The ADVANTAGE Seeding Trial: A Review of Internal Documents FREE

—The Editors

Although much has been written about the marketing tactics of the pharmaceutical industry (1 - 2), seeding trials have not been characterized in depth. Seeding trials are clinical trials designed by pharmaceutical companies to promote the use of pharmacotherapies that were recently approved or are under review by the U.S. Food and Drug Administration (FDA). Seeding trials are designed to appear as if they answer a scientific question but primarily fulfill marketing objectives. Kessler and colleagues (3) portrayed seeding trials as “attempts to entice doctors to prescribe a new drug being marketed by the company” while the company puts its product in the hands of practicing physicians, hoping that the experience of treating patients with the study drug and a pleasant, even profitable, interaction with the company will result in more loyal physicians who prescribe the drug (4). Despite attempts to call attention to seeding trials (5 - 6), limited information about them is available in the public domain.

Confidential internal communications made public as a result of recent litigation against Merck & Co. regarding the cardiovascular safety of Vioxx (rofecoxib; Merck & Co., Whitehouse Station, New Jersey) offer a view of the planning, implementation, and publication of a seeding trial from the pharmaceutical company's perspective. We examined the documents related to the ADVANTAGE (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness) clinical trial, a seeding trial designed and conducted by Merck that was published in the peer-reviewed literature on 7 October 2003 (7).

During Cona v Merck and Co., Inc., and McDarby v Merck and Co., Inc., documents produced by Merck in response to discovery requests were archived in an integrated database maintained by the plaintiff's attorneys. These documents were created between 1998 and 2006 and included Merck internal and external correspondence, reports, and presentations. As paid consultants to the attorneys representing the plaintiffs, we had access to all archived documents. We identified a subset of approximately 2000 relevant documents by using the following search terms: seeding, marketing, ADVANTAGE, and the names of Merck employees and academically affiliated authors known to be associated with the ADVANTAGE clinical trial. Document numbers are approximate because information within 1 document may overlap with another, making it difficult to determine the exact number of distinct documents.

One investigator read the identified documents to determine relevance to seeding trials. We identified approximately 100 relevant documents from the search, most of which were Merck internal correspondence and marketing reports, memos, and presentations.

Two investigators independently completed a line-by-line review of each identified document by using the “constant comparative method,” a systematic, verifiable technique (8 - 9), to identify broad themes reflecting the design and conduct of a seeding trial. In this iterative process, segments of text are catalogued according to their essential concepts (8 - 9). Similar methods have been used recently with court documents to examine tobacco marketing, pharmaceutical marketing, and ghostwriting for scientific papers (10 - 13). Next, all investigators reviewed pertinent documents again to identify and develop core themes. Then, 2 investigators reviewed all of the documents for additional evidence to support or refute the core themes. Each investigator re-reviewed a subset of pertinent documents to compare the content with the 3 core themes that emerged from our review. The team communicated regularly to resolve discordant views through negotiated consensus. Finally, the investigators completed another iteration of the negotiated consensus process after the initial manuscript review by Annals.

To better understand ADVANTAGE in the context of seeding trials, we conducted a systematic review of the literature and identified published manuscripts about seeding trials. First, we searched MEDLINE (from 1950 to March 2008) for the exploded Medical Subject Heading term clinical trials as topic and identified 201 557 publications. Second, we searched for the exploded Medical Subject Heading term drug industry and found 27 210 publications. Third, we did a search that included the exploded Medical Subject Heading terms prescriptions, drug, advertising as topic, and conflict of interest and the keywords marketing and seeding and identified 58 242 publications. Finally, we combined these 3 searches and identified 466 articles, 61 of which we excluded for not being published in English. Two investigators independently reviewed the titles and abstracts of retrieved publications and selected relevant articles for possible inclusion in our review. On the basis of this review, we excluded 400 publications that did not focus on seeding trials. We included the remaining 5 publications in our review and searched bibliographies of these articles for additional relevant publications; 1 was identified.

This research was exempt from review by the Yale University Human Investigation Committee. Neither the Hartford Foundation nor the Robert Wood Johnson Foundation had any role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; and preparation, review, or approval of the manuscript.

All authors were compensated for their work as consultants to the plaintiff's counsel in connection with suits against Merck related to Vioxx. This independent research was not sponsored by the plaintiffs or in any way related to the trial work.

In January 1999, before the launch of Vioxx, Merck's marketing division conceived the ADVANTAGE clinical trial (14). However, Merck did not reveal the key role of the marketing division and marketing objectives of the study. Instead, physician-investigators, participants, and institutional review board members were told that the purpose of the trial was to measure the gastrointestinal safety of Vioxx (15). Six hundred investigators enrolled and randomly assigned 2785 patients with osteoarthritis to Vioxx and 2772 patients to naproxen, with a target of 6 participants per site, for a 3-month trial starting on 27 March 1999, approximately 2 months before the drug's FDA approval on 22 May 1999 (16). A Merck marketing slide set used for the company's internal purposes stated that a goal of ADVANTAGE was for investigators to “[g]ain experience with Vioxx prior to and during the critical launch phase” (14).

Review of the Vioxx documents revealed 3 key themes that were related to the design and marketing objectives of the ADVANTAGE trial: The trial emerged from the marketing division with a marketing objective; Merck's marketing division collected, analyzed, and disseminated both the scientific and the marketing data; and Merck did not reveal the marketing purposes of the trial to participants, physician-investigators, and institutional review board members.

The Merck marketing division designed and executed the ADVANTAGE trial. Figure 1 shows an internal award nomination memo from Charlotte McKines, Executive Director of Marketing Communications at Merck, and Louis Sherwood, Senior Vice President for Medical and Scientific Affairs, that describes the influence of the marketing division (17).

The memo outlines 4 key Merck marketing principles: target the trial to a select group of customers—in this case, primary care physicians; use the trial to demonstrate the value of Vioxx to these physicians; integrate the marketing division and those responsible for trial-related operations in the field with the highest level of precision; and carefully track marketing-related results, that is, rates of Vioxx prescriptions written by study physicians.

According to an internal presentation on 16 March 1999 by Jan Weiner, Executive Director of Public Affairs at Merck, the responsibilities of the marketing division were to “[s]et objectives” and “[d]esign [the] protocol and oversee execution of [the] trial” (18) (Figure 2). In a memo, Merck explained why the company targeted primary care physicians (17) (Figure 1):

The internal memo also noted the importance of ADVANTAGE in creating positive perceptions of Vioxx and Merck among primary care physicians (17) (Figure 1):

We did not identify documents describing participation of the research division in the planning or implementation of ADVANTAGE from the database search. However, Dr. Edward Scolnick, the head of the research division at Merck Research Laboratories, wrote that ADVANTAGE and other “large marketing clinical studies” are “intellectually redundant” (19). In an e-mail on 4 April 2001 to a colleague about the impact of ADVANTAGE's cardiovascular safety data on Vioxx's status with the FDA, Scolnick wrote (typographical errors corrected and explanations of acronyms provided) (19):

Merck's marketing division, as illustrated by Jan Weiner's internal presentation, handled the scientific and marketing data, including collection, analysis, and dissemination (18) (Figure 2). The first author of the primary publication resulting from ADVANTAGE, Dr. Jeffrey R. Lisse, an academic physician not employed by Merck, told The New York Times that he did not have a role in data collection or analysis (20):

Merck collected detailed information about the prescribing habits of participating physicians, including the numbers of prescriptions written for Vioxx versus those written for a competing drug during the portion of the ADVANTAGE trial that took place after approval of Vioxx (21) (Figure 3). Merck summarized changes in prescribing habits that it believed to have occurred as a result of ADVANTAGE (17) (Figure 1):

Merck and its public relations corporation, Ogilvy, trained ADVANTAGE investigators for interaction with the media after the trial results were published. Investigators were given an information package that included a “sample pitch letter” (22):

Merck emphasized the importance of having all aspects of their marketing program ready when the FDA approved Vioxx in order to help accomplish objective “AAA,” or “Announce ADVANTAGE at Approval” (22).

Although ADVANTAGE was called a seeding trial in many internal documents (22 - 23), the marketing objectives of the trial were not described on the informed consent form (16). Charlotte McKines, Executive Director of Marketing Communications at Merck, and Louis Sherwood, Senior Vice President for Medical and Scientific Affairs, focused on primary care physicians as the target customer group and nominated the marketing personnel in charge of ADVANTAGE for the “Best Physician Program Award” in an internal memo (17) (Figure 1):

Similarly, Merck did not refer to the marketing objectives of the trial in submissions to the FDA. The Merck clinical study report describing the trial stated the primary objective of ADVANTAGE: “To compare the gastrointestinal (GI) tolerability of rofecoxib 25 mg q.d. and naproxen 500 mg b.i.d. in the treatment of osteoarthritis (OA) during a 12-week treatment period” (16).

However, Pharmaceutical Product Development, a contract research organization that assisted with the trial, was briefed by Merck's public affairs department in a slide presentation before the launch of ADVANTAGE. Separate bullet points described the “market dynamics [and] highly competitive situation” surrounding the ADVANTAGE trial and the “importance of investigators as key customers of Merck” (18). Merck officials were careful about references to the seeding objectives of the trial. In an e-mail to Kyra Lindemann and others in the division, Rebecca Higbee, an employee in the Merck marketing division, attempted to convince others to avoid using this term in describing ADVANTAGE: “It may be a seeding study, but let's not call it that in our internal documents” (22).

Our systematic review identified 6 publications about seeding trials and their conduct (Table): were editorials or commentaries, 2 discussed seeding trials within the context of the discussion of original research, and none directly referenced internal industry documents. In 1993, Stephens (5) characterized seeding trials as 1 of several theoretical marketing tactics used by pharmaceutical companies in postmarketing surveillance studies. Fretheim and Oxman (24) examined whether differences in prescribing patterns between the United Kingdom and Norway were caused in part by the presence of publicly funded pharmaceutical advisors in the United Kingdom as opposed to increased use of seeding trials in Norway. On the basis of communication with academic physicians, drug regulatory agencies, and medical directors of drug companies in these countries, they hypothesized that promotion of less expensive drugs by pharmaceutical advisors in the United Kingdom and the prevalence of seeding trials in Norway could help explain this disparity, although they did not provide documentary evidence. Psaty and Rennie (25) described a randomized, open-label trial of asthma medication (also a seeding trial) that used Danish national health care prescribing data (4), and represented an improvement over the nonrandomized trials described earlier by Kessler and colleagues (3). More recently, when commenting on the ENHANCE (Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery) trial, Greenland and Lloyd-Jones (26) wrote that, “Trials designed for marketing purposes should not be conducted.” They raised the concern that ENHANCE may have been a seeding trial for 3 primary reasons: The trial started at approximately the same time that the FDA approved ezetimibe; it was not conducted to earn a new drug indication with the FDA; and initial reporting of results of the trial occurred almost 2 years after the trial was completed, reinforcing the lack of scientific significance. In summary, these articles call attention to the practice of seeding trials, although they do not provide documentary evidence of the existence of seeding trials.

Merck conducted a seeding trial to promote the prescription of Vioxx. The trial coincided with the FDA's approval and the availability of the product on the market in 1999. Although billed as a gastrointestinal safety study, ADVANTAGE was actually a sophisticated marketing tool designed to allow optimal “seeding” of positive experiences with Vioxx among customers—primary care physicians—before its approval. As a result, 5557 participants received Vioxx and 600 investigators prescribed it just before it became available on the market, which generated positive publicity and anecdotes from physicians and patients ((7), (22)). Sales of Vioxx could then benefit from a “2-step flow” of media influence, with Merck's marketing enlisting ADVANTAGE investigators as advocates who in turn influenced many other physicians and patients (27).

To our knowledge, the confidential internal communications we examined provide the first strong documentary evidence of how a pharmaceutical company framed a marketing effort as a clinical trial. The ADVANTAGE trial was a seeding trial that was published in a major medical journal (7). Although seeding trials may have some positive aspects, such as education of community physicians and early access to medications for patients, the undisclosed use of research by corporate marketing divisions threatens the integrity of the relationship of industry, academia, patients, and society.

At least 3 elements of seeding trials are harmful to science and society. First, full informed consent is not possible without disclosing the full purpose of the trial. Physicians and patients participating in ADVANTAGE were informed of the scientific objectives of the study, but the research protocol and informed consent templates indicate that they were not told about the key role of Merck's marketing division in the trial or the true purpose of the trial (16). Second, good research practice is at risk when the marketing division designs and conducts a study. In a seeding trial, in order to fulfill strong marketing objectives, the recruitment of several research sites with fewer patients per site may result in less quality control from investigators and use of sites that have less research experience than academic centers or community physicians' offices, which may be more accustomed to hosting clinical trials. Quality control and rigorous research conduct may not receive adequate attention when marketing is the primary purpose of the study. Third, the study may have little scientific merit. Around the same time as ADVANTAGE, Merck launched the VIGOR (Vioxx Gastrointestinal Outcomes Research) trial to be the definitive study of gastrointestinal toxicity (28). The FDA required Merck to conduct VIGOR before putting claims of improved gastrointestinal safety on the Vioxx label. Thus, the purpose of ADVANTAGE was neither to seek a new indication nor to perform postmarketing surveillance.

Failure to disclose the primary purpose of a trial has ethical ramifications for patients, physicians, and the design of clinical trials. Seeding trials like ADVANTAGE, in which the study medication has yet to receive FDA approval, may cause patient injury for marketing purposes. Such trials may provide incremental scientific benefit: ADVANTAGE affirmed the increased cardiac risk for Vioxx compared with naproxen (29), which was originally seen in the VIGOR trial (30), although the number of cardiovascular events was misreported in the original publication (31). However, the primary marketing objectives of seeding trials are hidden from the public, the medical profession, and institutional review board members, preventing them from making a fully informed decision about the balance of benefits and harms to themselves and society.

Identification of seeding trials is likely to be difficult. Without access to internal documents, the intent of pharmaceutical companies in conducting clinical trials is nearly impossible to prove. Even with access to internal documents, study intent may be hard to prove. Seeding trials are a moral offense because the sponsor does not disclose the true purpose of the trials, but there are no reliable ways to identify, prevent, or punish them. Increasing awareness of this practice is only a small, initial step toward its prevention. Nevertheless, greater transparency into the clinical trial process, including public clinical trial registration and requirements for study protocols to be included with institutional review board submissions, may help to better illuminate this practice. Physicians and patients should be fully informed of all trial objectives as part of the consent process. Laws and regulations may be necessary to promote the disclosure of the true intent of research conducted with human participants.

Our review has several limitations. First, the use of litigation documents from 1 company provides a useful perspective on the practices of the pharmaceutical industry but may not be generalizable to other companies (32). We do not know how common these practices are. Second, our search may have missed relevant documents—for example, documents demonstrating that Merck disclosed some of the marketing objectives of the study to patients, physicians, or institutional review board members. We used comprehensive search terms to minimize this possibility. Third, those who wrote or produced documents we referenced did not have an opportunity to comment on the documents or explain their context. Finally, although the documents provide insight into how Merck planned to execute ADVANTAGE, they do not describe some aspects of the planning and execution of the trial, so we cannot verify important details of what actually transpired. For example, we did not identify, despite an exhaustive and systematic search strategy, documents detailing discussions between the marketing and research divisions, nor could we identify documents describing contracts between Merck and collaborating companies. However, we identified a statement by the head of the research division indicating that he did not believe in the value of ADVANTAGE.

This study reveals key themes in the design and conduct of a seeding trial and raises questions about embedding research within marketing divisions and using research methods to achieve marketing objectives. The absence of novel study questions; the quest to engage future prescribers; the execution of the study by the marketing division of a company; and, most important, the failure to disclose the true objectives of the trial to patients, investigators, or institutional review board members is not in the best interests of patients, the profession, or society.