BELMONT, Massachusetts—"Seeding" trials—studies that look like real clinical trials but are actually designed to lure doctors into using new drugs prior to approval—have been widely suspected. Now the trove of Merck internal documents made public as a consequence of Vioxx (rofecoxib) litigation has removed all doubt.

In an analysis published August 19 in the Annals of Internal Medicine, researchers show that a widely-reported study comparing rofecoxib with naproxen was actually a seeding trial designed to support a marketing campaign before the Vioxx launch.1 The study provides the first hard evidence that seeding trials exist. It analyzes internal Merck records disclosed during litigation and pertaining to the ADVANTAGE study.

“The documents indicate that ADVANTAGE was a seeding trial developed by Merck's marketing division to promote prescription of Vioxx (rofecoxib) when it became available on the market in 1999.”—Kevin P. Hill, MD, MHS
“Documentary evidence shows that ADVANTAGE is an example of marketing framed as science,” conclude researchers led by Kevin P. Hill, MD, MHS at McLean Hospital in Boston, Massachusetts, who obtained and reviewed court-ordered documents and e-mailed messages. “The documents indicate that ADVANTAGE was a seeding trial developed by Merck's marketing division to promote prescription of Vioxx (rofecoxib) when it became available on the market in 1999.” Merck did not tell institutional review boards, physicians, or patients the true purpose of the trial, Dr, Hill and colleagues write.

Annals Editors Misled About ADVANTAGE study

Several years ago, Annals published the seeding trial. “No one told Annals the true purpose of ADVANTAGE,” the journal’s editors write in an accompanying editorial.2 “We learned about it when we received a letter to the editor from Dr. David Egilman, who was a consultant to the plaintiffs' attorneys in the civil suits against Merck,” they write. “To our knowledge, [the] article is the first to provide documentary evidence that proves the existence of seeding trials. The article provides clear evidence that the intent of ADVANTAGE was to increase prescriptions of Vioxx.”

Going forward, “a bureaucratic solution, such as relying on institutional review boards, could help to rid us of seeding trials, but simply shining a bright light on their existence may have already sown the seeds of their destruction,” they note. “The next step would be a societal consensus that it is wrong to deceive institutional review boards and participants about the true purpose of a trial. Therein lies the importance of Hill and colleagues' article.”

Experts predict ethics trouble for future attempts at "seeding" trials

Arthur Caplan, PhD the Emanuel and Robert Hart Professor of Bioethics and the chair of the department of medical ethics and the director of the center for bioethics at the University of Pennsylvania in Philadelphia, said that the new report offers the first hard evidence that seeding trials exist.

“I don’t think people are surprised, but there has never been demonstrated proof that seeding trials exist,” he told MSKreport.com. “It’s significant because it does represent research ethics trouble for Merck and other companies because they are not being forthright about the nature of their studies. You can do marketing studies, but if you don’t tell subjects the truth, they can’t make reasonable decisions and the [institutional review boards] can’t make a reasonable determination about the risks and benefits of these trials,” he said. “I think [the new report] will make people very nervous that these marketing studies, if not properly disclosed, could be revealed in litigation and could create a tremendous liability.“

Reference
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. Sox HC, Rennie D. Seeding trials; just say no. Ann Intern Med. 2008;149:279-280.