Is the FDA Getting Tough on Surrogate Markers?

Allow me to introduce readers to PM, who will be guest blogging in this space from time to time. PM follows developments at the FDA closely.

Last week's surprise decision from the Food and Drug Administration that it will require a new cholesterol-lowering drug from ISIS Pharmaceuticals and Genzyme to actually reduce mortality from coronary artery disease may signal a subtle but significant shift in agency policy when approving new drugs that affect surrogate markers.

Cardiovascular (CV) surrogate markers are risk factors like high blood pressure, elevated blood sugar, low HDL cholesterol levels, and elevated LDL cholesterol levels that are associated with increased risk of heart attacks and strokes. In approving new drugs designed to prevent and treat CV disease, the FDA has often relied on improvements in the "surrogate endpoints," not the outcomes patients really care about -- reduced risk of heart attacks, strokes, heart failure and death. 
 
That approach has been unevenly applied over the years. Last month in The Journal of the American Medical Association, Bruce Psaty and Thomas Lumley noted the contrasting paths followed by the FDA with respect to two lipid-altering drugs, ezetimibe (Zetia and a component of Vytorin) and torcetrapib.  In the case of torcetrapib, a drug that raised "good" cholesterol (HDL) and lowered bad cholesterol (LDL), the sponsor carried out the ILLUMINATE trial, in which 15,057 patients with high CV risk were randomized to receive torcetrapib plus atorvastatin (Lipitor) or atorvastatin alone.  Although patients who received torcetrapib had higher HDL and lower LDL than patients who did not, the trial was stopped early because of an increase in the risk of CV events and total mortality in the torcetrapib group.  Pfizer subsequently halted the development of torcetrapib.
 
By contrast, ezetimibe was approved in October 2002 on the basis of its ability to reduce levels of LDL alone.  Clinical trials evaluating ezetimibe's impact on the risk of CV events were slow to start. Indeed, the ENHANCE trial, which evaluated the effect of ezetimibe on atherosclerosis, was not completed until 2006 -- four years after approval -- and the results were not reported until January of thsi year. Guess what? No effect on atherosclerosis was shown.

A large trial, IMPROVE-IT, to evaluate the effect of ezetimibe on CV events will not be completed until at least 2012.  If ezetimibe is ultimately shown to have no benefit for the prevention of CV events, thousands of patients will have been treated with an ineffective drug when more effective drugs were available.
 
Which brings us to this weekend's surprise announcement. Mipomersen, an LDL-lowering drug, is being developed by Isis Pharmaceuticals in partnership with Genzyme Corp.  While the sponsors announced Friday that the FDA was permitting reduction of LDL to be used as a surrogate endpoint for accelerated approval of mipomersen for patients with genetically-inherited high cholesterol (known as homozygous familial hypercholesterolemia or hoFH), the agency will require the companies to conduct a very large clinical trial with real clinical endpoints (heart attacks, strokes, death) if they want to expand its use to the broader population with high cholesterol levels.

It is unclear whether this represents a new FDA approach to approval of lipid-altering drugs when they are first-in-class, or whether the FDA has special concerns with mipomersen. The FDA has asked the companies to include data from two ongoing preclinical studies for carcinogenicity when it submits its filing in 2010, a year later than expected. Whatever the FDA's reason, it's the right approach to take. --PM