J&J/Merck is still pursuing an Rx-to-OTC switch of a 20 mg dose of the cholesterol-lowering therapy Mevacor (lovastatin), according to VP-Global Regulatory & Scientific Affairs Edwin Hemwall, PhD.

"We've been working with FDA quite productively to develop the type of labeling that needs to be tested, and working with them on the testing methodologies," Hemwall commented.

"It's probably believed that after our negative advisory committee meeting that the companies have given up on this endeavor, but in fact we're still trying to answer what we hope to be the final questions to bring it again in front of an advisory committee if necessary," he said.

There has been relatively little public discussion of OTC statins since FDA's Nonprescription Drugs & Endocrinologic & Metabolic Drugs advisory committees convened in January 2005 to review the Mevacor switch proposal. The committees voted 20-3 against the switch (¹ Also see "Mevacor OTC Panel Rejection Elicits Third Drug Class Talk" - Pink Sheet, 17 January, 2005., p. 3).

Despite the "many positive votes" from the committee on issues such as drug-drug interactions and liver side effects, the vote against approval organized around the concern about self-selection, Hemwall stated.

FDA feels "there needs to be a higher percentage of people appropriate to use the drug than there were shown in CUSTOM, where there were a larger number of especially underage and lower risk women using the product," Hemwall said.

"The focus of our research since that time [has been] to develop labeling and testing that can demonstrate that more of the right people are using" the drug and that women at lower risk can appropriately decide against its use.

As the company continues to pursue OTC status for Mevacor, an article published in the March 15 American Journal of Cardiology may provide additional support for the proposed switch.

The piece by former NDAC chair and Merck consultant Eric Brass, MD/PhD, Harbor-UCLA Center for Clinical Pharmacology, et al., analyzes data from Merck's Consumer Use Study of OTC Mevacor (CUSTOM) trial to determine the large-scale impact of OTC statin availability.

"On the basis of the 10-year Framingham risks calculated, the use of OTC lovastatin would result in the prevention of 33,124 CHD events per 1 mil. users within 10 years," the authors conclude.

CUSTOM was presented by the company during the January 2005 advisory committee meeting (² Also see "FDAers Sink Mevacor OTC At Panel Meeting With Unflinching Critique" - Pink Sheet, 17 January, 2005., p. 7).

The trial recruited consumers through advertising to visit a study site that simulated a pharmacy setting where 20 mg lovastatin was available for purchase. Of the 3,316 participants who visited study sites, 1,061 bought and used OTC lovastatin.

In their recent analysis, Brass et al. looked at participants' CHD risk factors and the relative risk reduction expected from use of 20 mg lovastatin, then extrapolated the findings to determine what the effect of OTC statin use might be over time.

CUSTOM participants' 10-year CHD risk (MI or coronary death) was estimated using the Framingham Point Scoring System.

Brass et al. assigned 981 CUSTOM participants into different risk strata depending on their Framingham Risk scores. The authors then calculated the number of CHD events prevented with OTC lovastatin use by using the Framingham score and the relative risk reduction associated with the drug.

Based on previous studies, the authors estimated for this analysis that lovastatin 20 mg is associated with a 25% relative risk reduction for CHD events.

The study "shows that there is a substantial number of people that could benefit from having access to a drug, even with the more modest effect that is seen with the lower dose of statin," Hemwall commented.

"The type of people that are interested in the product, that participated in this all-comers study, are people that can benefit. And even those that probably should have had doctor care were at least getting some benefit," he said.

According to Brass, the article provides a quantitative framework for debate about a statin switch. Previously, debate "has been based on presumptions about how consumers would behave, and what the implications of that behavior would be," he said in an interview.

"My intent was not to be lobbying for or against [a statin switch], but to try to elevate the debate into a more data-driven, evidence-based conceptualization," Brass said.

In addition to looking at the number of CHD events that could be prevented with OTC statin use, the authors consider factors such as inadequate treatment of higher risk individuals that could potentially "offset" the public health benefit of nonprescription statin sale.

"To the degree that consumers use OTC lovastatin instead of supervised, optimal statin therapy, the result would be an excess of CHD events in a public health model," the authors state.

"The use of 20 mg lovastatin versus no therapy would have prevented 17,250 CHD events per 240,000 higher risk OTC users. This would be in addition to the 15,874 events prevented in the lower and moderate risk CUSTOM subsets"

Comparatively, if those some 240,000 higher risk OTC users had received "optimal" supervised care, "34,500 CHD events would have been prevented; thus, OTC availability could be viewed as having resulted in an excess of 17,250 CHD events."

However, even in a "worst case scenario" of 30% of higher risk CUSTOM users taking an OTC statin rather than being supervised, "6,900 net events would still have been prevented among the higher risk subjects after allowing for the excess events resulting from suboptimal therapy," the authors state.

According to Brass, "people, including myself, in the past have said that there is the potential for this diversion from care to have a larger negative impact than the theoretical positive impact of reaching the targeted consumer."

"What we've done is used the CUSTOM data to show that the magnitude of that impact is not as big, not as negative as many would have feared," he said.

"One can still get a net positive public health benefit, but [the CUSTOM data] emphasizes the importance of optimizing the label and other marketing strategies to enrich the population to the degree possible with the intended target population," Brass said.

"The goal of the label is to make sure that OTC statins are being used instead of 'no therapy,' to which they are clearly superior, instead of supervised care for those who need it," he said.

"Dr. Brass' analysis shows that that so-called diversion from doctor care did not substantially reduce the overall benefit to the larger population," Hemwall said.

- Bridget Behling

Merck Regroups On Mevacor Switch; Could CUSTOM Analysis Pave The Way?

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