For pharmaceutical companies, off-label use of a drug represents a substantial “gray market,” to which the company is unable to sell their product directly, yet may be a significant revenue stream. Some drugs have been used more for off-label purposes than for originally approved indications.1
The Warner-Lambert settlement of 2004 made very clear how far some companies have gone to reach this gray market. As part of the settlement, the US Department of Justice noted strategic marketing plans detailing the company’s intent to illegally market an antiseizure drug for the treatment of bipolar disorder, as well as the company’s use of the following tactics2,3:
• Providing one-on-one sales pitches to physicians about off-label uses of the drug without prior acceptable research demonstrating efficacy of the treatment. As part of these sales pitches, the sales representatives used false or misleading statements about the drug’s efficacy and its approval for off-label uses.
• Paying doctors to attend “consultants meetings” that involved presentations about the off-label uses of the drug. These meetings were often held at desirable locations, such as Florida and Hawaii or the 1996 Atlanta Olympics.
• Recruiting doctors to call into teleconferences where they would hear a doctor or a Warner-Lambert employee speak about the drug’s off-label use.
• Sponsoring “independent medical education” events on off-label uses of the drug. These “independent” events involved extensive input from the drug company regarding topics, speakers, content, and participants. In addition, before the events, the drug company misled the medical community about the content and the company’s role in the shaping of key messages disseminated at the putatively educational sessions. At one event, a speaker with unfavorable remarks was countered by Warner-Lambert through “planted” people in the audience, who asked questions that highlighted the benefits of the drug.
• Paying physicians to allow sales representatives to be with them when physicians saw patients. Sales representatives then offered treatment advice biased toward the use of the drug.2,3
A close examination of the scientific literature supporting the use of Neurontin for bipolar disorder is equally surprising. The “evidence” for the off-label use of this drug for bipolar disorder was developed over 10 years and, not so coincidentally, dropped off abruptly after the settlement. A literature review published in 2008 as part of a supplement to the Journal of Psychiatric Practice4 found 29 articles published between 1997 and 2007 on the off-label use of Warner-Lambert’s drug. In most of these articles, the authors were optimistic about the drug’s effectiveness for its off-label use.
A closer examination, however, revealed that this evidence base, like the drug’s off-label efficacy for bipolar disorder, warranted more scrutiny. Fifteen of the 29 articles were uncontrolled case series. Six were reports of a single case. Four of the published articles involved small randomized trials that demonstrated little, if any, efficacy. Further still, 21 of the original 29 studies did not disclose funding sources or were funded by industry, and many of the articles did not include published conflict of interest statements. An additional 9 letters to the editor also reflected this same pattern. The findings presented in this collection of mainly case series and case reports were not sufficient to suggest a systematic change in practice, such as the treatment of bipolar disorder with Neurontin.
A supplement article in the Journal of Psychiatric Practice described how the impact of these papers had a significant domino effect. Using the ISI Web of Science to conduct citation searches, the authors found that each paper had been cited, on average, 35 times. The citations appeared in more than 400 unique articles and 150 unique journals. In addition, the authors of the original 29 articles appeared as authors accounting for more than a quarter of the 400+ articles. Moreover, certain authors of the first set of 29 articles appeared as authors of 130 of the subsequent set of 400+ articles referencing the original 29 papers. Clearly, the relatively few authors involved in the original 29 studies leveraged a limited research platform to reach a relatively wide audience of prescribing professionals, researchers, and practitioners looking for ways to treat this difficult disorder.
1. US Department of Justice. Press release: Warner-Lambert to pay $430 million to resolve criminal & civil health care liability relating to off-label promotion. May 13, 2004. http://www.usdoj.gov/opa/pr/2004/May/04_civ_322.htm. Accessed July 7, 2009.
2. Chen H, Reeves JH, Fincham JE, et al. Off-label use of antidepressant, anticonvulsant, and antipsychotic medications among Georgia medicaid enrollees in 2001. J Clin Psychiatry. 2006;67:972-982.
3. Steinman MA, Bero LA, Chren MM, Landefeld CS. Narrative review: the promotion of gabapentin: an analysis of internal industry documents. Ann Intern Med. 2006;145:284-293.
4. Carey TS, Williams JW Jr, Oldham JM, et al. Gabapentin in the treatment of mental illness: the echo chamber of the case series [published correction appears in J Psychiatr Pract. 2008;14:193]. J Psychiatr Pract. 2008;14(suppl 1):15-27.
5. Carey TS, Boden SD. A critical guide to case series reports. Spine. 2003;28:1631-1634.