Healthy Skepticism Library item: 14886

Warning: This library includes all items relevant to health product marketing that we are aware of regardless of quality. Often we do not agree with all or part of the contents.

Publication type: Journal Article

Landefeld CS, Steinman MA.
The Neurontin Legacy: Marketing Misinformation and Manipulation
The New England Journal of Medicine 2009 Jan 8; 360:(2):103
http://content.nejm.org/cgi/content/full/360/2/103

Full text:

Old drugs usually fade away. Sometimes, however, they leave surprising
legacies. In 1997, for example, a study comparing the effects of brand-name
and generic formulations of levothyroxine led to an uproar over the
discovery that the manufacturer of the brand-name product suppressed
publication of the result that the two formulations were equivalent.
Recently, lawsuits alleging damages from illegal marketing of another old
drug, gabapentin (Neurontin), have yielded remarkable discoveries about the
structure and function of pharmaceutical marketing.

Patented in 1977 and
approved by the Food and Drug Administration (FDA) in 1993 in doses of up to
1800 mg per day as adjunctive therapy for partial complex seizures,
Neurontin became a surprise blockbuster for Parke-Davis, a division of
Warner-Lambert, which was purchased by Pfizer in 2000. U.S. sales rose from
$98 million in 1995 to nearly $3 billion in 2004 before Neurontin faced
generic competition and lost most U.S. sales.

The rise of Neurontin would
have been unheralded except for a quirk of fate: a young biologist, David
Franklin, went to work for Parke-Davis on April 1, 1996. Fresh out of
postdoctoral training at Harvard, Franklin soon grew concerned that he was
participating in illegal marketing. At a training seminar for “medical
liaisons” on April 16, 1996, Franklin and his peers were told that FDA
regulations required a fair and balanced presentation and prohibited
promotion of a drug for off-label uses, selling by medical liaisons, and
soliciting of inquiries from physicians. Six days later, a Parke-Davis
executive reportedly told Franklin,

I want you out there every day selling
Neurontin. . . . We all know Neurontin’s not growing for adjunctive therapy,
besides that’s not where the money is. Pain management, now that’s money.
Monotherapy [for epilepsy], that’s money. . . . We can’t wait for
[physicians] to ask, we need [to] get out there and tell them up front.
Dinner programs, CME programs, consultantships all work great but don’t
forget the one-on-one. That’s where we need to be, holding their hand and
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 4800
mg/day. 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,
it’s a great drug.1

Three months later, Franklin left Parke-Davis and filed
a suit (ultimately,
United States of America ex rel. David Franklin vs.
Pfizer, Inc., and Parke-Davis Division of Warner-Lambert Company) alleging
that off-label marketing of Neurontin constituted “false claims” designed to
elicit payments from the federal government. On May 13, 2004, Warner-Lambert
agreed to plead guilty and to pay more than $430 million to resolve criminal
charges and civil liabilities. A class-action suit was filed the next day in
federal court on behalf of private parties who had paid for illegally
marketed Neurontin; this case (now known as In Re: Neurontin Marketing,
Sales Practices, and Products Liability Litigation) remains active.

The
Franklin case placed more than 8000 pages of corporate documents in
the
public domain; these documents are now available in a searchable digital
library at the University of California, San Francisco
(www.dida.library.ucsf.edu). The class-action suit also generated detailed
testimony and reports that are available through the Federal Judiciary’s
Public Access to Court Electronic Records Service Center (e.g.,
https://ecf.mad.uscourts.gov/doc1/09502786849).

The Neurontin cases have
revealed the mechanisms of action of a comprehensive marketing campaign
its goals and strategies, tactics and programs, and the participation of
particular physicians and institutions.2 The campaign involved the
systematic use of deception and misinformation to create a biased evidence
base and manipulate physicians’ beliefs and prescribing behaviors. These
marketing methods were not found to be illegal in themselves; they were
illegal insofar as they promoted off-label prescription. Thus, the
importance of the cases lies largely in the light they shed on marketing
methods that may be widespread but remain unseen because companies are
rarely prosecuted for illegal marketing.

The Neurontin marketing plan
consisted of both general strategies such as the promotion of Neurontin
use among high-prescribing physicians and cultivation of thought leaders
and tactical programs.2 Local physicians were recruited, trained, and paid
to serve as speakers in “peer-to-peer selling” programs, which the company
saw as “one of the most effective ways to communicate our message.” Academic
leaders were solicited with educational grants, research grants, and
speaking opportunities; some received up to $158,250 over a 4-year period.
Advisory boards and “consultants” were convened so that the firm could
cultivate
relationships with them and deliver “a hard-hitting message about
Neurontin.”

Marketing “tactics” included education, publications, and
research whose
promotional intent was disguised, in addition to more
transparent activities, such as advertising and sales visits.2 “Educational
programs” reflected the belief that “medical education drives this market!”
Teleconferences involving practicing physicians were moderated by physicians
who were paid as much as $176,100 over 4 years. Parke-Davis formed speakers
bureaus and sought “strong Neurontin advocates and users to speak locally
for Neurontin.” “Unrestricted educational grants” were made to for-profit
medical-education companies that produced programs to discuss unapproved
uses of Neurontin and to grant credit approved by the Accreditation Council
for Continuing Medical Education.

A “publication strategy” was designed to
increase the use of Neurontin for
neuropathic pain and bipolar disorder,
off-label indications with great revenue potential. Parke-Davis contracted
with medical-education companies to produce articles on prespecified topics,
target journals, titles, potential authors to be “chosen at the discretion
of Parke-Davis,” and “a consistent message” in keeping with promotional
goals; some articles were ghost-written.

“Research” was designed and
commissioned specifically to promote Neurontin use. A large seeding trial
was conducted to “teach physicians to titrate Neurontin to clinical effect”
and “to give neurologists the opportunity to titrate to higher doses [up to
twice the FDA-approved limit] when needed.” In a recently unsealed 318-page
analysis of research sponsored by Parke-Davis, epidemiologist Kay Dickersin
concluded that available documents demonstrate “a remarkable assemblage of
evidence of reporting biases that amount to outright deception of the
biomedical community, and suppression of scientific truth concerning the
effectiveness of Neurontin for migraine, bipolar disorders, and pain.“3 For
example, publication was delayed for a report on a multicenter,
placebo-controlled study that found no effect of Neurontin on the primary
outcome measure for neuropathic pain because “we [Parke-Davis employees]
should take care not to publish anything that damages neurontin’s marketing
success.” Ultimately,
ghost-written manuscripts downplayed the lack of
effect on the primary outcome and emphasized other outcomes and subgroup
analyses that favored Neurontin. Although guest authorship and commercial
bias in research are a well-recognized threat to scientific integrity, the
documentation of comprehensive manipulation of research and publication
related to Neurontin is remarkable.

What is Neurontin’s legacy? First, we
have learned that pharmaceutical marketing can be comprehensive, strategic,
well financed, disguised as “education” and “research,” influential, and
very effective. Promotion of Neurontin was neither discrete,
compartmentalized, nor readily apparent; instead, it was intercalated in
nearly every aspect of physicians’ professional lives, from the
accoutrements of practice to lectures, professional meetings, and
publications. Although some
pharmaceutical marketing may be less opaque,
deceptive, and manipulative,
evidence indicates that drug promotion can
corrupt the science, teaching, and practice of medicine.4

Second, such
comprehensive marketing involved many people and institutions that
apparently failed to recognize the serious ethical and legal problems with
their actions. Employees of Parke-Davis, the medical-education companies it
hired, and many physicians (consultants, advisors, educators, and
researchers) all participated knowingly. Universities, hospitals,
professional organizations, and foundations also participated, and oversight
agencies such as the FDA and the Department of Justice did not intervene
quickly. Apparently, there was a shared acceptance that Parke-Davis’s
marketing was simply business as usual.

Finally, these cases substantiate
the emerging conviction that “drastic action is essential” to preserve the
integrity of medical science and practice and to justify public trust.4 We
believe that such action should include the routine placement of legally
discovered documents in the public domain, the study of such documents to
inform strategies for minimizing abuses, the establishment of penalties that
eliminate the profit to be gained through illegal marketing, and the
independent public funding of peer-reviewed pharmaceutical research through
a National Institute for Pharmaceutical Research that might be funded by a
tax on
all drug sales.5

Will our profession soon feel compelled to advocate
for such actions to preserve our integrity, our social contract, and
ultimately our privileges? Neurontin’s most important legacy may be
promoting our discussion of these issues and perhaps pushing us beyond the
tipping point to action.

Drs. Landefeld and Steinman report serving as
unpaid consultants to the
plaintiff’s attorney in United States of America
ex rel. David Franklin vs.
Pfizer, Inc., and Parke-Davis Division of
Warner-Lambert Company and
participating in the creation of the Drug
Industry Document Archive by the
University of California, San Francisco,
Kalmanovitz Library, an effort that was funded in part by Thomas Greene,
whose law firm represented David Franklin in the case. Dr. Steinman also
reports receiving support from an educational grant funded by the Attorney
General Settlement Fund that arose from the Franklin case. No other
potential conflict of interest relevant to this article was reported.

The views expressed in this article are those of the authors and do
not necessarily reflect the official views of the Department of Veterans Affairs.

Source Information

Dr. Landefeld is a professor of medicine and
chief of the Division of Geriatrics at the University of California, San
Francisco (UCSF), San Francisco; associate chief of staff for geriatrics and
extended care at the San Francisco Veterans Affairs Medical Center (SFVAMC),
San Francisco; and a fellow at the Center for Advanced Study in the
Behavioral Sciences, Stanford University, Stanford, CA. Dr. Steinman is an
assistant professor of medicine at UCSF and a staff physician at SFVAMC.

References

1. Disclosure of information by relator David P. Franklin pursuant to 31
U.S.C. 3730 b(2), page 11. (Accessed December 16, 2008,
at
http://dida.library.ucsf.edu/pdf/rab00a10.)

2. Steinman MA, Bero LA, Chren MM, Landefeld CS. The promotion of
gabapentin: an analysis of internal industry documents. Ann Intern Med
2006;145:284-293. [Free Full Text]

3. Dickersin K. Reporting and other biases in studies of Neurontin for
migraine, psychiatric/bipolar disorders, nociceptive pain, and neuropathic
pain. August 10, 2008. (Accessed December 16, 2008,
at
http://www.pharmalot.com/wp-content/uploads/2008/10/neurontin-dickersin-2.pdf.)

4. DeAngelis CD, Fontanarosa PB. Impugning the integrity of medical science:
the adverse effects of industry influence. JAMA 2008;299:1833-1835. [Free
Full Text]
5. Landefeld CS. Commercial support and bias in pharmaceutical
research. Am J Med 2004;117:876-878.