Catching up on some older literature, I see that British sociologist John Abraham (last blogged about: http://brodyhooked.blogspot.com/2011/11/emergent-patient-industry-complex-and.html) and his associate Courtney Davis have produced an interesting paper comparing the drug regulation systems in the U.S. and the European Union, using diabetes as a case study-- specifically, the class of drugs called the glitazones.
They review the story of the approval process in each system for the drugs rosiglitazone (Avandia) and pioglitazone (Actos). Their principal conclusion is that what drove the regulatory approval process in the U.S., and to a somewhat lesser extent in Europe, was the "innovation" factor--that the glitazones were a new class of diabetes drugs and worked by a new chemical mechanism. This led the regulators to take their eye off what should have been the ball--the question of whether these drugs were safe and effective for patients with diabetes.
The FDA approved Avandia and Actos in 1999. Davis and Abraham tell us, "By 2007, the FDA had reached the uncomfortable conclusion that their medical optimism about the glitazones’ ‘wonderful’ and ‘unique’ mechanism had been little more than wishful thinking." They go on to suggest that such an outcome "is consistent with an ideology that mistakes technological novelty for public health benefit."
While the EU was to some extent driven by the same love affair with "innovation," the Europeans eventually became more hard-nosed than the Americans, demanding to see evidence of improved outcomes in diabetes (that is, longer life, or fewer major cardiovascular events) in comparison with existing drugs, while the US FDA was happy to require the companies merely to prove that their drugs did a better job than placebo at lowering blood sugar. Davis and Abraham explain, "The FDA justified its more permissive approach on the grounds that once efficacy is established, albeit against placebo, the drugs should be approved to find their place in the ‘market’ where doctors can judge which drugs are best for their patients." Conveniently left out of this FDA equation is how physicians are supposed to be able to "judge" when the industry gets to design all the studies of the new drugs and can avoid asking any of the hard scientific questions that might threaten drug sales--and when the FDA refuses to use its regulatory clout to force the companies to do the studies that would really prove that the drugs have a worthy role in therapy.
Moreover, "The glitazones highlight the ideological nature of the FDA’s expectations in relation to rational drug use because the hypothesized clinical benefits associated with the drugs’ innovative mechanism, on the one hand, and the comparative clinical evidence actually available, on the other, implied diametrically opposed clinical use. On the clinical trial evidence that the glitazones were less effective than existing drugs at lowering blood-glucose, glitazone use would be recommended after those other drugs had failed .... By contrast, the hypothesized benefits from the glitazones’ innovative mechanism implied that the drugs should be used early in therapy to prevent disease progression. The contradiction of the FDA’s approach is that to suggest such potential benefits from an innovative mechanism underlines the need for good comparative efficacy data because it is all the more important that information about the glitazones’ most effective use is available."
So, where does this worship of innovation come from? It is hard to blame industry fully. Physicians are always excited to hear that a new class of drugs has been discovered. Scientists are intrigued by novel mechanisms. These discoveries make the evening news and get patient-advocacy groups all in a lather about the latest "cure" or "miracle." But despite those other contributing factors, we cannot deny that it serves industry's interests to get the regulators to pay more attention to "innovation" than to actual patient outcome data: "Our case-study of ‘innovative’ pharmaceuticals suggest that even if ... the expectations of medical innovation are rarely proportionate to future therapeutic results, sales ‘results’ can prosper for years after because of immense promotional efforts by manufacturers and the ideological sway of the idea of innovation within neo-liberal regulation..."
Now, one interesting feature of this analysis is that Davis and Abraham don't really tell the whole glitazone story. They dismiss with one sentence what happened to the predecessor of both Actos and Avandia, troglitazone (Rezulin)--a drug that I found worthy of three pages of discussion in HOOKED. The first drug to be marketed in this class had to be withdrawn from the market due to liver failure. The British regulators took Rezulin off the market more than 2 years before the FDA did, and 63 people had to die in the US before the FDA finally took action. The love affair with "innovation" therefore claimed even more lives than David and Abraham indicate.
Since Rezulin had done its dirty work via the liver, the FDA thought ot was home free when it could see that neither Actos or Avandia caused similar liver problems. That distracted the agency from the real problem with Avandia, causing excess cases of heart failure. But you could argue that the FDA was even more distracted from the real issue, which is whether these drugs have any significant role at all in the treatment of diabetes--in the absence of any clinical data showing superior outcomes to the many other drugs already in use for diabetes.
A background assumption in most of the FDA actions taken on these drugs is that when a company goes to the trouble of actually discovering a branbd-new drug--instead of just making yet another me-too drug--it somehow deserves a reward for these efforts. This raises two questions. First, how low has the bar become for what counts as exemplary behavior by a drug company? Second, if the company deserves some sort of pat on the back for their work of scientific discovery, how does that translate into subjecting patients to a new drug that may be unsafe and that has not been shown to make them better?
Hat tip (again) to Primary Care Medical Abstracts for alerting me to this paper.
Davis C, Abraham J. The socio-political roots of pharmaceutical uncertainty in the evaluation of 'innovative' diabetes drugs in the European Union and the US. Social Science and Medicine 72:1574-1581, 2011.