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Editorials |19 August 2008

Seeding Trials: Just Say “No” Free

Harold C. Sox, MD, Editor; Drummond Rennie, MD

Harold C. Sox, MD, Editor
From Annals of Internal Medicine, Philadelphia, PA 19106, and JAMA, Chicago, IL 60610.

Drummond Rennie, MD
From Annals of Internal Medicine, Philadelphia, PA 19106, and JAMA, Chicago, IL 60610.

Article, Author, and Disclosure Information
Author, Article, and Disclosure Information
  • From Annals of Internal Medicine, Philadelphia, PA 19106, and JAMA, Chicago, IL 60610.

    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, hsox@mail.acponline.org.

    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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The public has lacked convincing documentary evidence of a long-suspected drug company practice: promoting a new drug by sponsoring a randomized trial in which participating physicians use the drug as they follow the trial protocol. This practice—a seeding trial—is marketing in the guise of science. The apparent purpose is to test a hypothesis. The true purpose is to get physicians in the habit of prescribing a new drug.
Why would a drug company go to the expense and bother of conducting a trial involving hundreds of practitioners—each recruiting a few patients—when a study based at a few large medical centers could accomplish the same scientific purposes much more efficiently? The main point of the seeding trial is not to get high-quality scientific information: It is to change the prescribing habits of large numbers of physicians. A secondary purpose is to transform physicians into advocates for the sponsor's drug. The company flatters a physician by selecting him because he is “an opinion leader” and incorporates him in the research team with the title of “investigator.” Then, it pays him good money: a consulting fee to advise the company on the drug's use and another fee for each patient he enrolls. The physician becomes invested in the drug's future and praises its good features to patients and colleagues. Unwittingly, the physician joins the sponsor's marketing team. Why do companies pursue this expensive tactic? Because it works (1, 2).
It works, but it may endanger the unwary physician. The tide is turning against the physician who accepts emoluments from drug companies. Academic institutions and professional organizations are issuing ethical guidelines that proscribe transactions in which drug companies pay physicians an amount that is disproportionate to the services that the physician provides (3, 4). The office of the U.S. Inspector General has issued guidance about which transactions are legal. Although its guidance focuses on gifts, it also states that payments for participation in research “should be fair market values for legitimate, reasonable, and necessary services” (5). Moreover—and most ominously for the future of seeding trials—“postmarketing research activities should be especially scrutinized to ensure that they are legitimate and not simply a pretext to generate prescriptions of a drug” (5).
Several years ago, Annals published a seeding trial (6). Merck & Co. (Whitehouse Station, New Jersey) sponsored ADVANTAGE (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness), a large, community-based, randomized comparison of a cyclooxygenase-2 inhibitor (Vioxx [rofecoxib]) and a nonselective cyclooxygenase inhibitor (naproxen). At the end of the 3-month follow-up, the proportion of patients who discontinued naproxen was larger (8.1% vs. 5.9%) than that of those who discontinued Vioxx. We published the study because we thought that physicians would be interested in the low discontinuation rates for both drugs and the small difference between them.
No one told Annals the true purpose of ADVANTAGE. 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 (7). He had access to publicly accessible trial documents, which included Merck employees' e-mail messages that disclosed the true intent of the ADVANTAGE trial. These messages are the meat of the article about seeding trials published in this issue by Hill and colleagues (8). To our knowledge, this article is the first to provide documentary evidence that proves the existence of seeding trials. Other than an excerpt from a single industry document cited in an article by Kessler and colleagues (9), we have not had “smoking gun” evidence, in which the perpetrators are on public record about why they conducted a trial like ADVANTAGE. The article provides clear evidence that the intent of ADVANTAGE was to increase prescriptions of Vioxx (the study outcome of greatest interest to Merck seems to have been Vioxx prescribing rates). However, despite the large body of documents searched by the authors, they discovered few details about exactly how Merck's marketing division carried out ADVANTAGE.
The documents do tell us that deception is the key to a successful seeding trial. That information—once it becomes general knowledge—could be the fatal blow for seeding trials. Institutional review boards, whose purpose is to protect humans who participate in research, would probably not likely approve an action that places patients in harms' way in order to influence physicians' prescribing habits. If they knew, few established clinical researchers would participate as coinvestigators. Few physicians would knowingly enroll their patients in a study that placed them at risk in order to provide a company with a marketing advantage, and few patients would agree to participate. 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. Academic physicians agree to be on the byline of an article that someone else wrote about a study that someone else designed and paid for because there is considerable prestige, little effort, and low risk (10). A practicing physician says, “Why not?” when he learns that he has been selected to participate in an important clinical trial and receives inducements designed to make it an offer he will not refuse. Our parents prepared us for this moment when they warned us to ask questions when someone offers us easy money. We owe it to them and especially our patients to ask if we are being recruited to participate in a seeding trial.
How can people with decisional responsibility—institutional review boards, researchers, physicians, and patients—identify a seeding trial? They could ask the about the intent of the trial. If the answer was “It's a seeding trial,” most would say no, and seeding trials would soon fade away; but this scenario is a fairy tale, because sponsors would probably ascribe a scientific purpose to the trial and proving otherwise would be difficult. Nonetheless, institutional review boards could routinely ask, “Is this a seeding trial?” Sponsors would think twice about lying to an institutional review board, an institution that has so much legal and public support, especially in an era in which e-mail messages seem to live on forever, awaiting discovery by a curious someone.
Asking about intent may be the wrong approach. Does the goodness of a trial inhere in its intent or in something else? An adequately powered trial is good if it tries to answer an important scientific question on which patients should be in equipoise, even though participating physicians will become familiar with a new drug and be more likely to prescribe it. Is the same trial bad if its main purpose is to increase drug sales by habituating trial physicians to prescribing a new drug? Couldn't the answer to this question depend on the scientific importance of the question that it addresses? The trial would be bad if it addressed a question that lacked merit but good, despite its intent, if the question had intrinsic merit. Does the motivation for the trial make it wrong to participate in it, or does addressing an important, unsettled question make the study worthwhile, despite its intent? Perhaps physicians should focus less on intent and more on the scientific question. The ADVANTAGE physicians should have been asking whether the trial addressed an issue that previous trials had already answered—or should have answered.
This line of reasoning suggests that institutional review boards, researchers, physicians, and patients should be asking about the study hypothesis and whether it addresses a settled question. Physicians have a fiduciary obligation to ask these questions on behalf of their patients, as do institutional review boards and researchers, which have the skill set and personnel to judge whether a trial is asking an already-answered question. They could look for other clues, such as a study with 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, and so forth (1, 8, 9). None of these clues is highly specific, but institutional review boards should start asking questions when a study has several of them.
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. 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 (8).

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3 Comments

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.

Conflict of Interest:

Executive Director, Global Center for Scientific Affairs, Merck Research Laboratories

Alexander Rabin

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.

Conflict of Interest:

None declared

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

Conflict of Interest:

None declared

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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.

DOI: 10.7326/0003-4819-149-4-200808190-00012

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2008 American College of Physicians
26 Citations

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The ADVANTAGE Seeding Trial: A Review of Internal Documents
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ADVANTAGE: Merck Does Say No
ADVANTAGE: Merck Does Say No
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