By Bruce W. McNulty, MD
This article is part of our MedRIB project and was published September 17, 2008.
Vioxx is a medication in the NSAID group, similar to Motrin/Ibuprofen, but one that had the apparent advantage of not causing the gastric/stomach side effects that this group of medications caused. Given the many patients with chronic pain and arthritis that need these medications on a daily basis, this medication had the potential for a huge market in the U.S. and abroad. However the medication was withdrawn from the market by its manufacturer Merck Pharmaceuticals, after an increase in cardiovascular death was noted in clinical trials. The potential misrepresentation of this evidence has been widely discussed. There has been extensive reporting on matters pertaining to Vioxx, but a helpful overview of the events appears in Wikipedia at http://en.wikipedia.org/wiki/Vioxx. (For further information, readers may be interested in the book just being released in mid-September 2008 called, Poison Pills: The Untold Story of the Vioxx Drug Scandal, by Tom Nesi. Although we have not yet had a chance to read this book, it appears to be a thorough review of the Vioxx case.)
Rather than review the Vioxx case generally, however, I would like to discuss a paper published in August 2008 in the Annals of Internal Medicine entitled Ã¢â‚¬Å“The Advantage Seeding Trial: A Review of Internal Documents,Ã¢â‚¬Â by Ross et al. The link can be found at http://www.annals.org/cgi/content/full/149/4/251 while an accompanying editorial can be found at http://www.annals.org/cgi/content/full/149/4/279
Although long suspected, but difficult to prove, the concept of a Ã¢â‚¬Ëœseeding trialÃ¢â‚¬â„¢ is this: just prior to or at the time of a new drugÃ¢â‚¬â„¢s launch into the market, the pharmaceutical
companies who developed the drug conduct a Ã¢â‚¬ËœstudyÃ¢â‚¬â„¢ that enrolls selected doctors to prescribe a drug to patients under the guise of a research study, when, in fact, the purpose is to fulfill marketing objectives.
Clearly, if this is being done, it would be difficult to prove with certainty. The issues with the ADVANTAGE (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness), trial discussed in this paper were only discovered because the authors were expert witnesses for plaintiffs involved in the litigation against Merck with regards to Vioxx. This gave these physicians access to internal documents at Merck that made the true purpose of the ADVANTAGE trial apparent to them.
The article describes how, with review of internal company documents, in January 1999, before the launch of Vioxx (but after FDA approval), the marketing division conceived the ADVANTAGE trial. Six hundred investigators were enrolled and 2785 patients were randomly assigned to Vioxx vs. 2772 to generic naprosyn. A Merck marketing slide described the goal of the trial was for investigators to Ã¢â‚¬Å“gain experience with Vioxx prior to and during the critical launch phaseÃ¢â‚¬Â; clearly not to assess the GI side effects of the medication, which was the stated purpose of the trial.
The authorÃ¢â‚¬â„¢s review of the documents describe 3 key themes related to the design of the trial: it emerged from the marketing department with a marketing objective; the data was collected analyzed and disseminated by the marketing division; and the company did not reveal the true purpose of the trial to the physician or patient participants or their review boards.
The authors were able to find a memo nominating the trial for a marketing division award! They quote directly from the nominating memo:
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 the early uptake and advocacy for VIOXX, the large majority of prescriptions in the arthritis and analgesia market (~60%) come from primary care physicians. The ADVANTAGE trial utilized this important group of prescribers as investigatorsÃ¢â‚¬Â¦the design of the trial focused on demonstrating the value of VIOXX to this important audience.
The paper describes the first author on the trial, Dr Jeffrey Lisse, a physician not employed by Merck, telling the NY Times that he did not have a role in data collection or analysis, but that the company came to him after the study was complete and initial paper was written, saying Ã¢â‚¬Ëœ we want your help on this paperÃ¢â‚¬â„¢.
In their discussion Ross et al go on to describe how at least 3 elements of seed trials that are harmful:
Ã¢â‚¬Â¢ Full consent of patients in not possible without disclosing the purpose of the study
Ã¢â‚¬Â¢ Good research practice is at risk when marketing divisions design and conduct studies. To fulfill the marketing objectives, doctors are targeted based on certain demographics, not on scientific principles
Ã¢â‚¬Â¢ The study may have little scientific merit. In fact, seeding trials in which the medication has yet to receive FDA approval may cause patient harm for marketing purposes only
Given how difficult it may be to identify this practice, increasing awareness is an initial step. Ross et al. appropriately state that greater transparency into the clinical trial process Ã¢â‚¬â€ including clinical trial registration, and requirements for study protocols to be included with institutional review board submissions Ã¢â‚¬â€ may help better identify this practice. Clearly patients and doctors must be made aware of the true purpose of a study if they are to give informed consent.