San Francisco Chronicle
February 27, 2005

The side effects of drug promotion
Aggressive ads for painkillers left more patients exposed to risks
- Bernadette Tansey, Chronicle Staff Writer

The painkillers Vioxx, Celebrex and Bextra may go down in history as a
classic example of the danger posed by aggressive industry promotion of
prescription drugs to both patients and doctors.

When Vioxx and Celebrex hit the market in the late 1990s, they were
touted as a breakthrough class of arthritis drugs that would help avoid
ulcers and other digestive ailments linked to medicines such as
aspirin.

With their debut coinciding with a surge in advertising aimed directly
at consumers, they and Bextra, which was approved in 2001, quickly
became one of the most heavily promoted drug classes.

In 2003, their manufacturers spent more than $1.5 billion to promote
the drugs through television spots, print ads and pitches to doctors.
By 2003, sales topped $5.3 billion, according to IMS Health, a
pharmaceutical information and consulting company.

But now that the drugs have been linked to an increased risk of heart
attacks and strokes, critics say millions of people were needlessly
exposed to those dangers as intense advertising helped make the
painkillers some of the most widely prescribed medicines in the United
States.

Studies show that many patients took the expensive new drugs
unnecessarily, because they were never at risk for ulcers or other
digestive problems.

Now, as the FDA considers recommendations from an advisory panel that
it ban consumer advertising of the drugs, many health experts say the
case has delivered a harsh lesson -- that the FDA needs to change the
way drugmakers launch their new products.

Former FDA commissioner David Kessler said the rapid adoption of new
drugs -- fueled by heavy promotional campaigns -- is an inherent threat
to the public.

"The way it used to be, if a drug got approval, its use would increase
gradually over time," said Kessler, who is dean of the UCSF School of
Medicine. Thus, when unexpected side effects surfaced, he said,
relatively few people had been exposed to the risk.

In recent years, though, new medicines explode into widespread use
before they build up a safety track record, said Kessler, who prevented
the widespread use of drug commercials on television when he was FDA
commissioner. "Many more people are going to be exposed. That's the
nightmare."

Free speech battle looms

As the FDA prepares to decide how Celebrex and the other drugs, which
together are known as COX-2 inhibitors, can be marketed, some people
doubt the agency has the authority to limit consumer advertising if the
pharmaceutical industry takes it to court.

While critics say overpromotion sends poorly informed patients
clamoring to their doctors for medicines whose benefits are exaggerated
and risks are obscured, drug companies argue adamantly that patients
gain important information from advertising.

On Feb. 18, a federal safety panel advised the FDA to ban consumer
advertising of the COX-2 drugs. In general, the FDA frequently adopts
the recommendations of its advisory panels. But at the panel hearing,
the agency's director of the Office of New Drugs, Dr. John Jenkins,
said the agency lacks the power to impose the ban.

When asked to elaborate on Jenkins' comment, the FDA gave no direct
answer.

"The tools we have to regulate prescription drug promotion include
untitled letters, warning letters, consent decrees, and referrals for
criminal prosecution," according to a statement provided by the FDA
press office.

FDA can wield power

But former FDA officials, including Kessler, say the agency clearly has
the power it needs.

"I think there is no doubt that the agency could, on its own, tighten
up direct-to-consumer advertising and impose requirements on that
advertising to make sure that the promotion is in the public interest,"
he said.

Kessler's former deputy commissioner, Mary Pendergast, said the agency
can ask for voluntary advertising restrictions and can also seek court
orders telling drugmakers to curb consumer ads when such promotion
could threaten public health.

"They're not helpless," said Pendergast, now a private consultant in
Washington, D.C. "In my opinion they can bring an injunction,
especially if there have been past shame-on-you warnings" about
promotional campaigns.

History of complaints

Celebrex, Vioxx and Bextra promotions have all drawn such FDA warnings,
according to a review of agency records. Celebrex promotions to
consumers and doctors were the subject of eight separate complaints
between 1997 and 2005, spanning a period when the drug changed hands
among three different companies.

Among the accusations: Doctors were being encouraged to give as much as
double the maximum dose on Celebrex's FDA-approved label -- a
disquieting charge in light of evidence now indicating that
cardiovascular risks emerge when the drug is given at those higher
doses.

Although Bextra's manufacturer, Pfizer Inc., denies promoting the drug
directly to consumers, the FDA sent the company a letter in January
faulting a TV infomercial and direct mail brochures sent to patients
for misrepresenting or completely omitting information about serious
risks.

In 2001, the FDA faulted a Vioxx campaign denying that the drug boosted
heart attack risks, in spite of troubling evidence that had already
surfaced by then that the risk could be four or five times greater.

Neither Vioxx manufacturer Merck & Co. nor Pfizer Inc., which makes
Celebrex and Bextra, would say whether they will agree voluntarily to
forego direct-to-consumer ads permanently if the FDA requests it, or
would mount a legal battle if the FDA sought a court injunction. Pfizer
honored the FDA's request for a suspension of consumer ads for Celebrex
after Merck's voluntary withdrawal of Vioxx from the market last year
raised concerns that the whole COX-2 group increased heart risks.

Both drugmakers said they are focusing first on negotiations with the
FDA over possible changes to the drug labels that could incorporate
strong safety warnings also advocated by the advisory panel.

"The label defines everything we can say about any medication, and
until that process is completed, we're not thinking about our
direct-to-consumer advertising," said Pfizer spokeswoman Susan Bro.

Consumer pitch unfolds

The era of direct-to-consumer advertising, augmenting traditional
campaigns aimed at doctors, began in the 1980s when manufacturers of
two products ventured into the arena. At that point, the FDA requested
a voluntary moratorium on the ads while it reviewed their possible
impact on public health.

After a couple of years, the FDA withdrew the request. But for a long
period, the agency limited the use of TV ads by requiring the short
spots to include information on possible health risks. It was a rule
Kessler refused to eliminate. But once he left, drugmakers were allowed
to refer TV viewers to other sources like Web sites for the risk
information. That rule change in 1997 opened the floodgates to the
pervasive drug commercials seen today.

The first FDA complaint about misleading promotion of a COX-2
painkiller was sent the same year.

In 1997, more than a year before Celebrex received marketing approval,
the FDA accused its maker at the time, G.D. Searle, of touting it over
the Internet as "a breakthrough in arthritis therapy," and suggesting
that it caused no gastrointestinal bleeding.

That was certainly the hope held out for the COX-2 drugs as they were
being developed. Doctors needed a solution to a serious dilemma
discovered in the mid-1990s by researchers like Dr. James Fries, a
Stanford rheumatology expert. Arthritis patients needed relief from
chronic pain, but the drugs they used could cause stomach bleeding and
other gastrointestinal problems serious enough to land patients in the
hospital -- and sometimes cause deaths.

Misleading claims

But in fact, Searle was not able to get that claim of gastrointestinal
safety included in the Celebrex label when the drug was approved for
marketing. Yet Celebrex manufacturers, from Searle to its successors
Pharmacia and finally Pfizer, were each reprimanded by the FDA for
stating or implying in promotional campaigns that the drug was better
than traditional painkillers because it posed no gastrointestinal
risks.

In Bextra's case, the direct mail piece that Pfizer was warned about in
January said "your stomach stays protected," even though the drug label
lists gastrointestinal damage as a risk.

The Pfizer spokeswoman, Bro, acknowledges that the Celebrex label still
includes gastrointestinal side effects as a risk for the drug, but she
said recent studies show that Celebrex is gentler than other
painkillers.

Fries said both Pfizer and Merck are still getting away with a
"marketing ploy" by positioning their drugs as gentler on the
gastrointestinal tract than other painkillers. Although Vioxx trial
data show somewhat lower gastrointestinal impact than some of the
older, cheaper painkillers, it is no better than several others, Fries
said.

The case of the COX-2 drugs has turned Fries, who once supported
direct-to-consumer advertising, into an opponent.

"We should empower the consumer, but they should be empowered against
getting brainwashed," he said.

Closer COX-2 drug scrutiny

The scientific controversy over the COX-2 drugs is by no means over.
More studies are planned, and some FDA safety advisers have raised the
point that little is known about the possible cardiovascular risks of
some of the other painkillers used as alternatives.

The FDA safety panel, after hearing testimony that some patients might
do better on the COX-2s than other drugs, recommended keeping them on
the market. But the majority advocated so-called "black box warnings"
of the heart and stroke risks for all three drugs.

If the FDA accepts that recommendation, its decision would probably
inhibit the manufacturers from using one type of consumer ad. Under
long-standing FDA policy, drugs with such warnings can't be promoted
with "reminder ads," which simply mention the name of the drug without
identifying its uses.

Other pitches aimed at consumers would be permitted, though, unless the
FDA takes additional action as advocated by the panel. Such ads would
have to detail the drug's risks.

If the FDA does attempt to block consumer advertising for the drugs
permanently, it could be headed for a showdown with Pfizer.

Pfizer and free speech

Pfizer, the world's largest drug company, has been one of the most
tenacious industry proponents of the position that many FDA rules
restricting drug promotion violate the free speech rights of
manufacturers. That First Amendment argument has made significant
headway in a number of court cases, Pendergast acknowledged.

But she said the FDA could still win a case for promotional limits if
it marshals evidence that public health could be at risk.

"You don't have a First Amendment right to lie, to say false and
misleading things," she said.

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Perceptions are frequently wrong, particularly when based on poor
information.