Healthy Skepticism Library item: 1480

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Publication type: news

Wilde Mathews A, Landers P.
An FDA Shift Could Transform Market for Statins: Agency Will Consider Allowing Over-the-Counter Sales Of Cholesterol Medicine
The Wall Street Journal 2003 Nov 12

Full text:

Statins are the best-selling class of drugs in the U.S., widely used to lower cholesterol and reduce the risk of heart attacks. With $12.5 billion in annual sales here, they’re also considered some of the most effective medicines on the market.

But are they safe enough for people to take without a doctor’s prescription?

The Food and Drug Administration will soon be facing that question. A joint venture between Merck & Co. and Johnson & Johnson is planning to ask the FDA for permission to sell Mevacor, the oldest statin drug, over the counter. Bristol-Myers Squibb Co. may eventually do the same with its competing statin Pravachol, though it declines to talk about its plans beyond saying company officials are “continuing to evaluate our options.”

The FDA gave a verdict on over-the-counter statins in 2000: No. But now there are signs the agency is ready to reconsider the issue. New studies and medical guidelines say that more people could benefit from anticholesterol drugs such as statins, while years of wide use argue that the drugs are broadly safe and effective. At the same time, the FDA commissioner says he wants to encourage more over-the-counter drugs, which he believes can help increase access and lower costs for consumers, though he declines to comment on statins in particular.

Switching statins to over-the-counter status could transform the market for one of the most important drug categories. Pfizer Inc.‘s Lipitor, the top-selling statin, could be hurt by less-expensive nonprescription rivals. On the other hand, Pfizer may be able to promote Lipitor, which is expected to top $5 billion in U.S. sales this year, as more powerful than over-the-counter drugs. Pfizer has used that tactic to boost sales of its allergy drug Zyrtec, which competes with over-the-counter Claritin.

A statin switch could also affect the treatment of millions of people by making the drugs more easily accessible. Cardiovascular disease, which includes a range of heart problems, is the single biggest cause of death in the U.S., responsible for killing about 950,000 people each year — one in every 2.5 deaths. Federal guidelines released in 2001 suggested that as many as 36 million people in the U.S. might need some sort of cholesterol-lowering drug, most likely a statin, to reduce their risk of heart attacks. Currently, more than eight million Americans are estimated to take statins.

Meanwhile, if the FDA approves the change, it could open the door for the agency to consider switching medicines in other areas, such as hypertension and birth control, that haven’t traditionally been viewed as over-the-counter candidates.

Back in 2000, when weighing whether to let statins be sold over the counter, FDA advisers questioned whether consumers, without a doctor, could make the right decisions about how to treat such a potentially serious problem. They also asked if the benefits of the low proposed over-the-counter dosage outweighed risks tied to the drugs, which include occasional muscle ailments that can become serious and very rarely fatal.

A switch for statins could signal a shift at the FDA, which has almost always reserved over-the-counter status for medicines that ease temporary symptoms, rather than chronic conditions without symptoms. Even aspirin makers aren’t allowed to have consumer labels touting a daily dose to help prevent heart disease.

Now FDA Commissioner Mark McClellan says he sees a potentially broader role for over-the-counter medicines in general. “There’s certainly a broader range of products being developed and products out there that we need to consider” for over-the-counter availability, says Dr. McClellan. In cases where drugs are sold over the counter now, “the experience is much wider use and much lower cost, and that translates into broader access to the treatments and better public health.” He declines to speak about specific drugs, saying each will be reviewed on its merits.

An over-the-counter face-off would be the latest phase of a decade-long battle between Merck and Bristol-Myers. In 1987, Merck unveiled Mevacor, which, like other statins, works by stopping the activity of an enzyme that triggers production of a type of cholesterol called low-density lipoproteins, or LDL. In 1991, Bristol-Myers launched its own statin, Pravachol. Then more potent statins began entering the fray. Merck unveiled Zocor in 1992, and five years later Pfizer started selling Lipitor. Merck put most of its marketing muscle behind Zocor. Bristol-Myers’s Pravachol fell to a distant third behind Zocor and Lipitor.

By the late 1990s, Bristol-Myers and Merck were ready to consider a new path for Mevacor and Pravachol: over-the-counter sales. It was a bold gambit, because it was clear that the FDA frowned on the idea. Bristol-Myers was turned back in 1995 and 1997 when it sought to take an older-generation cholesterol drug over the counter. Then in 1997, the FDA published a document that said it didn’t think cholesterol drugs were appropriate for nonprescription use. And the agency wouldn’t guide companies seeking such switches — a major handicap.

Bristol-Myers and Merck plowed ahead anyway. Both companies’ drugs would lose their U.S. patent protection within a few years — 2001 for Mevacor and 2006 for Pravachol — after which they would likely face competition from a host of generics. A 1984 law offered the companies another big incentive: If the companies got over-the-counter approval, they would get exclusive rights to sell their drugs in that market for three years, provided they had to do clinical studies to justify the changeover. This would give the companies time to build consumer awareness before generics flooded the over-the-counter market.
STATIN STORY
Key events in the history of cholesterol-fighting statins
1987: Merck’s Mevacor, the first statin, goes on the market.
1991: Bristol-Myers Squibb starts selling the second statin, Pravachol.
1992: Merck brings a new, stronger statin called Zocor to the market.
1995: Bristol-Myers fails to get FDA approval to sell an older cholesterol-lowering drug over the counter.
1997: Pfizer begins selling Lipitor, today the top-selling statin.
2000: Merck and Bristol-Myers fail to get FDA approval to sell Mevacor and Pravachol over the counter.
2001: Mevacor loses patent protection.
2003: Merck says it will try again to get over-the-counter approval for Mevacor; Bristol-Myers studying the idea for Pravachol.
2006: Zocor, Pravachol to lose patent protection.
2011: Lipitor to lose patent protection.

On July 13, 2000, an FDA advisory committee gathered for a two-day session at a Bethesda, Md., hotel. On the first day, the group weighed Mevacor. Merck presented a series of studies showing that Mevacor could cut cholesterol and carried few risks. The company — which had formed a joint venture with Johnson & Johnson to tap J&J’s over-the-counter expertise — promised detailed labeling and education efforts to ensure consumers used the drug properly.

FDA officials took a skeptical tone. One said there was “no evidence from controlled clinical trials” that the low dose proposed by Merck, 10 milligrams a day, could bring a clinical benefit to the recommended consumers. The agency raised concerns that consumers might not be able to monitor the drug’s risks, particularly when combined with other medicines. Potential side effects for all statins range from muscle ache or weakness all the way up to a very rare, severe muscle condition called rhabdomyolysis, which is potentially fatal if not treated quickly enough. Patients taking statins are supposed to get regular blood checks for elevated liver enzymes, which could possibly indicate a liver problem.

On the most important question — whether Mevacor should be approved for over-the-counter use — the committee’s vote was lopsided. One member said yes, and one abstained. Eleven voted “no.”

The next day, Bristol-Myers executives gave their pitch. They aimed their low dose, also 10 mg, at a population with a slightly different age range than Merck had targeted. The committee decided 12-2 against the switch.

But below the surface, there were signs of hope for the companies. The committee voted that both drugs would be safe in an over-the-counter setting and could help cut cholesterol for the target population. Several members said their concern was the low doses hadn’t been widely shown to prove clinical benefits such as reducing the risk of heart attacks for a population without an immediate heart-disease risk.

The committee meetings helped spark a change in the FDA’s thinking. “The basis on which they were turned down was not that this was a complete nonstarter … but that additional work needed to be done,” says David Orloff, who heads the FDA’s division of metabolic and endocrine drug products. On Aug. 3, 2000, the agency withdrew the document that opposed over-the-counter cholesterol drugs. And FDA officials were ready to talk to the companies about how they could prove their drugs could meet the agency’s requirements.

Dr. Orloff says statins should be reconsidered, citing the “increasing recognition of the widespread heart-disease risks in the population, the information that’s come on the benefits of statins, and a tremendous experience that speaks to their safety and tolerability.”

Still, to succeed this time around, the companies will have to convince the FDA of several things: that over-the-counter status would indeed get statins to more of the people who need them; that consumers will be able to take the drugs properly and handle their risks; and that patients who need more serious treatment will still get it, rather than simply buying the prescription-free pills.

According to industry and government officials, there have been continuing conversations about what kind of research is needed to prove that case. Bristol-Myers declines to comment on whether it has discussed Pravachol with the agency. FDA officials never comment on the status of existing or potential drug applications.

Executives at the Merck/Johnson & Johnson joint venture say they’re ready to try again, though they decline to say when, and they have crafted their new plan with FDA input. To respond to the committee’s concerns about the very low dose, the new Mevacor over-the-counter proposal will double the amount, to 20 mg a day. It will also come packaged with much more consumer information and offer additional resources on a Web site. And the drug’s backers are doing an elaborate six-month trial to make sure that consumers follow the directions properly and will see a doctor if they move outside the guidelines on the drug’s labeling, which include recommended cholesterol levels and age ranges.

New health recommendations and research seem to justify broader use of the statins. In May 2001, the National Cholesterol Education Program, a quasigovernmental group, released guidelines that called for an expanded role for drugs, particularly statins, in treating people at high risk for cardiovascular disease, such as those with diabetes. The report didn’t take a stand on nonprescription statins, but it did say that people at risk of heart disease should see a doctor.

A study of more than 20,000 people, unveiled in November 2001 and later published in the Lancet, found that a broad range of patients at risk of heart disease, regardless of cholesterol levels, could benefit from a statin. Zocor, the drug used in the study, cut the rate of heart attacks and strokes by a quarter. Merck was among the co-sponsors of the study with the U.K. Medical Research Council and the British Heart Foundation. Researchers said they alone were responsible for the study’s data collection and analysis.

Even as evidence of their benefits has piled up, statins have drawn questions about side effects. In 2001, Bayer AG withdrew the statin Baycol after 31 patients in the U.S. reportedly got rhabdomyolysis and died while taking the drug. An analysis published in the New England Journal of Medicine in 2002, based on FDA and industry data, found that the reported deaths appeared far more frequent for Baycol than any other statin.

In response, several leading medical associations recommended that doctors monitor patients taking statins, though the groups found the drugs “extremely safe in the vast majority of patients.” The consumer group Public Citizen called for stronger warnings on the labels of statins.

In the agency’s budget request for the current fiscal year, now pending in Congress, Dr. McClellan is seeking extra money to bulk up the FDA’s over-the-counter division, to help smooth the review of such drugs. There are strong incentives for companies to consider the changeovers. Generic competitors are growing stronger, which cuts into the exclusivity of brand-name drugs. Patients are growing more sophisticated, and more willing to seek out treatments on their own. And some insurers and employers, hoping to encourage more over-the-counter switches and cut down on rapidly increasing prescription costs, are increasingly willing to help pay for over-the-counter treatments.

Recent switches show the potential. Schering-Plough Corp.‘s Claritin went over the counter in December 2002, and it has recorded $319 million in over-the-counter sales in the first nine months of this year. Prilosec made the switch in September, and Procter & Gamble Co., which markets the drug, credited it with driving a 23% increase in its health business during the third quarter.

It’s too early to know what effect Prilosec’s switch has had on the prescription market. Claritin’s effect has been mixed. Pfizer’s Zyrtec has thrived by presenting itself as a more effective alternative. U.S. sales of Zyrtec rose 22% in the first three quarters of 2003 to $980 million. But U.S. sales of Allegra, a prescription allergy drug sold by Aventis SA, have fallen by 15%, or $201 million, to $1.1 billion in the first three quarters of this year. That followed double-digit growth in previous years.

Both Prilosec and Claritin have pushed the envelope on over-the-counter pricing, selling at nearly a dollar a pill. Merck/Johnson & Johnson would likely aim for that price with an over-the-counter version of Mevacor. The 20 mg dose of Mevacor now retails for a little more than $2 a pill.