Pharma’s Cutting Edge

Well, as you’ll read some action is happening in the US Senate to address the authorized generics conundrum. You’ll recall that the issue has sparked consternation among major generics makers–and some lawmakers–who compete for 180-day exclusivity under Hatch-Waxman. The authorized generic effectively undermines the first-to-file generic house from enjoying the 6-month monopoly aimed at encouraging challenges to innovator patents and thus earliet possible generic entries. However, Merck’s recent tactic of undercutting the price of a first-to-file generic (Teva) with their brand drug (Zocor) would not be affected by pending legislation that seeks to limit authorized generics until after the 180-day exclusivity period has expired.

It remains to be seen how effective Merck’s Zocor strategy will be relative to (1) the no-generic (i.e. “usual”) approach and (2) the authorized-generic approach, and whether it will be imitated by other innovators. In particular, analysts will be looking at whether low Zocor prices return the same profit to Merck as does Merck’s authorized generic simvastatin sold by Dr. Reddy’s. As pricing for Zocor will be likely be more variable than the pricing for the authorized generic, with little local-market overlap between the two, apples to apples comparisons will be difficult. Was Merck anticipating legislation limiting AGs, and did anticipation lead to their bold pricing experiment with Zocor? If they were, they haven’t said so publicly.

This week, once again, FDA’s ability to impartially assure the safety of medicines was called into question. A call by Sen. Grassley for the HHS inspector to investigate whether FDA officials collaborated with Merck to squelch criticism of Vioxx by David Graham was the latest blow. It seems that a memo from Brian Harvey (Director of the GI Division in the New Drug Office) to Merck’s Ned Braunstein (Sr. Director at MRL primarily responsible for communicating Vioxx safety information) suggests that FDA was advising Merck how to confront Graham’s charges. Not smart. It’s no secret that many staffers in the new drugs office deem Graham to be a loose cannon, but they need to remember which team they play for. Grassley intends to remind them. In related news, 15% of 1,000 respondents to a survey of FDA personnel conducted by the Union of Concerned Scientists indicated that they had been “asked, for non-scientific reasons, to inappropriately exclude or alter technical information or my conclusions in an FDA scientific document.” The initial FDA response was to call the survey findings misleading.

Don’t be surprised to see some personnel shake ups in the new drugs office this fall.

In related news, on Tuesday, Sens. Kennedy and Enzi released a draft bill that would give FDA power to alter labels in response to emerging postmarketing safety information. It would also create a Drug Safety Oversight Board to mediate disputes between sponsors and FDA.

The linked NYT article briefly discusses one of the more salient economic points faced by sponsors and academics interested in developing predictive tests of drug efficacy with established drug classes. It’s also a point that I’ve seen very little attention paid to in the lay media. I’m taking about the issue of class effects. Predictors of efficacy when the clinical read out (i.e. time to definitive efficacy determintation) is protracted have the potential to be useful, even when the drug class is associated with low toxicity and low cost. This utility is heightened when the disease being treated is serious. CHF fits this profile tightly. Beta blockers are cheap and relatively non-toxic and CHF is serious with a protracted time between therapy initiation and definitive efficacy. But they’re an established class, with many members. It’s likely that a predictive test will exhibit specificity spill-over among class members, as the article implies. The only way to to test for such spillover is a very large clinical trial that no single sponsor will want (or be able) to conduct. Even a consortium of sponsors would not be able to study every beta blocker, and only those beta blockers that will still be under patent protection after the trial is over would be considered worthy of study by the industry.

Governments have not even begun to come to grips with the implications of this situation. In the U.S., absent a single point of responsibility for public health economic policy, agencies such as CMS, AHRQ, NIH and FDA should ideally collaborate to determine whether and how such studies should be conducted and funded. The calculus will boil down to likelihood of finding predictive markers, the cost of developing the markers (including the mega study), the predictive value of the markers and the cost to use them routinely, and the potential cost savings to the healthcare system (particularly the publicly funded portion of that system) resulting from deployment of such tests. My sense is that we are unlikely to see such mega studies in the forseeable future, as the potential risk-adjusted, discounted cost savings will be found to be marginal relative to the costs of deployment in nearly all cases. As a result, when such tests are introduced after being studied for one member of a class, researchers will undoubtedly study them retrospectively (i.e. apply the tests to case series and prospective clinical studies done for other reasons) and then apply the tests clinically (usually off-label and without insurance coverage) based on these post hoc inferences. It’s far from ideal scientifically or policy-wise, but it’s going to be the reality for many established drug classes. It’s the main reason why governments should continue to encourage predictive tests of efficacy as new members of recent and new classes are developed.

Unfortunately, you’ll need a subscription to read this WSJ article. Fortunately, I can summarize it in one sentence. The FDA is finally planning to release a guidance for the design, conduct and analysis of adaptive clinical trials. And my one-sentence commentary: It’s about freakin’ time.

I’ve been doing quite a bit of thinking about our microbiome (the collection of microorganisms that inhabit our bodies) of late. I’m thinking that we (as an industry) have grossly underappreciated its importance to intra- and inter-individual variability in disease phenotype and response to therapies, especially oral drug therapies. Pharmaceutical scientists whose work involves studying such variability and designing strategies to exploit and/or overcome it should immerse themselves in this rapidly growing field. The blog post I’ve linked to provides a good initial reference list. The work of Jeremy K. Nicholson at the Imperial College in London and Jeffrey I. Gordon of the Washington University in St. Louis is particularly important and provocative. Let’s add microbiomics to our pharmaceutical lexicons and give the 100 trillion bugs that inhabit our guts the attention and respect they warrant.