An FDA Shift Could Transform Market for Statins

November 11, 2003 
 
PAGE ONE  
  
An FDA Shift Could Transform Market for Statins
Agency Will Consider Allowing Over-the-Counter Sales Of Cholesterol
Medicine

By ANNA WILDE MATHEWS and PETER LANDERS 
Staff Reporters of THE WALL STREET JOURNAL


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.
 
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.

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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.
  
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