Harold C. Sox, MD, Editor; Drummond Rennie, MD
Potential Financial Conflicts of Interest: None disclosed.
Requests for Single Reprints: Harold C. Sox, MD, American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106; e-mail, email@example.com.
Current Author Addresses: Dr. Sox: American College of Physicians, 190 N. Independence Mall West, Philadelphia, PA 19106.
Dr. Rennie: JAMA, 515 North State Street, Chicago, IL 60610.
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Jonathan M Edelman
Merck & Co., Inc
August 21, 2008
ADVANTAGE: Merck does say "no"
As Drs. Sox and Rennie point out in their editorial (1), there will always be debate about the true intent of clinical research conducted by a pharmaceutical company in the process of discovering, developing and commercializing new medicines. Merck agrees that the appropriate approach for investigators, editors and readers is to consider the scientific importance of the question being asked without regard to the commercial benefits that might accrue to answering the question.
However the article published by Annals, written by paid consultants for plaintiffs' lawyers in lawsuits against Merck, falsely labeled ADVANTAGE as a seeding trial and constitutes litigation in the guise of science (2).
In the case of ADVANTAGE, which was conceived when COX-2 inhibitors entered the medical landscape, the study was designed to answer scientific concerns: the need to study the use of VIOXX in osteoarthritis patients in the primary care setting, in more real world conditions than in the development program, against a commonly used comparator for which no previous data existed. These were important, unanswered scientific questions about comparative safety, efficacy and tolerability.
Sox and Rennie claim that information brought to the attention of the Annals in a letter in 2006 from a consultant to plaintiffs' lawyers citing court documents(3) and reiterated in the article by Hill et al has convinced them that Annals was duped into publishing the ADVANTAGE study. But according to their own recommendations for how to recognize seeding trials, this claim lacks credibility. In 2003 Annals assessed the scientific importance of the question that was asked and the results that were obtained from the ADVANTAGE trial, and decided that the information was important enough to publish(4). That the editors were unaware of marketing activities associated with the study in no way diminishes the study's scientific validity or their decision to publish it.
In the interest of fairness Merck would have preferred an opportunity to present our side of the issue before the editors so readily accepted the conclusions of paid consultants to plaintiffs' attorneys. Merck applauds Sox and Rennie in their effort to shine a light on seeding trials. But ADVANTAGE was not a seeding trial.
References (1)Sox HC and Rennie D. Seeding trials: just say "no". Ann Intern Med. 2008;149:279-280. (2)Hill KP, Ross JS, Egilman DS, Krumholz HM. The ADVANTAGE seeding trial: a review of internal documents. Ann Intern Med. 2008;149:251-258. (3)Egilman DS, Presler AH. Report of specific cardiovascular outcomes of the ADVANTAGE trial [Letter]. Ann Intern Med. 2006;144:781 (4)Mulrow CD. ADVANTAGE acceptance letter. Bates No. MRK-APQ0006943 to MRK-APQ0006948. Accessed at http://www.merck.com/newsroom/vioxx/pdf/annals.pdf on 19 August 2008.
Executive Director, Global Center for Scientific Affairs, Merck Research Laboratories
Harvard Vanguard Medical Associates, Mount Auburn Hospital
August 25, 2008
Just Say "No" and the crisis in primary care
JUST SAY "NO" AND THE CRISIS IN PRIMARY CARE
TO THE EDITOR: In their article "The ADVANTAGE Seeding Trial: A Review of Internal Documents" Kevin P. Hill and colleagues seem to put the blame on the pharmaceutical company "Merck and Co" and participating physicians. We think, however, that it is the system which is mostly at fault. "Merck" is a commercial enterprise, whose major goal is to make a profit, using all possible legal tools available. They tried to make their customers believe that their product is better then others in the competitive market. As all major religions at their early stage, they came to proselyte to most disadvantaged group among American physicians force, primary care doctors, who are often looked at by their academic colleagues with lesser degree of respect. Besides money, "Merck" offered primary care doctors something much more valuable: an opportunity to participate in clinical research and be consultants and experts in drug therapy, a prestige which primary care physicians, as "Merck" pointed out, coveted highly. No wonder they were enrolling in this study in droves. Should they have noticed that this was a seeding trial? How could they, if even "Annals of Internal Medicine" published it later on? Now, in his editorial article "Seeding Trials: Just Say No" authors preach to primary care doctors to refuse participating in seeding trials. The reason the seeding trials exist, they argue, is because doctors say "yes" to them. They even quote our parents, who warned us to ask question when we are offered the easy money. Those greedy community doctors! Just say "No!" What a contempt. Nevertheless, while there are enterprises, whose goal is to make a profit, and a group of practitioners, who lack respect and desperately need it (why do you think we have a crisis in primary care?), the practice will continue. Moralization will not help. Involvement of the primary care doctors to academic affairs will.
Potential Financial Conflict of Interest: None.
References: 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". Editorial. Ann. Intern. Med. 2008;149:279-280. 3.Lisse JR, Perlman M, Johanson J, Shoemaker JR, Schechtman J, Skalky CS, et al. ADVANTAGE Study Group. Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann. Intern. Med. 2003;139;539-546.
Harold C. Sox
American College of Physicians
August 28, 2008
Author's Response: ADVANTAGE: Merck does say "no"
Dr. Edelman writes that ADVANTAGE could not have been a seeding trial because the Annals editors decided to publish it, which would imply that it had scientific value (1). We knew about the VIGOR trial (2), which was published in 2000 and compared Vioxx to naproxen in patients with rheumatoid arthritis. VIGOR showed that Vioxx had significantly fewer gastrointestinal side effects than naproxen. We published the ADVANTAGE trial because it framed the same findings in a different way: it showed that the margin between the new drug and the comparator"”also naproxen"”was narrow (5.9% discontinuation rate with Vioxx vs. 8.0% with naproxen) (3). We thought this information help doctors to decide which drug to use to start treatment. We thought the scientific value of the finding was modest, and the company's chief scientist said as much in an email message to a colleague (4). We thought its expository value was considerable.
What was the company's prime motivation for ADVANTAGE? Although the company denies that it was a seeding trial (1), we remain convinced that a principal purpose was to promote adoption of Vioxx by physicians who participated in the trial. First, we interpret the language of the company's internal messages"”excerpted in the Hill article but available in full through the Internet"”to mean that a principal purpose was to market Vioxx. We believe that most readers would agree. Second, it is our opinion that the company would not incur the expense of a trial involving 5500 patients and 600 physicians to confirm what VIGOR trial had already shown for patients with rheumatoid arthritis: that patients with osteoarthtitis would tolerate Vioxx better than naproxen, the primary hypothesis listed in the study protocol distributed at an ADVANTAGE Study Investigators Meeting in 1999 (5).
Was it important to know if ADVANTAGE was a seeding trial? We think so. If it was a seeding trial, patients agreed to participate without knowing something that might have decided them against participating: that one of the company's principal motivations for the trial was to accustom their doctor to using Vioxx. Is the rationale for a study important? We think it is because the main reasons that patients agree to participate in clinical research is potential benefit to themselves and to mankind (6). We believe that many patients would not participate in a trial if they knew that it tested a hypothesis that had already been convincingly addressed and that a principal study objective was to market a new drug.
In the end, the discussion about seeding trials is a discussion about maintaining trust in a system"”clinical trials of new drugs"”that allows a few people to benefit millions by agreeing to participate in a human experiment. We argue that they need to know everything that might affect their decision to participate. And so does everyone else whose cooperation is necessary to do the research.
1. ADVANTAGE: Merck does say "no" Edelman JM. Annals Online, 22 Aug 2008. Accessed at http://www.annals.org/cgi/eletters/149/4/279#105263 on August 28, 2008. 2. Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ. N Engl J Med 343:1520, November 23, 2000 3. Lisse JR, Perlman M, Johansson G, Shoemaker JR, Schechtman J, Skalky CS, et al. ADVANTAGE Study Group. Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann Intern Med. 2003;139:539-46. 4. Scolnick E. E-mail to Greene D. ADVANTAGE CV events tables. 7 April 2001. Bates No. MRK-ACR0009150. Accessed at http://dida.library.ucsf.edu/tid/vio22x10 on 28 August 2008. 5. Proceedings of the ADVANTAGE Study Investigators Meeting, Los Angeles, California, 25 March 1999. Bates Nos. MRK-APU0025051 to MRK-APU0025303. Accessed at http://dida.library.ucsf.edu/tid/vio29x10 on 28 August 2008. 6. Sugarman J, Kass NE, Goodman SN, Perentesis P, Fernandes P, Faden RR. What patients say about medical research. IRB. 1998;20:1-7
Sox HC, Rennie D. Seeding Trials: Just Say “No”. Ann Intern Med. 2008;149:279–280. doi: 10.7326/0003-4819-149-4-200808190-00012
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Published: Ann Intern Med. 2008;149(4):279-280.
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