John W. Williams Jr, MD

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.

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 tactics

• 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.

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 

 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.

 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.

Further adding to these weak findings was what the authors found when they reviewed the actual documents from the Warner-Lambert settlement. Documents found on the Drug Industry Document Archive (DIDA; 

) indicate that authors of 8 of the 29 articles referenced above may have taken part in a company-sponsored meeting, been paid as a speaker, or worked with ghostwriters. Unfortunately, information available from DIDA was not sufficient to directly tie an individual author’s specific involvement with Pfizer or Warner-Lambert to their work on specific publications.

 supplement article documents how drug marketing can influence publication in scientific and clinical research literature as backdoor, off-label drug marketing. Prescribing professionals should be aware of the damage that such tactics can cause in individuals who were prescribed an ineffective drug by physicians mistakenly relying on what they believed to be emerging literature supporting its efficacy.

The tactics used to market Neurontin should be a wake-up call as cases of off-label marketing continue to flow through the legal system. In 2008, Pfizer settled lawsuits costing more than $60 million in 33 states and Washington, DC, for charges that the company used illegal tactics to off-label market its drug Celebrex. As recently as early 2009, Eli Lilly and Company pleaded guilty and paid $1.4 billion for promoting Zyprexa for unapproved uses-such as treatment for dementia in the elderly.

Given the prevalence of these cases, it’s imperative that physicians and other prescribing professionals scrutinize the medical and scientific literature with the awareness that sometimes scientific publication is part of an organized marketing campaign.

A standardized protocol on how to conduct such scrutiny might make the task less burdensome and time-consuming. When reading case series or cohort studies, professionals should view articles through an evidence-based prism and ask the following questions when reading literature supporting the off-label use of any drug:

1. Are the case studies presented clearly and completely, with full disclosure by the author(s)? There is relatively little guidance on how to evaluate the quality of a case study, but an article appearing in the journal 

5 suggests that high-quality case studies should have the following:

• Study populations and results that are well described.

• Outcome measures that have been validated.

• Discussions and conclusions clearly supported by the data.

• Funding sources that are fully dis- closed or, when no funding source exists, a statement to that effect.

2. Is there an inexplicably small group of individuals repeatedly publishing positive case series without follow-up controlled trials?

3. What is the quality of the peer review of the journals in which the studies are being published? Are there published policies regarding peer review and conflict of interest disclosure?

4. Are the funding sources of studies disclosed? If so, are the studies being funded by the company that owns the drug? If not, have the authors received funding from the company that owns the drug?

5. Do the studies make sense? For instance, if the illness is chronic, do case series studies only present short-term results or do conclusions from randomized controlled trials (if available) contradict conclusions/recommendations from case studies?

Just as no 2 manufacturers produce the same quality cars, computers, or televisions, the same is true for the articles produced by authors, editors, and publishers. The discovery that relatively few individuals could significantly affect the literature shows why clinicians and researchers must apply their own judgments when considering off-label uses for their patients. Part of this process should involve reading articles carefully to identify weaknesses and missing information within the articles themselves, and then comparing articles across journals to see whether the weaknesses have been adequately addressed elsewhere. Systematic reviews, conducted by researchers without conflict of interest, are one way to efficiently sort through the literature. Unbiased online resources such as the Drug Effectiveness Review Project (

) or the Agency for Healthcare Research and Quality (

Finally-and perhaps most important-prescribing professionals must temper anything they read with their 2 most important tools: experience and common sense.

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

 Chen H, Reeves JH, Fincham JE, et al. Off-label use of antidepressant, anticonvulsant, and antipsychotic medications among Georgia medicaid enrollees in 2001. 

 Steinman MA, Bero LA, Chren MM, Landefeld CS. Narrative review: the promotion of gabapentin: an analysis of internal industry documents. 

 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 

 Carey TS, Boden SD. A critical guide to case series reports. 

Articles

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

John W. Williams Jr, MD

Articles

Marketing Off-Label Uses: Shady Practices Within a Gray Market