A joint FDA advisory committee review of J&J/Merck's nonprescription Mevacor Daily centered in part on long-term consumer compliance with the indicated cholesterol-lowering regimen.

Some members of FDA's Nonprescription Drugs and Endocrinologic & Metabolic Drugs advisory committees expressed concern over a lack of study data with a follow-up period of longer than 18 months.

The panels voted 20-3 with two abstentions that Mevacor should not be marketed over the counter.

NDAC panelist Neal Benowitz, MD, University of California-San Francisco, compared the prospects of compliance for an OTC low-dose statin to nonprescription smoking cessation therapies.

"Even for the short-term, for three months, OTC [smoking cessation] instruction compliance is terrible," Benowitz asserted during the Jan. 13 joint panel meeting in Bethesda, Md. "Most people stop taking it after a few weeks."

"The more you comply, the better you do, and I'm very concerned that this six-month trial will not reflect the six years that it takes" to reduce cholesterol to the specified level, Benowitz said.

J&J/Merck VP-Global Regulatory Affairs Ed Hemwall, PhD, countered that compliance for the OTC 20 mg lovastatin dose compared favorably to Rx statin studies.

"I think we do have some good data - it's certainly not five- or six-year data - but this is data that are fairly unique for an OTC drug," Hemwall explained.

An 18-month compliance study from Merck's earlier 10 mg dose program found more than half of patients were still taking the nonprescription statin at the end of the trial.

"These numbers actually compare very favorably to what is seen in the prescription environment and their numbers are, in some cases, dramatically worse than this," Hemwall claimed, citing Rx compliance rates in the 30% range. He also pointed out that similar Rx statin studies did not last longer than two years.

Hemwall maintained that chronic, asymptomatic OTC therapy has a "strong precedent with OTC aspirin, which people take every day fairly easily and simply without any concern."

"We have very good data from the aspirin manufacturers on this regular compliance over the long term," said Hemwall.

Hemwall called the compliance data "typical of the user that might use a product like this: the heart-healthy motivated consumer, which would again show that they would have higher compliance levels possibly than their prescription counterparts."

Mevacor Daily targets potential users with LDL cholesterol in the 130-170 mg/dL range, plus one or more CHD risk factors including smoking, high blood pressure and HDL cholesterol below 39 mg/dL.

The 20 mg dose is intended to lower an individual's LDL to less than 130 mg/dL.

NDAC chair Alastair Wood, MD, Vanderbilt University, questioned how the target population would have the ability to self-diagnose against a gold standard of physician care when doctors were unable to appropriately diagnose the same group of patients for high cholesterol and prescribe a statin.

"It seems to me that there's an underlying assumption that is somewhat untested and probably wrong," Wood said. "That is, the comparison for OTC lovastatin that should be made is one against physician care, which is 100% perfect - and that's what I mean by probably wrong."

"The first way we know it's wrong is that almost the only way that someone can get cholesterol measured is by going to a physician, so almost by definition the population you have studied have to be a population of patients who have failed to receive adequate cholesterol control in spite of being seen by a physician," Wood continued.

He added that consumers did not follow warnings of toxicity on Rx statins even though they were under the supervision of a doctor.

"There's an unspoken assumption, which is also I think probably wrong, and that is if patients indeed saw a physician, that the warnings would be clearly followed explicitly and absolutely," Wood maintained. "We know from lots of data [from Bayer's recalled statin Baycol and other recalled drugs] that only a tiny percentage of patients were following the specific monitoring warnings."

Wood concluded: "I was a bit surprised that you all did not address that in the presentation."

Merck presenter Jerry Cohen, MD, St. Louis University, responded that the sponsor was unable to determine whether physicians diagnosed patients inappropriately or patients did not follow through on obtaining prescription cholesterol-lowering therapy.

"What is unique about this population is that it is an OTC-driven type population where they say 'an Rx is for a sick guy...I am a healthy person, I'm concerned that my cholesterol is too high,'" Cohen remarked.

J&J/Merck VP-New Product Development & Consumer Research Jerry Hansen described the target population as "very active in their own healthcare" and more likely than the average consumer to engage in dieting and exercise, take aspirin for heart health and use vitamins and nutritional supplements.

Hansen cited data from a National Consumer League survey in which 76% of untreated or known moderate risk respondents said they would be more likely to consider taking an OTC statin than an Rx statin, indicating a preference for self-medication.

The meeting also included an extensive discussion on Mevacor Daily's contraindication for pregnant women.

J&J/Merck hinted FDA's Category X (human fetal risk outweighs clinical benefit) contraindication for pregnancy may be excessive, although the firm is not disputing the designation. An FDA assessment of recent neurodevelopmental data found potential fetal risk resulting from lovastatin exposure.

However, a Merck consultant maintained the data represent "non-specific findings, not indicative of a direct fetal toxic or teratogenic effect," and that lovastatin "certainly has an adequate safety margin relative to other over-the-counter products."

"There's no evidence that we've seen in our database that exposure during early pregnancy is associated with increased risk of any specific congenital anomaly," Hemwall added.

Hemwall claimed the data suggest a fetal risk "very much similar to what would normally be a Category C [no human/animal studies show fetal risk] drug," but lovastatin is designated Category X due to a lack of clinical benefit in pregnant women.

"The risk to a mother who has an inadvertent exposure, however much we try to minimize the frequency of that event, is very low, especially compared to the overall benefit to the large population of people that should be getting this drug, lowering their cholesterol and lowering their risk of cardiovascular disease," Hemwall concluded.

FDA Division of OTC Drug Products Director Charles Ganley, MD, said he was less concerned with late-stage pregnancy and more with CUSTOM's results indicating that women of child-bearing age used the product contrary to label directions.

"I think the issue that I have is this child-bearing potential and what really is that risk in that first trimester," he explained. "If [the label] said that this is for a woman [older] than 55, why did women [younger] than 55 take it other than being overridden by a doctor?"

Some panelists suggested more specific pregnancy labeling. NDAC member Leslie Clapp, MD, asserted she was "not sure if there is clarity on the package with regard to the reasons that women under 55 should not take the medication."

There is "room to strengthen the message in the Mevacor label beyond just 'do not use if you are pregnant or breast-feeding,'" Hemwall noted. He drew a comparison to non-sedating antihistamines, which carry "specific labeling warnings about not using the product in the third trimester."

The panels also discussed the possibility that a 20 mg dose of lovastatin could cause liver damage. J&J/Merck maintained liver-related risks were minimal for the target population.

"In all the [statin] clinical trials that have been done, there really has not been a signal for clinically significant liver disease relative to placebo arms," said Merck consultant Paul Watkins, MD, University of North Carolina.

Watkins called the risks of developing liver injury as a result of statin use in combination with pre-existing liver disease "very small."

Hemwall further noted that a 7,000-patient Kaiser Permanente study currently is underway examining the relationship between lovastatin and liver abnormalities, with early results indicating the incidence of liver disease may be higher in patients not taking lovastatin.

Mevacor Daily Regimen Compliance Questioned By FDA Committees

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