The fallout from Schering-Plough and Merck’s ENHANCE study results has the medical community questioning whether lowering cholesterol with statins is still considered beneficial, a concern that has caught the attention of FDA’s top medical officer. “(A)n aspect of the current discussion that troubles me greatly is the implication in some stories that we’re not so sure anymore that even lowering cholesterol with statins is all that clearly beneficial, CDER Office of Medical Policy director Robert Temple told FDA Webview 4/1. “As the recent Crestor story reminds us (for people without known cardiac disease, by the way) we sure do know it is beneficial and people who need that treatment will pay with their lives if they’re encouraged to avoid treatment.”
It seems the debate on whether ENHANCE’s results could be interpreted as not showing much benefit for lowering LDL cholesterol levels was triggered by a New England Journal of Medicine (NEJM) editorial entitled “Does ENHANCE Diminish Confidence in Lowering LDL or in Ezetimibe?” The editorial raises some doubt on the two-decade old mantra “lower is better” when it comes to lowering cholesterol. It notes that ENHANCE’s lack of benefit in the reduction of carotid plaque may be explained by “previous plaque lipid depletion, in which case a similar but longer trial in patients who have not undergone previous therapy could well show the anticipated clinical benefit of ezetimibe. Alternatively, these findings plus future biologic and clinical evidence could confirm that the benefits of lowering LDL cholesterol may depend not only on ‘how low you go’ but also on ‘how you get there.’”
So far, ENHANCE’s results have not persuaded Temple to draw any conclusion on Vytorin’s claim of added ineffectiveness. “What people allege the ENHANCE trial showed is lack of expected benefit, which to me seems a questionable assertion,” he told us, pointing out that his comments do not necessarily reflect FDA’s position on the surrogate itself. “The only ‘finding’ I’m aware of is failure to show an added effect on carotid plaques, a surrogate endpoint at best, and one that rates, as a surrogate for predicting coronary events, in my book below LDL cholesterol, in a study that was far too small to be an outcome study. It does appear that the ezetimibe did lower CRP (c-reactive protein) some, something many people would think desirable. Of course, we do not yet have actual outcome data so we cannot know that ezetimibe will add to the effect of the simvastatin in Vytorin. I don't, however, see any reason to doubt that Vytorin will have an effect at least equal to its simvastatin component alone.”
Meanwhile, FDA says it will take about six months to fully process ENHANCE’s data before drawing any conclusions, according to Office of New Drugs director John Jenkins. “As we also said in January, we believe that it is premature based on this single study to alter our approach to the approval of lipid-lowering drugs,” he told FDA Webview 4/1. “The NEJM publications spelled out a number of potential reasons why the ENHANCE study failed to meet its primary endpoint and the results of the ongoing IMPACT-IT study should help to clarify whether there is an incremental benefit on CV risk reduction for Vytorin over simvastatin alone, as would be predicted by the increased LDL lowering seen with Vytorin in the ENHANCE study… Physicians and patients should consider all available data and the labeling for all lipid lowering drugs as they make individual treatment decisions.”
