Chicago, IL - A large randomized trial, publicly identified as a safety study for rofecoxib (Vioxx, Merck), was designed and carried out specifically to promote the drug to primary-care physicians with the intent of expanding its sales, conclude researchers, on the basis of an analysis of internal company documents [1].

According to the authors, led by Dr Kevin P Hill (McLean Hospital, Belmont, MA), their analysis shows that the Assessment of Differences Between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness (ADVANTAGE) trial [2] was a "seeding" trial, designed to seed the field of potential prescribers with positive rofecoxib experiences and enhance their goodwill toward the company as the FDA's review of the drug was under way. Further, they note, the company kept its intended purpose for the trial secret from institutional review boards and participating physicians and patients.

ADVANTAGE was marketing disguised as science.

Hill et al had gained access to the Merck documents as paid consultants for the plaintiffs in litigation against the company. They screened several thousand documents and scrutinized about a hundred of them according to validated methods, according to the group.

"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 group writes in the August 19, 2008 Annals of Internal Medicine. The documents, according to the report, show that Merck's marketing team actually conceived, designed, and executed the ADVANTAGE trial. The group infers, moreover, that ADVANTAGE was scientifically redundant; that is, if not for its marketing purpose, there would have been no reason for it.

The trial, conceived in 1999 (the documents say) and published in 2003, compared rofecoxib against naproxen for gastrointestinal tolerability in 5557 patients with osteoarthritis. The two drugs were about equally effective for arthritic pain in the trial, but significantly fewer patients on rofecoxib dropped out due to GI effects.

"I think that ADVANTAGE was marketing disguised as science," Hill told heartwire. "Physicians have long suspected that seeding trials go on and that they've been an effective tool used by pharmaceutical companies to jump-start sales for medications that are coming to market." It's something everyone tends to be aware of but is nearly impossible to prove, he said. Seldom, for example, are a company's intimate internal communications made public on the scale that occurred in this case.

One document highlighted by Hill et al is a memo from a Merck manager that lauds the marketing division for its broad ADVANTAGE strategy and describes its synergy with the company's clinical development program (CDP), "a part of Merck's marketing division," according to Hill et al.

"The trial was designed and executed in the spirit of the Merck marketing principles," the memo stated. Its design "was the result of a close collaboration between CDP and marketing and . . . focused on a gap not filled by the pivotal clinical program." It further notes that "execution of the trial was of the highest level, involving integration of the field, marketing, and CDP."

"These companies are very competitive," Hill observed. "They know about the techniques that other companies use, what works and what doesn't work. They spend a lot of money in marketing. And so I think it's reasonable to imagine that other companies are running trials very similar to ADVANTAGE."

According to Dr Robert M Califf (Duke University, Durham, NC), "the distinction between clinical research people and marketing people at a lot of pharma companies is not as clear as you might think." At many of them, he told heartwire, postmarket studies are run primarily by a unit that is blend of marketing and clinical research.

People need to trust the science behind clinical trials, and seeding trials shake that trust.

"The most important question is, is the trial fairly designed?" according to Califf. "Many people, like me, have argued that we need to have a different system for deciding what questions are going to be answered by trials and what their designs will be for answering the questions. Companies can't look at both sides of the coin; they're obligated by their fiduciary responsibilities to look at questions that are likely to come out positive for them."

Califf, who is vice chancellor for clinical research at Duke Medical Center and directs the Duke Translational Medicine Institute, was the founding director of the Duke Clinical Research Institute.

The problem for Merck here, he observed, "is that this turned out to be a very high-profile case. From my view, they were acting like most companies act, and I've certainly seen more egregious behavior." At Duke, "we're not allowed nor would I want to sign a contract with a company that works that way," he said. "To my knowledge, the majority of industry-sponsored trials do not have an independent executive committee or an independent data monitoring committee."

The case of ADVANTAGE is noteworthy also because rofecoxib's safety issues involved more than GI upset. The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, published in 2000 [3], was the first to suggest that rofecoxib could be prothrombotic compared with another drug, naproxen. As extensively reported by heartwire, years of controversy about an increased cardiovascular risk with the drug culminated, although it did not end, with Merck's worldwide withdrawal of its product from the market in 2004.

It's that shadow of harm from rofecoxib, combined with Merck's secrecy about the real goals of ADVANTAGE, that makes this case stand out, according to Hill: patients and physicians didn't have all the information they needed to make an informed decision about whether to participate.

It's hard for physicians to say no to trials like this, which can be very lucrative and prestigious.

"People need to know what they are signing up for. People need to trust the science behind clinical trials, and seeding trials shake that trust and trust in the scientific process. They shake the trust of the physicians who participate, as well," Hill said. "Patients risked their health, in this case, solely to boost Merck profits."

An accompanying editorial asserts that such secrecy is fundamental to the very existence of seeding trials and suggests it's not only companies that should be held accountable [4]. It spends considerable space on questions that could be raised by "institutional review boards, researchers, physicians, and patients" to help prevent them.

"The [Merck] documents do tell us that deception is the key to a successful seeding trial. . . . Seeding trials can occur only because the company does not disclose their true purpose to anyone who could say 'no.' It is also true that seeding trials exist only because physicians say 'yes' to a deal that seems too good to be true," write the editorialists; Dr Harold C Sox is the editor of the Annals of Internal Medicine, which published the results of the ADVANTAGE trial and therefore actually represents another player in the story, and Dr Drummond Rennie is a deputy editor of the Journal of the American Medical Association.

"We hope that a study like this, if brought to the attention of the public, will get people to ask more questions about what the objectives of a trial are, and also from the physician's standpoint, to think about what kind of trial they're participating in," Hill agreed. Seeding trials can be extremely hard to identify, he said, and "it's hard for physicians to say no to trials like this, which can be very lucrative and prestigious."