Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints

Aaron Kesselheim and colleagues analyzed unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing, and develop a taxonomy of the various off-label practices. Background: Despite regulatory restrictions, off-label marketing of pharmaceutical products has been common in the US. However, the scope of off-label marketing remains poorly characterized. We developed a typology for the strategies and practices that constitute off-label marketing. Methods and Findings: We obtained unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing (January 1996–October 2010) and conducted structured reviews of them. We coded and analyzed the strategic goals of each off-label marketing scheme and the practices used to achieve those goals, as reported by the whistleblowers. We identified 41 complaints arising from 18 unique cases for our analytic sample (leading to US$7.9 billion in recoveries). The off-label marketing schemes described in the complaints had three non–mutually exclusive goals: expansions to unapproved diseases (35/41, 85%), unapproved disease subtypes (22/41, 54%), and unapproved drug doses (14/41, 34%). Manufacturers were alleged to have pursued these goals using four non–mutually exclusive types of marketing practices: prescriber-related (41/41, 100%), business-related (37/41, 90%), payer-related (23/41, 56%), and consumer-related (18/41, 44%). Prescriber-related practices, the centerpiece of company strategies, included self-serving presentations of the literature (31/41, 76%), free samples (8/41, 20%), direct financial incentives to physicians (35/41, 85%), and teaching (22/41, 54%) and research activities (8/41, 20%). Conclusions: Off-label marketing practices appear to extend to many areas of the health care system. Unfortunately, the most common alleged off-label marketing practices also appear to be the most difficult to control through external regulatory approaches. Background: Before a pharmaceutical company can market a new prescription drug in the US, the drug has to go through a long approval process. After extensive studies in the laboratory and in animals, the pharmaceutical company must test the drug's safety and efficacy in a series of clinical trials in which groups of patients with specific diseases are given the drug according to strict protocols. The results of these trials are reviewed by Federal Drug Administration (FDA, the body that regulates drugs in the US) and, when the FDA is satisfied that the drug is safe and effective for the conditions in which it is tested, it approves the drug for sale. An important part of the approval process is the creation of the “drug label,” a detailed report that specifies the exact diseases and patient groups in which the drug can be used and the approved doses of the drug. Why Was This Study Done?: Physicians can, however, legally use FDA-approved drugs “off-label.” That is, they can prescribe drugs for a different disease, in a different group of patients, or at a different dose to that specified in the drug's label. However, because drugs' manufacturers stand to benefit financially from off-label use through increased drugs sales, the FDA prohibits them from directly promoting unapproved uses. The fear is that such marketing would encourage the widespread use of drugs in settings where their efficacy and safety has not been rigorously tested, exposing patients to uncertain benefits and possible adverse effects. Despite the regulatory restrictions, off-label marketing seems to be common. In 2010, for example, at least six pharmaceutical companies settled US government investigations into alleged off-label marketing programs. Unfortunately, the tactics used by pharmaceutical companies for off-label marketing have been poorly understood in the medical community, in part because pharmaceutical industry insiders (“whistleblowers”) are the only ones who can present in-depth knowledge of these tactics. In recent years, as more whistleblowers have come forward to allege off-label marketing, developing a more complete picture of the practice is now possible. In this study, the researchers attempt to systematically classify the strategies and practices used in off-labeling marketing by examining complaints filed by whistleblowers in federal enforcement actions where off-label marketing by pharmaceutical companies has been alleged. What Did the Researchers Do and Find?: In their analysis of 41 whistleblower complaints relating to 18 alleged cases of off-label marketing in federal fraud cases unsealed between January 1996 and October 2010, the researchers identified three non–mutually exclusive goals of off-label marketing schemes. The commonest goal (85% of cases) was expansion of drug use to unapproved diseases (for example, gabapentin, which is approved for the treatment of specific types of epilepsy, was allegedly promoted as a therapy for patients with psychiatric diseases such as depression). The other goals were expansion to unapproved disease subtypes (for example, some antidepressant drugs approved for adults were allegedly promoted to pediatricians for use in children) and expansion to unapproved drug dosing strategies, typically higher doses. The researchers also identified four non–mutually exclusive types of marketing practices designed to achieve these goals. All of the whistleblowers alleged prescriber-related practices (including providing financial incentives and free samples to physicians), and most alleged internal practices intended to bolster off-label marketing, such as sales quotas that could only be met if the manufacturer's sales representatives promoted off-label drug use. Payer-related practices (for example, discussions with prescribers about ways to ensure insurance reimbursement for off-label prescriptions) and consumer-related practices (most commonly, the review of confidential patient charts to identify consumers who could be off-label users) were also alleged. What Do These Findings Mean?: These findings suggest that off-labeling marketing practices extend to many parts of the health care delivery system. Because these practices were alleged by whistleblowers and were not the subject of testimony in a full trial, some of the practices identified by the researchers were not confirmed. Conversely, because most of the whistleblowers were US-based sales representatives, there may be other goals and strategies that this study has not identified. Nevertheless, these findings provide a useful snapshot of off-label marketing strategies and practices allegedly employed in the US over the past 15 years, which can now be used to develop new regulatory strategies aimed at effective oversight of off-label marketing. Importantly, however, these findings suggest that no regulatory strategy will be complete and effective unless physicians themselves fully understand the range of off-label marketing practices and their consequences for public health and act as a bulwark against continued efforts to engage in off-label promotion. Additional Information: Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000431.