More disturbing evidence about the pharmaceutical industry’s dirty marketing tricks emerged Monday in a report published in the Archives of Internal Medicine.
According to the report, a major 1995 study of the anti-seizure drug Neurontin (gabapentin) was not designed to determine the medication’s safety and effectiveness, as claimed by its manufacturer, Parke-Davis (now a subsidiary of Pfizer). Instead, it was a “seeding trial” — a study whose real purpose was to get more doctors to prescribe the drug.
Here’s how the sham study worked: Parke-Davis recruited 772 neurologists into a Phase IV clinical trial it called STEPS (“Study of Neurontin: Titrate to Effect, Profile of Safety”). The study’s purpose, Parke-Davis told the neurologists (and apparently non-skeptical institutional review boards or IRBs), was to determine the right dosing of the drug.
As the authors of the report in the Archives of Internal Medicine note, the trial was poorly designed — uncontrolled and unblinded, for starters. The study’s design problems did raise some criticism at the time from a few outside sources (including an IRB at Johns Hopkins University), but not enough to stop it from going forward.
Not that Parke-Davis was concerned with those design flaws. As its own internal documents make clear, the company was less interested in how Neurontin affected patients as in how it influenced the doctors, particularly, the doctors’ prescribing habits.
Every aspect of the trial was viewed by Parke-Davis as an opportunity to increase sales — even patient recruitment.
“Company representatives were encouraged to ask site investigators to institute ‘Shadow Days,’ during which patients with epilepsy would make up the bulk of the clinic day’s schedule, permitting representatives to be present and encourage patient enrollment while simultaneously promoting gabapentin,” write the authors of the Archives of Internal Medicine report. “The company also suggested offering promotional rewards to achieve enrollment goals. For example, company salesrepresentatives rewarded some investigators for achieving specific recruitment milestones; physicians were given a free lunch after recruiting 3 patients and a free dinner after 7 patients.”
And it worked: After the neurologists attended an introductory briefing about participating in STEPS, prescriptions of the drug increased by 38 percent. Individual dosages increased by an average of 10 percent.
Of course, patients were never told of Parke-Davis’ recruitment rewards for the doctors — which raises the question of whether the patients had received all the information necessary for informed consent.
Pfizer, by the way, paid $430 million in criminal fines and penalties in 2004 for marketing gabapentin for non-FDA-approved uses, such as for the treatment of migraines and pain.
Built on deception
Seeding trials are not illegal, only unethical. How many other seeding trials have been done — or are being done? That’s an unknown. They’re extremely hard to uncover, and only one other company has gotten caught: Merck conducted a seeding trial for the now notorious and withdrawn-from-the-market painkiller Vioxx.
“Deception is not just an incidental part of a seeding trial, but rather the very success of the trial depends on such deception, since few institutional review boards, investigators, clinicians, or patients would willfully participate in a study with marketing objectives and little or no scientific value,” wrote Dr. G. Caleb Alexander, a general internist and medical ethicist at the University of Chicago, in a commentary accompanying the Archives of Internal Medicine report.
Alexander and the authors of the report urge institutional review boards — who are, after all, supposed to be critically evaluating studies to make sure they are both safe and ethical — to be more diligent in identifying and rejecting seeding trials.
Footnote: Two of the authors of the Archives of Internal Medicine report, Drs. Samuel Krumholz and David Egilman, are paid consultants to lawyers who are involved in gabapentin-related litigation against Pfizer. The third author, Dr. Joseph Ross, is an unpaid consultant in that same litigation.