The
Neurontin Suicides: Risks Kept Hidden For Years
By Evelyn Pringle
25 February, 2007
Countercurrents.org
The
all-time poster child for a drug illegally promoted for off-label uses,
is Neurontin, marketed by Warner-Lambert, and its Parke-Davis division,
until Pfizer acquired the company in 2000.
The term "off-label"
means prescribing a drug for indications not listed on the label, upping
the recommended dose, prescribing a drug in combination with other medications,
or using a drug with a patient population, such as children, not listed
on the label.
As part of the approval process,
the FDA reviews the drug's labeling, which must include the proposed
claims about the drug's risks and benefits, as well as the directions
for use.
If an indication is not listed,
it means the drug maker has not submitted the required studies to prove
the drug is safe and effective for that use. While physicians may prescribe
a drug approved by the FDA for an unapproved use, it's against the law
for a drug maker to influence doctors to prescribe a drug for uses outside
the label.
Pfizer completed the acquisition
of Warner-Lambert in June 2000, and four years later in May 2004, Pfizer
pleaded guilty to illegally marketing Neurontin for unapproved uses
and agreed to pay a $430 million, the second-largest settlement ever
in a health care fraud prosecution, to settle charges brought by the
US Department of Justice that included defrauding public health care
programs.
The case specifically sought
to recover the losses to public programs resulting from the off-label
promotion of a drug and focused primarily on Medicaid, which spent an
estimated $422 million on Neurontin between 1994 to mid-2000.
In the end, Pfizer paid $83.6
million to the federal government and $68.4 million to the 50 states
and the District of Columbia. In addition, Pfizer agreed to pay the
states a total of $38 million to settle liabilities under state consumer
protection laws, and a $240 million criminal fine, according to the
DOJ.
However, the settlement with
the DOJ did not include damage awards for patients who may have been
injured by Neurontin and many patients, or families representing deceased
Neurontin victims, have filed lawsuits against the company.
Many of the cases are wrongful
death actions based on the company's failure to warn about the risk
of suicidality associated with the drug. In 2004, attorneys Derek braslow
and Harris Pogust of the Pennsylvania law firm, Pogust & Braslow,
began filing lawsuits on behalf of victims who became suicidal.
Pogust & Braslow represent
plaintiff, Natalie Biedenbender, whose husband Mark committed suicide
on July 9, 2005, at age 39, after being prescribed Neurontin off-label
for back pain, in a wrongful death lawsuit.
According to the lawsuit,
from July 1995 through at least August 5, 2002, the company engaged
in a marketing program "to induce physicians to prescribe Neurontin,
for medical conditions for which the FDA had not approved Neurontin
to be used."
That program, the complaint
charges, included (a) illegally promoting the sale and use of Neurontin
for a variety of conditions "for which defendants had not performed
the required FDA testing or established safety and efficacy;" and
(b) offering and paying illegal remuneration to doctors, "either
directly or through third parties, to induce them to promote and prescribe
Neurontin for off-label uses."
On May 17, 2004, Andrew Finkelstein,
of the New York law firm of Finkelstein & Partners, submitted a
citizen's petition to the FDA requesting that a black box suicide warning
be added to the label and that a Dear Doctor letter be sent out to instructing
physicians to be on alert for increased depression in patients taking
the drug.
Mr Finkelstein also continued
to remind the FDA about the rising number of suicides. In a March 21,
2005, letter to Dr Russell Katz, he wrote in part: "Enclosed you
will find two hundred fifty eight MedWatch forms ... Each represents
a suicide of an American who was on Neurontin when he or she took his
or her own life."
"Many of these suicides
likely could have been prevented," he said, "had both the
treating physician and unsuspecting families been armed with full knowledge
of the risks of suicide that was known to both the FDA and the manufacturer."
But as it turns out, the
FDA was fully aware of the suicidality risk when Neurontin was recommended
for approval in 1992, and Dr Katz oversaw the FDA's analysis of the
clinical data provided to support the New Drug Application.
According to Mr Finkelstein,
the evaluation of serious adverse events during the original clinical
trials showed the risk of suicide was known and a major concern. In
the letter to Dr Katz, he pointed out that an FDA reviewer specifically
stated in December, 1992:
Serious adverse events may
limit the drug's widespread usefulness. Depression, while it may not
be an infrequent occurrence in the epileptic population, may become
worse and require intervention or lead to suicide, as it has resulted
in some suicidal attempts during clinical trials.
In fact, in the clinical
trials, Neurontin was attributed to four people actually attempting
suicide, two more having depression with suicidal ideations, and 22
participants reporting depression so severe it required pharmacologic
intervention. Most alarming was that 19 of the 78 participants who reported
depression had no prior history of depression.
"Clearly," Mr Finkelstein
told Mr Katz, "the FDA did not approve this drug with any expectation
of use beyond the approved indication."
Documents that surfaced in
litigation also show that the FDA was aware of the off-label marketing
scheme eight years before the DOJ settlement. In July, 1996, FDA official,
Lesley Frank, wrote to Parke-Davis and said in part:
Parke-Davis may be promoting
Neurontin for off-label' uses ... in printed promotional materials,
in detail or sales presentations to physicians, and through the use
of company-solicited physician participation in a series of teleconferences.
These promotions of Neurontin
for off-label uses included, but were not limited to, its use in chronic
pain, bipolar disorders, and other psychiatric conditions. As you are
aware, Neurontin's only approved indication was for adjunctive therapy
in the treatment of partial seizures with and without secondary generalization
in adults with epilepsy.
The documents show that after
11 months, Parke-Davis sent a written response denying all the allegations
and the FDA accepted the denials and the matter was dropped.
In reality, $430 million
was chickenfeed to Pfizer, considering that at the time of the settlement,
Neurontin sales were up 32% from 2003, and the 2004 sales were expected
to exceed the $2.7 billion mark set in 2003. In actuality, the settlement
amounted to only about 15% of the gross sales of Neurontin in 2003.
By 2002, a full 94% of Neurontin
sales were for off-label use and according to the August 16, 2004, USA
Today, when Pfizer settled the lawsuit, the Wall Street firm Lehman
Bros estimated that 90% of the sales were still off-label.
At the time, Pfizer issued
a statement that said the illegal practices took place before Pfizer
acquired Warner-Lambert. However, sales figures clearly show that Pfizer
was still reaping the benefits of the illegal promotion of Neurontin
at the time of the settlement.
"Although Neurontin
is prescribed for scores of off-label indications," Attorney Braslow
reports, "since 2000 off-label use continues to be most common
in the areas where the company focused its illegal marketing efforts
such as bipolar disorder, peripheral neuropathy and migraine headaches."
"This increase,"
he points out, "is most likely a direct result of sales representatives
and leading physicians, who were paid by the company recommending its
use for these conditions."
According to Attorney Pogust,
"there are no scientific studies that support Neurontin's use for
pain disorders."
"But as a result of
the company's previous promotional activities," he says, "tens
of thousands of patients who could use other pain killing drugs whose
effectiveness has been established, are given Neurontin."
"These prescriptions
for pain," Mr Pogust notes, "are still being written, as a
direct result of past illegal promotional activities."
"Likewise," he
points out, "the off-label prescriptions of Neurontin for bipolar
disorder, attention deficit disorder, and depression are also without
any scientific evidence supporting such uses."
The off-label scheme was
first revealed by whistleblower, David Franklin, a former Park-Davis
employee who worked as a medical liaison, in a lawsuit against Warner-Lambert
and its Parke-Davis division filed under the federal False Claims Act.
By Mr Franklin's estimates,
as much as 90% of prescriptions for Neurontin were written off-label
as a result of the illegal scheme which prosecutors claim dates back
to1995. To back up his allegations, Mr Franklin offered a voicemail
he saved from his boss that stated:
I want you out there every
day selling Neurontin... holding their hand, whispering in their ear,
Neurontin for pain, Neurontin for monotherapy, Neurontin for bipolar,
Neurontin for everything. I don't want to see a single patient coming
off Neurontin before they've been up to at least 4,800 milligrams a
day.
His boss concluded by stating:
"I don't want to hear that safety crap either. It's a great drug"
As a whistleblower in a case
to recover federal funds, Mr Franklin was entitled to a percentage of
the settlement and received $24.6 million.
The Drug Industry Document
Archive (DIDA), created by the Center for Knowledge Management at the
University of California San Francisco Library in collaboration with
faculty members, contains roughly 1,000 documents drawn primarily from
the case titled, United States ex rel David Franklin vs Parke-Davis,
Division of Warner-Lambert, which describe all the specific details
on the Neutontin off-label marketing scheme.
In settling the charges,
Pfizer pleaded guilty only to conduct occurring before August 21, 1996,
even though the DOJ determined that illegal activities had occurred
much later, making it possible for Pfizer to continue to participate
in federally funded health care programs despite a health care fraud
law that went into effect on August 21, 1996, that would have required
its exclusion from public programs.
Pfizer escaped the severe
penalties, that many critics say would have sent a clear message to
companies engaging in such conduct to knock it off or risk losing the
most treasured customer base of all public health care programs, even
though Warner-Lambert had been convicted of a felony in 1995, for failing
to report failures concerning other drugs, which meant the new charges
were second offenses "punishable as felonies without regard to
proof of intent to defraud or mislead."
Initially, Neurontin was
approved only to treat epilepsy in combination with another drug, and
at a maximum 1800 mg daily dose. But the DOJ found the drug was being
promoted for a multitude of pain uses, psychiatric conditions such as
bipolar disorder and anxiety, social phobia, and general mood stabilization,
as well as certain unapproved uses within epilepsy treatment. According
to the DOJ, the list of unapproved uses became so long that company
employees called it the "snake oil" list.
Over all, the DOJ listed
the potential harm caused by the illegal scheme as:
(1) public health care programs
paid more in reimbursement;
(2) consumers paid for ineffective,
experimental use and may have been improperly medicated;
(3) patient's unnecessary
exposure to adverse side effects; and
(4) improper medication may
have resulted where Neurontin was not as effective as another approved
drug.
The DOJ listed six tactics
involved in carrying out the off-label scheme as:
(1) Detailing by sales representatives;
(2) Use of Medical Liaisons;
(3) Preceptorships;
(4) Consultant meetings,
speakers bureaus and advisory boards;
(5) Series of teleconferences
to disseminate off-label uses; and
(6) Control of Purportedly
Independent Medical Education.
Another element of the overall
scheme to increase profits was to convince doctors to prescribe Neurontin
at substantially higher doses than the maximum approved dose.
The DOJ produced evidence
to show that Parke-Davis had arranged hundreds of teleconferences, meetings,
and educational seminars, in addition to the detailing of individual
doctors by sales representatives, to promote the off-label use of Neurontin.
In 1996, a Parke-Davis sales
representative created a document that said sales representatives could
ask doctors if they ever used other antiepileptic drugs for painful
neuropathies and then mention that approximately 35% of all Neurontin
use is non-seizure. This same document, entitled "Neurontin Can
Do/Can't Do," also stated that sales representatives could present
lunch programs on Neurontin and pain.
According to Mr Franklin,
the company gave financial incentives to hundreds of doctors by inviting
them to dinners, sports outings, and weekend trips to resorts where
fellow-physicians were paid to speak about the use of Neurontin for
unapproved indications.
The company founded a speakers'
bureau, as a method of making large payments to physicians who gave
presentations and court documents show doctors were paid to listen to
speeches that took place on a "Bus to Yankee Stadium," a "World
Yacht Cruise," and the "Braves Stadium."
During one trip in 1996,
Parke-Davis paid for 18 doctors and their spouses to stay in Atlanta
for 5 days to attend the Summer Olympics. The company paid for their
meals, use of a resort, and travel to the games while the agenda for
the seminar listed only 10.5 hours of business meetings, including one
devoted to off-label uses for Neurontin.
The DOJ determined that the
company kept track of how well these marketing efforts paid off. For
instance, in a memo dated June 26, 1995, a marketing executive reported
that doctors who attended dinners and listened to speeches from other
physicians, wrote 70% more off-label prescriptions than doctors who
did not attend.
Documents show that the company
intentionally hired influential doctors from major teaching hospitals
to speak at these events. For instance, Dr Steven Schachter, a professor
at Harvard Medical School, received $71,477 between May 1994 and September
1997, and Dr B J Wilder, a former professor at the University of Florida,
was paid more than $300,000, and other doctors received more than $100,000
each.
The company also paid to
disseminate papers and articles on off-label uses throughout the medical
literature so that doctors would find themselves bombarded with information
about the many uses for Neurontin, made to look like independent scientific
papers.
For some uses, like monotherapy,
the research was used to support an attempt to obtain FDA approval.
But in other cases, the company's goal was to disseminate the information
as widely as possible to increase off-label prescribing for conditions
like pain and bipolar disorder, without ever trying to obtain approval.
To carry out this part of
the scheme, Warner-Lambert hired two marketing firms to write the articles
and then found doctors willing to sign on as authors. According to Mr
Franklin, the PR firms were paid $12,000 per article and the doctors
were paid $1,000.
The DOJ found more than twenty
20 articles published in various medical journals that were fully paid
for by Parke-Davis. Critics say this tactic still affects off-label
prescribing today. According to Mr Braslow, "since 1999, the types
of off-label are most likely weighted in the precise areas where the
drug maker focused its illegal marketing efforts: bipolar disorder,
peripheral neuropathy, migraine, depression, etc."
"Because physicians
were inundated with false information for years," Mr. Pogust says,
"they continue to prescribe it for off-label uses for which there
is no reliable scientific support."
Parke-Davis also infiltrated
the continuing education arena where doctors were misled into believing
that seminars on the off-label uses for Neurontin were independent educational
programs, when they actually were marketing events set up by Park-Davis.
For example, prosecutors
found an undisclosed relationship with a firm known as Physicians World
where Parke-Davis employees transferred to the firm to run the company's
speakers bureau.
At the same time, the DOJ
discovered that in a division of Physicians World, known as Professional
Post-Graduate Services, which purported to be an independent education
provider presenting programs on anticonvulsants for pain to thousands
of US doctors, Parke-Davis employees actually planned and developed
the programs.
According to the DOJ, in
late 1995, the company took the position that medical liaisons could
discuss off-label issues with doctors, so long as the doctor asked a
question about the topic first. Because physicians believed medical
liaisons were persons with a scientific background and not employed
to sell Neurontin, they were often able to gain access to doctors that
the sales representatives could not.
For example, Mr Franklin
was trained to increase the rate of prescriptions of Neurontin as monotherapy,
and one of the ways he was able to gain access to doctors was by fraudulently
presenting himself as a neurology specialist conducting research on
epilepsy and the actions of anticonvulsant drugs.
Company records reveal an
extensive pattern of misuse of medical liaisons. A January 31, 1996,
memo describes a goal to "utilize the medical liaison group to
target the Neurontin, Pain & Psychiatric market."
"Objective to conduct
twice weekly Pain Teleconferences moderated by key Neuro Consultants,"
the memo states. "Goals 250 Physician participants quarterly."
One of the most alarming
sales tactics identified during the DOJ's investigation was that sales
representatives were allowed to review patient records, suggest an increase
in Neurontin dosage, and "shadow" doctors while they examined
patients, in exchange for paying the doctor a few hundred dollars a
day.
According to the DOJ, at
various times Parke-Davis made a conscious decision to not seek approval
for a new use because it would have required solid proof from clinical
trials that could not be provided.
Documents show that Parke-Davis
even went to the trouble of determining how much could be made off Neurontin
for a new approved use, compared to sales from marketing the drug off-label
for the same use.
For example, a May 19, 1995,
Marketing Assessment forecast potential revenue from Neurontin for bipolar
without approval at $6 million in 1997, rising to $36 million in 1999.
On the other hand, with approval, forecasted sales were almost $12 million
in 1997, to over $80 million in 2002, but the company still decided
not to seek approval for bipolar.
The DOJ found that similar
projections were made for other uses including various types of pain
but again, after evaluating the potential sales with and without approval,
Parke-Davis decided to market Neurontin off-label instead of seeking
approval.
The company also kept track
of doctor's prescribing habits for Neurontin's competitors. In October
of 1995, Parke-Davis determined that two competing epilepsy drugs, Tegretol
and Depakote, had total sales of 18-27% for bipolar disorder, and up
to 9% for pain, while at the time, only 1-2% of sales for Neurontin
were for pain and bipolar.
The company continued to
market the drug for bipolar even after studies showed it was ineffective
for that use. The DOJ's sentencing Memorandum states: "One of the
psychiatric uses for which Neurontin was promoted ... bipolar disorder,
was particularly troubling because the Company had very weak evidence
of Neurontin's efficacy in treating this condition."
"Indeed," the prosecutor
wrote, "in one study ... the placebo was as effective or more effective
than was Neurontin."
Yet with full knowledge of
this study, medical liaisons told psychiatrists that early results from
clinical trials indicated a 90% response rate for bipolar. Likewise,
they told pediatricians that Neurontin was effective for children with
attention deficit disorder, when no data other than occasional anecdotal
evidence supported that claim.
And although no studies existed
to prove that Neurontin was even as effective as inexpensive pain killers
already on the market, medical liaisons told doctors that clinical trials
demonstrated that Neurontin was highly effective in treating various
pain syndromes and reported once again that a 90% response rate was
found in the treatment of pain.
The DOJ also reports that
the company continued to promote Neurontin for monotherapy even after
the FDA refused to approve it. Parke-Davis sought approval in September
1996, but because one of the 2 clinical trials submitted with the application
showed no demonstrable monotherapy efficacy, the application was denied.
Nonetheless, the DOJ produced
evidence showing that Parke-Davis continued to promote Neurontin for
monotherapy through at least 2000, without ever mentioning the rejected
application, and that at one 1998 event, Parke-Davis went so far as
to state that Neurontin is "now approved as monotherapy for seizures."
When caught red-handed promoting
drugs for unapproved uses, drug makers always feign ignorance of the
high rate of off-label prescribing. However in this instance, company
documents show that Warner-Lambert regularly obtained detailed information
on the number of prescriptions written for Neurontin and what indication
they were written for.
Neurontin sales did finally
drop to $182 million in the first quarter of 2005, but as a result of
new generic competition on the market, according to USA Today on April
20, 2005.
Persons seeking information
about Neurontin representation can contact the Pogust & Braslow
law firm at 610-941-4204, or http://www.pogustbraslow.com/
Evelyn Pringle is an investigative
journalist. She can be reached at: [email protected]
(This article is part of
a series on Neurontin related litigation and is sponsored by the Pogust
& Braslow law firm)