According to a paper published in the current issue of Annals of Internal Medicine, Merck conducted a sham clinical trial whose purpose was to turn 600 physician-researchers into marketing seeds to boost sales of its arthritis medication Vioxx. This study, called the ADVANTAGE trial, was billed by the company as a placebo-controlled study comparing Vioxx with the pain reliever Naproxen. However, according to internal company documents obtained in the course of a trial involving Merck, the research was designed and conducted by the marketing division as a “seeding trial,” intended to induce the researchers and their colleagues to prescribe more Vioxx after the clinical trial was over. (More coverage of this story here and here.)
This new variation on the theme of marketing-disguised-as-science is a little complicated, so I interviewed the lead author on this paper, Kevin Hill, M.D., a former Robert Wood Johnson Clinical Scholar at Yale, about the issue. Dr. Hill is now Addiction Psychiatry Fellow at McLean Hospital
Dr. Carlat: What is a “seeding” trial?
Dr. Hill: A seeding trial is a study that is designed to appear as though it is answering a scientific question but whose true purpose is to market a medication.
Dr. Carlat: But how is this different from any industry-funded trial? Anytime a drug company compares its drug with placebo or another drug, aren’t they planning to use the results to help market their drug?
Dr. Hill: That’s true, but a seeding trial is different. In the usual clinical trial, the goal is to answer an important scientific question about your drug and, perhaps, end up with a scientific finding that is advantageous for your drug. You then take that finding, and advertise it to doctors and patients. So the research study itself is not a marketing activity; the marketing comes after the study is over and you have your findings.
In Merck’s seeding trial, their primary interest was not in assessing the gastrointestinal tolerability of Vioxx, because they already had a sense of it from other research they had done. ADVANTAGE was not necessary to address the question of tolerability.
Dr. Carlat: So what was the point of the trial if they weren’t interested in the findings?
Dr. Hill: The point of the study was to market Vioxx directly to the researchers involved. The ADVANTAGE trial recruited a large number of community physicians—600—as “researchers.” The point was to get Vioxx into the hands of all these doctors very early in the game, before the drug came to market. Merck hoped that these doctors would find Vioxx helpful, and that they would spread a positive marketing message to other doctors by word of mouth. The company also paid these doctors to go to researchers’ meetings, and paid them a substantial amount of money for every patient they recruited. They hoped that this financial arrangement would also induce loyalty to Merck and, indirectly, lead them to prescribe even more Vioxx.
Dr. Carlat: I see. So the “seeds” are the physician/researchers, and the hope is that these seeds grow into a positive buzz for Vioxx among colleagues.
Dr. Hill: Exactly.
Dr. Carlat: It seems like we hear about companies manipulating research in various ways all the time. Why is this a particularly objectionable practice?
Dr. Hill: A number of reasons. First and most importantly, doctors and patients were not told about any of these marketing objectives, so they were not given all of the information about what they were signing up for. Generally, patients choose to participate in clinical trials either because they think they might benefit from a treatment, or because they have an altruistic notion of wanting to help the cause of medical science. But if these patients had been told that the trial was designed in order to boost profits of a drug company, I suspect that many might not have participated. In this case, a lot of people risked their health for marketing purposes, and ADVANTAGE is a particularly poignant example because Vioxx increased their chances of having heart attacks.
A second problem is that, as opposed to most clinical trials, Advantage was conceived and run solely by Merck’s marketing division without any input from Merck’s scientific division. We had access to company documents, and what was striking was how frank they were that this study was a marketing exercise. There was little pretense within the company that this was in the service of clinical science.
Dr. Carlat: What were some of the company documents you saw?
Dr. Hill: One of the most revealing was a memo describing an award given by Merck executives to the those in the marketing division who conducted ADVANTAGE . The award describes the trial, quite blatantly, as a marketing program. They were very proud of how they were able to quickly and efficiently get the medication into doctor’s hands.
[Ed. note: This memo is published in the Annals article. Here is one excerpt in which the research is described:
“The objectives were 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 the Merck marketing principles, as described below."]
Another remarkable document was an email written by Dr. Edward Scolnick, the head of the research division at Merck. He said that this trial was “intellectually redundant,” and lamented how ADVANTAGE could exacerbate an already complicated situation as Merck was addressing the safety of VIOXX.
Dr. Carlat: Did Merck make any effort to track the success of the seeding?
Dr. Hill: Yes. We published some of these documents. For example, they did an analysis 6 months after the launch of Vioxx and found that the Advantage researchers prescribed significantly more Vioxx than a control group of primary care physicians who were not part of the research. They also graded a group of rheumatologists from A+ to D based in part on their use of Merck products.
Dr. Carlat: Do seeding trials still go on?
Dr. Hill: Probably, but we don’t know for sure. We only have documentary evidence for ADVANTAGE. The problem is that they often look like legitimate scientific trials. The only reason we knew Advantage was a seeding trial is because we had access to company documents. Merck went to great lengths to hide the nature of this trial. In one memo, an employee in the marketing division wrote: “It may be a seeding study, but let’s not call it that in our internal documents.”