FDA Gets Out in Front on Vytorin, Defends LDL Endpoint

The Food & Drug Administration is weighing in on the Vytorin controversy via an "early communication" on the study results.

Given the hue and cry over the drug since Merck and Schering-Plough finally disclosed disappointing data from the ENHANCE trial January 14, many may wonder how FDA can say it is "early" with its response. After all, didn't Steve Nissen, the United States Congress, and seemingly every media outlet in the country already tell us what to think?

As far as Vytorin goes, the FDA announcement indeed is decidedly anti-climactic. The agency summarized the results already made public by the company, and said it would review the data fully once it is submitted by the sponsor. On a media call, Office of New Drugs Director John Jenkins said it may be another couple of months before the data is submitted, and up to six months before the agency completes its review.

And, Jenkins added, it is not like there is much to expect from the regulatory review itself. Vytorin is already clearly labeled as not showing any demonstrated benefits in long term outcomes data. The agency will be looking carefully for any new safety information in the data, Jenkins said, but it is not aware of any red flags at this time.

So not much new there.

But there is an important way in which FDA is getting out in front of the Vytorin story. One of the primary messages of the early communication and the media call was to try to diminish speculation that the ENHANCE trial calls into question one of the basic tenents of cholesterol therapy: the focus on LDL levels as a key marker for treatment.

The agency's main message: it remains confident that LDL reduction is a fully validated surrogate endpoint as a basis of approval for cholesterol treatments--and that LDL reduction is an appropriate therapeutic goal for physicians and patients. (Recall that the Schering-ENHANCE study failed to show the expected benefit of combination therapy with Vytorin versus single-agent simvastatin, despite showing significantly better LDL reductions.)

"It would be premature to embark on any systematic change in how we approve lipid-lowering drugs," Jenkins said. "We have a long track record" of success in basing approvals on LDL, he noted.

In fact, Jenkins added, LDL reduction is a much more fully validated than the arterial plaque endpoint used in ENHANCE.

"It is tempting to think of" changes in arterial plaque "as a direct measure of what these drugs do," Office of Medical Policy Director Robert Temple added. But "that may not be the best measure." He noted that statin drugs show improved outcomes in a matter of months--before any measurable changes in arterial plaque are observed.

"The surrogate that really works is LDL cholesterol," Temple stressed. "I'm very concerned that this will lead to people becoming indifferent" to their LDL levels, rather than seeking treatment.

That message may or may not help Vytorin in the marketplace--but it is great news for all cholesterol drug development companies.