It can take years to establish the safety and efficacy of new drug therapies. What should we do in the meantime?
Tom StosselIdeally, evidence proving the effectiveness and safety of pharmaceutical products would inform all efforts to prevent and cure disease. However, establishing such proof takes years. What should we do in the meantime?
While subject to much criticism, FDA has established a reasonable solution. If its thorough review indicates that a treatment safely promises potential benefits, the agency can approve its use before decisive evidence exists.
Unfortunately, grandstanding by individuals I define as “pharmaphobes,” some of whom have achieved influential status in medicine, can sabotage this sensible compromise. A prime example was exposed recently when the New England Journal of Medicine reported results of a clinical trial dubbed “IMPROVE-IT.”
In that study, more than 18,000 subjects who had previously suffered heart attacks were randomly prescribed one of two drugs designed to lower “bad” cholesterol (LDL-C), high levels of which are linked to heart attacks and strokes. One of the drugs, simvastatin (Zocor; Merck), inhibits the liver’s ability to produce LDL-C; the other, Vytorin, combined that statin with another chemical, Zetia (ezetimibe; Merck/Schering Plough), which prevents absorption of cholesterol from food and had been used previously to lower LDL-C in patients unable to tolerate statins.
The IMPROVE-IT results were decisive. They confirmed that Vytorin is safe and, in addition, clearly superior in lowering LDL-C, significantly diminishing the incidence of heart attacks, strokes, and related deaths.
Vytorin should have been a great public-health success story, but it has fallen short of its promise. Here’s why.
High LDL-C levels have been documented in heart attack and stroke patients since the 1950s, but skepticism reigned as to whether the elevated LDL-C actually caused these complications. Nevertheless, in 1987 FDA approved the first statin solely on the basis of its LDL-C-lowering ability, leaving prescribing physicians to decide whether doing so would have any clinical benefit. In 1994, the results of a clinical trial eliminated those doubts: The statin reduced heart attacks by 30%.
Subsequently, accumulated evidence indicated that what we used to think were “normal” LDL-C levels were too high, and additional LDL-C reduction, achievable with more potent statins, has contributed to a steady decline in death and disability resulting from vascular disease. Vytorin reduces LDL-C and is an alternative remedy for individuals who cannot tolerate statins or are unresponsive to them.
As with the first statin, FDA initially approved Vytorin in 2004 solely on the basis of its ability to reduce LDL-C safely. While physicians then prescribed it for patients, Vytorin’s makers could not claim that the lower LDL-C actually improved health outcomes. Therefore, the manufacturers sponsored leading clinical trial experts to conduct IMPROVE-IT in hopes of proving Vytorin’s clinical benefits.
In early 2008, prominent pharmaphobes pounced on a study Vytorin’s manufacturers had hoped might be a shortcut to demonstrating those benefits. Researchers compared the ability of Vytorin to that of a statin alone to widen the inner diameters of blood vessels in the neck. They saw no differences.
The study methods were controversial, the number of test subjects small, and reasonable explanations existed for the negative outcome. Nevertheless, the New England Journal of Medicine editorialized that patients who did not respond adequately to statins should resort to diet, exercise, and other drugs available at the time. Those drugs, however, are not well tolerated and were subsequently shown, like diet and exercise, to be ineffective at lowering cholesterol.
Other pharmaphobes piled on. The press disseminated the opinions of prominent academic physicians calling for a moratorium on the use of Vytorin or characterizing it as “an expensive placebo.”
The prescribing of Vytorin abruptly declined, and the market capitalization of Vytorin’s manufacturers fell by $22 billion within a week. The reduction in Vytorin prescribing engendered by these events nearly doubled the time – and expense – required to complete the IMPROVE-IT trial.
In consequence, thanks to the authoritative opinion that precipitated the underutilization of Vytorin while we awaited the hoped-for reassurance that Vytorin really works, statin-resistant patients were deprived of its benefits and physicians were deprived of legitimate prescribing options.
Thomas P. Stossel is American Cancer Society Professor of Medicine at Harvard Medical School and a visiting scholar of The American Enterprise Institute. His book, Pharmaphobia: How the Conflict of Interest Myth Undermines American Medical Innovation, was recently published by Rowman & Littlefield.