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Scientific enthusiasm shouts, but evidence whispers: Which should drive policy?

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June 18, 2015

Vikas Saini, MD

The recent media attention to two kinds of cholesterol drugs provides some useful context for the ongoing debate about conflicts of interest in medicine, and whether they distort medical research. Ezetimibe was studied in the recently-released IMPROVE-IT trial, which was hailed as a success for reducing a composite primary endpoint of cardiovascular outcomes. An accompanying editorial presented the trial as strong confirmatory evidence that reduced levels of LDL cholesterol are very important for reducing heart attacks and strokes. Similarly, evolocumab and alirocumab, two injectable anti-cholesterol drugs, were recently recommended for approval by an FDA panel based on evidence that they drastically reduce LDL levels, but before any evidence that they will reduce heart attacks. Those studies have yet to be completed.

Why do these drugs matter? Why was there such a bally-hoo about the relatively modest results in IMPROVE-IT? In part, it was supported by the view that, however slightly, “lower is better” for LDL cholesterol levels. It’s doubtful that many cardiologists will turn to ezetimibe in many patients, since the results were so modest and methodological issues limit the ability to usefully apply IMPROVE-IT. Those issues have been pointed out by Stephen Martin, MD and Lisa Plymate, MD; Richard Lehman, MD; and David Newman, MD, among others. But it did serve one important function: In the court of mainstream medical opinion, it set up the expectations for the PCSK9 inhibitors, which do lower LDL dramatically. For the marketing directors of PCSK9, the timing of IMPROVE-IT was perfect.

Without data on hard outcomes, the revolutionary potential of PCSK9 agents remains an extrapolation. A plausible extrapolation, perhaps, but nevertheless an extrapolation. If the drugs cost only pennies, and there were only a very remote chance of harms, greater certainty wouldn’t matter. But given the stakes, and the long history of medical misadventures (remember Baycol?), we ought to know better.

This is the context in which to understand the issue of conflicts of interest. Because like in so many other cases, the breathless excitement over PCSK9 inhibitors runs far ahead of what we know for sure, but the hope for large benefits for patients seems to be enough for many physicians to want to change the rules – even if it is “just this once.” And we find ourselves asking “why?”  Is this really a good way for a great nation to run public policy? Larry Husten notes that Steven Nissen, MD, a keynote speaker at our Road to RightCare Conference and a strong and passionate voice against overtreatment, is a prominent supporter of PCSK9 inhibitors, and is currently leading an industry-funded trial of the drugs.

Nissen’s case is a perfect example of the difficulty posed by the way we have organized pivotal clinical research trials in close collaboration with industry: It is natural for physicians, who have an impulse to do everything they can to help their patients, to want to bring game changing treatments into use. To his credit, Nissen doesn’t take a salary directly from the drug companies, but the funds do support his institution, and members of his team, so his involvement in the trial at least has the potential to color his judgement. Our concerns are amplified because we know there is a long and clear record of bias in industry-funded studies, which often capture clinicians’ enthusiasm while the jury is still out.

What this illustrates most is that conflicts of interest are often not financial, nor are they necessarily driven by the mere fact of money changing hands. As intimate collaborations between industry and academia have become a part of business as usual in the last few decades, so too has managing conflicts of interest become far more than an academic or moralistic dispute. It’s harder to implement evidence-based policy when there is a well-funded stampede to one side of an issue. The case of flibanserin is a perfect example. Doctors who are excited about a new drug should be free to shout their enthusiasm from every corner. But when it comes to releasing new chemicals into the bodies of millions of people, the public is better served with a different team, one without a dog in the fight, taking a close and hard look at the facts.