FDA Advisors Say Greater Insight Needed On Self-Selection Of OTC Statins

More information from "real world" experiences on how consumers make OTC selections may be needed to pull off a successful Rx-to-OTC switch of a statin.

FDA's Nonprescription Drugs and Endocrinologic and Metabolic Drugs advisory committees on Dec. 13 recommended against approving Merck's third switch application for OTC Mevacor Daily .

Some members suggested Merck should have conducted another actual use study following its unsuccessful 2005 application in addition to modifying the proposed label and performing new label comprehension studies.

Meeting in Silver Spring, Md., the committees voted 10-2, with one abstention, against recommending Merck's proposal to switch its lovastatin 20 mg cholesterol-lowering drug.

The joint panel also voted 11-2 that Merck's consumer behavior study did not demonstrate consumers can make an appropriate self-selection decision on their own.

Merck sought an indication for Mevacor Daily to be used for the prevention of a first heart attack and for use in women age 44 and older and men age 45 and older with moderately elevated cholesterol and one or more heart disease risk factors (¹ (Also see "Merck’s Mevacor Returns For OTC Switch Consideration" - Pink Sheet, 29 Oct, 2007.), p. 10).

Ed Hemwall, Merck's VP of global OTC regulatory and scientific affairs, said the firm "presented a compelling case to the committee" that the switch "would be a valuable option for motivated consumers who know they have moderately elevated cholesterol and certain risk factors and are already talking with their health care provider."

Hemwall told "The Tan Sheet" the panel's recommendation does not appear to reflect the information presented in the meeting. Additional time for the committees to consider and discuss the information would be valuable, he said.

"We, including FDA, continue to underestimate the unpredictability of the advisory committee process and the overall difficulty of helping them reach a consensus on the complexities of a switch application and consumer behavior within the span of a few hours," he said in an e-mail.

One of the committee members who voted in favor of approval, Thomas Pickering, a cardiologist and an assistant professor at the Columbia University Medical Center, said the benefits outweigh the risks.

However, members who voted against the approval said they were concerned about inappropriate self-selection.

"It seemed to me the patients couldn't figure out whether the drug was for them," said William Shrank, an instructor at Harvard Medical School's Division of Pharmacoepidemiology and Pharmacoeconomics.

Merck Says SELECT Refutes Doubts

In Merck's 2005 switch attempt, the panel suggested more insight was needed - beyond the data from the firm's Consumer Use Study of Over-the-Counter Lovastatin study - to determine if consumers could self-select in an unsupervised setting (² (Also see "Merck Regroups On Mevacor Switch; Could CUSTOM Analysis Pave The Way?" - Pink Sheet, 20 Mar, 2006.), p. 4).

Merck's third application included data from its latest study, Self-Evaluation of Lovastatin to Enhance Cholesterol Treatment. Conducted in seven U.S. cities in 2006, SELECT evaluated consumers' decision-making in an attempt to learn more on the reasoning behind those decisions (³ (Also see "Merck’s Mevacor Switch Bid Digs Deeper Into Consumers’ Self-Selection" - Pink Sheet, 10 Dec, 2007.), p. 8).

Hemwall told "The Tan Sheet" the most "legitimate concern" of the committee was "the participants in the SELECT study who were already on lipid-lowering therapy and wanted to use Mevacor Daily."

However, he said consumer behavior in the study was "exaggerated" by the recruitment which "attracted people already taking the medication."

"Enhanced labeling and the complete consumer support and education program would minimize this situation in the market," Hemwall added.

The committee discussed the need for more realistic, actual-use studies of how consumers would act in an unsupervised setting, with several saying "real world" information is needed to determine whether to switch statin drugs or other Rx products.

"The interest ... is to do an actual use study so people are replicating what would happen in a real-world environment that they would indeed make an appropriate decision in terms of purchasing," said Mary Tinetti, chief of the geriatrics division at Yale University's School of Medicine and chairwoman of the panel.

Old Information Not Enough

At a briefing following the meeting, Tinetti said Merck did not present sufficient new data to convince the panel to support the switch.

"The only new data that were presented to us today was a change in the label from the labeling that we saw in 2005," she said.

"In 2005, there was a concern that people didn't quite understand some of the issues so [Merck] thought if they changed the label people would select themselves better. They did not repeat an actual use study."

Tinetti noted as an example that the panel was concerned whether consumers with high LDL would comply with Mevacor Daily usage instructions.

The panel would want to see "some measure of adherence that they would get their LDL checked in appropriate times" as well as "evidence ... that indeed LDL did improve, or if it didn't, that they took appropriate action," she said.

The committee discussed the amount of information on the new label, with some members raising concerns it may be too much information for consumers to absorb at one time.

"My own personal opinion is that the more information you put on the label, the less each of those pieces of information will be absorbed," Tinetti said at the briefing. "And that we have to learn ... entirely new paradigms for how we provide consumers with the information that is necessary to make an informed decision."

The committees also voted 9-4 that the presentation by the firm supports adequate consumer understanding of the pregnancy and potential pregnancy warnings on the label. The panel also voted almost unanimously, 12-1, that the data support adequate consumer understanding of the muscle pain warning.

NDAC member Ruth Parker pointed out the warning not to use the product if allergic to lovastatin is high on the label, but the pregnancy warning was 20 to 25 lines below that.

"What am I supposed to think about that if people have trouble reading" through the label? asked Parker, a pediatrician and a professor at the Emory University School of Medicine.

The members voted 9-3, with one abstention, that Merck's data demonstrates consumers with common asymptomatic liver disease can safely use the product at 20 mg without liver function monitoring.

The committee also voted 10-2, with one abstention, against a total cholesterol-based label approach during their discussion of Merck's self-selection tests using different labels with LDL criteria or with total cholesterol criteria.

National Cholesterol Education Program guidelines use LDL criteria as the basis for determining therapeutic targets and selecting populations for treatment. The 2005 joint panel that discussed OTC lovastatin 20 mg agreed the population of subjects selected using an LDL-based label paradigm was appropriate for drug treatment.

Mevacor first faced the panel in 2000 alongside Bristol-Myers Squibb's application to switch its statin, Pravachol (pravastatin). Bayer is currently pursuing a switch of the drug under an agreement with BMS (⁴ 'The Tan Sheet' July 2, 2007, In Brief).

FDA's Director of the Division of Nonprescription Clinical Evaluation, Andrea Leonard-Segal said FDA is "open-minded" when asked if the agency would consider a fourth attempt by Merck.

"We have not formulated a final decision," she said. "We are going to think about the interesting and informative thoughts that we heard expressed by different committee members and then we will make the decision about what to do."

According to a statement, Merck expects FDA to make its decision by Jan. 26.

- Katie Stevenson ([email protected])