Researchers poring over Merck's internal documents have concluded that Vioxx's 1999 ADVANTAGE clinical study was “marketing framed as science,” according to a report published in the Annals of Internal Medicine.
The authors described the ADVANTAGE (Assessment of Differences between Vioxx And Naproxen To Ascertain Gastrointestinal Tolerability) study as a “seeding trial” designed to get docs prescribing the drug ahead of approval. The study did not disclose marketing objectives to physician-investigators, participants and institutional review board members, who “were told that the purpose of the trial was to measure the gastrointestinal safety of Vioxx,” according to the report. As a result, “600 investigators enrolled and randomly assigned 2,785 patients with osteoarthritis to Vioxx and 2,772 patients to naproxen…for a three-month trial,” the report found.
Internal documents indicate, among other things, that Merck's marketing department nominated five employees as recipients of the Best Physician Program Award, since the objectives of ADVANTAGE “were to provide product trial among key physician group [sic] 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…,” according to an email included in the report. Full text of all internal emails and legal documents used in the report can be found here. The report itself is here.
Merck responded to the report in a statement, disputing many of the authors' claims. According to the statement, Dr. Jonathan Edelman, head of scientific affairs at Merck Research Laboratories, said the authors "erroneously claim that the objectives of the ADVANTAGE study were not scientific, and base this spurious conclusion on their review of a limited selection of documents produced in the VIOXX litigation. The authors appear to purposely fail to distinguish between the various departments of Merck's USHH organization, including its scientific research and marketing departments." Merck's statement is here.
The Annals of Internal Medicine report, written by Kevin Hill, Joseph Ross, David Egilman and Harlan Krumholz, attempts to describe what they believe to be seeding trials, or trials “designed to seem as if they answer a scientific question, but primarily fulfill marketing objectives,” according to the report. On Aug. 19, Hill told Pharmalot.com that the idea of seeding trials isn't new:
“Physicians have been recruited to participate in marketing studies in order to allow them to become familiar with a drug,” said Hill. “And that's what happened here. This trial allowed physicians to have experience with Vioxx. But as far as I know, our paper is the first to show how a pharmaceutical company planned and executed a seeding trial. There are documents showing how Merck could have gained an advantage. But what's troubling is that physicians and patients weren't told of the objective of the trial. And that's problematic, because patients risk their health when they are signed up for such a trial, instead of advancing the cause of science.”
In a discussion of the report's findings, the authors outline three main criticisms of such trials:
- Full informed consent is not possible without disclosing the full purpose of the trial.
- Good research practice is at risk when the marketing division designs and conducts a study – the report says recruitment of several research sites with fewer patients, in the case of ADVANTAGE, may “result in less quality control from investigators and use of sites that have less research experience than academic centers or community physicians' offices.”
- The study may have negligible scientific merit, given Merck's VIGOR (Vioxx Gastrointestinal Outcomes Research) trials, which were also conducted in 1999. “The FDA had 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.”