The Neurontin Legacy — Marketing through Misinformation and Manipulation...

[JacquesL]

Un article du NEJM, sur une manipulation à grande échelle de Parke-Davis (racheté par Pfizer) pour promouvoir le Neurontin auprès des prescripteurs. C'est assez édifiant sur le degré de subtilité et la stratégie à multiples niveaux de Big Pharma pour nous faire avaler ses pilules..

The Neurontin Legacy — Marketing through Misinformation and Manipulation
C. S. Landefeld and M. A. Steinman - 8 Jan, 2009

http://content.nejm.org/cgi/content/full/360/2/103

Volume 360:103-106      January 8, 2009      Number 2

The Neurontin Legacy — Marketing through Misinformation and
Manipulation
C. Seth Landefeld, M.D., and Michael A. Steinman, M.D.

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. [CrossRef][ISI][Medline]

Résumé :
Ça concerne le Neurontin, anti-épileptique qui allait être génériqué et qui est passé de 98 millions de dollars en 1995 à près de 3 milliards en 2004 pour avoir obtenu un nouvelle indication comme antalgique à forte dose après avoir été racheté par Pfizer.
Pour obtenir ce résultat, après une magouille judiciaire que j'ai pas comprise mais qui permet de suivre les méthodes de marketing qui ont propulsé le Neurontin: leaders d'opinion recrutés pour faire la pub, FMC, subventions à des leaders universitaires, bourses de recherche, consultants, publications prêtes à signer, enfin tout ce qu'il est possible de mettre en oeuvre avec de très gros moyens pour obtenir une indication pour la douleur (c'est le cas en France, le Neurontin a l'AMM) et les troubles bi-polaires à une posologie deux fois supérieure à celle qui avait été approuvée.

L'article met l'accent sur la haute stratégie de la firme, ses très gros moyens et sa capacité à taper tous azimuts (université, hôpitaux, organisations professionnelles, autorités de contrôle..) pour imposer son produit..
L'auteur estime qu'une action radicale est nécessaire pour préserver l'intégrité du milieu scientifique (hmm) et la confiance publique, en rendant publique ce type d'épopée et en pénalisant la firme pour lui faire cracher son bénef et lui passer l'envie de recommencer.