Testimony before the FDA Endocrinologic/Metabolic
and Non-Prescription Drugs Advisory Committees
Sidney M. Wolfe, M.D. Director, Health Research Group at Public Citizen
Merck is again engaged in its desperate effort to gain OTC approval for a drug that could well cause more harm than benefit were it to be approved. In today’s Chicago Tribune, a Merck spokesperson is quoted as saying their studies show “overwhelmingly favorable results that consumers can self-assess and make the appropriate decision to purchase over-the-counter Mevacor.”
On the contrary, in the company’s new SELECT study, the overwhelming majority of patients who, after reading the product label, made a decision on their own to purchase Mevacor, made the wrong decision. From 65 percent to as many as 93 percent (overall 75 percent) of people deciding on their own to purchase Mevacor in the study were not appropriate candidates for the drug (varying between men and women and which part of the SELECT study they were in). The FDA medical officer who made this analysis commented that these results were “sobering.”
Among the reasons why the decisions in the SELECT study to purchase were wrong and potentially dangerous for such a large proportion of people were:
- 21.5 percent of people deciding on their own to purchase OTC Mevacor had a less risky cardiovascular risk profile than the threshold (5 percent or higher risk of coronary heart disease-CHD-in 10 years) for which there is evidence that the drug would be of any benefit to them. This large proportion of purchasers would therefore be exposed to the risks of Mevacor-such as liver damage, muscle damage and other adverse effects-without evidence of any benefit.
- Others who decided on their own to purchase OTC Mevacor did not qualify for primary prevention (the intended OTC indication) because they had already had a heart attack, stroke or other evidence of cardiovascular disease. On average, about 30 percent of those participants with CHD, diabetes or stroke wanted to purchase the product. One-half of those in this group who were already taking prescription statins or other lipid-lowering drugs indicated they would instead switch to OTC Mevacor, which, for most of these people, would mean substituting a weaker statin for the drug they were currently using. This could clearly lead to deterioration in treatment for their cardiovascular disease. In addition, almost one-third of those making a purchase decision to use OTC lovastatin who were already on another lipid-lowering drug said they would add the OTC statin to the prescription drug they were already taking. According to the FDA Briefing Document for this hearing, “taking two statins or another statin with a lipid-lowering drug may increase the risk of myopathy/rhabdomyolysis.” 
- Many women of child-bearing age who were too young (<55) to qualify for the drug nevertheless made decisions to use the drug. If they should become pregnant, they would expose the fetus to the only pregnancy Category X drug that would be approved for OTC use. (FDA Definition: “Human/animal fetal risk outweighs clinical benefit”)
29 percent of women who made the assessment in the SELECT study that they were candidates for the drug were actually younger than 55. In the previous USE study, presented at the 2005 meeting of this committee, 11 percent of women who decided to purchase and use Mevacor were younger than 45 years of age and, therefore, that study, according to the FDA reviewer, “failed to demonstrate that women of childbearing potential would avoid using this product based on selection by age alone”.
Although Merck attempted to get lovastatin reclassified so it would not be in such a dangerous pregnancy risk category, their attempt was rejected by the FDA and the current Pregnancy Category X labeling reads:
…cholesterol and other products of the cholesterol biosynthesis pathway are essential components for fetal development, including synthesis of steroids and cell membranes. Because of the ability of inhibitors of HMG-CoA reductase such as MEVACOR to decrease the synthesis of cholesterol and possibly other products of the cholesterol biosynthesis pathway, MEVACOR is contraindicated during pregnancy and in nursing mothers. MEVACOR should be administered to women of childbearing age only when such patients are highly unlikely to conceive. If the patient becomes pregnant while taking this drug, MEVACOR should be discontinued immediately and the patient should be apprised of the potential hazard to the fetus (see PRECAUTIONS, Pregnancy).
A recently published NIH review of reports of pregnancy exposure in women using statins found that “of 214 ascertained pregnancy exposures, 70 evaluable reports remained after excluding uninformative cases. Among 31 adverse outcomes were 22 cases with structural defects, four cases of intrauterine growth restriction, and five cases of fetal demise.” The authors concluded that “while a small case series is unable to test the hypothesis of statin teratogenicity, the patterns of defects seem sufficiently provocative to indicate that this hypothesis be pursued fully.”
In the UK, where one statin, simvastatin, was made available behind-the-counter with pharmacist intervention in 2004, there were serious concerns about this kind of availability of the drug. Major concerns expressed by pharmacists, who were surveyed after the program had been implemented, included the need for full cardiovascular risk assessment of patients before deciding on the use of the statin and access to full clinical information prior to statin use.
I agree with Dr. Frank Davidoff, former Editor of the Annals of Internal Medicine and formerly a member of this committee as well as one of the 20 members opposing the OTC switch in 2005, who stated in an article in Clinical Pharmacology and Therapeutics that:
The efficacy of primary prevention with statins, estimated from AFCAPS/ TexCAPS to be an NNT [number needed to treat] of about 35 patients treated for six years to prevent one cardiovascular event, thus melts away under conditions of OTC use. In effect, approving statins for OTC primary prevention would amount to a huge uncontrolled experiment, in which neither the benefit nor the risk side of the equation was known.
When I recently called Dr. Davidoff to see if his opinion had changed in the past two years, he replied that: “I haven’t changed my mind. If anything, I’m probably less enamored of the idea than I was before, partly because the number of people taking prophylactic low-dose ASA has grown so much, partly because the toxicities and side-effects of statins have become clearer.”
In summary, the contrast between rational and successful OTC use of analgesics and antihistamines versus a statin such as lovastatin could not be sharper. For pain and allergies, the ability for people to make an accurate assessment of these symptoms, to quickly be able to measure the success of the treatment on the symptoms and to adjust the dose accordingly based on these assessments is quite clear. For statins, none of these criteria are met. In addition to the necessary measurement of total and/or LDL-cholesterol in such asymptomatic people, the need to consider a myriad of additional risk factors makes an accurate assessment as to whether someone is or is not a candidate for primary prevention extremely limited, as evidenced by the “sobering” results of the SELECT study. In addition, the ability to assess the impact of treatment and to adjust the dose is similarly extremely limited, at best.
As in earlier testimonies at the 2000 and 2005 FDA advisory committee meetings, we strongly oppose the switch of lovastatin or any other statin to OTC status. With each look at the latest evidence, the case against such a switch becomes clearer.
 According to 2006 IMS data, Merck’s prescription Mevacor has less than 0.25 percent of the overall market for lovastatin because of generic competition. OTC approval would temporarily grant exclusive OTC sales status to Merck for three years.
 FDA Clinical Review of Safety and Efficacy for this meeting, page 28. (in the previous CUSTOM use study, only 14 percent of participants “initially self-selected correctly according to the label without a physician’s intervention”.-page 19 of this same review)
 FDA Briefing Document, page 56.
 FDA Clinical Review of Safety and Efficacy for this meeting, page 14.
 American Journal of Medical Genetics 131A:287–298 (2004)
 Pharm World Sci (2007) 29:380–385
 Clin Pharmacol Ther 2005;78;218-20.