When clinical trials are designed by the marketing department

ResearchBlogging.orgI must be slipping.

Well, not really. It doesn’t bother me that blog bud and fellow skeptical physician PalMD beat me to an important publication that came out a couple of days ago in the Annals of Internal Medicine. I’m a surgeon and a translational/basic scientist; so Annals is not usually one of the journals I read regularly. I usually read individual studies as I find out about them referenced elsewhere, usually Eureka Alert! or when an Annals study sufficiently interesting to motivate me to surf on over to the website and download the article. Be that as it may, this article is highly relevant to the overall themes of this blog because it shows yet another manner in which science-based medicine can be undermined. This time around, though, it’s not so-called “complementary and alternative medicine.” It’s not woo-meisters. It’s not even the infiltration of pseudoscience into academic medical centers.

No, this time around it’s big pharma doing the sorts of things that produce such marked distrust, even among advocates of science-based medicine.

The problem highlighted by this article is a phenomenon known as a “seeding” trial, specifically a seeding trial carried out by Merck for Vioxx. Seeding trials are a special breed of trial that is carried out either shortly after the Food and Drug Administration (FDA) approval of a new drug or while a drug is being considered for approval by the FDA. Normally, one would think that a trial shortly after FDA approval would be for the purposes of post-approval surveillance of a drug for safety and efficacy. After all, the phase III clinical trials that are used pre-approval to establish the value of a new drug are not and cannot cover nearly as many patients as will be taking the drug after it’s approved. There are sometimes rare effects that show up only after a drug has been administered to hundreds of thousands or millions of people. Given that it’s utterly impractical to test a drug on that many people before its approval, and post-approval monitoring is essential.

That’s not what we’re talking about here.

No, what we’re talking about is a study that appears to be a valid clinical trial but is designed for a different, unspoken and unrevealed purpose. This type of trial, known as a seeding trial, involves coming up with a hypothesis to be investigated that isn’t really that important and then designing a study in such a way as to get the new drug into the hands of as many primary care physicians as possible. Community primary care doctors rarely participate in clinical trials. The reason for this is because they are very busy, and signing up patients for clinical trials is very time-intensive. It takes hours to check patient eligibility, explain the trial, obtain informed consent, register a patient with the clinical trial office doing the trial, and doing the necessary documentation. Most community physicians have not been trained in clinical research and do not have the skill set to deal with clinical trial issues themselves. Moreover, many community primary care practitioners operate on razor-thin margins; spending that much time signing up patients can seriously jeopardize the financial health of their practice.

Enter the drug company and the seeding trial. In such trials, many, many physicians are signed up as investigators, so that each only has to sign up a few patients, and the drug company pays them for each patient and provides all the support necessary for monitoring and paperwork. Meanwhile the reward for physicians participating is the prestige of being an investigator for a clinical trial, coupled with in essence no penalty because the drug company more than reimburses for the time spent, which isn’t all that much given that each physician only has to sign up a few patients. In reality, however, the design of the trial is very inefficient. For a real scientific question being tested in a clinical trial, it would be far more efficient to concentrate the patient accrual in a few large academic centers that could find patients much more quickly and already have the infrastructure to do clinical trials. But for seeding trials the scientific question is almost besides the point, an afterthought. The real, unstated purpose of such trials is to expose as many doctors as possible to using the drug and thereby make them comfortable using it. The real purpose of seeding studies is to make these physicians advocates for the new drug. The real purpose of seeding trials is marketing, not science.

The Annals article drives this home quite effectively with a case study of the ADVANTAGE (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness) clinical trial run by Merck. The stated purpose of this trial, which involved 5,557 patients at 600 different sites, was to compare gastrointestinal side effects and tolerability of Merck’s new drug Vioxx with those of an established drug (Naproxen) whose results were published in 2003 in–of all journals–the Annals of Internal Medicine. Not surprisingly, the results of the ADVANTAGE trial showed that Vioxx was superior to Naproxen when it came to gastrointestinal side effects. However, there was a huge problem.

As Merck internal documents clearly show, the ADVANTAGE trial was primarily a marketing tool. Think of it as a direct-to-physician sales pitch, as demonstrated quite clearly by this document, which I urge you to take the time to read. Here’s a key passage from this document originating from Merck’s marketing department:

The ADVANTAGE (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness) trial is the largest ever initiated prior to the launch of a Merck product. The objectives were to provide a 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 trial was designed and executed in the spirit of the Merck marketing principles, as described below.

First, the trial was targeted to a select group of critical customers. The clinical trial program for VIOXX focused primarily on specialists. While they would be critical to early uptake and advocacy for VIOXX, the large majority of prescriptions in the A&A market (~60%) come from primary care physicians. 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.

In other words, the introduction to clinical research was secondary, and the actual scientific question to be answered was dead last in Merck’s considerations. Indeed, the most important part of the memo appears to be the part where it is emphasized is the careful tracking of marketing-related results; i.e., rates of Vioxx prescriptions written by study physicians. There’s also this slide from a Merck presentation, which defined the role of the marketing department in the design and execution of ADVANTAGE thusly:

  • Design protocol and oversee execution of trial
  • Select investigator sites
  • Run investigator meetings
  • Choose and manage CRO (clinical research organization)
  • Perform data analyses
  • Prepare publications

Worse, even though the first author of the main publication resulting from ADVANTAGE was Dr. Jeffrey R. Lisse, an academic physician not employed by Merck, as reported in the New York Times, he did not have a role in data collection or analysis and was quoted thusly:

“Merck designed the trial, paid for the trial, ran the trial,” Dr. Lisse said. “Merck came to me after the study was completed and said, ‘We want your help to work on the paper.’ The initial paper was written at Merck, and then it was sent to me for editing.”

Clearly, Dr. Lisse was seriously compromised ethically by Merck, as well. He should have either refused to help or demanded a much greater role in the analysis of the data. To do otherwise is to let oneself become in essence a front man for a big pharma-produced marketing document.

To boil it all down, here’s my perspective on why seeding trials such as this are inherently unethical, regardless of whether the clinical scientific question under study is worthy or the design of the trial can produce an answer. It all comes down to one issue: Deception. There is no way to carry out such a trial without deceiving everyone involved below the level of study designers. First, the physicians recruited as investigators can’t know that they are in fact the real study subjects, given that the real purpose of a seeding study is to determine whether giving them exposure to using the drug will change their prescribing habits and make them advocates. the renumeration and stroking by the drug company also compromise their objectivity to an unacceptable degree. (No clinical investigator can ever be truly 100% objective, because all clinical investigators have some degree of an emotional investment in the outcome of the studies they design and perform. That’s why we have so many safeguards on clinical trials.) Second, the patients recruited as human subjects can’t know one of the major questions of the study, again whether physicians’ prescribing habits can be changed. This alone means that truly informed consent is impossible. Finally, the very committee charged with protecting the interests of human subjects in clinical trials, the Institutional Review Board (IRB), must also be kept in the dark regarding the marketing purpose of the study. The reason is obvious. No IRB would approve a human subjects study whose primary purpose is clearly marketing more than an important scientific question.

As an accompanying editorial by Harold C. Sox, MD, Editor of Annals of Internal Medicine, and Drummond Rennie, MD, puts it:

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.”

The problem for clinical investigators and busy clinicians, as well as IRBs, is identifying a seeding trial. It’s not as easy as it may seem. For example, ten years ago, when the ADVANTAGE trial was being planned and submitted to IRBs, the scientific question to be answered by the trial was not an unreasonable one. Moreover, there are perfectly valid reasons for doing a trial using many community practitioners rather than academic centers, inefficiencies of this approach notwithstanding. The key advantage is to obtain “real world” data about side effects and efficacy when a drug is prescribed “in the real world,” so to speak. Academic medical centers that do a lot of clinical trials are places with a rarified atmosphere and resources not available to most community physicians. It is often of interest to know how a drug will work “in the wild.” In addition, some inducement is necessary to get community physicians on board, given that the constraints on their time and finances usually make being an investigator in a clinical trial too onerous. Indeed, that the ADVANTAGE trial was a seeding trial did not become apparent until long after it was published, and an article in the New York Times suggested that its purpose was more for marketing than for science.

One characteristic that is common in a seed trial is that it is redundant. In other words, it is asking a question that has already been answered. Certainly, this was the case with the ADVANTAGE trial, as the incidence of gastrointestinal side effects had already been assessed and shown to be lower than those due to Naproxen in an earlier trial known as the Vigor Trial.

Given the huge expenses involved in developing new medications and bringing them to market, I am under no illusions that drug development will ever be done to a significant degree by any other entities than for-profit companies. Indeed, the profit motive, when harnessed and regulated, is a powerful incentive, although it can also motivate trials like the ADVANTAGE trial. Nor am I under any illusion that the authors of this study are as pure as the driven snow. All of them were compensated for participation in litigation against Merck at the request of plaintiffs, and their access to internal Merck documents came through the discovery process during litigation against Merck. They are all hired guns for the plaintiffs suing Merck. No doubt this article will feature prominently in the many lawsuits against Merck and represents just one side of the story. Even so, that side of the story is so compelling that it is hard to imagine a defense that would excuse the clear marketing purpose of the ADVANTAGE study. Although it is (barely) conceivable that that mitigating documents might come to light during Merck’s defenses against Vioxx lawsuits internal documents mostly speak for themselves. They make it very clear that the ADVANTAGE trial was a seeding trial using a previously answered scientific question as the basis of a redundant clinical trial whose real main purpose was to “seed” experiences prescribing Vioxx to several hundred primary care physicans.

For science-based medicine to be accepted and trusted by the public, the public must be sure that the clinical trials designed to test the safety and efficacy of new drugs conform to the highest standards of science. More importantly, they must know that these trials are as free from bias and hidden agendas as is humanly possible to achieve. Also, a personal standpoint, I detest Merck’s actions because it will make it that much more difficult for honest clinical investigators like myself to win patients’ trust and persuade them to agree to participate in clinical trials, particularly trials in which a pharmaceutical company is involved but the distrust will spill over to all clinical trials, even NIH-funded trials. The reason seeding trials like ADVANTAGE are so pernicious is because they undermine faith in science-based medicine and contribute to the distrust of “conventional” medicine by corrupting academic physicians, community physicians induced to take part in them, and even clinical science itself.

REFERENCES:

1. Hill, K.P., Ross, J.S., Egilman, D.S., Krumholz, H.M. (2008). The ADVANTAGE Seeding Trial: A Review of Internal Documents. Annals of Internal Medicine, 149(4), 251-258.

2. Sox, H.C., Rennie, D. (2008). Seeding Trials: Just Say “No”. Annals of Internal Medicine, 149(4), 279-280.