Monday, June 2, 2014

Comparative Effectiveness: A Major Priority for Pharmaceutical Policy

Last week, FiercePharma contained a story that referred to the superior efficacy of Roche's newest anti-CD20 antibody Gazyva compared to the original anti-CD20 antibody, Rituxan, in the treatment of chronic lymphocytic leukemia (CLL).1 However, just this week another head-to-head study in CLL, comparing a kinase inhibitor, Ibrutinib, against yet another anti-CD20 antibody, was published in the New England Journal of Medicine.2 The study concludes that Ibrutinib was superior to the antibody Ofatumumab in both progression-free survival and overall survival. Now is it also better than Gazyva? Who knows? So let me use this week's post to make a few additional comments on comparative efficacy.  Download PDF

A dozen years ago, I spoke at the Fifth Annual Managed Care Summit of the ABA Section of Health Law and my remarks were edited and published in the proceedings of that meeting.3 The point that I made there was that the use of formularies was essential to managing health care costs to achieve optimal results for the amount expended, but that crafting formularies to achieve optimal results required much better data than is generally available. A dozen years after my ABA talk, the need for better data for formulary construction is greater than ever. The best data for comparing two or more drugs requires head-to-head, randomized trials of those drugs and the private sector will rarely if ever fund those trials. To belabor this last point just a bit, the only private sector entities with both a potential interest in such trials are pharmaceutical companies and health insurors. First, pharmaceutical companies are not going to invest in rigorous head-to-head studies of their drugs against competitor drugs because those trials are fraught with risk and not often necessary. The two best examples of the risk of such studies can be drawn from the statins. In both cases the companies undertaking the studies were motivated because they were either rapidly losing market share or facing an imminent drop in market share: Bristol Myers Squibb (BMS) and the PROVE-IT trial comparing Pravachol and Lipitor in 20044; and, Astra Zeneca (AZ) and the SATURN trial comparing Crestor and Lipitor in 2011.5

In the PROVE-IT trial BMS was hoping to stop a loss of market share for its drug Pravachol to Lipitor, a later entrant that was achieving greater reductions in LDL and total serum lipids by demonstrating that the additional reduction in serum lipids did not, in fact, result in a reduction in cardiovascular morbidity and death. In the end, the result was a great boost for Lipitor, which did in fact produce a significant additional incremental reduction in cardiovascular moribidity and mortality. In the SATURN trial, AZ was facing a potentially huge loss of market share when Lipitor was scheduled to become available as a low-cost generic in December 2011. Possibly because AZ had learned from BMS's mistake, the SATURN trial was not designed to show that Crestor could produce an even greater reduction in cardiovascular morbidity than Lipitor. Instead, AZ designed a trial to show that their drug, which did produce greater reductions in lipid levels, produced greater reductions in coronary atherosclerosis, which is to say that the endpoint of the trial was the size, or volume, of the opening in the coronary arteries. AZ hoped to be able to market its drug by hyping a greater reduction in atherosclerosis as pointing to an unproven, but theoretically plausible, reduction in actual disease and death. Unfortunately for AZ, the very expensive trial showed that the two drugs achieved similar reductions in atherosclerosis. AZ's loss was a win for containing healthcare costs because insurors have ample justification for putting inexpensive generic lipitor at the top of their formularies with hurdles for other statins to meet even with higher copays. However, the result was not likely to encourage other pharmaceutical companies to gamble on head to head studies very often. As I noted in my April 26, 2014 post, Competition in the Pharmaceutical Marketplace: It's Not About Prices, pharmaceutical companies prefer to compete on whatever endpoints they can point to. AZ is not about to stop selling Crestor, but is going to make a lot of noise about Crestor's class-leading reductions in LDL and increases in HDL.

If pharmaceutical companies will rarely fund the head-to-head studies needed to permit the optimal design of formularies and the optimal use of drugs, what about health insurors? Here the problem is very different-- the trials are expensive and if United Healthcare, for example, actually invested the money to undertake one or more such studies, it would be subsidizing its competitors who can then benefit from the data without having to spend their own money. That is why my 2002 talk to the ABA Health Law section called for government funding for such trials, and why in 2009 one of the fiercest battles in the enactment of the Affordable Care Act was over the funding of comparative effectiveness research, including both pharmaceuticals as well as medical procedures. While there have been discussions of the nature of the controversy over comparative effectiveness research that point to its relationship to rationing of health care or "big government decision-making,"6 I believe the simpler explanation is that the issue pits gigantic lobbies against one another-- the health insurance lobby on one side and the pharmaceutical and medical device lobbies on the other side.

In the end, the necessary data will come slowly, but it will come. What the most recent head-to-head studies in CLL demonstrate is that we need those studies, and in some cases, we need to ensure that those studies are really fair. Only an unbiased third party funding head-to-head trials can insure that the doses chosen for the study and the study's endpoints fairly demonstrate the relative effectiveness of the agents being studied. We cannot rely entirely upon the pharmaceutical companies to provide us with the data that we need. It was true in 2002 when I first suggested government funding of comparative effectiveness trials. It was true in 2009 during the debate over the Affordable Care Act and it is true today.

1. Eric Palmer, Roche Gets Thumbs Up For CLL Use Of Gazyvaro In Eu, FiercePharma, May 23, 2014, available at (last visited June 1, 2014).
2. John C. Byrd et al., Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia, N/ Eng. J. Med. (2014), (last visited Jun 2, 2014).
3 Robert A. Bohrer, The Trouble With Formularies: Where is the Data When You Need It? in Proceedings of the 5th Annual Managed Care Law Summit (ABA Press 2002).
4 Eric J. Topol, M.D., Intensive Statin Therapy — A Sea Change in Cardiovascular Prevention, 350 N. Eng. J. Med.1562-1564 (April 8, 2004).
5 Stephen J. Nicholls, M.B., B.S., Ph.D., Effect of Two Intensive Statin Regimens on Progression of Coronary Disease, 365(22) N. Eng. J. Med. 2078 (December 1, 2011).

6Neumann and Weinstein, Legislating Against Use of Cost-Effectiveness Information, 363 N. Eng. J. Med. 1495-1497 (October 14, 2010).

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