Mevacor Study Comparing Rx, OTC Use Is Among FDA Panel Suggestions

Merck should conduct a head-to-head comparison study of Mevacor use in prescription and over-the-counter settings, Endocrinologic & Metabolic Drugs Advisory Committee member William Tamborlane, MD, said during a review of Merck's OTC switch application for lovastatin 10 mg.

Yale University School of Medicine's Tamborlane proposed a "study that actually would compare the prescription use versus the standard 10 mg dose [administered OTC] over a relatively short term, a year or something like that, [to determine] if you had comparable lipid-lowering effect."

Office of Drug Evaluation I Director Robert Temple, MD, indicated an interest in the recommendation. "You might take a population...and randomize them to aggressive monitoring by a physician, [which would allow dose] titration, or alternatively, to just give them 10 mg and ignore them," Temple said. The endpoint of such a trial would be a reduction in LDL-cholesterol.

The Nonprescription and E&M Drugs Advisory Committees voted 11-1 that Merck failed to adequately demonstrate consumers could achieve clinical benefit with the product in an OTC setting.

Merck is seeking an OTC indication to treat men at least 40 years of age and postmenopausal women with total cholesterol levels of 200 mg/dL to 240 mg/dL and low density lipoprotein-cholesterol levels of at least 130 mg/dL.

The suggestion for a head-to-head comparison study followed a discussion of how efficacy could be demonstrated in the target OTC population. NDAC Chair Eric Brass, MD/PhD, initially suggested a long-term clinical trial with cardiovascular endpoints would be necessary.

Merck Clinical & Regulatory Development Senior VP Eve Slater, MD, argued such a study would require "tens of thousands of patients for an extraordinarily long period of time to absolutely defer this decision to a point when it will be likely irrelevant."

While committee members unanimously agreed lovastatin 10 mg had been demonstrated to have adequate clinical benefit of reducing LDL cholesterol levels in the target population, they also voted that clinical benefit based on cardiovascular endpoints had not been shown.

Merck argued that clinical benefit could be extrapolated from a subset of the Air Force/Texas Coronary Atherosclerosis Prevention Study, which found that lovastatin 20 mg-40 mg reduced the incidence of a first coronary event by 37%. The study has already been used by Merck to expand its Rx indication to patients with average to moderately elevated cholesterol levels.

Tamborlane questioned whether it was appropriate to extrapolate the potential cardiovascular benefit demonstrated in the AFCAPS study to the OTC setting. "AFCAPS [patients] tended to have much lower HDL values than the HDL values" of patients enrolled in Merck's actual use studies supporting the OTC application.

There is no observed risk reduction in patients with HDL cholesterol levels higher than 40, FDA Medical Officer Mary Parks, MD, explained. "Importantly, in the sponsor's OTC target population, we see that 78%...had HDLs greater than 40," she pointed out.

"In other words, of the sponsor's estimated 15.5 mil. people who are eligible for lovastatin OTC, [in] about 12.5 mil. people, there is no evidence of benefit of drug treatment," Parks said. "Within the remaining 3 mil., we are not certain about the benefit of the 10 mg dose because, prospectively, it has never been [studied] in a clinical trial."

Merck Worldwide OTC Development Clinical Research Director Polly Beere, MD/PhD, pointed out that clinical trials "show the magnitude of risk reduction is related to LDL reduction independent of HDL" levels. She acknowledged "there is more absolute benefit if your HDL is lower, but that didn't influence the magnitude of treatment effect on LDL."

In Merck's OTC application for lovastatin, "there is no hypothesis other than the plausibility that some OTC eligible patients will get at least a de minimus risk reduction in CHD in a realistic (not controlled) setting," Parks argues in FDA's May 21 Statistical Review & Evaluation.

In order to determine if Mevacor should be recommended for OTC use, Temple suggested a study should "focus on a population that has a poorer HDL, because there we have the data."

Temple also asked the committees to consider a different OTC lovastatin dose. "Do you all have any sympathy for the idea that the choice of dose is a problem?...And that focusing much more on identifying a group with an explicitly low HDL would be sort of a preliminary basis for starting to do the studies to see whether it would be used OTC?"

"The question could become, can you deliver that treatment" demonstrated in the AFCAPS study with a 20 mg-40 mg dose "in an OTC setting," he explained.

NDAC member Julie Johnson, University of Florida College of Pharmacy, expressed concern that including HDL cholesterol level criteria in the Mevacor label would result in "capturing the AFCAPS population and [then] treating less effectively than the AFCAPS study," since OTC patients would not have access to a learned intermediary.

"At least you're talking about OTCness again," Temple said. "There are people who will come before you and say, well yes, the [OTC] compliance isn't as good if someone is actually with his/her physician but I'll treat so many more people...than I otherwise would and that would be a net benefit."

Brass commented that use of a higher dose may increase the sponsor's ability to convince the committees of clinical benefit based on cardiovascular endpoints. Temple's suggestion to test a higher dose in an OTC setting "would make it easier to extrapolate the benefit [from the trials used to gain Rx approval] and more challenging to show that the OTC population replicated that benefit and safety," he added.

The need "to convince the committee that the OTC population would use it the same way - to replicate that efficacy that would be seen in the prescription setting - would still be there," as would the need to define the safety in a real OTC setting, Brass said.

"In order to try and conceptualize the kind of vast body of information that you folks are asking for is just not practical," Merck's Slater maintained.

Brass questioned whether the sponsor should use the AFCAPS study as a precedent for OTC efficacy.

"It seems to be that what you've done is proved the opposite - that, in fact, you need a target to achieve that degree of efficacy and you need a learned intermediary to ensure proper dose titration," he said. There was no evidence in the sponsor's OTC program that "letting consumers do their own thing would yield that same efficacy," he maintained.

Merck proposes to market OTC Mevacor in conjunction with an extensive patient support program (¹ (Also see "Toll-Free Screening, Advice Service Would Enchance OTC Mevacor - Merck" - Pink Sheet, 17 Jul, 2000.)).