Michael A. Steinman, MD; Lisa A. Bero, PhD; Mary-Margaret Chren, MD; C. Seth Landefeld, MD
Acknowledgment: The authors thank Elizabeth Boyd, PhD, for her careful review of the manuscript.
Grant Support: By a Veterans Affairs Health Services Research & Development Research Career Development Award (Dr. Steinman); by grants from the California Tobacco-Related Disease Research Programs (13RT-0108) (Dr. Bero), the National Institute of Arthritis and Musculoskeletal and Skin Disease (AR02203) (Dr. Chren), the National Institute on Aging (AG00912), and the John A. Hartford Foundation (2003–0244) (Dr. Landefeld); and by the Health Services Research Enhancement Award Program at the San Francisco Veterans Affairs Medical Center.
Potential Financial Conflicts of Interest: Drs. Steinman, Chren, and Landefeld served as unpaid expert witnesses for the plaintiff in the lawsuit that generated these documents (United States of America ex. rel. David Franklin vs. Pfizer, Inc., and Parke-Davis, Division of Warner-Lambert Company). Dr. Bero was not involved in this or any other legal action involving Pfizer or Parke-Davis. Seed funding for an online searchable archive of documents from the gabapentin litigation (dida.library.ucsf.edu) was provided by a gift from Thomas Greene, lawyer for the whistleblower plaintiff in this litigation, to the University of California Board of Regents. Drs. Steinman and Landefeld participated in the creation and development of the archive, including solicitation of start-up funding from Mr. Greene. The cost of obtaining and photocopying documents used in this research was paid by the archive, which incorporated these documents into the collection.
Requests for Single Reprints: Michael A. Steinman, MD, San Francisco Veterans Affairs Medical Center, 4150 Clement Street, Box 181G, San Francisco, CA 94121; e-mail, email@example.com.
Current Author Addresses: Drs. Steinman and Landefeld: San Francisco Veterans Affairs Medical Center, 4150 Clement Street, Box 181G, San Francisco, CA 94121.
Dr. Bero: University of California, San Francisco, 3333 California Street, Suite 420, Box 0613, San Francisco, CA 94143.
Dr. Chren: San Francisco Veterans Affairs Medical Center, 4150 Clement Street, Box 151R, San Francisco, CA 94121.
Internal documents from the pharmaceutical industry provide a unique window for understanding the structure and methods of pharmaceutical promotion. Such documents have become available through litigation concerning the promotion of gabapentin (Neurontin, Pfizer, Inc., New York, New York) for off-label uses.
To describe how gabapentin was promoted, focusing on the use of medical education, research, and publication.
Court documents available to the public from United States ex. rel David Franklin vs. Pfizer, Inc., and Parke-Davis, Division of Warner-Lambert Company, mostly from 1994–1998.
All documents were reviewed by 1 author, with selected review by coauthors. Marketing strategies and tactics were identified by using an iterative process of review, discussion, and re-review of selected documents.
The promotion of gabapentin was a comprehensive and multifaceted process. Advisory boards, consultants meetings, and accredited continuing medical education events organized by third-party vendors were used to deliver promotional messages. These tactics were augmented by the recruitment of local champions and engagement of thought leaders, who could be used to communicate favorable messages about gabapentin to their physician colleagues. Research and scholarship were also used for marketing by encouraging “key customers” to participate in research, using a large study to advance promotional themes and build market share, paying medical communication companies to develop and publish articles about gabapentin for the medical literature, and planning to suppress unfavorable study results.
Most available documents were submitted by the plaintiff and may not represent a complete picture of marketing practices.
Activities traditionally considered independent of promotional intent, including continuing medical education and research, were extensively used to promote gabapentin. New strategies are needed to ensure a clear separation between scientific and commercial activity.
Prescriptions for gabapentin, by diagnostic category.
Estimates of diagnosis-linked prescribing provided by Pfizer, Inc. (2–4). Each diagnosis was assigned to a diagnostic category by the authors. *Adjunctive treatment of epilepsy in adults older than age 12 years was the only U.S. Food and Drug Administration–approved use of gabapentin during the time period shown.
Table 1. Timeline*
Table 2. Draft Advertising and Promotion Budget for Gabapentin for 1998, by Strategy and Tactical Category*
Framework for gabapentin marketing.
In this model, marketing strategy and tactical planning allocate resources to different types of activities. Activities are divided into 3 categories according to the extent to which their promotional intent is generally known to physicians (for example, in directly sponsored continuing medical education [CME], the pharmaceutical company is known to be the direct source of funding, but because the event is framed as an educational program, its promotional intent may be obscured). Each of these activities can directly influence prescribing by practicing physicians. In addition, activities in the lower half of the figure can also influence prescribing through physician-to-physician communication, in which opinion leaders and local gabapentin champions are directly or indirectly engaged to communicate favorable messages about gabapentin to their colleagues. Physician prescribing patterns and other outcomes are then monitored to assess the effectiveness of marketing tactics, which influences future marketing planning decisions. For the sake of simplicity, other relationships are not shown in this diagram. For example, many marketing tactics can work synergistically, such as the use of research findings to promote gabapentin in CME settings.
When Proworx finally received each of the abstracts [for talks by two speakers] within the week prior to the actual program, they were immediately forwarded to both Vic and Allen [Parke-Davis marketing employees] for their comments. Upon receipt of Dr. B's abstract, Vic called Bina [a project director at Proworx] to express his concerns. However, Bina had already contacted [the accrediting institution] to establish what could be done, within the accreditation guidelines, to address these concerns. At that point, Dr. B. was contacted and told that the accrediting institution had asked that she revise her abstract to remove any specific product information that she could not provide references for. She then revised her abstract and faxed it back again for our review. Lisa, the copy writer for the Parke-Davis account, was then contacted and asked to make any further revisions.
Although the abstract had been revised, there were still concerns on Proworx's and Vic's part in regard to Dr. B's presentation. Her abstract illustrated that [she] was clearly not planning on presenting what had originally been agreed upon. Therefore, Proworx immediately looked at what possible options were available, aside from canceling her talk, to counteract a possible ‘negative’ presentation. [The accrediting institution] was contacted to address accreditation issues and the CDM [Cline, Davis & Mann, an advertising firm that was the corporate parent of Proworx] account team met with Bina to identify what key issues needed to be presented to give attendees a ‘positive message’ to go away with.
At this point, Proworx requested that Dr. B. forward a copy of her slides for our review. Upon review, we determined that the slides did not include any specific negative information in regard to Neurontin or anticonvulsants as a whole, and that we should concentrate on creating a setting in which she would have no choice but to address the issue she had originally agreed to present. Therefore, when meeting with the CDM account team, pre-written questions were developed to address any issues that were not mentioned in Dr. B's presentation, as well as questions counteracting negative comments … .
It was then decided that the best option, while not crossing over [American Council of Graduate Medical Education] guidelines, was to present questions at the Q & A session, which would take place immediately following her presentation. This did indeed lead Dr. B. to address some of the positive aspects of anticonvulsants and of Neurontin … .
If this had not been an accredited program, Proworx would have been able to probe the faculty further to definitively establish program content and make the appropriate changes and/or recruit an alternative speaker.
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Benjamin L Sapers
August 23, 2006
Re August 15th Issue
In the great 1942 movie Casablanca, Captain Renault (Claude Rains) orders his men to close Rick's bar, saying he was "shocked, shocked to find that gambling (was) going on"¦"at the bar. The cashier hands him his winnings. In the August 15th Issue of the Annals, there is an article discussing the value of "financial incentives" and "[paying] for performance" to make physicians do the right thing (1). Twelve pages later, we have a well-researched indictment of a drug company trying to sell its product (2). Do we see ourselves as physicians and patients or as health suppliers and demanders? If we are the former, then we should act as such, and we must demand that those organizations with whom we must work (insurance companies, drug companies and, recently, the FDA) behave less like business people and more like professionals. If we are the later, then let us do what is right for capitalism: deregulate the health care market, let drug companies pedal their wares in peace, and let herbalists and other traditional healers compete on even ground for the attention of health care consumers. 1. Petersen, LA et alia.Does Pay-for-Performance Improve the Quality of Health Care. Ann Intern Med. 2006; 145:265-272 2. Steinman, MA et alia. Narrative Review: The Promotion of Gabapentin: An Analysis of Internal Industry Documents. Ann Intern Med. 2006;145: 284-293
Thomas E. Finucane
Johns Hopkins Bayview Medical Center
September 13, 2006
Annals of Internal Medicine
To the Editor:
Steinman and colleagues describe an explicit promotional campaign by gabapentin's vendor that included efforts to inflate the literature on gabapentin "by contracting with medical education companies to develop review papers, original articles, and letters to the editors" favorable to gabapentin and then hiring physicians and pharmacists to be authors on these papers. Knowing this was done makes the literature on gabapentin very difficult to interpret.
A pub med search of gabapentin limited to randomized controlled trials done on August 25, 2006, found 148 RCTs. In this primary research literature, there are multiple positive trials of gabapentin for hot flashes, bi-polar disorder, alcohol withdrawal, pain syndromes, spasticity, restless leg, chronic headache and acquired nystagmus, among a myriad of other conditions. Limiting the search to clinical trials yields 285 studies, ranging from hiccups to priapism.
Either this drug has extremely broad (and biologically implausible) effectiveness for a variety of unrelated conditions or the literature is so corrupt as to be unsalvageable.
Unfortunate consequence of this is we are unlikely to know for what conditions that gabapentin is actual useful.
Eric D Peterson
North American Association of Medical Education and Communication Companies
September 28, 2006
Separation of Scientific and Commercial Interests
In the August 15, 2006 issue, Steinman and colleagues offered a purportedly "unique window for understanding the structure and methods of pharmaceutical marketing," concluding that "new strategies are needed to ensure a clear separation between scientific and commercial activities."1 The authors explored the well-documented abuses related to the off-label marketing of gabapentin. Unfortunately, they seem to imply that these actions are representative of current practice. Worse, the authors call for various reforms, but seem unaware that many such reforms have already taken place. They state only that "a complex system has evolved" that has been "largely ineffective," a claim that cannot be supported by the references cited, since the referenced publications predate most of the reforms.
The Pharmaceutical Research and Manufacturers of America (PhRMA) Code on Interactions with Healthcare Professionals, released April 19, 2002, has effectively stopped the abuse of advisory boards as described in the article.2 The recommendation that grant functions be separated from marketing functions detailed in the 2003 HHS OIG Compliance Program Guidance for Pharmaceutical Manufacturers3, has resulted in organizational changes within pharmaceutical companies that have removed marketing personnel from decisions related to CME grants. Additionally, most pharmaceutical companies now generally prohibit medical education companies that receive CME grants from having any role in promotional or marketing activities. Most medical education and communications companies have also made organizational changes that separate independent education from promotion.
In September 2004, the Accreditation Council for Continuing Medical Education (ACCME) adopted new Standards for Commercial Support. These Standards obligate providers to develop education that is independent from commercial influence, and require providers to identify and resolve conflicts of interest for faculty or authors, who develop or contribute content.4 Finally, the International Committee of Medical Journal Editors undertook major revisions of their Uniform Requirements for Manuscripts Submitted to Biomedical Journals in 2001, 2003, and 20065, aimed at preventing the abuses of the publication process described in the article.
While seemingly provocative, the findings of Steinman and colleagues are mostly of historical interest. To imply that these findings are indicative of current practices is both inaccurate and misleading. The North American Association of Medical Education and Communications Companies (NAAMECC), an association of over 70 companies involved in CME, is deeply concerned about, and works to ensure, the integrity, quality, and educational value of CME. We assert that the CME of today has little in common with the actions described in the article.
For the NAAMECC Board of Directors,
Eric D. Peterson, Past President Kurt Boyce, President Karen Overstreet, EdD, President Elect
1. Steinman MA, Bero LA, Chren M, Landefeld CS. The promotion of gabapentin: an analysis of internal industry documents. Arch Intern Med. August 2006;145:284-293.
2. Pharmaceutical Research and Manufacturers of America. The PhRMA code on interactions with healthcare professionals. Available at: http://www.phrma.org/files/PhRMA%20Code.pdf. Accessed August 21, 2006.
3. Health and Human Services Office of the Inspector General: OIG compliance program guidance for pharmaceutical manufacturers. Federal Register. May 2003;68:23731-23740.
4. Accreditation Council for Continuing Medical Education. Standards for commercial support: standards to ensure the independence of CME activities. Available at: http://www.accme.org/dir_docs/doc_upload/68b2902a-fb73-44d1-8725- 80a1504e520c_uploaddocument.pdf. Accessed August 22, 2006.
5. International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals: writing and editing for biomedical publications. Available at: http://www.icmje.org/. Accessed August 22, 2006.
Michael A. Steinman
San Francisco VA Medical Center and University of California
November 9, 2006
Dr. Finucane's enumeration of the large variety of controlled clinical trials of gabapentin is consistent with the company's support of small research projects to promulgate messages about the drug in the world's medical literature. Although one might apply principles of evidence-based medicine to each of these studies, in practice it is difficult for practicing physicians to critically evaluate the effectiveness of gabapentin for such a wide range of disorders.
We applaud the positive steps outlined by Drs. Peterson and Boyce to reduce commercial influence on educational activities. However, we remain sceptical of the claim that the practices we identified are of historical interest only. Current codes of conduct are largely self-administered and lack an enforcement mechanism, and we are aware of little systematic data on the extent to which they are being followed in letter and in spirit. Similar codes enacted by the pharmaceutical industry, the American Medical Association, and the Accreditation Council for Continuing Medical Education (ACCME), which were in force during the period we studied, were often ignored.(1-3) Other research has shown frequent violations of self-regulation by the pharmaceutical industry.(4) Thus, we affirm that self-regulation by all parties in these interactions has been insufficient to control undue commercial influence on the practice of medicine.
The risk of such influence persists because of a fundamental conflict of interest whereby medical education and communications companies (MECCs) and other providers of CME face an incentive to cast the sponsor's products in a favorable light, so as to attract future funding from the same sponsor. Despite recent efforts to strengthen guidelines on commercial support of CME, opportunities for abuse still exist.(5) Current guidelines allow commercial supporters to raise concerns about content and permit CME providers to consult with commercial supporters about suggested speakers and topics. This creates a condition analogous to what Dr. Sapers identifies as the situation of individual physicians, balancing our ethical and professional obligations against financial interests. However, while physicians and universities that host CME programs have both financial incentives and a fiduciary responsibility to patients and the public, the private, for-profit status of MECCs raises special concern that financial interests may encroach on the scientific integrity of their educational programs.
Recent strengthening of codes of conduct, stimulated in part by the threat of federal prosecution, has been a welcome improvement in the management of direct and indirect forms of pharmaceutical promotion.(6) However, major conflicts of interest and loopholes persist, and must be addressed by vigorous regulation with independent oversight to separate commercial from scientific activities.
Michael A. Steinman, MD San Francisco VA Medical Center and University of California, San Francisco firstname.lastname@example.org
Lisa A. Bero, PhD University of California, San Francisco
Mary-Margaret Chren, MD University of California, San Francisco and San Francisco VA Medical Center
C. Seth Landefeld, MD University of California, San Francisco and San Francisco VA Medical Center
(1) Code of Pharmaceutical Marketing Practices. Washington, D.C.: Pharmaceutical Manufacturers Association, 1990.
(2) Council on Ethical and Judicial Affairs, American Medical Association. Gifts to Physicians from Industry. JAMA 1991; 265: 501.
(3) Standards for Commercial Support of Continuing Medical Education. Chicago, IL: Accreditation Council for Continuing Medical Education, 1992.
(4) Herxheimer A, Collier J. Promotion by the British pharmaceutical industry, 1983-8: a critical analysis of self regulation. BMJ 1990; 300: 307-11.
(5) Steinbrook R. Commercial support and continuing medical education. N Engl J Med 2005; 352: 534-35.
(6) Studdert DM, Mello MM, Brennan TA. Financial conflicts of interest in physicians' relationships with the pharmaceutical industry self-regulation in the shadow of federal prosecution. N Engl J Med 2004; 351: 1891-1900.
Opinions expressed in this letter are those of the authors and do not reflect positions of the government or the Department of Veteran Affairs
Drs. Steinman, Chren, and Landefeld served as unpaid expert witnesses in the litigation on which their manuscript was based, and Drs. Steinman and Landefeld participated in the creation of an online searchable archive of documents funded by the plantiff's lawyer in that litigation
Steinman MA, Bero LA, Chren M, et al. Narrative Review: The Promotion of Gabapentin: An Analysis of Internal Industry Documents. Ann Intern Med. 2006;145:284–293. doi: https://doi.org/10.7326/0003-4819-145-4-200608150-00008
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Published: Ann Intern Med. 2006;145(4):284-293.
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