are demanding absolute positive safety,” Ruffolo tells us.

Now sure, comprehensive safety data within the reasonable bounds of clinical trials is crucially important to getting a drug approved. But if, as Ruffolo contends, regulators—whether or not under pressure from politicians and lobbyists—become obsessed with safety and fail to grant equal attention to benefit, there may be little point in even pursuing drug development within certain classes. Hence, “I’m worried that what saw with Avandia will kill off an entire area of research.” (Add, perhaps, CB1-antagonists to the list, since rimonabant was unanimously rejected by an FDA advisory committee yesterday.)

Avandia, like Lilly/Takeda's Actos (which will also get a black box warning following the NEJM report) is a PPAR gamma agonist. Developers of such single PPARs have already had a rocky road: despite many attempts, they remain the only compounds in their class on the market (there used to be three -- until the FDA forced Warner-Lambert (now Pfizer)’s Rezulin off the market). And Avandia and Actos already in 2002 had their labels updated to reflect safety concerns around congestive heart failure resulting from fluid retention. Meanwhile, every one of the next generation dual alpha-gamma PPAR agonists to get close to the FDA has also failed: remember AstraZeneca’s Galida, discontinued last year because of kidney toxicity; or Merck & Co.’s MK-767; or the compound Merck in-licensed to replace it, Bristol-Myers' Pargluva (whose main antagonist, like Avandia's, was Cleveland Clinic's Steve Nissen).

One might argue, given the list of casualties, that the PPAR class is doomed and it is in fact better that researchers leave it well alone. After all, who wants me-toos? We have a couple of PPARs already out there, the safety-scare will discourage their further usage, and that will force the industry to look elsewhere, for ‘real’ innovation.

But ‘real’ innovation and progress don’t generally happen in giant leaps, they happen in increments. There are plenty of reasons for bringing new versions of Avandia to market, Ruffulo argues, just as there are plenty of good reasons to have a variety of Cox-2 drugs, or a palette of cancer treatments. It’s well known that individuals respond differently to the same drug; in cancer, there’s also the issue of resistance.

Getting back to the PPARs: designing drugs that target different ratios of PPAR alpha, gamma and delta receptors might just improve the side-effect issues that Nissen highlighted, if indeed they are worthy of a black box warning. Despite the failures, companies including GlaxoSmithKline and Sanofi-Aventis are still working on next-generation subsets of PPARs, including dual PPARs and PPAR delta agonists.

So why is Ruffolo so riled up? Wyeth doesn’t have a PPAR agonist (it isn't in diabetes), and, for that matter, doesn’t have a Cox-2 either. In fact, Ruffolo contends, the company has been a little more protected than some from the worst of the safety storm around primary care drugs, in part thanks to its focus on more specialist areas like rheumatoid arthritis (and CNS in primary care, where FDA appears particularly open to new treatment options).

But Wyeth has been hit by its fair share of safety crises—including the Women's Health Initiative study in 2002 which apparently showed an increased risk of breast cancer, among patients taking Wyeth's combined estrogen/progestin hormone replacement therapy Prempro. Positive benefits such as a decrease in hip fractures were overlooked, contends Ruffolo. So are more recent data analyses this year reversing some of the earlier findings on heart attack risk. In today's regulatory reality, meta-analyses count when they’re negative on safety, but not when they’re positive on efficacy. In other words, drug labels can only get worse.

The industry itself is partly to blame for this onslaught, though. Its behavior hasn't exactly been squeakly clean--think enquiries into dubious promotional techniques, accounts of negative trials being swept under the carpet, and the 'dodgeball' that reps were encouraged to play with Vioxx when faced with difficult questions.

Ruffolo acknowledges that the industry makes mistakes. But that won't help the sector out of its plight, nor will blaming eager politicians and watchdogs. For that, drug firms should start rebuilding consumer trust. Perhaps this safety storm will push them into doing so--the silver lining in an otherwise black cloud.