Content Analysis of False and Misleading Claims in Television Advertising for Prescription and Nonprescription Drugs

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Abstract

False and misleading advertising for drugs can harm consumers and the healthcare system, and previous research has demonstrated that physician-targeted drug advertisements may be misleading. However, there is a dearth of research comparing consumer-targeted drug advertising to evidence to evaluate whether misleading or false information is being presented in these ads.

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The Cost of Pushing Pills: A New Estimate of Pharmaceutical Promotion Expenditures in the United States

Marc-André Gagnon, Joel Lexchin (2008)

In the late 1950s, the late Democratic Senator Estes Kefauver, Chairman of the United States Senate's Anti-Trust and Monopoly Subcommittee, put together the first extensive indictment against the business workings of the pharmaceutical industry. He laid three charges at the door of the industry: (1) Patents sustained predatory prices and excessive margins; (2) Costs and prices were extravagantly increased by large expenditures in marketing; and (3) Most of the industry's new products were no more effective than established drugs on the market [1]. Kefauver's indictment against a marketing-driven industry created a representation of the pharmaceutical industry far different than the one offered by the industry itself. As Froud and colleagues put it, the image of life-saving “researchers in white coats” was now contested by the one of greedy “reps in cars” [2]. The outcome of the struggle over the image of the industry is crucial because of its potential to influence the regulatory environment in which the industry operates. Fifty years later, the debate still continues between these two depictions of the industry. The absence of reliable data on the industry's cost structures allows partisans on both sides of the debate to cite figures favorable to their own positions. The amount of money spent by pharmaceutical companies on promotion compared to the amount spent on research and development is at the heart of the debate, especially in the United States. A reliable estimate of the former is needed to bridge the divide between the industry's vision of research-driven, innovative, and life-saving pharmaceutical companies and the critics' portrayal of an industry based on marketing-driven profiteering. IMS, a firm specializing in pharmaceutical market intelligence, is usually considered to be the authority for assessing pharmaceutical promotion expenditures. The US General Accounting Office, for example, refers to IMS numbers in concluding that “pharmaceutical companies spend more on research and development initiatives than on all drug promotional activities” [3]. Based on the data provided by IMS [4], the Pharmaceutical Research and Manufacturers of America (PhRMA), an American industrial lobby group for research-based pharmaceutical companies, also contends that pharmaceutical firms spend more on research and development (R&D) than on marketing: US$29.6 billion on R&D in 2004 in the US [5] as compared to US$27.7 billion for all promotional activities.[4] In this paper, we make the case for the need for a new estimate of promotional expenditures. We then explain how we used proprietary databases to construct a revised estimate and finally, we compare our results with those from other data sources to argue in favor of changing the priorities of the industry. The Case for a New Estimate of Pharmaceutical Promotion There are many concerns about the accuracy of the IMS data. First, IMS compiles its information through surveys of firms, creating the possibility that companies may systematically underestimate some of their promotional costs to enhance their public image. Second, IMS does not include the cost of meetings and talks sponsored by pharmaceutical companies featuring either doctors or sales representatives as speakers. The number of promotional meetings has increased dramatically in recent years, going from 120,000 in 1998 to 371,000 in 2004 [6]. In 2000, the top ten pharmaceutical companies were spending just under US$1.9 billion on 314,000 such events [7]. Third, IMS does not include the amount spent on phase IV “seeding” trials, trials designed to promote the prescription of new drugs rather than to generate scientific data. In 2004, 13.2% (US$4.9 billion) of R&D expenditures by American pharmaceutical firms was spent on phase IV trials [5]. Almost 75% of these trials are managed solely by the commercial, as opposed to the clinical, division of biopharmaceutical companies, strongly suggesting that the vast majority of these trials are done just for their promotional value [8]. Finally, IMS data seem inconsistent with estimates based on the information in the annual reports of pharmaceutical companies. For example, in an accounting study based on the annual reports of ten of the largest global pharmaceutical firms, Lauzon and Hasbani showed that between 1996 and 2005, these firms globally spent a total of US$739 billion on “marketing and administration.” In comparison, these same firms spent US$699 billion in manufacturing costs, US$288 billion in R&D, and had a net investment in property and equipment of US$43 billion, while receiving US$558 billion in profits [9]. Annual reports, however, have their own limitations. First, pharmaceutical firms are multinational and diversified; their annual reports provide no information on how much they spend on pharmaceutical marketing, as compared to the marketing of their non-pharmaceutical products, and they do not provide information about how much is spent on marketing specifically in the US. Second, annual reports merge the categories of “marketing” and “administration,” without delineating the relative importance of each. Finally, “marketing” is a category that includes more than just promotion; it also includes the costs of packaging and distribution. In terms of offering a more precise estimate of overall expenditures on pharmaceutical promotion in the US, annual reports are thus far from satisfactory. In the absence of any collection of information on promotional spending by government or any other noncommercial source, the market research company IMS has long been the only source of such information, which it gains by surveying pharmaceutical firms. Since 2003, however, the market research company CAM has been providing comprehensive information on promotion expenditures by surveying doctors instead of firms. (In July 2005, CAM was merged into the Cegedim Group, another market research company.) We chose to compare IMS data to those produced by CAM in order to provide a more accurate estimate of promotional spending in the US. Other proprietary sources of data do not break down promotional expenditures into different categories and therefore were not used in our comparison. Methods According to its Web site (http://www.imshealth.com/), IMS provides business intelligence and strategic consulting services for the pharmaceutical and health care industries. It is a global company established in more than 100 countries. IMS gathers data from 29,000 data suppliers at 225,000 supplier sites worldwide. It monitors 75% of prescription drug sales in over 100 countries, and 90% of US prescription drug sales. It tracks more than 1 million products from more than 3,000 active drug manufacturers. IMS data for 2004 were obtained from its Web site for the amount spent on: visits by sales representatives (detailing), samples, direct-to-consumer advertising, and journal advertising. The Cegedim Web site (http://www.cegedim-crm.com/index.php?id=12) describes CAM as a global company dedicated to auditing promotional activities of the pharmaceutical industry, established in 36 countries worldwide. CAM annually surveys a representative sample of 2,000 primary care physicians and 4,800 specialists in a variety of specialties in selected locations in the US. From CAM's newsletter [10], we obtained access to data from CAM for the same promotion categories as from IMS. In addition, CAM provided figures for the amount of spending on company-sponsored meetings, e-promotion, mailings, and clinical trials. We used 2004 as the comparison year because it was the latest year for which information was available from both organizations. We focused on the US because it is the only country for which information is available for all important promotional categories. The US is also, by far, the largest market for pharmaceuticals in the world, representing around 43% of global sales [11,12] and global promotion expenditures [10,13]. We asked both CAM and IMS about the procedures that they used to collect information on different aspects of promotion. Based on the answers we received, we determined the relevant figures for expenditures for samples and detailing. Each author independently decided on which values should be used, based on an understanding of the methods that the companies used to collect the information and the limitations of those methods. Differences were resolved by consensus. We queried CAM and IMS about the estimated value of unmonitored promotional expenditures. IMS did not provide an answer to this question. In order to validate its estimates, CAM relies on a validation committee that includes representatives from various pharmaceutical firms, including Merck, Pfizer, Bristol-Myers Squibb, Eli Lilly, Aventis, Sanofi-Synthelabo, AstraZeneca, and Wyeth. Under a confidentiality agreement, the firms supply CAM with internal data related to their detailing activity and promotional costs in the US. Through the validation committee, CAM can thus compare totals obtained through its own audits with the firms' internal data about their promotional budgets in order to evaluate if all promotion has been properly audited through its physician surveys. As a result of this comparison, CAM's validation committee considers that about 30% of promotional spending is not accounted for in its figures. CAM is unable to provide an exact breakdown of unmonitored promotion, but it believes that around 10% is due to incomplete disclosure and omissions by surveyed physicians and the remaining 20% comes from a combination of promotion directed at categories of physicians that are not surveyed, unmonitored journals in which pharmaceutical promotion appears, and possibly unethical forms of promotion. We adjusted total expenditures to account for this unreported 30%. Results For 2004, CAM reported total promotional spending in the US of US$33.5 billion [10], while IMS gave the figure of US$27.7 billion for the same year [4]. Both CAM and IMS cited the media intelligence company CMR as the source for the amount spent on direct-to-consumer advertising (US$4 billion), and they also gave the same figure for journal advertising (US$0.5 billion). There were two major differences between the two sets of figures: the amounts spent on detailing and the amounts spent on samples. IMS estimated the amount spent on detailing at US$7.3 billion [4] versus US$20.4 billion for CAM [10], and while IMS gave a retail value of US$15.9 billion for samples [14], CAM estimated a wholesale value of US$6.3 billion [10]. Using the IMS figure of US$15.9 billion for the retail value of samples, and adding the CAM figures for detailing and other marketing expenses after correcting for the 30% estimate of unaccounted promotion, we arrived at US$57.5 billion for the total amount spent in the US in 2004, more than twice what IMS reported (see Table 1). Table 1 Pharmaceutical Marketing Expenditures in the United States in 2004: Data from IMS, CAM, and Our New Estimate Discussion Our revised estimate for promotional spending in the US is more than twice that from IMS. This number compares to US$31.5 billion for domestic industrial pharmaceutical R&D (including public funds for industrial R&D) in 2004 as reported by the National Science Foundation [15]. However, even our revised figure is likely to be incomplete. There are other avenues for promotion that would not be captured by either IMS or CAM, such as ghostwriting [16] and illegal off-label promotion [17]. Furthermore, items with promotional potential such as “seeding trials” or educational grants might be included in other budgets and would not be seen in the confidential material provided to CAM's validation committee. IMS and CAM data were used for comparison purposes for a number of reasons: data from both were publicly available, both operate on a global scale and are well regarded by the pharmaceutical industry, both break down their information by different categories of promotion, and, most importantly, they use different methods for gathering their data, thereby allowing us to triangulate on a more accurate figure for each category. Methodological differences between the ways that IMS and CAM collect data will affect the values for promotional spending depending on the category being considered. Because of the problematic nature of some data from each firm, we believe that the most precise picture of industry spending can be obtained by selectively using both sets of figures. CAM compiles its data on the value of detailing and samples through systematic surveys of primary care providers and specialists and by estimating an average cost for each visit by a sales representative according to the type of physician. By contrast, IMS compiles its data on the value of detailing through surveys of firms, while its data on samples are obtained by monitoring products directly from manufacturers. There is a significant discrepancy between the two sets of data in the cost of detailing: US$7.3 billion for IMS and US$20.4 billion for CAM. This difference can be explained by the fact that CAM offers a more complete data set since it includes in the average cost of a call (a sales representative's visit to a physician) not only the “cost to field the rep” (salary and benefits of the representative and the transportation cost) but also the costs for the area and regional managers, the cost of the training, and the cost of detail aids such as brochures and advertising material. By contrast, in reporting the cost of detailing IMS only considers the “cost to field the rep.” Furthermore, relying on physician-generated data to estimate the amount spent on detailing is likely to give a more accurate figure than using figures generated by surveying firms. Companies may not report some types of detailing, for example, the use of sales representatives for illegal off-label promotion, whereas doctors are not likely to distinguish between on- and off-label promotion and would report all encounters with sales representatives. In the case of samples, there is also a large difference between the IMS (US$15.9 billion) and CAM (US$6.3 billion) estimates. CAM estimates the amount spent on samples by multiplying the number of samples declared by physicians with their wholesale value. The latter is determined by using the average wholesale price (AWP), which is the amount set by manufacturers and used by Medicare in the US to determine reimbursement. CAM then divides that amount in half to account for the fact that samples are frequently given out in small dosage forms. CAM admits, however, that the amount for samples is understated because, when physicians fill out their survey, any quantity of samples of the same product left during a call is considered to be only one sample unit. CAM's calculations also rely on the AWP, which has been criticized for not taking into account the various discounts and rebates that are negotiated between manufacturers and purchasers [18]. IMS provides exact figures for the retail value for samples by monitoring 90% of all pharmaceutical transactions and by tracking products directly from manufacturers. This method for calculating the value of samples is much more direct than CAM's and therefore is likely to be subject to less error. Using the wholesale value for samples, the CAM figure would be appropriate if we were arguing that the money spent on samples should go to another activity such as R&D. However, we have used the retail value of samples because this is consistent with companies' reporting of drugs they donate [19]. As these are both categories of products that are being distributed without a charge to the user, it is inconsistent for donations to be reported in terms of retail value and samples in terms of wholesale value. We believe that it is appropriate to correct for unmonitored promotion and that the figure we used is a reliable estimate. The 30% correction factor is based on a direct comparison that CAM is able to make between the data it collects through its surveys and the amount reported by companies. There are other ways of combining the data that we have presented, but with the exception of choosing the lower amounts for detailing and samples and ignoring the 30% for unmonitored promotion, all of them yield a higher figure than the one from IMS. Some examples of alternative estimates follow: using the CAM estimate for the wholesale value of samples and the 30% adjustment, the total amount would be US$47.9 billion; without the 30% adjustment CAM's estimate is US$33.5 billion. Adding the figures for the categories that IMS does not cover (meetings, e-promotion, mailing, clinical trials) boosts its estimate to US$31 billion; using the lower figures for detailing and samples plus the CAM amounts for the other categories and applying the 30% adjustment gives an amount of US$29.1 billion. Therefore, the actual amount could range from a low of US$27.7 billion to a high of US$57.5 billion. Our analysis shows, however, that the figure of US$57.5 billion is the most appropriate one when using the most relevant figures for each category of promotional spending. Excluding direct-to-consumer advertising, CAM considers that around 80% of the remaining promotion is directed towards physicians, with 20% of this figure going to pharmacists. (IMS does not provide any comparable values.) With about 700,000 practicing physicians in the US in 2004 [20], we estimate that with a total expenditure of US$57.5 billion, the industry spent around US$61,000 in promotion per physician. As a percentage of US domestic sales of US$235.4 billion [21], promotion consumes 24.4% of the sales dollar versus 13.4% for R&D. Our new estimate of total promotion costs and promotion as a percentage of sales is broadly in line with estimates of promotional or marketing spending from other sources. The annual reports of Novartis distinguish “marketing” from “administration.” Marcia Angell extrapolates from this annual report to the entire industry and calculates a figure of US$54 billion spent on pharmaceutical promotion in the US in 2001 [22]. As a proportion of sales, she estimates 33% is spent on marketing. Using similar methodology, the Office of Technology Assessment derived an estimate for marketing costs in the US by extrapolating from the cost structure of Eli Lilly. The Office of Technology Assessment considers that firms spend around 22.5% of their sales on marketing [23]. Based on United Nations Industrial Development Organization estimates, a report from the Organization for Economic Cooperation and Development estimated that, in 1989, pharmaceutical firms globally spent 24% of their sales on marketing [24], but few details of the methodology used were provided, making it impossible to verify the accuracy of the estimate. Finally, in 2006 Consumers International surveyed 20 European pharmaceutical firms to obtain more information about their exact expenditures on drug promotion. Among the 20 firms contacted, only five agreed to provide separate figures for marketing, which ranged from 31% to 50% of sales depending on the firm [25]. The results are also consistent with data on the share of revenue allocated to “marketing and administration” according to annual reports of large pharmaceutical companies, if we consider that the largest part of “marketing and administration” is devoted to promotion. Lauzon and Hasbani found that 33.1% of revenues was allocated to “marketing and administration” [9], similar to the 31% reported by the Centers for Medicare and Medicaid Services [26] and the 27% from Families USA [27]. The value of our estimate over these others is that it is not based on extrapolating from annual reports of firms that are both diversified and multinational. Our estimate is driven by quantifiable data from highly reliable sources and concerns only the promotion of pharmaceutical products in the US. The derivation of our figure is thus transparent and can form the basis for a vigorous debate. Conclusion From this new estimate, it appears that pharmaceutical companies spend almost twice as much on promotion as they do on R&D. These numbers clearly show how promotion predominates over R&D in the pharmaceutical industry, contrary to the industry's claim. While the amount spent on promotion is not in itself a confirmation of Kefauver's depiction of the pharmaceutical industry, it confirms the public image of a marketing-driven industry and provides an important argument to petition in favor of transforming the workings of the industry in the direction of more research and less promotion. Supporting Information Abstract S1 English abstract (20 KB DOC). Click here for additional data file. Alternative Language Abstract S1 Translation of the abstract into French by MAG (20 KB DOC). Click here for additional data file. Appendix S1 The Web links displayed in the footnotes 4,7,10,13,14, and 21 are now defunct. In order to make accessible all data we used for this article, this appendix provides supporting information or alternative sources for the defunct Web links. (994 KB PDF). Click here for additional data file.

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Creating demand for prescription drugs: a content analysis of television direct-to-consumer advertising.

Dominick Frosch, Patrick M. Krueger, Robert C Hornik … (2015)

American television viewers see as many as 16 hours of prescription drug advertisements (ads) each year, yet no research has examined how television ads attempt to influence consumers. This information is important, because ads may not meet their educational potential, possibly prompting consumers to request prescriptions that are clinically inappropriate or more expensive than equally effective alternatives. We coded ads shown during evening news and prime time hours for factual claims they make about the target condition, how they attempt to appeal to consumers, and how they portray the medication and lifestyle behaviors in the lives of ad characters. Most ads (82%) made some factual claims and made rational arguments (86%) for product use, but few described condition causes (26%), risk factors (26%), or prevalence (25%). Emotional appeals were almost universal (95%). No ads mentioned lifestyle change as an alternative to products, though some (19%) portrayed it as an adjunct to medication. Some ads (18%) portrayed lifestyle changes as insufficient for controlling a condition. The ads often framed medication use in terms of losing (58%) and regaining control (85%) over some aspect of life and as engendering social approval (78%). Products were frequently (58%) portrayed as a medical breakthrough. Despite claims that ads serve an educational purpose, they provide limited information about the causes of a disease or who may be at risk; they show characters that have lost control over their social, emotional, or physical lives without the medication; and they minimize the value of health promotion through lifestyle changes. The ads have limited educational value and may oversell the benefits of drugs in ways that might conflict with promoting population health.

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

Aaron S. Kesselheim, Michelle M. Mello, David Studdert (2011)

Introduction In the US, a setting dominated by aggressive advertising of prescription drugs to patients and physicians, off-label marketing has been a controversial subject area. Physicians are permitted to prescribe drugs “off label”—that is, for purposes and patient populations outside of those formally approved by the US Food and Drug Administration (FDA). However, the FDA prohibits pharmaceutical companies from engaging in direct promotion of those unapproved uses [1]. The rationale is that such marketing can lead to widespread uses of a drug that are not based on evidence of efficacy and safety, expose patients to uncertain benefits and the prospect of adverse effects, and undermine incentives for manufacturers to conduct clinical trials necessary to achieve FDA approval for new uses [2]–[5]. Despite regulatory restrictions on off-label marketing, the practice appears to have flourished [6],[7]. In 2009, Pfizer paid US$2.3 billion to settle allegations that it marketed its drugs illegally to physicians—the largest federal health care fraud settlement in US history [8]. In 2010, at least six other manufacturers settled charges pertaining to off-label marketing, and more were under investigation [9]–[15]. The widely publicized litigation over the anti-inflammatory drug rofecoxib (Vioxx) also exposed marketing practices, such as seeding trials and ghost-writing of medical journal articles, that could promote off-label uses [16],[17]. What is known about off-label marketing practices comes largely in this form—namely, episodic reporting of high-profile prosecutions in the popular media [18]–[20], or personal testimony or congressional investigations arising from these same cases [21],[22]. There has been no systematic collection and analysis of these cases, which makes it difficult to identify larger themes and draw conclusions about the favored tactics. An accumulating number of these cases over the last decade makes such an analysis feasible. Moreover, the data available to conduct this type of analysis are remarkably rich because virtually all of the major cases have been instigated by “whistleblowers” whose complaints provide detailed, firsthand knowledge of the practices at issue [23]. Because off-label marketing activities are secretive and difficult to detect and examine through other means [24], reports from these insiders provide a uniquely illuminating perspective on the range and nature of practices pursued. We analyzed whistleblower-initiated legal complaints filed in off-label marketing cases over the last 15 y to shed more light on this widely discussed but poorly understood challenge for health regulation. We aimed to create a typology for understanding these cases and a coherent thematic model for mapping pharmaceutical companies' fraudulent promotional behaviors and strategies. Improved understanding in this area has the potential to contribute to the development of strategies for better detection and enforcement. Methods Design Overview The primary data for this study consisted of complaints filed by whistleblowers in “qui tam” cases brought under the US federal False Claims Act (FCA). In brief, the FCA prohibits the submission of false claims to the government for reimbursement. Private citizens who notice potential violations of the FCA can file a sealed complaint in federal court; those who do nearly always retain a personal attorney to represent them and help them write their complaint. The allegations in the complaint are then investigated by the US Department of Justice (DOJ)-Civil Division, which, depending on the strength of the evidence, may elect to intervene and take over the enforcement action, essentially inserting the government as the lead party in the case. At this point, the original whistleblower's complaint is usually unsealed. Multiple complaints may be filed against the same company, but the DOJ intervenes only on the first complaint brought to its attention or subsequent complaints that provide new information (other nonintervened complaints against the same company are usually dismissed and remain sealed). Because of this screening process and the clout of the DOJ, nearly all complaints in which the DOJ intervenes lead to a settlement or judgment against the defendant company. This study focused on cases against pharmaceutical manufacturers for off-label marketing of prescription drugs in which the DOJ intervened. Setting and Participants Officials in the DOJ-Civil Division provided us with a full list of pharmaceutical-related federal qui tam cases in which the DOJ intervened and that were settled between January 1996 and 2005. We updated the list to include all DOJ-intervened cases through October 2010 by conducting a search of DOJ press releases [25] and electronic media reports in Lexis-Nexis. We cross-checked the final list with data compiled by Taxpayers Against Fraud, a nongovernmental organization that tracks federal fraud actions. We then obtained the unsealed complaints in these cases from the DOJ, on-line searches of archives of US federal court filings [26], and direct approaches to lawyers involved in the litigation. Complaints are written documents that generally consist of a summary of the allegations, a description of the whistleblower(s) and defendants, and a detailed account of the allegations and the evidence supporting them. They may be amended during the course of the investigation. We used the most recent versions of the whistleblower-filed complaints available and accessible at the extraction date (6 November 2010). We searched the summaries of the allegations to determine which made allegations about unlawful off-label marketing by the defendant company; 41 complaints in 18 cases did. These complaints formed our analytical sample. Copies of the complaints can be found at http://www.drugepi.org/education/primarydocs.php. Qualitative Analysis We designed a structured instrument for abstracting information from the complaints. An initial typology was generated using a standard coding methodology [27],[28]. Two investigators (ASK and DMS) acting independently conducted a preliminary review of 20% of the complaints. After comparing and discussing results of these reviews, we identified two major descriptive domains for further analysis: the strategic goal of the off-label marketing scheme and the specific practices manufacturers used to achieve that goal. We also identified categories and subcategories within each of those domains. One of us (ASK) then read each complaint and coded the details provided into the prespecified categories and subcategories in each domain. It is important to note that the range of off-label marketing strategies and behaviors we identified and report below are drawn from across the sample of cases as a whole; no manufacturer was accused of all of them. Results A total of 41 complaints arose from 55 whistleblowers (Table 1). At the time of the alleged fraud, the whistleblowers worked as pharmaceutical sales representatives (39/55, 71%), sales or accounting managers (11/55, 20%), and unaffiliated physicians (5/55, 9%). The cases were brought against 18 manufacturers, including both large companies with diverse drug portfolios (e.g., Pfizer, Eli Lilly) and smaller companies selling a relatively narrow range of products (e.g., Orphan Medical, Medicis). At the time of analysis, settlements had occurred in 16 of the 18 cases and totaled US$7.9 billion in damages. 10.1371/journal.pmed.1000431.t001 Table 1 Pharmaceutical fraud cases related to off-label marketing, January 1996–October 2010. Company Name Complaints Complainants Drug(s) Case Status Parke-Davis/Warner-Lambert 1 Medical marketing liaison Gabapentin (Neurontin) Settled in 2004 (US$430 million) Serono 3 Sales representatives, marketing managers, unaffiliated nonprofit organization Somatropin (Serostim) Settled in 2005 (US$704 million) InterMune 1 Sales representative Interferon gamma 1b (Actimmune) Settled in 2006 (US$37 million) Bristol Myers-Squibb 1 Business manager Pravastatin (Pravachol), Metformin (Glucophage), others Settled in 2007 (US$515 million) Cell Therapeutics 1 Sales representative Arsenic trioxide (Trisenox) Settled in 2007 (US$11 million) Orphan Medical 1 Sales representative Sodium oxybate (Xyrem) Settled in 2007 (US$20 million) Medicis 1 Sales representatives Ciclopirox gel (Loprox) Settled in 2007 (US$10 million) Cephalon 4 Sales representatives, sales manager, unaffiliated physician Modafinil (Provigil), Tiagabine (Gabitril), Fentanyl buccal (Actiq) Settled in 2008 (US$425 million) Eli Lilly 4 Sales representatives Olanzapine (Zyprexa), others Settled in 2009 (US$1.4 billion) Pfizer 8 Sales representatives, sales managers, unaffiliated physician Valdecoxib (Bextra), Ziprasidone (Geodon), Pregabalin (Lyrica), others Settled in 2009 (US$2.3 billion) AstraZeneca 1 Sales representative Quetiapine (Seroquel) Settled in 2010 (US$520 million) Ortho-McNeil-Janssen 2 Sales representatives, unaffiliated physician Topiramate (Topamax) Settled in 2010 (US$81 million) Novartis 1 Marketing managers Tobramycin (TOBI) Settled in 2010 (US$72.5 million) Forest 2 Sales representative, unaffiliated physician Citalopram (Celexa) and Escitalopram (Lexapro) Settled in 2010 (US$313 million) Allergan 3 Sales representative, managers, unaffiliated physician OnabotulinumtoxinA (Botox) Settled in 2010 (US$600 million) Novartis 4 Sales representatives Oxcarbazepine (Trileptal), others Settled in 2010 (US$422.5 million) Scios 2 Sales directors Nesiritide (Natrecor) Complaints unsealed (2009) Wyeth 1 Sales representatives Sirolimus (Rapamune) Complaint unsealed (2010) 41 US$7.9 billion Off-Label Marketing Strategies According to the complaints, manufacturers aimed to increase use of their products through off-label marketing schemes in three non–mutually exclusive ways. They sought to expand uses to different disease entities, to variations on the approved indication, and to alternatives to the approved dosing schedule (Table 2). 10.1371/journal.pmed.1000431.t002 Table 2 Frequency of off-label marketing strategies and practices reported in whistleblower complaints. Descriptor n/N, Percent Off-label marketing strategies Expansion to different disease entity 35/41, 85% Similar symptoms, different disease 17/35, 49% Expansion to variation of approved indication 22/41, 54% Different patient subgroup 10/22, 45% Expansion to variation of approved dosing schedule 14/41, 34% Off-label marketing practices Prescriber-related 41/41, 100% Direct financial incentives 35/41, 85% Distorted presentation of supporting evidence 31/41, 76% Influence on continuing medical education programs 22/41, 54% Influence on peer-reviewed literature, including ghost-writing 20/41, 49% Recruitment as clinical trial investigators 8/41, 20% Free samples 8/41, 20% Internal practices 37/41, 90% Intramural meetings 27/37, 73% Internal documents, brochures 17/37, 46% Use of company-based physicians and scientists 19/37, 51% Cloaking strategies 25/37, 68% Sham warnings from legal counsel 16/25, 64% Direct orders to conceal activities 12/25, 48% Financial incentives to employees 15/37, 41% Payer-related 23/41, 56% Discussions with prescribers about how to ensure reimbursement 18/23, 78% Development of billing systems that circumvent restrictions 13/18, 72% Falsification of billing codes 11/18, 61% Direct approaches to payers to ensure presence on formulary 8/23, 35% Consumer-related 18/41, 44% Direct identification of/approaches to consumers through physician office or pharmacy 10/18, 56% Funding of consumer organizations 3/18, 17% Expansion to unapproved disease entities The most prevalent strategy involved expanding use on the basis of diagnosis—that is, seeking off-label uses for disease entities distinct from those approved by the FDA (35/41, 85%). For example, gabapentin (Neurontin), approved as adjunctive treatment for certain types of epilepsy, was also allegedly promoted as therapy for patients with psychiatric disease such as bipolar disorder or depression [29]. Another case involved Pfizer's alleged promotion of sildenafil (Viagra) to treat low libido and to “restore and increase orgasmic sensations” in women [30]. In some cases, a reported rationale for pursuing this type of expansion was that limiting sales to the FDA-approved indication could not sustain needed levels of revenue. One whistleblower from a small, single drug-focused company stated that she was told “that management wanted to sell the company, and that in order to make it a more attractive acquisition target, it was necessary to show increased sales revenue” [31]. In many examples of this marketing strategy, the drug was promoted for treatment of similar symptoms across disease classes (17/35, 49%). For example, modafinil (Provigil), initially approved for narcolepsy-related sleepiness, was allegedly promoted for many types of sleepiness in non-narcoleptic patients [32]. Another example related to the anti-inflammatory drug valdecoxib (Bextra), which was approved for a limited number of pain-related indications and then allegedly promoted by Pfizer for pain relief more broadly [33]. Expansion to unapproved indications The second most common strategy for off-label promotion was to expand the product's use to different variations of the same condition (22/41, 54%). In some cases, the off-label disease was closely related to the approved one—for example, when a product was specifically approved for a severe manifestation of a condition but then promoted for milder forms. In the case of nesiritide (Natrecor), the drug was approved for “acutely decompensated heart failure” and was allegedly promoted in patients with chronic stable heart failure as a preventative measure [34]. Although both groups of patients had heart failure, they were quite different manifestations of the disease. One prominent subcategory of this type of off-label promotion focused on patient subgroups different from those contemplated in the FDA approval (10/22, 45%). For example, ciclopirox gel (Loprox) was approved for fungal dermatoses in patients over age 10, but allegedly promoted by its manufacturer to manage diaper-related fungal dermatitis in babies [35]. In some of the antidepressant drugs in our sample, the product was approved for adult use, but allegedly promoted to pediatricians and family practice physicians specifically for young patients who demonstrated signs of depression [30],[36]. In the case of citalopram (Celexa), studies that had shown dangers with using the drug in pediatric populations were allegedly withheld from physicians as part of the marketing campaign [36]. Expansion to unapproved dosing strategies The final, and least common, variety of off-label expansion was off-label prescribing based on different dosing regimens than that approved by the FDA (14/41, 34%). Typically, manufacturers promoted higher doses to enhance revenues by encouraging sale of more units of the product. For example, the manufacturer of oxcarbazepine (Trileptal) allegedly promoted use of the antiepileptic drug “as monotherapy for seizures using extremely high dosages” [37]. By contrast, the manufacturer of sirolimus (Rapamune), which was approved for transplant patients in combination with cyclosporine and corticosteroids, allegedly trained its staff to encourage its use in combination with “any drug or combination of drugs that a physician could be convinced to prescribe” to enhance its market possibilities [38]. Off-Label Marketing Practices The marketing practices manufacturers allegedly employed to achieve these strategic goals for off-label use fell into four non–mutually exclusive categories: internal practices, payer-related practices, prescriber-related practices, and consumer-related practices. We defined internal practices as incentives and other aspects of the employment environment at the defendant manufacturer that encouraged employees to promote off-label uses. Payer-related practices were strategies aimed at encouraging insurers to pay for off-label prescriptions. Prescriber-related and consumer-related practices involved direct promotion of off-label drug use to prescription writers and consumers, respectively. Prescriber-related practices All of the complaints we analyzed detailed off-label promotion to prescribers; this was generally the centerpiece of the whistleblowers' complaints. Though manufacturers are not supposed to discuss off-label uses unless a physician inquires, many were accused of either flouting that rule or designing their representatives' presentations in such a way as to guarantee that discussion would inevitably lead to off-label uses. According to the complaints, off-label use was frequently encouraged through self-serving presentations of the scientific literature through which physicians were given false or unbalanced study data supporting the unapproved use (31/41, 76%). A common example was selective presentation of favorable studies, where dangers from the off-label uses allegedly being promoted were not mentioned [39]. Other examples included presenting one drug as being superior to another when no head-to-head studies had been conducted [40] and characterizing reports of individual cases or poorly designed studies as definitive evidence supporting an off-label use [41]. A number of whistleblowers alleged that free samples had been provided (8/41, 20%) as a way to promote off-label use. The whistleblowers in this group reported that these samples were intended to encourage physicians to use a product on the basis of convenience, even though it might not be approved for a certain use. In addition, many described how free samples were intended to introduce unapproved patient populations to the manufacturer's product with the intention of stimulating their continued use. Complaints alleged that manufacturers also encouraged off-label use through direct financial incentives to physicians. Lavish gifts or honoraria were mentioned in most complaints (35/41, 85%), with many whistleblowers reporting strategies to target these gifts to physicians who were high off-label prescribers (18/41, 44%). In some cases, physicians might be invited to serve in focus groups or as consultants to the manufacturer, although it was alleged that the association was intended not to obtain expert advice, but to provide money to prescribers to positively reinforce off-label use (15/41, 37%). Finally, off-label use was encouraged among prescribers through teaching and research activities. In over half the cases, Continuing Medical Education (CME) seminars were organized with speakers known to promote off-label uses (22/41, 54%). In a few cases, whistleblowers reported that CME activities were organized by shell corporations to impart an appearance of scientific neutrality [34]. Nearly half of whistleblowers also alleged that manufacturers sought to promote off-label drug use through journal publications (20/41, 49%). These practices included falsely reporting outcomes from patients in manufacturer-sponsored studies [42] and publishing “ghostwritten” articles supporting an unapproved use written by the manufacturer under the name of a respected scientist [43]. Finally, a minority of whistleblowers alleged that manufacturers recruited physicians to conduct clinical trials for them with the intent of encouraging off-label use (“seeding trials”), rather than for any useful scientific or information-gathering reasons (8/41, 20%). Internal practices Thirty-seven of the whistleblower (90%) complaints detailed particular internal manufacturer practices intended to bolster the off-label marketing (two of the four complaints where these were not mentioned were filed solely by whistleblowers positioned outside the companies). All of the practices described were reported to be company-wide, rather than the work of an individual manager or group of managers. In 73% (27/37) of these cases, the off-label marketing strategy was implemented through intramural meetings and seminars in which marketing practices were discussed; in 46% (17/37) of them, it was also implemented through development of brochures and other materials for dissemination; in 51% (19/37), employees other than the sales representatives, such as internal physicians and scientists, were involved. Many of the complaints describing internal practices (25/37, 68%) pointed to specific efforts by drug manufacturers to conceal off-label marketing activities. Some described warnings from legal teams to avoid off-label marketing (16/25, 64%). These were generally understood by employees as providing “plausible deniability” to the company [33], and were widely undermined through strategies such as verbal orders diverging from what was declared in their company policies [31]. For example, one whistleblower reported that his company purposefully designed “do not detail” labels on materials related to off-label uses that could easily be removed by a sales representative [30]. A third of complaints included reports of direct orders to conceal, such as “cleaning” internal reports and memoranda of all mentions of off-label marketing (12/25, 48%). The complaints frequently described use of financial incentives for employees to engage in off-label marketing. Forty-one percent (15/37) of the reports of internal strategies described incentives or other aspects of employees' compensation plans that were directly tied to effectively implementing an off-label prescription strategy. In one case involving a drug approved by the FDA for a rare indication, a whistleblower reported that the company imposed sales quotas on representatives that could only be met through expanding use beyond the limited approved indication [31]. Other examples included an internal sales “contest” for employees who could demonstrate greatest compliance with marketing programs encouraging off-label use [44] and direct payments to employees to encourage them not to report off-label marketing practices [35]. Payer-related practices Payer-related promotional practices were reported in just over half of the complaints (23/41, 56%) and fell into two categories: discussions with prescribers about ways to ensure insurance reimbursement for their off-label prescriptions (18/23, 78%) and direct discussions with payers themselves (8/23, 35%) (three complaints described both). The reports of discussions with prescribers in complaints described efforts to educate them about how to manage the billing system to ensure that off-label prescriptions were reimbursed, including advice on ways to bypass insurers' restrictions on prescriptions of the product (13/18, 72%). For example, one whistleblower reported being taught to overcome a requirement that patients receive a trial of a competitor's drug first by instructing physicians to issue two different prescriptions at the same time: one for the competitor's drug that the patient could ignore, the other for the company's drug [45]. The other strategy commonly reported was to encourage providers to falsify billing codes (11/18, 61%). Seven complaints reported that manufacturers interacted with payers to encourage off-label drug use by ensuring drugs were on a formulary for off-label uses (four reports) or developing organizational protocols that included the off-label use (four reports; one reported both). One whistleblower described a bolder tactic for ensuring formulary coverage for off-label use of a product: directing “their sales representatives to garnish physician and patient letters of support to encourage reimbursement” by Medicare intermediaries [46]. Consumer-related practices Nearly half the complaints described off-label marketing practices focused directly on consumers (18/41, 44%). The most common example involved identifying consumers who could be off-label users (10/18, 56%)—for instance, by conducting chart reviews in physicians' offices. The next step was bringing those patients eligible for an off-label use to the physician's attention, thereby fusing a consumer-focused practice with a prescriber-focused one. Other practices intended to directly encourage off-label use among consumers allegedly included promotion of consumer demand for off-label uses through payments to nonprofit, consumer-focused disease management organizations in exchange for their support of the off-label use [43]. Another complaint described on-line resources presented by a “noncommercial public interest organization” that were intended to promote off-label use of the product, but which were developed by a marketing firm linked to the defendant company [47]. In a third case, the whistleblowers alleged that the company provided indigent patients with “gift certificates, phone cards, and bus tokens” as inducements to seek out prescriptions of a drug for an off-label purpose [48]. Discussion Through a comprehensive review of whistleblower complaints, to our knowledge the first of its kind, we found descriptions of a range of marketing practices related to off-label promotion of prescription drugs. All of the strategies and behaviors we outlined were alleged by whistleblowers with special knowledge of company practices, although none of the complaints was subject to full trial and evaluation by a judge or jury. The study provides a basic empirical snapshot of the extent to which each of these strategies and practices have been employed, at least among cases exposed in qui tam litigation. Our findings show that off-label marketing practices have a broad reach. Similar behaviors and strategies were linked to manufacturers of varying sizes across drugs in virtually all therapeutic classes; they extended to many aspects of the health care system; they affected a multitude of players (prescribers, pharmacies, disease advocacy groups, CME organizations, consumers); and were pursued through virtually every facet of physician-industry relationships (paid consultancies, preceptorships, and collaboration in clinical trials and research publications). The alleged tactics in our analytic sample ranged from subtly encouraging physicians to ask for information about off-label uses to providing strong financial rewards for encouraging off-label uses; they also included targeting multiple links in the prescription production chain, from company scientists and sales representatives to prescribers. Some of the practices we identified have been highlighted in anecdotal reports and are relatively well known. Others have received little or no attention, such as pharmaceutical marketing representatives working directly with physicians and their office managers to circumvent reimbursement restrictions set by government payers and other insurers. Nearly a quarter of the whistleblowers alleged that pharmaceutical sales representatives were given access to patients' confidential medical records at physicians' offices for the purposes of trolling for prospective targets for illegal direct-to-consumer promotion of off-label uses. Despite the remarkable prevalence of this practice among the complaints we analyzed, media coverage has tended to center on other, more institutionally focused aspects of fraud. New regulatory strategies, both public and private, aimed in part at preventing off-label marketing, have proliferated in recent years. Medical journals have changed their authorship standards to foil ghostwriting [49]; following the example of several states, the federal health care reform legislation requires disclosure of pharmaceutical industry payments to physicians [50]; the leading pharmaceutical manufacturers' association, PhRMA, has adopted a Code of Ethics that prohibits certain types of gifts [51]; and a handful of academic medical centers have restricted or prohibited visits by pharmaceutical sales representatives [52]. Our findings support the need for these measures to combat gifts to physicians, which we identified as the single most prevalent modality of off-label promotion reported by whistleblowers. However, our results also suggest that additional steps will likely be necessary to curb off-label marketing. For example, interventions seeking to insulate physician education from industry influence have largely been limited to programs in which the manufacturer controls the content, but the reports in this study suggest that even so-called “unrestricted” educational grants from industry may be deployed to effect off-label marketing. A better policy solution would be fully independent programs of continuing medical education, an approach that has received limited support in a few states and has been proposed (but not enacted) in US Congress. Another potential solution is a central repository, independent from any physician or health care organization, where manufacturers can donate money that is then distributed for educational purposes. Some experts have suggested that fraudulent off-label marketing might be prevented through more substantial fines for manufacturers under investigation or other penalties for company managers [53]. Criminal prosecutions of executives are rare [54], but the DOJ has signaled increasing interest in using this approach [53]. While seeking to fortify deterrence through such tactics might address some behaviors, our findings suggest that some common off-label marketing practices may be difficult to control through external regulatory approaches because of their deep-seated nature. Whistleblowers in most of the cases we reviewed reported that private conversations between sales representatives and prescribers were a leading strategy for off-label promotion. The opportunity to prompt and answer physicians' questions about off-label uses, address their individual concerns, and provide a digest of empirical evidence that can be slanted as needed likely makes these conversations a particularly effective form of marketing. The fact that so many of the communications are oral and take place in private offices makes them very difficult for regulators to monitor and sanction. It is impossible to conceive of how anyone other than a company insider or a physician could bring many of these marketing practices to light (indeed, this underlines the distinctive strength of our data source). The move by a few prominent academic medical centers to ban sales representatives from the premises is a bold and powerful one, but it has not, as yet, been followed by many hospitals or physician practices. Changes in the PhRMA Code are a positive sign that the industry is responsive to public concerns about inappropriate marketing practices. In some news reports, manufacturers have described new corporate cultures that avowedly reject the illegal tactics described in the whistleblower complaints [55]. However, in many of the cases we studied, manufacturers were reported to demonstrate awareness of existing regulations and engage in strategic behaviors to work around them (e.g., by giving employees lectures about the regulatory environment that were understood to be a smokescreen) or to mask their violations of the law (e.g., by encouraging employees to not enter off-label marketing calls in their logs). Our approach has limitations. First, although the DOJ conducted thorough investigations of each complaint in the study sample, the settled cases concluded without a full trial, which would have included formal fact-finding by a judge or jury. Thus, some allegations may be false and, for nearly all complaints, internal company documents that might have corroborated the complainants' specific reports remained confidential. Second, our analyses were conducted mainly at the complaint level, but nine of the 18 cases involved more than one complaint (the DOJ permits multiple complaints when each brings new information to bear on the case); the clustering of complaints in some cases may have inflated the reported prevalence of certain behaviors. Third, most whistleblowers were US-based sales representatives with a particular field of vision in relation to their companies' off-label marketing practices. It is possible that other behaviors and strategies exist that the whistleblower did not observe and the government investigations did bring to light. Our reliance on the text of the complaints means that we would have missed these. Finally, the complaints were composed to support claims of fraud under certain specific legislation, including the False Claims Act. Conclusion Off-label marketing has been ubiquitous in the health care system and features some behaviors and strategies that may be resistant to external regulatory approaches. Our findings suggest that no regulatory strategy will be complete and effective without physicians themselves serving as a bulwark against off-label promotion. Aside from sales representatives and other company insiders, who play important roles as whistleblowers, physicians are alone in having a full view of many of the most insidious forms of illegal marketing outlined in the complaints we reviewed. As physicians' understanding of these practices and the consequences of inappropriate off-label promotion for public health evolves, so may their enthusiasm for shutting them down.