Strike Three: Expert FDA Panel Again Says No to Over-the-Counter Lovastatin

December 14, 2007

December 14, 2007 (Silver Spring, MD) - Merck and Co went down swinging this week after an expert advisory panel urged the US Food and Drug Administration (FDA) not to approve the company's third request in seven years to make lovastatin (Mevacor) available without a prescription. The panel, a joint meeting of the Nonprescription Drugs Advisory Committee (NDAC) and the Endocrinologic Drugs Advisory Committee (ENDAC), voted 10-2, with one abstention, against recommending over-the-counter (OTC) use of lovastatin 20 mg in patients considered to be at moderate risk of coronary heart disease (CHD).

During the daylong advisory panel meeting, experts expressed concern about whether patients were capable of determining if they were appropriate candidates for the lipid-lowering medication. The panel members were concerned that patients who did not need the drug--those at low risk for future cardiovascular events--and those who should be under the care of a physician--those considered high risk--would inappropriately take lovastatin if it was available OTC.

"It seemed to me that patients couldn't figure out whether the drug was for them, certainly for the ones that chose to use the drug," said panel member Dr William Shrank (Harvard Medical School, Boston, MA). "Frequently, it wasn't right for them."

The Treatment-Gap Problem

Merck sought approval of OTC once-daily Mevacor 20 mg to help lower cholesterol and planned to target consumers at moderate risk of heart disease--women aged 55 years and older and men aged 45 years and older with moderately elevated cholesterol and one or more heart disease risk factors. Merck estimates that there are 20 million Americans in this moderate-risk group, with less than one third currently taking any medication for their elevated cholesterol levels.

In front of the advisory panel, Merck's Edwin Hemwall (vice president, regulatory and scientific affairs) said the company hoped to close the gap in the moderate-risk CHD patients, as well as send more high-risk patients to their doctors. At the moment, said Hemwall, the only options to control cholesterol levels are unregulated dietary supplements and prescription medications, but an OTC statin would add something in the middle of these two extremes.

Merck told the advisory committee that OTC lovastatin would be aimed at the "motivated health-conscious consumer," and acknowledged the importance of ensuring that patients appropriately self-select the OTC statin. The company presented data from the SELECT trial, a study that evaluated the consumer's ability to appropriately determine whether he/she is a candidate for OTC statin therapy.

Conducted in seven cities at 14 sites, the SELECT trial included 1497 patients, but the data were not compelling enough for the advisory committee to vote to recommend OTC lovastatin. For example, among those at higher CHD risk--those with a 10-year Framingham risk score >20%--more than half wanted to purchase the product. Among those with a history of CHD, stroke, or diabetes, and among those with cholesterol levels above the guidelines outlined on the package, more than 30% of consumers in both instances wanted to buy OTC lovastatin. In line with treatment-gap data, though, many of these patients--including 67% with a history of heart disease, diabetes, and stroke--were not taking any medication.

Although there were patients outside the "sweet spot"--those who specifically met the criteria for OTC lovastatin 20 mg--Merck told the advisory panel that even among those with low cholesterol levels--those considered low risk--there would still be a cardiovascular benefit with further lipid lowering. Among the high-risk consumers, considering the large treatment-gap problem in the US, OTC statin therapy would provide a benefit and get more of these patients in to see a doctor, a recommendation outlined on the product label.

Odds Against Merck From the Beginning

The push for approval of OTC lovastatin had the backing of the National Lipid Association and the Preventive Cardiovascular Nurses Association, but the heavyweights refused to get on board. The American Medical Association refused to support the availability of OTC statin therapy in the US, as did the American College of Cardiology (ACC).

"Although statins have tremendous benefits and are effective in many patients, there are risks associated with taking the wrong dosage, not adjusting the dosage after condition improvement, and not adhering to specific usage guidelines," an ACC statement issued to the press read. "Patients get the best treatment when their progress is monitored, and physician involvement is paramount in ensuring that patients receive optimal medical treatment."

The UK was the first country to introduce OTC statins, with the launch of Zocor Heart-Pro in July 2004. This product, which contains 10 mg of simvastatin, is aimed at the same group of people--those with a moderate risk of heart disease. But the switch was easier in the UK, because it has an intermediate category of medicines called "pharmacy-only medicines," which allows certain products to be bought only under the supervision of a pharmacist, who can check that they will be used appropriately.

Votes in Favor

One of the two panel members who voted for the approval of OTC lovastatin was Dr Thomas Pickering (Columbia University Medical Center, New York).

"There is a huge unmet need for people who should be taking statins but who are not," said Pickering in explaining his vote. "I have patients who take all kinds of things, including red rice yeast, which they assume is safe because it's natural, whereas they won't take a statin because it's a synthetic drug and they think it will damage their liver and muscles. There is no question that [statins] really do lower risk. . . . In my view the benefits greatly outweigh the risk."

That view, however, was the minority. Dr Clifford Rosen (Maine Medical Center Research Institute, Scarborough) agreed that there is an unmet need in the management of elevated cholesterol levels, but was wary of undertreatment in high-risk and overtreatment in low-risk patients if an OTC statin was made available. In addition, according to consumer representative Dr Arthur Levin (Center for Medical Consumers, NY), "we haven't learned how to present information in a way that allows consumers to make an informed decision for themselves. Until we get to that point, I don't feel comfortable with this kind of switch."

"At this point, we're not in a situation where patients can make an informed decision," added NDAC chair Dr Mary Tinetti (Yale University School of Medicine, New Haven, CT).

Panel Not Willing to Take the Risk

Merck had reworked the label for the OTC product to better communicate the requirements necessary to be eligible to take the statin, and also planned to supply an expanded support program aimed at consumers before and after they bought the product. The label was strengthened to warn women who were thinking they might become pregnant not to take OTC lovastatin, and listed contraindications for pregnant or breastfeeding women.

Most panel members considered the 20 mg dose of lovastatin to be safe and effective. According to Dr Robert Taylor (Howard University College of Medicine, Washington, DC), the second panel member to vote for approval, the label has improved since Merck last came before the advisory panel in 2005.

"We have a safe drug; the label has been improved, although it still needs some work," said Taylor. "I am a bit worried about the folks who might be at high risk, but I think we have a major problem with this elevated cholesterol, so I'm willing to take a chance."

If approved by the FDA, which is now unlikely given the recommendation of the advisory committees, lovastatin would be sold by GlaxoSmithKline, which recently licensed the US rights to OTC Mevacor from Merck. A decision from the FDA is expected in early 2008.

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