Phase IV trials for postmarketing surveillance of drugs are common and are permitted by the regulators. But it is a different matter when trials are done primarily to promote prescriptions of the drug. They are called the ‘seeding trials.’
“The main point of the seeding trial is not to get high-quality scientific information: It is to change the prescribing habits of a large number of physicians,” notes an Editorial in the journal Annals of Internal Medicine.
The latest online issue of Science shows how Merck undertook one such trial and what its primary objective was.
The conclusions were arrived at by studying Merck’s internal documents, notes and emails that became available following the litigation.
The pharmaceutical company enrolled about 5,500 arthritis patients for the 1999 ADVANTAGE seeding trial to compare the safety of Vioxx with an existing drug. “But the internal company documents suggest that the trial had little to do with science and much to do with marketing,” notes the journal Science.
According to the paper published in the Annals of Internal Medicine, the marketing division had “designed and executed the ADVANTAGE trial.”
It states: “the trial was designed by Merck’s marketing division to fulfil a marketing objective; Merck’s marketing division handled both the scientific and the marketing data, including collection, analysis and dissemination.”
Though the reasons for companies conducting seeding trials are well known, Merck documents “provide the first strong documentary evidence.” An email sent by a Merck employee in the marketing division noted: “It may be a seeding study, but let’s not call it that in our internal documents.”
The seeding trial was done around the same time the company undertook the VIGOR trial — a definitive study of gastrointestinal toxicity. The FDA required Merck to undertake the VIGOR trial before the company could “claim of improved gastrointestinal safety on the Vioxx label.”
“The purpose of ADVANTAGE was neither to seek a new indication nor to perform postmarketing surveillance,” notes the paper. It was more to “lure physicians into the habit of prescribing Vioxx.”
The real purpose of the trial was not made clear to patients, doctors or regulators.
And the reason for choosing 600 primary care physicians was deliberate, as the company memo revealed.
“The clinical trial program for Vioxx focussed primarily on specialists. While they would be critical to the early uptake and advocacy for Vioxx, the large majority of the prescriptions in the arthritis and analgesia market (about 60 per cent) come from primary care physicians. The ADVANTAGE trial utilized this important group of prescribers as investigators.”
The paper in the Annals of Internal Medicine, which has a note by the Editor, states: “Seeding trials deceive trial participants and their protectors [doctors].”
But it is an irony that the ADVANTAGE trial results were published in the Annals of Internal Medicine in 2003. But the Editor of the journal now says that it “would not have published the results had it known of the trial’s apparent purpose.”
But can journals shirk their responsibility so easily? Is it not their duty to find out the real intention and refuse to publish the results? Is it not the peer reviewers’ job to detect and expose the real intent of the study?
Deception the key
“Deception is the key to a successful seeding trial,” notes the Editorial in the Annals of Internal Medicine. But it adds a rider, though.
“It’s up to the reviewers, doctors, and even the patients to ask questions that might reveal when promotion is masquerading as research.”
This news on Merck’s manipulation comes a few months after new evidence published in the Journal of the American Medical Association (JAMA) revealed how Merck was aware of the dangers of the drug much before it withdrew it from the market (The Hindu, April 24, 2008).