Monday, August 18, 2008

Sowing the Seeds of Vioxx

A new article in the Annals of Internal Medicine lays bare how research was commandeered by marketing in the promotion of Vioxx, Merck’s former all-star painkiller and personkiller. The article is based on a chunk of internal Merck documents revealed during legal proceedings (not unlike the infamous Zyprexa documents). Merck set up the study known as ADVANTAGE, in which 2785 arthritis patients were given Vioxx and 2772 arthritis patients took naproxen. Physicians across the nation were recruited to enroll patients to participate in the study, which was intiated during the FDA approval process for Vioxx.

The study, however, was conceived and conducted by Merck’s marketing department. Why? As Vioxx was about to come to market, Merck needed to develop a need for their product. By hiring physicians to participate as “investigators” on this trial, Merck was exposing its product to an important group of potential customers. To quote Merck:

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 trial was designed and executed in the spirit of the Merck marketing principles.

Other snippets from a Merck marketing memo, with pithy commentary added free of charge:

  • "...the trial was targeted to a select group of critical customers.” So the main qualification to be a “research investigator” in this trial was to be a customer that Merck wanted to win over.
  • The sales force nominated potential investigators and completed intake forms, allowing a very large number of sites to be evaluated and enrolled and ensuring equal distribution of investigators across the business groups.” Again, the sales force chose the physicians, apparently based on how easily they could be swayed to prescribe Vioxx as a result of participating in this study.
  • An analysis performed at 6 months post launch demonstrated a significantly higher level of prescribing for VIOXX among primary care ADVANTAGE investigators compared to a control group of VIOXX 99 prescribers (see attached). Feedback from the field has been overwhelmingly positive about their ability to access key customers and the influence that being involved in the trial has had on their perceptions of VIOXX and Merck.” The program apparently had its desired results – more docs prescribing Vioxx as a result of their participation in Merck marketing-designed “research.” As for the patients dying due to taking Vioxx, well, what’s a little collateral damage when there are quarterly sales goals to be met?

The name for such an exercise in marketing is a “seeding trial,” referring to a company planting seeds in physicians to use their product under the guise of research.

II. What about getting the results out?

According to Merck: “Preparations are now underway for analysis and publication of the data, which will utilize key investigators as authors and advisors.” Turns out that worked pretty well – as the lead author on the main ADVANTAGE publication told the New York Times that “Merck designed the trial, paid for the trial, ran the trial. 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.” – it was sent to him to place a veneer of academic credibility on Merck’s marketing-run trial.

Even Merck’s head of research said that trials such as ADVANTAGE are “intellectually redundant” – as they tend to focus on results that are already well-established, such as showing Vioxx to be somewhat easier on the gastrointestinal tract that naproxen.

Harold Sox and Drummond Rennie, also writing in the Annals of Internal Medicine, in a critique of Vioxx’s marketing wrote:

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.

This is hardly the biggest problem with Vioxx, as its tendency to kill people en masse via heart problems is obviously a far more important issue. And we all know at this point that Merck made sure to underplay the risks of Vioxx, and that the medical community was also asleep at the wheel when it came examining published studies on the risks of Vioxx. Nonetheless, using the guise of science to recruit naive (or greedy) physicians to serve as Vioxx pushers is contemptible.

Merck was out pushing how wonderfully safe and well-tolerated was via a “study” designed solely to turn “investigators” into top Vioxx prescribers, while at the same time, more and more people were meeting an early end due to this purportedly safe new drug.

For more hot Vioxx action, check out this site.

Update (8-19-08): Check out an interview with Dr. Kevin Hill, lead author of the investigation of the ADVANTAGE trial, over at the Carlat Psychiatry Blog. As always, Pharmalot also has a good post on the topic.

4 comments:

A. Piacentino said...

Thought you might be interested in this open letter from John Edelman, M.D. of Merck Research Labs:

August 18, 2008

An Open Letter to the Editors of The Annals of Internal Medicine

In this open letter to the editors of The Annals of Internal Medicine, Merck would like to put in perspective the latest article by four authors who served as paid consultants to plaintiffs' lawyers in the VIOXX litigation against Merck. We are troubled by the biased article, which contains numerous inaccuracies, and wonder about the motivation behind this attack on Merck's scientific excellence and integrity.

It is unfortunate that the authors and journal editors chose not to contact Merck before finalizing these publications. Had any of these individuals contacted Merck, factual errors could have been avoided.

The ADVANTAGE clinical trial was designed, conducted, analyzed, interpreted and published by the scientific department of Merck's U.S. Human Health (USHH) organization, Clinical Development (CDP), in conjunction with participating investigators. CDP was part of the Medical and Scientific Affairs department of USHH and was separate from the marketing department within USHH.

In the article, the authors erroneously claim that the objectives of the ADVANTAGE study were not scientific, and base this spurious conclusion on their review of a limited selection of documents produced in the VIOXX litigation. The authors appear to purposely fail to distinguish between the various departments of Merck's USHH organization, including its scientific research and marketing departments.

There's no doubt that the ADVANTAGE clinical trial had a legitimate scientific purpose. That purpose was to assess the gastrointestinal tolerability of VIOXX compared to naproxen – a commonly used arthritis medicine with known tolerability problems – in the treatment of patients with osteoarthritis in a primary care setting, and for the first time allowed patients taking concomitant aspirin to participate.

ADVANTAGE was a double-blind, randomized, controlled clinical trial with a legitimate scientific purpose designed to answer previously unanswered questions about the use of VIOXX in osteoarthritis in a primary care setting. It was not a seeding study.

The study assessed GI tolerability by seeing whether VIOXX or naproxen, at the highest approved doses for long-term treatment of osteoarthritis, caused fewer adverse events like abdominal pain, epigastric discomfort, diarrhea, heartburn, nausea, and dyspepsia.

ADVANTAGE was important because although the earlier VIOXX clinical trial program provided extensive data on efficacy and safety, it did not include naproxen as a comparison medication, and did not conduct research in the primary care setting, where patients with osteoarthritis would likely be seen by physicians who would consider VIOXX as a treatment option.

In addition, ADVANTAGE was the first study of VIOXX conducted by Merck that allowed the concomitant use of aspirin by patients participating in the trial. Indeed, the very journal that published the article that is the subject of this letter previously published the results of the ADVANTAGE study back in 2003, and at the time acknowledged that physicians would be interested in the type of results ADVANTAGE produced.

In the end, ADVANTAGE showed a different gastrointestinal profile between VIOXX and naproxen that was unaffected by concomitant use of aspirin. This was an important medical result for physicians. In addition to measuring the GI tolerability of VIOXX, investigators also monitored patients for adverse events, which were required to be submitted to the FDA. Therefore, in ADVANTAGE, Merck was further evaluating any potential risks of VIOXX.

It is important to emphasize that ADVANTAGE met all the Merck requirements for clinical research. All studies sponsored by Merck must have a protocol that describes the scientific, administrative, and regulatory aspects of the study in a manner that is consistent with currently accepted scientific methodology, FDA’s Good Clinical Practice guidance and worldwide regulatory requirements.

We also want to underscore that the scientific purpose of ADVANTAGE was properly disclosed to physicians-investigators, participants, and institutional review boards, and Merck's business interests were clearly understood. As is always the case, a scientifically sound and properly conducted study that further demonstrates the benefits of a drug would have a favorable impact on patients with debilitating arthritis, doctors searching for ways to treat their pain, and the pharmaceutical company that produced the drug. Such studies also further our understanding of the drug’s potential risk.

Merck firmly believes there is great value in understanding questions physicians want answered and in conducting rigorous, scientific clinical studies to address those questions. We believe we acted appropriately with respect to the ADVANTAGE trial, and stand behind our strong beliefs in the principles of scientific integrity. In publishing the paper and accompanying editorial in question, without further investigating readily available information, we believe that the Annals failed to act in the best interests of their readers or the scientific community.

Sincerely,
Jonathan M. Edelman, M.D.
Executive Director, Global Center for Scientific Affairs
Merck Research Laboratories

CL Psych said...

Thanks for the letter. At least in part, it's the Zyprexa defense -- if you could only have seen all of our documents, you'd clearly see how wonderful of a company we are...

OK, then why don't you show us the documents that would provide context.

As for Merck's "principles of scientific integrity," do a little reading about how they handled concerns about the risks of Vioxx and laugh (or cry) until you fall over.

Anonymous said...

Are you really that naive? These are commercial companies, selling a product. They aren't non-profits. They have shareholders, boards, and investors who expect a return - a profit - on the product. What's wrong with marketing your product? Do you think Budweiser tells us to "drink responsibily" because they don't want us to buy their product? Does Ford tell us to "fasten your seatbelts" becaue they don't want us to buy their cars?

I'm so tired of this constant carping about the "big, bad drug companies" when they use common marketing techniques used in all businesses.

Seeding trials have been around for as long as there have been pharma companies. Everyone in this trial received medication under a doctor's supervision. And they didn't pay for the meds or the care. So who got a bad deal?

UCSF LTDL said...

The nine Merck documents cited in the Hill paper, and others, can be viewed at the University of California, San Francisco's Drug Industry Document Archive (http://dida.library.ucsf.edu) by entering "cs:humeston" without the quotations in the query box.

Kim Klausner
Digital Libary Manager