Work has been brilliantly busy of late, more so than usual, which has kept me off-grid far more than I’d like. One of the main culprits has been the Evidence-Based Medicine rotation I run several times a year for my residents, which is both a highlight of my job and inconveniently-timed with the start of Dragon*Con. 🙂
A conveniently-timed article, however, hit this last week with the start of the course, and is worth mention. In the August 19 issue of the Annals of Internal Medicine, The ADVANTAGE Seeding Trial: A Review of Internal Documents was published. The authors were consultants to the attorneys representing plaintiffs in two lawsuits brought against Merck pertaining to its product Vioxx. What they found from access to Merck’s internal correspondence during the trial sheds some documented light on drug company practice when it comes to scientific studies, and serves as a reminder to examine such studies with a thorough and skeptical eye.
By way of background, Vioxx was a medication that was marketed in the US from 1999 to 2004, and primarily used for the treatment of osteoarthritis and acute pain syndromes. It was of a class of medications called COX-2 inhibitors, similar to common NSAID (Non-Steroidal Anti-Inflammatory Drug) pain relievers such as ibuprofen and naprosyn, but designed to have less stomach irritation as a side effect. Vioxx was pulled from the market by Merck in 2004 due to evidence of increased risk of cardiac events and stroke in patients taking it on a long-term basis. Much controversy focusing on the integrity of study publication in major journals, the FDA approval of medications, and pharmaceutical company marketing practices resulted.
The Annals trial from last week examines an aspect of the case that hasn’t yet been documented in detail – the concept of a seeding trial, and whether one of Merck’s studies of Vioxx was of this type. A seeding trial is a study that isn’t intended to actually result in meaningful scientific information, but instead is to increase the exposure of a new medication among physicians participating in the trial, with the hope that these physicians will then preferentially prescribe said medication and boost sales. While often suspected, this type of study is difficult to prove without access to a pharmaceutical company’s internal materials, as the trial itself is outwardly marketed as having scientific merit.
In this case, the ADVANTAGE (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal tolerability and Effectiveness) trial was created by Merck to ostensibly show that Vioxx had less stomach irritation than naprosyn. At the time of it’s publication in 2003, there were several aspects noted that made the true intent of the study dubious – it was conducted at the same time as the FDA was approving the medicine in 1999; it involved 600 investigators, many of whom had no experience in clinical trials; it had a relatively short duration of only 12 weeks; it was being published four years after it was completed, implying that the scientific results of the study were not important for immediate publication; and the same outcome was already being looked at in another Merck study, the VIGOR trial, which was much larger and more “definitive.” Said another way, it looked like the ADVANTAGE trial was not being done to seek FDA approval (which was already in process at that point) or to investigate a certain side effect (that was the role of the VIGOR trial), but instead was getting many potential prescibers “hands-on” experience and positive exposure to the medication at the time it was coming on to the market.
What did last week’s Annals publication show? Internal Merck correspondence demonstrated that the study was designed by the marketing department (not the research and development department) for a marketing purpose, with the intent to boost familiarity with Vioxx among potential prescribers, and as a result, sales. Essentially, this is confirmation that ADVANTAGE was a seeding trial, not designed to generate meaningful science, and that this true purpose of the study was not disclosed to investigators or institutional review boards involved (for obvious reasons). ’nuff said.
Merck, at you I point the EPIC Finger of Shame.
Drug companies are not all evil, and not all pharmaceutical-funded studies are deceptive. That said, the primary goal of the drug industry is to do profitible business as opposed to engage in pure science, but this does not absolve them in any way from their responsibility to do so with the utmost ethics, especially as their products have such a potential for health… and harm. Studies funded by pharmaceutical companies deserve extra scrutiny in terms of their data, conclusions, and context.