--The Illegal Corporate
Creation of a Blockbuster Drug
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A March 14, 2002,
New York Times article revealed that the manufacturer of the seizure medication
gabapentin (NEURONTIN) illegally promoted the drug to prescribing physicians
for at least 11 "off-label" (unapproved) medical conditions, using their
own employees, euphemistically called "medical liaisons." Many of the bases
for the safety and effectiveness of gabapentin for these 11 unapproved
uses appears to have been fabrications by the corporation. This included
paying physicians to appear as the authors of medical journal articles
on unapproved uses for gabapentin when the articles had actually been written
by others working under the direction of the company’s marketing department.
This article is based
on the Times story and publicly available court documents from a civil
complaint filed by the U.S. government against gabapentin’s manufacturer.
Gabapentin was originally
sold by Parke-Davis, a subsidiary of Warner-Lambert, which in turn was
a corporation acquired by Pfizer, Inc., in 2000. Gabapentin is currently
approved by the Food and Drug Administration (FDA) only as supplementary
treatment for a specific type of seizure know as partial seizures after
maximum tolerated doses of older drugs are used. This is a relatively small
potential market for gabapentin.
The 11 illegally
promoted unapproved uses for gabapentin as outlined in the court documents
are:
1. Bipolar
Disorder. Psychiatrists were told that early results from trials evaluating
gabapentin in the treatment of bipolar disorder indicated a 90 percent
response rate when the drug was started at 900 milligrams per day and increased
to 4,800 milligrams per day. No such results existed. In fact, the only
type of clinical trial being conducted at the time was a pilot study. According
to the court documents, Parke-Davis was in possession of clinical data
indicating that increasing the dose did not increase gabapentin’s effect.
The FDA-approved dosage for gabapentin in adults is 900 to 1,800 milligrams
per day.
Any data regarding
gabapentin in bipolar disorder was anecdotal and of unclear scientific
value. Most of the published reports on the use of gabapentin in bipolar
disorder had been written and sponsored by Parke-Davis, a fact that was
hidden. Medical liaisons of the company were trained to tell psychiatrists
that there were no reports of adverse reactions with gabapentin when used
in psychiatric illness. In fact, such reports had been given to Parke-Davis
by health care professionals but the company attempted to hide this information
from physicians.
2. Pain Syndromes,
Peripheral Neuropathy, and Diabetic Neuropathy. Parke-Davis medical liaisons
were trained and instructed to report that "leaks" from clinical trials
demonstrated that gabapentin was highly effective in the treatment of a
number of pain syndromes and that a 90 percent response rate in the management
of pain was being reported. No such evidence existed. Medical liaisons
were trained to claim support for these findings as a result of inside
information despite the fact that no such information existed. The only
basis for these claims were anecdotal evidence of minimal, if any, scientific
value. Many of the published case reports, according to the court papers,
had been created and sponsored by Parke-Davis in articles that frequently
hid the company’s involvement in the creation of the article. The company’s
payment for the creation of these case reports was also concealed.
3. Treatment of Epilepsy
alone (as monotherapy). Medical liaisons were strongly encouraged to push
neurologists to prescribe gabapentin as the only drug to treat epilepsy,
in spite of the fact that studies found it safe and effective only when
used in combination with other seizure drugs. Neurologists were told that
substantial evidence supported the company’s claim that gabapentin was
effective when used alone for seizure. In fact, at the time the court papers
were filed, Parke-Davis knew that clinical trials using gabapentin alone
in seizure were inconclusive. One of Parke-Davis’ clinical trials showed
that gabapentin alone was not effective. The vast majority of patients
in the study taking gabapentin were unable to continue with gabapentin
alone. In the same study, there was no significant difference between doses
of 600, 1,200 or 2,400 milligrams. Nevertheless, Parke-Davis continued
to urge doctors to use higher doses than approved by the FDA.
In 1997, the FDA
rejected the company’s application for approval of gabapentin as monotherapy
in the treatment of seizures.
4. Reflex Sympathetic
Dystrophy (RSD). Physicians were informed that extensive evidence demonstrated
the efficacy of gabapentin in the treatment of RSD, a condition of pain
and tenderness following traumatic injury to a limb. Again, the only evidence
was in anecdotal reports of little or no scientific value. The Parke-Davis
medical liaisons were trained to imply that case reports, most of which
had been created or sponsored by the company, were actually studies.
5. Attention Deficit
Disorder (ADD). Pediatricians were told that gabapentin was effective for
the treatment of ADD. No hard data to support this claim existed--only
occasional anecdotal evidence. Parke-Davis medical liaisons were trained
to report that large numbers of physicians had success in treating ADD
with gabapentin, when no such case reports existed.
6. Restless Leg Syndrome
(RLS). This is another condition in which company medical liaisons were
trained to refer to a growing body of evidence relating to the RLS, when
no such scientific data existed. The only reports were anecdotal, the majority
of which had been sponsored or created by Parke-Davis.
7. Trigeminal Neuralgia.
The company represented gabapentin as a treatment for trigeminal neuralgia,
a syndrome of severe bursts of facial pain, when no scientific data supported
this claim; only occasional anecdotal reports. No evidence was available
that gabapentin was as effective as currently available less expensive
painkillers.
8. Post-Hepatic Neuralgia
(PHN). This is a syndrome of severe pain following a herpes virus infection.
Physicians were told that 75 to 80 percent of all PHN patients were successfully
treated with gabapentin. Again, no clinical trial data supported such a
claim.
9. Essential Tremor
Periodic Limb Movement. No scientific data supported Parke-Davis’ claim
that gabapentin was effective for this disorder, just anecdotal reports
of dubious scientific value.
10. Migraine. Claims
that gabapentin was effective in the treatment of migraine headache were
made by company medical liaisons and were alleged to be based on early
results from clinical trials. Pilot studies had been suggested and undertaken,
but no early results existed to support these claims. The data were purely
anecdotal and most case reports were either created or sponsored by Parke-Davis.
11. Drug and Alcohol
Withdrawal Seizures. It was suggested by the company that gabapentin be
used in the treatment of drug and alcohol withdrawal seizures despite the
lack of any evidence supporting the use of the drug for these conditions.
Parke-Davis’
concocted uses for gabapentin turned the drug into a "blockbuster." A blockbuster
is the Wall Street description for any drug that sold $1 billion per year
or more. In 2000, the company reported that gabapentin had earned $1.3
billion. As much as 78 percent of these sales were for uses without evidence
that gabapentin was safe and effective. In 2001 a market research firm
estimated that gabapentin sales totaled $1.7 billion.
The court papers
offer a remarkable insight into the ethics (or lack thereof) of a major
multinational pharmaceutical company. A senior marketing executive at Parke-Davis
was quoted during a teleconference as saying to medical liaisons:
Pain management,
now that’s money. Monotherapy, that’s money. We don’t want to share these
patients with everybody, we want them on Neurontin only. We want their
whole drug budget, not a quarter, not half, the whole thing....That’s where
we need to be holding their hand and whispering in their ear: ‘Neurontin
for pain, Neurontin for monotherapy, Neurontin for everything’ ... I don’t
want to hear that safety crap either, have you tried Neurontin, every one
of you should take one just to see there is nothing [that the drug is safe],
it’s a great drug.
Pfizer has scored
about $3.0 billion in gabapentin sales over the short term of the past
two years, 2000 and 2001. The company may also reap a long term benefit
from sales of the drug. Physicians’ prescribing practices, also known as
prescribing habits, are not likely to be cured of the gabapentin habit
just by The New York Times article. In addition, as of March 28, 2002 the
National Library of Medicine listed 729 English language articles published
in the medical literature on gabapentin use in humans. Of course, not all
these articles are corporate creations but the disturbing point is that
there may not be any attempt to purge the medical literature of these company-contrived
studies, leaving patients, even years from now, at risk of exposure to
gabapentin for inappropriate uses.
There is nothing
new in the Parke-Davis gabapentin escapade and the company’s drug promotion.
Over 30 years ago Senator Gaylord Nelson (D-WI) held a series of hearings
on problems with the drug industry. In a 1969 hearing it was learned that
drug companies employed physicians and scientists to prepare articles for
medical journals. In those days these "kept" scientists and doctors were
known in the trade as "the stable." With time comes status inflation, and
now these individuals are called "medical liaisons."
The last serious
Congressional hearings on the promotional practices of the pharmaceutical
industry were held in 1990. During these hearings Dr. Sidney Wolfe, co-founder
of the Health Research Group, played a central role in exposing widespread
bribing of doctors by drug companies.
Recent events have
properly raised the question whether federal watchdogs have become lap
dogs, lazy dogs or just sleeping dogs when it comes to the public interest.
The degree of vigilance of the FDA watchdog over the pharmaceutical industry
is directly in the hands of the United States Congress. Judging by the
amount of time that has lapsed since Congress has held meaningful hearings
on either the drug industry or the FDA, it looks as if the "top dog" (Congress)
got some bones and went to sleep.
What You Can Do
If you or a family
member are taking gabapentin for one of the 11 unapproved, often apparently
concocted, uses listed above, you and the prescribing doctor should evaluate
the need for gabapentin.
Copyright ©2000
by Public Citizen's Health Research Group
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