Kevin P. Hill, MD, MHS; Joseph S. Ross, MD, MHS; David S. Egilman, MD, MPH; Harlan M. Krumholz, MD, SM
Note: All legal documents used in the article are available at http://dida.library.ucsf.edu.
Acknowledgment: The authors thank Leslie Curry, PhD, for her advice on our methods for review of the litigation documents and Greg Mulvey for his help in organizing the documents.
Grant Support: Dr. Hill was a Scholar in the Robert Wood Johnson Clinical Scholars Program sponsored by the Robert Wood Johnson Foundation while working on this project. Dr. Ross is currently supported by the Hartford Foundation.
Potential Financial Conflicts of Interest: All authors were compensated for participation in litigation against Merck at the request of plaintiffs.
Reproducible Research Statement:Study protocol and statistical code: None. Data set: Available at http://dida.library.ucsf.edu.
Requests for Single Reprints: Kevin P. Hill, MD, MHS, McLean Hospital, 115 Mill Street, Belmont, MA 02478; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Hill: McLean Hospital, 115 Mill Street, Belmont, MA 02478.
Dr. Ross: Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029.
Dr. Egilman: 8 North Main Street, Attleboro, MA 02703.
Dr. Krumholz: Yale School of Medicine, 333 Cedar Street, I-456, SHM, New Haven, CT 06510.
Author Contributions: Conception and design: K.P. Hill, J.S. Ross, D.S. Egilman, H.M. Krumholz.
Analysis and interpretation of the data: K.P. Hill, J.S. Ross, D.S. Egilman, H.M. Krumholz.
Drafting of the article: K.P. Hill.
Critical revision of the article for important intellectual content: K.P. Hill, J.S. Ross, D.S. Egilman, H.M. Krumholz.
Final approval of the article: K.P. Hill, J.S. Ross, D.S. Egilman, H.M. Krumholz.
Provision of study materials or patients: K.P. Hill, D.S. Egilman.
Administrative, technical, or logistic support: K.P. Hill.
Collection and assembly of data: K.P. Hill, D.S. Egilman.
Hill K., Ross J., Egilman D., Krumholz H.; The ADVANTAGE Seeding Trial: A Review of Internal Documents. Ann Intern Med. 2008;149:251-258. doi: 10.7326/0003-4819-149-4-200808190-00006
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Published: Ann Intern Med. 2008;149(4):251-258.
People have long suspected that drug companies use seeding trials to promote a new drug by getting physicians to use it as they follow the protocol of a clinical trial. Strong documentary evidence has been lacking.
The authors obtained court-ordered documents, some of which were e-mailed messages, that showed that the marketing division of Merck & Co. (Whitehouse Station, New Jersey) conducted the ADVANTAGE (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness) randomized trial to promote the use of Vioxx (rofecoxib) by physicians—the drug prescribed to patients assigned to the active intervention. The company did not tell institutional review boards, physicians, or patients the true purpose of the trial.
The documents lack many details about ADVANTAGE.
Seeding trials deceive trial participants and their protectors.
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).
Merck executives nominate those responsible for the design and execution of ADVANTAGE for an internal marketing award. A& = arthritis and analgesia; CDP = clinical development program; NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis. USHS = United States Human Health.
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):
CDP = Clinical Development Program; CRO = Clinical Research Organization.
First, the trial was targeted to a select group of critical customers. The clinical trial program for VIOXX focused primarily on specialists. While they would be critical to the early uptake and advocacy for VIOXX, the large majority of prescriptions in the A&A [arthritis and analgesia] market (~60%) come from primary care physicians. The ADVANTAGE trial utilized this important group of prescribers as investigators. In addition to gaining experience with VIOXX, many of these physicians gained a highly coveted introduction to clinical research. Second, the design of the trial focused on demonstrating the value of VIOXX to this important audience.
The internal memo also noted the importance of ADVANTAGE in creating positive perceptions of Vioxx and Merck among primary care physicians (17) (Figure 1):
Feedback from the field has been overwhelmingly positive about their ability to access key customers and the influence that being involved in the trial has had on their perceptions of VIOXX and Merck.
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):
[T]he reason we have resisted doing large marketing clinical studies is just this. It opens a lot of data to FDA that compromises the large clinically meaningful trials. Small marketing studies which are intellectually redundant are extremely dangerous and the PAC [Products Advisory Committee] system with the marketing emphasis in CDP [Clinical Development Program, a part of Merck's Marketing Division] on all their studies opens Pandora's box which we have urged against from the beginning of time. Their budget is now 179 million for CDP—as much as our phase 2/3 new chemical entities used to be. I have told [another Merck colleague] I think it is wasteful.
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 designed the trial, paid for the trial, ran the trial. Merck came to me after the study was completed and said, “We want your help to work on the paper.” The initial paper was written at Merck, and then it was sent to me for editing.
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 tracked new prescriptions written for both Vioxx and Celebrex (celecoxib; Pfizer, New York, New York) by ADVANTAGE investigators in the months after the trial. Investigators were given a portfolio profile grade of A+ to D on the basis of their prescription history of using Merck products. Arth CR = Arthritis Clinical Report no. 9907; AVG = average; Meded = medical education branch of the Institute for Internal Research; NRX = new prescriptions; RHU = rheumatologists.
An analysis performed at 6 months post launch demonstrated a significantly higher level of prescribing for VIOXX among primary care ADVANTAGE investigators compared to a control group of VIOXX 99 prescribers [primary care physicians not chosen to participate in ADVANTAGE].
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):
Marketing Communications package: To help local physicians market their involvement with the trial as well as their expertise in the field, we would design an ADVANTAGE communications kit to be distributed to all investigators involved in the trial.
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):
The objectives were to provide [a] product trial among a key physician group to accelerate uptake of VIOXX as the second entrant in a highly competitive new class and gather data important to this customer group.
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.
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Jonathan M Edelman
Merck & Co., Inc
August 21, 2008
ADVANTAGE: Science first, marketing second
Merck would like to correct numerous inaccuracies in the latest article authored by paid consultants to plaintiffs' lawyers in the VIOXX litigation against Merck and respond to this biased attack on Merck's scientific integrity.1
The scientific purpose of the ADVANTAGE trial was to answer unaddressed questions about VIOXX. The study, a double blind, randomized, controlled trial, was designed, analyzed and published by the Clinical Development (CDP) unit of Merck's US Human Health (USHH) organization, in conjunction with investigators. CDP was part of the Medical and Scientific Affairs department of USHH and was separate from the Marketing department within USHH contrary to the assertion of Hill et al. ADVANTAGE does not meet the definition of a seeding study in any of the references cited by the authors in their paper.2,3
The scientific objectives of the ADVANTAGE study are clearly detailed in the protocol, which was reviewed and approved in February, 1999, through the routine channels including sign off by senior Merck Research Laboratories (MRL) officials.4 These documents were produced to plaintiffs in the VIOXX litigation and available to Hill et al for their analysis and contained keywords from their purported search, despite their assertion that they could find no evidence of MRL involvement in the study. The scientific purpose of ADVANTAGE was properly disclosed to physicians-investigators, participants and institutional review boards and Merck's business interests were understood. The editors of Annals documented in their letter of acceptance for publication of the study in 2003, that physicians would be interested in the type of results ADVANTAGE produced.5
As is always the case, a scientifically sound, rigorously conducted study that shows the benefits of a drug for patients and doctors would also benefit the company that produced the drug. Accordingly, Marketing would be expected to evaluate the commercial possibilities of ADVANTAGE.* This does not change the fact that the primary intent of the study was to answer scientific questions of importance to primary care physicians.
Merck believes there is great value in conducting scientifically based clinical studies to address scientific questions. We believe we acted appropriately in the ADVANTAGE trial, and stand behind our strong beliefs in the principles of scientific integrity. We regret that neither the authors nor editors chose to contact Merck to verify their information or to discuss their conclusions. We encourage readers to read Merck's open letter at: http://www.merck.com/newsroom/press_releases/corporate/. * Note that the correct date of the Marketing memo represented in Figure 1 in the paper by Hill et al. was January 4, 2000, when the study was substantially complete, not 1999.
References: 1. Hill KP, Ross JS, Egilman DS, Krumholz HM. The ADVANTAGE seeding trial: a review of internal documents. Ann Intern Med. 2008;149:251-258. 2. Kessler DA, Rose JL, Temple RJ, Schapiro R, Griffin JP. Therapeutic-class wars "“ drug promotion in a competitive marketplace. N Engl J Med. 1994;331:1350-3. 3. Psaty BAM, Rennie D. Clinical trial investigators and their prescribing patterns: another dimension to the relationship between physician investigators and the pharmaceutical industry [Editorial]. JAMA. 2006;295:2787-90. 4. Carbone KK. ADVANTAGE protocol approval memo. Bates No. LEH804576 to LEH804584. Accessed at http://www.merck.com/newsroom/vioxx/pdf/protocol_approvals.pdf on 19 August 2008. 5. Mulrow CD. ADVANTAGE acceptance letter. Bates No. MRK-APQ0006943 to MRK-APQ0006948. Accessed at http://www.merck.com/newsroom/vioxx/pdf/annals.pdf on 19 August 2008.
Conflict of Interest:
Executive Director, Global Center for Scientific Affairs, Merck Research Laboratories
Lowell General Hosptial
September 2, 2008
A Proposal for Funding Ethical Clinical Trials
To The Editor
Many Phase III (pre-FDA approval) and Phase IV (post-marketing) clinical drug trials are conducted by the pharmaceutical industry, whose goal is to (rightfully) maximize their profit. When a clinical trial demonstrates that a drug is not effective or has side effects, we have seen pharmaceutical companies suppress/delay the release of this information, as they (literally) have billions of dollars at risk. We now learn(1) that the inherent design of pharmaceutical trials is done as an extension of the pharmaceutical company's marketing division. In the end, the public's health is ill-served by a clinical trial that is designed, funded and conducted by a pharmaceutical company which has a vested interest in the outcome of the trial.
One solution to this dilemma would be for the FDA, and the major medical journals, to refuse to accept Phase III and Phase IV trial results that were funded by, or under the guidance of, any entity that has a financial interest in the outcome of the trial. Instead, pharmaceutical companies, upon the completion of their Phase II clinical trials, should be required to pay a "clinical trial fee" to the FDA. The "clinical trial fee" would be used to fund all Phase III and Phase IV trials. These FDA funded trials would then be conducted by academic clinician-scientists, who have no financial interest in the outcome of the trial.
This proposal would help to ensure that clinical trials are properly designed, provide financial support to the FDA and academic clinician-scientists, while also ensuring that the public's health interest is the first priority. And, this solution should not be any more expensive for the pharmaceutical industry than the current situation.
1) Kevin P. Hill, MD, MHS; Joseph S. Ross, MD, MHS; David S. Egilman, MD, MPH; and Harlan M. Krumholz, MD, SM; The ADVANTAGE Seeding Trial: A Review of Internal Documents. Ann Int Med 2008 ; 149: 251
Tim M Reynolds
Queen's Hospital, Burton-on-Trent, UK
September 12, 2008
So What's New?
For the ten years, I have participated in ethical review of research studies, both as an ordinary member of research ethics committees (institutional review bodies) and as chairman. In all of that time we have had the practice of describing certain studies as a "Marketing-study." Such studies are very easy to identify because they usually compare new wonder drug against the currently popular teatment and usually are sufficient to prove statistically that the treatment being tested is "not inferior" to the old treatment. If drug companies did not fund such projects however, there would be little research carried out into the efficacay of drugs and therefore it is illogical to ban the carrying out of "marketing" studies.
The solution does not lie in preventing information from being created; it lies in ensuring that the people who read studies have sufficient education to be able to identify when a study is clearly biased in favor of a particular viewpoint. Usually, this is very simple - all that is necessary is to look at the funding body listed in the acknowledgements. If it is the company whose product whose virtues are extolled, any good results should be discounted by at least 50%.
Kevin P Hill
September 15, 2008
Re: ADVANTAGE: Science first, marketing second
The evidence that Merck pursued a seeding trial to support sales of Vioxx is clear and is derived from their own internal documents.
Dr. Edelman states that ADVANTAGE was developed by a group that was separate from the Marketing department. David Anstice, the former President of Merck's Human Health organization, which had overarching responsibility for the study, affirmed in court, under oath, that ADVANTAGE was initiated and conducted by doctors in marketing (1).
ADVANTAGE is not a case, as suggested by Dr. Edelman, in which marketing is leveraging a study that originates within a company's research division "“ ADVANTAGE is a study that was developed by marketing to boost sales. In the published Merck memo about the Merck Marketing Annual Awards, the objectives of ADVANTAGE were described as "to provide product trial among a key physician group to accelerate uptake of Vioxx as the second entrant in a highly competitive new class and gather data important to this customer group. The trial was designed and executed in the spirit of Merck marketing principles"¦" (2).
Dr. Edelman claims that the purpose of ADVANTAGE was to answer unaddressed scientific questions. The stated objective was "to assess the tolerability of rofecoxib compared with naproxen for treatment of osteoarthritis" even as the drug had already been compared with other non- steroidal anti-inflammatory drugs. The claim of the scientific value of the study is countered by the assessment of Dr. Edward Scolnick, former President of Merck's Research division, who called the study "intellectually redundant" (3).
Dr. Edelman states that Merck's business interests were understood by physician-investigators, participants and institutional review boards. Although these groups would know that Merck is a for-profit company, we doubt that they understood the extent to which marketing played a role in the design and execution of the study. Moreover, the physician-ivestigators likely did not know that they were the subjects of a study of the effect of ADVANTAGE on the prescribing habits of the physician- investigators.
Dr. Edelman states that ADVANTAGE does not meet the definition of a seeding trial. We believe otherwise and find it very consistent with the definition by Kessler and colleagues (4). ADVANTAGE has many of the key attributes of a seeding trial. It included a scientific objective of limited value, the recruitment of investigators because they are frequent prescribers, and the sponsorship of the studies by the company's sales and marketing division rather than its research department.
Finally, as a clarification, the date of the Marketing memo represented in Figure 1 was 1/4/99, and a revision in 12/1999 is noted in the bottom right corner, indicating that the original memo was created before the start of ADVANTAGE (4).
1. Trial testimony of David Anstice; Hermans v. Merck; 27 January 2007; page 620, lines 2 to 16.
2. McKines C, Sherwood L. Memo to Merck Marketing. Best Physician Program Award. 4 January 1999. Bates No. MRK-ACJ0000495. Accessed at http://dida.library.ucsf.edu/tid/vio21x10 on 15 September 2008.
3. Scolnick E. E-mail to Greene D. ADVANTAGE CV event tables. 7 April 2001. Bates No. MRK-ACR0009150. Accessed at http://dida.library.ucsf.edu/tid/vio22x10 on 15 September 2008.
4. Kessler DA, Rose JL, Temple RJ, Schapiro R, Griffin JP (1994) Therapeutic- class wars--- drug promotion in a competitive marketplace. N Engl J Med 331: 1350-1353.
All authors were compensated for participation in litigation against Merck at the request of plaintiffs.
Jeffrey R. Lisse
University of Arizona
October 3, 2008
Advantage Seeding Trial: A Review of Internal Documents
To the Editor:
In light of the recent publication by Hill, et. al.(1), I feel that it is appropriate for me to clarify my role in the ADVANTAGE trial (2). The trial was performed in the late 1990s. I was the principal investigator for this trial at my site at the University of Texas Medical Branch. The study was approved by our Institutional Review Board before we participated in the study.
After the initial draft of the paper, preparation for submission and publication was a collaborative effort among the authors, including myself, other co-investigators, and collaborating authors at Merck.
As noted in a letter by Braunstein and Polis (3), the decision to report cardiovascular outcomes was trusted to "external blinded panels of medical specialists." The numbers of events reported in the original article published in the Annals of Internal Medicine were correct to the best of my knowledge when the article was published. Other information from other sites that I was not privy to and any other conclusion was solely the responsibility and determination of Merck.
I participated in the article's preparation and publication because I thought and still believe ADVANTAGE addressed a valid scientific question. The editors and external reviewers of the Annals agreed with this by publishing the article as did at two internationally attended scientific meetings that accepted scientific abstracts for presentation based on data from the study (4,5).
1. Hill, K.P., Ross, J.S., Egliman, D.S., Krumholz, H.M. The ADVANTAGE Seeding Trial: A Review of Internal Documents. Annals Int. Med. 2008;149:251-8.
2. Lisse, J.R., Perlman, M., Johansson, G., Shoemaker, J.R., Schechman, J., Skalky, C.S., Dixon, M.E., Polis, A.B., Mollen, A.J., Geba, G.P. Gastrointestinal Tolerability and Effectiveness of Rofexcoxib, versus Naproxyn in the Treatment of Osteoarthritis. Annals. Int. Med. 2003;139:539-546.
3. Braunstein, N., Polis, A. Report of Specific Cardiovascular the Outcomes ADVANTAGE Trial. Annals Int. Med. 2005;143:158-159.
4. Geba GP, Lisse JR, Perlmam M, Polis AB, Dixon ME, et al; Gastrointestinal tolerability in primary care patients treated with naproxen or rofecoxib for osteoarthritis: the advantage trial; Annals of Rheumatology Disease; July 2001; Vol. 60, (Suppl.) 1, SAT0096.
Matthew P Doogue
Department of Clinical Pharmacology, Flinders Medical Centre, Adelaide, Australia
October 7, 2008
Multicentre trials arose in the 1960s in response to two needs. Firstly the need for power, to accumulate sufficient subjects in a timely manner to meet the aims of the study. Secondly the need to minimise bias due to investigator or site specific factors not otherwise identifiable. Current study designs meet the first need, but sadly fail to meet the second need.
Site or investigator bias can be detected by testing that the estimated effects are consistent across sites and or investigators. Power to achieve this is dependent on numbers of events & subjects at each site and is greatest with many subjects from a few sites. However most "modern" multicentre trials recruit small numbers of subjects at many sites. With many sites investigator bias is more likely to occur and less likely to be detected than with fewer sites.
Multicentre trials are thus usually 1. unable to detect site or investigator bias; 2. more likely to be affected by site or investigator bias. Such multisite study designs are also more expensive. Therefore why are they done?
One answer is improved validity through wider subject representation and ability to detect e.g. interethnic differences. However, a more plausible answer is marketing.
Any multicentre study with large numbers of investigators and sites has marketing advantages and scientific disadvantages. In particular seeds of bias from sites or investigators are likely to occur and unlikely to be detected.
Thomas L. Perry
Department of Anesthesiology, Pharmacology & Therapeutics; University of British Columbia
October 10, 2008
Re: Seeding bias vs. clinical trials aimed at improving health
Ethical clinical trials should be aimed first at improving patient or public health by learning the truth(s) about new drugs, and comparing them with established alternative treatments. If this is true, then ethics review boards which approve experiments designed primarily to benefit third parties might themselves be considered "unethical".
Why are relatively few non-conflicted doctors involved in the enrolment and assessment of patients for controlled trials? An obvious reason is that pharmaceutical companies orient their experiments, as well as their largesse, to doctors perceived to be "friendly" opinion leaders. They are less likely to seek out principal or co-investigators known for their independent judgement or scepticism, let alone physicians who might criticise a new drug were it to prove inferior.
The solution is to return to the roots of ethical medical science. We need to design more high quality trials and fund them publicly, so that we base therapeutic strategies on high quality science rather than "junk science". Ultimately this strategy would be far more beneficial for individual patients and for society, and much less costly for those who pay for health services.
Many physicians, both academic and non-academic, might welcome the chance to enrol patients in truly scientific trials. In recent years, UKPDS (diabetes) , HOPE (cardiovascular disease), or AD2000 (dementia), each provided widely useful insights not available from the typical marketing trials.
It's time for our professional societies and the leaders of clinical trial design to mobilize the rest of us. Why not reclaim control of the research agenda? After all, we doctors will one day be patients and have the same interest as anyone else in knowing objectively what are the best treatments.
"Dr. Perry has been paid for expert opinion as a consultant to plaintiff in litigation against Pfizer Inc. in regard to alleged off-label marketing of gabapentin for pain."
October 22, 2008
Building the Evidence Base Beyond Regulatory Approval
An August 19, 2008 Annals of Internal Medicine article, The ADVANTAGE Seeding Trial: A Review of Internal Documents" by Kevin Hill and colleagues raises questions about research at pharmaceutical companies extending well beyond their appropriate concern regarding "seeding" clinical experience through the guise of a clinical trial. Most notably, Hill et al question the scientific merit of all research after a medicine's approval beyond that required by the FDA. In doing so, they ignore some nearly universal gaps in knowledge regarding the safety and effectiveness of new medicines at the time of approval in the US.
Why is additional research needed post approval? Approval of medicines in the US typically requires evidence of efficacy and safety in carefully diagnosed populations treated according to well defined and fixed treatment protocols in comparison to placebo. This evidence leaves many critical questions unanswered about most new medicines: how does it compare to other treatments? How does it perform in a setting where patients have a variety of concomitant illnesses and treatments or do not always comply with treatment? These questions are increasingly echoed by insurers, public health administrators, and federal legislators who now call for studies involving representative populations treated in typical practice settings, and relevant comparator treatments.[2,3] The Medicare Prescription Drug Act allowed up to $50 million for research on "comparative effectiveness", although clearly this will not be sufficient to address the need. To the question posed by Drs Sox and Rennie  in an accompanying editorial, "Why would a drug company go to the expense and bother of conducting a trial involving hundreds of practitioners "“ each recruiting a few patients "“ when a study based at a few large medical centers could accomplish the same scientific purposes much more efficiently? "“ we would respond "so that doctors have medical evidence appropriate to community-practice patients and so that healthcare systems have the evidence needed to determine access to medical innovation".
Ultimately, we agree with the conclusions reached by Sox that the 'goodness' of any trial is inherent in whether it addresses an important, new question in a well designed study. Accordingly, the decision to conduct a trial is a serious responsibility and one that should be reached through input from a diverse group of experts in and outside of pharmaceutical companies.
Ignoring or discounting appropriately designed and conducted trials denies physicians important evidence on which to base treatment decisions.
1. The ADVANTAGE seeding trial: a review of internal documents. Hill KP, Ross JS, Egilman DS, Krumholz HM. Ann Intern Med 2008; 149:251-258.
2. Tunis, S.R., D.B. Stryer, and C.M. Clancy, Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA, 2003. 290(12): p. 1624-32.
3. Wilensky, G.R., Developing a center for comparative effectiveness information. Health Aff (Millwood), 2006. 25(6): p. w572-85.
4. Seeding trials: just say "no". Sox HC and Rennie D. Ann Intern Med 2008; 149:279-180.
Authors are employees of Pfizer
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