In March 1999, just three months before the FDA gave its blessing to the ill-fated arthritis drug Vioxx, Merck & Co. had everything in place for an award-winning marketing campaign.
It was a clinical trial. At least it looked like one.
In fact, according to four physicians in the Aug. 19 issue of the Annals of Internal Medicine, Merck's clinical trial had a purpose very different from the goal of rigorously assessing the effectiveness and safety of Vioxx — the blockbuster painkiller drug that Merck withdrew from the market in September 2004 after it was linked to a possible doubling of a patient's risk of heart attack and stroke.
The clinical trial known as ADVANTAGE was a "seeding trial," write the four authors — all of whom have served as expert witnesses in court cases brought against Merck in connection with Vioxx. It was designed, they write, to speed and increase the rate at which doctors accepted and prescribed the new drug, to gather inspiring "patient stories" for future use by reporters and marketers, and to court the goodwill of front-line physicians with the promise of professional prestige, research funds and the chance to be among the first to try a vaunted new remedy for an age-old scourge.
Gadflies and watchdogs have long charged that drug makers routinely drum up "seeding trials" in order to spread financial largesse to favored doctors and boost what's known in drug marketing as the "uptake" of a new product by patients and their physicians. But the Annals study is the first to describe such a marketing ploy in detail — based entirely on internal Merck documents, which have become public record as part of the court cases surrounding damage claims over Vioxx. Th documents starkly detail the effort as an undertaking that was conceived, planned and executed as a marketing effort.
"ADVANTAGE is an example of marketing framed as science," wrote Dr. Kevin P. Hill of McLean Hospital in Belmont, Mass., and his three co-authors. Ironically, the final coup of the ADVANTAGE trial was an article published in the Annals of Internal Medicine in October 2003 — the same journal that published this week's dissection of the practice of seeding trials.
Merck's ADVANTAGE trial had all the trappings of the real thing, Hill and his co-authors note. It was referred to by the kind of long acronym that gives many large-scale drug assays the appearance of scientific legitimacy (ADVANTAGE stood for Assessment of Differences Between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness). It had 5,557 subjects enrolled, and 600 primary-care physicians gathering and submitting data for analysis. In the end, it had a reputable physician — Dr. Jeffrey R. Lisse of the University of Arizon's Department of Rheumatology — to author the study and a berth in the esteemed Annals of Internal Medicine.
In fact, however, the article documents that Merck's marketing and sales force nominated the 600 primary-care physicians they thought could be most influenced — and influential — in their prescribing of Vioxx. After Vioxx was approved by the FDA, the Annals study found, Merck's marketers then monitored those doctors' prescribing practices to ascertain whether they were more likely to prescibe Vioxx than doctors who had not been chosen as trial investigators (begging the question — who WERE the subjects in this trial?). The marketing department handled all the collection, analysis and dissemination of the ADVANTAGE data, and wrote up the study on which Lisse became the principal author, the Annals article says. And after it was all over, the Annals authors presented internal memos showing that the marketing department nominated itself for an award for its work on the ADVANTAGE trial.
The authors write that all of this happened over the objection of the head of the research division at Merck's Research Labs — the department that would normally oversee all company-sponsored clinical trials. In an internal communication cited by the authors of the recent Annals article, Merck's Dr. Edward Scolnick said that such studies are "wasteful," "intellectually redundant" and "extremely dangerous" in that their findings often invite FDA scrutiny and open a "Pandora's Box" for legitimate company researchers.
Dr. Hill and his co-authors go much further in their criticism: seeding trials, they contend, are dishonest, a corruption of science and unethical in that they do not reveal to study subjects, investigators or the editors or readers of the journals in which they are sometimes published their true objectives: to sell drugs.
Dr. Jonathan Edelman, head of scientific affairs at Merck Research Laboratories, told the Associated Press on Monday that "the ADVANTAGE study was primarily a scientific study" designed and executed by the company's clinical research unit and that any later use of data for marketing was a separate operation.
That would be a problem with any drug, of course, since the search for new medicines depends on scientific honesty and protection of research subjects from avoidable harm. The ADVANTAGE trial was perhaps more problematic than most, since it was arguably instrumental in helping make Vioxx one of the most prescribed drugs of all time (an estimated 20 million took it, and its 2003 sales reached $2.5 billion).
Dr. Adriane Fugh-Berman, a physician at Georgetown University and director of the watchdog organization Pharmed Out (http://pharmedout.org), says the Annals article is an excellent description of a practice long suspected but little appreciated among doctors. "I hope it helps wake physicians up to one out of a broad range of tactics used to market drugs. Many believe that industry-funded research is always fine, but a lot of such research is managed by the marketing department."
Fugh-Berman says that the pharmaceutical industry now says that seeding trials are a thing of the past. "That probably means that they have eliminated the term, not the practice," she adds.
Without access to drug companies' internal documents and communications, seeding trials are easily disguised as the real thing, and "likely to be difficult" to identify, Hill and his co-authors add. "Laws and regulations may be necessary to promote the disclosure of the true intent of research conducted with human participants," the four authors write.
— Melissa Healy
AP Photo/Daniel Hulshizer