Sowing the Seeds of Unethical Research: The Story of the STEPS Trial

According to a review of documents revealed in litigation, a large phase IV clinical trial of gabapentin was merely a ploy to sell more of the drug.

"Seeding trials" — industry-funded, phase IV clinical trials that typically use trifling hypotheses about already-approved drugs or devices — aim to sell more of a product, not to advance science. Those who agree to participate, as investigators or subjects, are often unaware of the marketing intent. Institutional review boards (IRBs) rarely identify the false intent or provide critical feedback. Quality control is often lax. So it was with STEPS (Study of Neurontin: Titrate to Effect, Profile of Safety), conducted in the 1990s.

These authors, who had consulted to plaintiffs in a suit involving gabapentin (Neurontin), have now analyzed documents on marketing, sales practices, and product liability litigation. STEPS recruited 772 physician-investigators and enrolled 2759 subjects. The informed consent document stated that STEPS was designed to study the efficacy and tolerability of gabapentin (titrated from 900 to 3600 mg/day) in patients whose partial seizures were not controlled by other drugs. The study was uncontrolled and unblinded.

Documents revealed that study sites were not audited before the trial began. Sales representatives assisted in collecting and recording data from trial subjects. Promotional rewards were offered to achieve enrollment goals. After physician-investigators attended an introductory briefing about the trial, their prescription rates and average prescribed doses increased substantially. An internal company report, produced before any trial results were disseminated, touted the increase in these prescribing habits. Overall, the narrative evidence demonstrated the intent of STEPS to promote gabapentin and to increase prescribing among investigators.

Comment: How can neurologists, patients, academics, independent reviewers, and editors alike be deceived by such "trials"? Among the many reasons for this blind spot, one has to consider whether the presence of Big Pharma's money creates a lax ethicality that affects judgments about social value, scientific standards, and fairness. Because the FDA has no authority over most phase IV postmarketing studies, other oversight mechanisms are needed.

An extreme solution would be a moratorium on all postmarketing studies without clear purposes, such as to elucidate long-term drug effects or expand labeling indications. Certified surveillance programs for studies with such purposes could minimize bias and ensure quality. Absent extreme solutions, neurologists, clinical researchers, and instititutional review boards must, at a minimum, increase their awareness of seeding trials and learn to probe the ethical intent of postmarketing studies. A posture of "unethical until proven otherwise" might allow us to better detect shoddy research practices, focus biomedical research on more socially valuable activities, and enable us to recognize when we fall short of our own standards.

— Robert Holloway, MD, MPH

Dr. Holloway is Professor of Neurology and Community and Preventive Medicine at the University of Rochester Medical Center.

Published in Journal Watch Neurology August 2, 2011
Citation(s):

Krumholz SD et al. Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) Trial: A narrative account of a gabapentin seeding trial. Arch Intern Med 2011 Jun 27; 171:1100.

Alexander GC. Seeding trials and the subordination of science. Arch Intern Med 2011 Jun 27; 171:1107.