BELMONT, Mass., Aug. 18 -- The ADVANTAGE trial comparing Merck's rofecoxib (Vioxx) with naproxen (Aleve) was designed and executed primarily for marketing purposes, said researchers here, but the company has denied the allegation.

Internal documents made public as part of Vioxx-related litigation show that Merck's marketing department conceived the trial as a way to introduce the drug to primary care physicians and turn them into advocates for the product, reported Kevin P. Hill, M.D., M.H.S., of McLean Hospital, and colleagues in the August 19 issue of Annals of Internal Medicine.

Action Points Explain to interested patients that the study found corporate documents showing that a trial comparing rofecoxib (Vioxx) with naproxen (Aleve) had been designed primarily to market the drug to primary care physicians.

Explain that Vioxx is no longer available in the United States.

The researchers said it was the first clearly documented example of a "seeding trial," where marketing a drug to physicians is the main goal, rather than responding to regulatory requirements or answering a scientific question.



They said the practice "threatens the integrity of the relationship of industry, academia, patients, and society" insofar as it disguises the true purpose of clinical trials, thereby undermining the principle of informed consent.



Such trials have long been rumored to be common practice, but documentary evidence had been lacking, Dr. Hill and colleagues said.



Recently, an editorial in the Journal of the American Medical Association suggested that the ENHANCE study of the ezetimibe-simvastatin combination product (Vytorin) was really a seeding trial. However, the authors cited only circumstantial evidence for the allegation.



Jonathan Edelman, M.D., executive director of Merck Research Labs' Global Center for Scientific Affairs, denied that the ADVANTAGE trial had originated with the company's marketing division.



"ADVANTAGE was scientifically driven by [Merck's] clinical research division," he said, which conceived the study and worked with the investigators.



Dr. Edelman said the Annals of Internal Medicine authors "wrongly characterized" the study on the basis of a misreading of the Merck memos and e-mails and a misunderstanding of the company's structure.



The ADVANTAGE study -- published in Annals of Internal Medicine in 2003 -- recruited some 600 primary care physicians as investigators, with each treating about nine patients on average. The trial was conducted just before rofecoxib's FDA approval in 1999, with arthritis patients randomized to rofecoxib or naproxen.



"The purpose of ADVANTAGE was neither to seek a new indication nor to perform post-marketing surveillance," Dr. Hill and colleagues said, noting that the drug's efficacy and tolerability were already addressed at least as thoroughly in other trials.



The researchers found internal Merck memos and presentations in which executives described the ADVANTAGE study's purpose as almost entirely about marketing the drug.



For example, in a memo nominating the trial for an internal marketing award, Merck executives wrote, "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 memo noted that primary care physicians write 60% of prescriptions for arthritis drugs. "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."



It also revealed that Merck sales personnel identified physicians to be recruited for the trial and helped monitor the trial's progress.



Dr. Edelman responded that the "objectives" to which the memo referred were not for the study itself, but rather for the separate marketing campaign designed to capitalize on the results.



He also said the involvement of sales staff in the study was limited to nominating potential investigators. The final selection was handled by the clinical research division, he said.



Dr. Edelman said another marketing memo, which explicitly called ADVANTAGE a seeding trial, was written by someone who did not understand what the term meant.



Dr. Hill and colleagues said Merck and its PR firm provided media-relations training to ADVANTAGE investigators after the results were published to help them participate in the resulting publicity, according to the document trove.



And in another memo unearthed by Dr. Hill and colleagues, Edward Scolnick, M.D., then head of Merck research, called seeding trials "intellectually redundant" and "wasteful" and said the effort "compromises the large clinically meaningful trials."



However, Dr. Edelman rejected the suggestion by Dr. Hill and colleagues that ADVANTAGE was scientifically redundant with other rofecoxib studies.



He said ADVANTAGE was the only rofecoxib study until then that allowed concomitant use of aspirin, which the company anticipated would be common once the drug reached the market. Other studies also did not include many primary care practices, he said.



Dr. Edelman also pointed out that Annals of Internal Medicine published the study following peer review, an indication that independent scientists believed it had merit.



An earlier review of court documents in the Vioxx lawsuits had disclosed that the 2003 paper had been ghostwritten. In 2005, the study's lead author said a draft had already been prepared by Merck personnel when he was brought in. (See: Fewer Medical Journal Articles Planted by Phantom Authors tb 9084)



Merck has insisted that the named authors were "intimately involved" with the study.



Dr. Hill and colleagues said it would be difficult for outsiders to know when a study is actually a seeding trial.



"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," they wrote.



In an accompanying editorial, Harold Sox, M.D., editor of Annals of Internal Medicine, and Drummond Rennie, M.D., deputy editor of the Journal of the American Medical Association, said there may be clues.



"An open-label design, no control group, a very large projected enrollment relative to the importance of the question, a short-term study of a chronic disease, a study of an already approved drug" are all features that could signal a trial conducted more for marketing than science, they said.



They laid responsibility for screening out seeding trials on institutional review boards, would-be investigators, and patients.



The editorial omitted scientific journals from the list, but in an interview, Dr. Sox said they had a role to play too.



He said journals should conduct the same evaluations as institutional review boards, that is, determining whether the research addresses a genuine scientific question.



"If journals are interested in publishing findings that are new and likely to change practice, they are likely to turn down seeding trials," he said.



That did not happen with the ADVANTAGE trial, he acknowledged.



"We thought there was an important message [in the trial,] but not the one that Merck was pushing," Dr. Sox said.



The trial found that discontinuations in the trial occurred at a 5.9% rate with rofecoxib versus 8.1% with naproxen. Although the difference was statistically significant, Dr. Sox said it was clinically marginal, especially given rofecoxib's much greater cost.



"Having been burned on this one, we're going to be more careful," he added.



In the editorial, he and Dr. Rennie said they hoped the revelations on ADVANTAGE may discourage future seeding trials.



"Simply shining a bright light on their existence may have already sown the seeds of their destruction," they wrote. "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."