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www.thestate.com/mld/thestate/7168713.htm
www.thestate.com
Posted on Mon, Nov. 03, 2003
Off-label drug sales soar
Sales reps, free samples can lead to prescriptions for unapproved uses
By CHRIS ADAMS and ALISON YOUNG
Knight Ridder Newspapers
MEMPHIS, Tenn.
Dr. Gary Murray, a cardiologist, was faced with a common
medical problem: He had no idea what was wrong with his patient.
Milton Cole, a 71-year-old man in generally good health, was complaining
of chest pains. A battery of cardiac tests couldn't pinpoint the problem. To
blunt the pain, Murray gave his patient a prescription and some free
samples of the drug.
The drug Murray prescribed was Prozac, a popular antidepressant that isn't
approved by the Food and Drug Administration for treating chest pain.
Murray later said he had no idea that experts had debated for years whether
Prozac caused suicide.
Thirteen days after that visit to the doctor, on June 28, 2001, Cole's
wife, Amby, found him hanging from a beam in a back room of their shop.
"This was a patient of mine, and I was trying to help him," Murray
recalled. "I'm completely upset. ... I'll be that way forever."
That a heart specialist even had free supplies of a drug that's usually
the province of psychiatrists says a lot about how drug marketing today
encourages physicians to prescribe medications for unapproved, or
off-label, uses.
By offering specialty drugs to nonspecialists, sending salesmen to
doctors' offices and medical conventions, and touting their drugs' benefits on the
slimmest of evidence, pharmaceutical companies have sent off-label retail
sales soaring.
Off-label sales of the top-selling drugs Knight Ridder studied hit $12.9
billion in the last year, producing nearly a quarter of those drugs'
retail sales.
With an aging population, a shift to drug-based health care and the
prospect of a massive government prescription-insurance plan, prescriptions for
unapproved uses are only likely to accelerate.
Promoting this growth is a symbiotic relationship between physician and
drug makers in which sales representatives routinely target doctors untrained
in the basics of drug therapy and with little time, inclination or
independent information to assess a medication's usefulness or its risks.
Consider this courtroom conversation involving a lawyer representing
Schering-Plough Corp., the mammoth U.S. drug maker.
A quizzical U.S. District Judge Lawrence McKenna of New York asked whether
doctors "in any significant number" really based their opinions about
drugs on pitches from sales reps.
"Yes, your honor," said Gregory Diskant, Schering-Plough's outside
attorney.
"That's scary, isn't it?" the judge asked.
"It is scary. It is scary, but it is true," Diskant said. "You know what
the truth is? ... (Sales calls) are the quickest, easiest way for the doctor
to learn about the drug. ... It is a dangerous, largely unregulated phenomena
in the wrong hands."
'I THOUGHT IT WAS ... PRETTY HARMLESS'
The day Cole came in for his checkup, Murray had a drug closet stocked
with dozens of medicines that cardiologists commonly prescribe, as well as some
that general practitioners and other specialists use.
With little to go on beyond Cole's complaints of chest pain, Murray said,
he had a choice between doing nothing and attempting to ease his patient's
pain.
"I chose Prozac probably because I had samples of it," he said in an
interview. "I thought it was a pretty harmless thing to do."
The FDA has approved Prozac to treat depression, panic,
obsessive-compulsive disorder and an eating disorder, but not pain. Murray didn't think Cole
was depressed. The Brighton, Tenn., resident was upbeat, busy with friends and
church, and preparing for a new grandchild and a new house.
Doctors have prescribed antidepressants off-label for years to manage
chronic pain, and as far as Murray knew, Prozac didn't have any serious
side effects. He said he had never heard it might cause suicide. Articles
debating the issue were published primarily in psychiatric journals
throughout the 1990s.
A Knight Ridder analysis of government data found that over the last
decade, 40 percent of Prozac prescriptions were written by nonpsychiatrists. Over
the past year, 500,000 Prozac prescriptions were for off-label uses.
Prozac didn't help Cole's chest pain.
Soon, he complained of feeling jittery. His fingers tingled; he became
easily aggravated. Days later, he hanged himself.
Amby Cole blames drug maker Eli Lilly for not warning that Prozac could
cause her husband's suicide, and her lawyer, Andy Vickery of Houston, has
accused Lilly of over promoting Prozac to nonpsychiatrists. Lilly settled
the case earlier this year. The amount is confidential.
Vickery said it was his third settlement with Lilly over Prozac-suicide
cases and off-label uses. Patients in the other two cases were given
Prozac to treat migraines and for Tourette's syndrome, a neurological condition
that produces uncontrollable tics.
Lilly officials said they had settled some lawsuits for economic reasons
but wouldn't comment on specifics. A spokeswoman, Tarra Ryker, said Lilly
"does not condone or encourage off-label use of any of our medications,
including Prozac."
The company long has contended depression, not Prozac, causes suicide.
Even so, U.S. and British regulators warned last summer that Paxil, a drug in
the same class as Prozac, may increase the suicide risk for children and
adolescents, reviving a debate that has simmered for a decade. Ryker said
this had no bearing on Prozac.
'SIGNIFICANT OPPORTUNITIES'
Federal law prohibits drug makers from advertising or promoting off-label
drug uses. Since 1998, the FDA has cited companies nearly 70 times for
improperly promoting their drugs that way, a review of its records shows.
Yet off-label promotions are commonplace, as was alleged in a recent
whistleblower lawsuit against a company that's now part of Pfizer Inc. A
former employee of the drug company said it employed a range of tactics to
boost off-label sales of the epilepsy drug Neurontin. The widely reported
case is pending.
Getting around FDA marketing rules isn't difficult. The agency
acknowledges it's impossible to police the millions of conversations between drug
companies and doctors.
At the annual conference of the American Academy of Pain Management this
summer at the Adam's Mark hotel in downtown Denver, 75 makers of drugs,
medical devices and dietary supplements staffed sales booths, beckoning
doctors with trinkets, slick promotional brochures, medical journal
articles, even stopwatches.
One of the biggest booths was for Cephalon Inc., based outside
Philadelphia. Two big signs pitched Gabitril, a drug approved only to treat seizures.
Four sales representatives in blue blazers answered questions.
Why, one was asked, was an epilepsy drug being hawked at a conference for
pain doctors? "Most of the anti-epileptics have multiple other uses,"
replied Cephalon's Janeen Morgan.
Cephalon relies more on off-label sales than other companies. A Wall
Street analyst touted "significant opportunities for off-label sales" as a reason
to be bullish on the company. At times, Cephalon has aggressively marketed
its drugs off-label; a 2002 letter from the FDA cited the company for
making "misleading claims" about a "variety of unapproved uses" for another of
its drugs, Provigil.
The company's messages apparently got through to doctors.
In Maine, for example, state Medicaid officials in 2002 noticed a growing
amount of Provigil use.
Although approved at the time only for patients with narcolepsy, a
disorder associated with feelings of pronounced sleepiness, Medicaid officials were
receiving claims for its use to treat multiple sclerosis fatigue,
attention deficit disorder, depression and "miscellaneous fatigue."
The Medicaid claims topped $1 million, with one doctor responsible for
$370,000 of them, state records show.
From 2000 to 2003, 60 percent of Cephalon's sales were of Gabitril or
Provigil, two drugs for which the majority of the written prescriptions
are off-label. According to the prescription data that Knight Ridder analyzed,
88 percent of Gabitril's retail sales were off-label over the last year.
Cephalon has told the Securities and Exchange Commission the "market for
the approved indications of two of our three largest products is relatively
small."
Even as the company begins to study whether Gabitril works for pain, tens
of thousands of prescriptions for that use were filled in the last year,
Knight Ridder's analysis showed.
Michael Fielder of Kansas City, Mo., said he'd taken Gabitril for the last
18 months to curb the pain of sickle cell anemia, a debilitating blood
disorder. He got relief only after his doctor added morphine to the mix.
When asked for evidence their drug may be useful for pain, Cephalon
officials cited five studies, including four with 10 or fewer patients.
Fielder is still taking Gabitril, because, he said, his doctor believes it
helps. Over the years, doctors have given him Neurontin, another epilepsy
drug, and Paxil, the antidepressant, for pain. None of them worked well,
he said.
"When they try out something new, sometimes I don't think the doctors know
if what they are using works," Fielder, 27, said recently.
'WHAT GETS MARKETED HARD ... GETS PRESCRIBED'
Court records contain dozens of comments by some of the government's top
health experts about doctors and prescription drugs. Many of them aren't
flattering. The assessments about off-label prescribing are worse.
The FDA's lawyers said in a 1998 brief: "While physicians may believe that
they are in a better position than FDA to evaluate off-label claims, both
the evidence and the law say otherwise. ... Physicians tend to have
confidence in their own ability to critically assess off-label
information. The studies demonstrate, however, that such confidence is often
unwarranted and incorrect."
Michael Wilkes, the vice dean of the medical school at the University of
California, Davis, doesn't think that's surprising.
"I think it is embarrassing that so much of our practice is prescribing
drugs, and it's a joke how little our students and residents know about
pharmacology," he said. "And once you graduate, how does a doctor learn
about new medicines? It's from the pharmaceutical companies."
Wilkes, who studied the issue of off-label promotion for the FDA in the
late 1990s, pointed to two rigorous studies that concluded doctors - despite
their protestations to the contrary - are swayed by pharmaceutical
promotions.
"What gets marketed hard is what gets prescribed," said Jay Cohen, an
adjunct associate professor of family and preventative medicine at the
University of California-San Diego.
The marketing is massive.
Over the last decade, the number of drug company sales reps has more than
doubled to 94,000, one for every seven doctors in the nation. In 2002, the
value of the free drug samples passed out to physicians reached $11.9
billion, up more than 140 percent since 1996.
'IT WORKED'
At first glance, the results of a clinical study of Evista, an Eli Lilly
osteoporosis drug, looked promising. Among other things, researchers
noticed slightly fewer breast cancers among women who took Evista versus those who
were given sugar pills.
As baby boomers age, that could mean the makings of a blockbuster drug.
Unfortunately for Lilly, cancer experts didn't think the numbers meant
much.
On May 18, 1998, Eli Lilly convened a focus group of doctors who were
attending the American Society of Clinical Oncology annual meeting. Shown
the Evista breast cancer data, they responded the study was too small, the
time frame too short and the risk of patients having strokes too great.
Promoting the drug to prevent breast cancer would be "an egregious
stretch," one doctor said. It also was called an attempt to "cash in on a byproduct
of the study." A proper study to measure breast cancer prevention "should
last at least 10 years, preferably 20," doctors said, according to the
company's meeting notes.
Even so, the cancer physicians feared primary-care and women's-health
doctors would prescribe Evista for breast cancer prevention anyway.
A month later, Lilly conducted a different survey, this one of 341
primary-care physicians and women's-health doctors. The company tested
various advertising messages about Evista, finding that "PCPs are more
promising ... indicate they will put more patients on Evista ... and think
the breast cancer data is more compelling."
Although the FDA had told the company it found "critical problems" with
the Evista study and didn't approve the drug for preventing breast cancer,
according to FDA records, it allowed Lilly to make a minor change in the
drug's label. The company inserted three sentences that detailed the
precise numbers of breast cancer cases from the study as well as the following:
"The effectiveness of (Evista) in reducing the risk of breast cancer has not
been established."
That was all Lilly needed to do. Company officials got the word to 1,000
sales representatives. In its plan "Maximizing the Breast Cancer Label
Change," it scripted answers to deal with expected concerns, including the
"relatively small number of cases" in its study.
The new sales strategy irked one of Lilly's competitors, now known as
AstraZeneca PLC, the maker of tamoxifen, which the FDA has approved to
prevent breast cancer.
The British company did its own survey of primary-care and women's-health
doctors and found that nearly 65 percent of them learned about Evista from
sales reps, not the medical literature. Another survey showed that 22
percent thought Evista was FDA-approved for preventing breast cancer.
AstraZeneca took the case to court, demanding that Lilly stop such
practices and divulge the "call notes" its sales representatives wrote after visits
to doctors. The case was settled, and the details are confidential. Evista
someday may prove to be good for preventing breast cancer, although Lilly
said it was at least two years away from completing the study that may
allow it to apply to the FDA for such a use.
As for those call notes, some were illuminating.
"Told MD about the new indication of EV to prevent breast cancer," one
sales rep wrote in December 1998.
One physician told the sales rep he was "extremely excited about the
breast data!! Said that if his wife were eligible, he would put her on Evista."
"Sit down detail w//MD," another note read. "Went through entire Evista
message w//disclaimer at first to let him know I could not talk about
stuff that was off label unless he asked questions first. It worked. He asked
all about breast cancer."
Researcher Tish Wells contributed to this article. Reach Young at
ayoung@krwashington.com; reach adams at cadams@krwashington
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