Yale School of Medicine researchers have revealed the intimate details of a clinical trial of the GABA analog Neurontin (gabapentin) that was long thought to be a "seeding trial" for the drug's makers, Warner-Lambert and Pfizer.

Neurontin was approved by the Food and Drug Administration (FDA) in 1994 for use as an adjunctive medication to control partial seizures. The drug's sponsor, Parke-Davis (now owned by Pfizer), then conducted a phase 4 uncontrolled, unblinded, postmarketing trial known as the Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) trial, with the stated objective of studying efficacy, safety, tolerability, and quality of life among gabapentin users while determining optimal dosage.

But the STEPS trial—rather than being a clinical investigation—was used primarily to promote gabapentin and increase prescribing among the trial's investigators, and marketing was extensively involved in its planning and implementation, maintained Joseph Ross, M.D. M.H.S., an assistant professor of general internal medicine at the Yale University School of Medicine, and his colleagues in the June 27 Archives of Internal Medicine.

After extensive examination of thousands of documents related to the STEPS trial, produced during 2004 litigation in which Pfizer and Warner-Lambert pleaded guilty to civil and criminal charges of illegal marketing of Neurontin for off-label purposes, Ross and colleagues detailed how Parke-Davis recruited 772 investigators and 2,759 patients for the STEPS trial, fewer than four patients per investigator. Participants gave informed consent to a study "designed to assess the safety and tolerability of doses of Neurontin (gabapentin) from 900 to 3,600 mg daily whose partial seizures are not completely controlled by other drugs," without mention of marketing objectives.

The authors described how Parke-Davis monitored investigators' prescribing of gabapentin during and after the completion of the STEPS trial through analyses completed by its Precision Marketing Department and by IMS Health's Promotrak division, without informing investigators or patients that these analyses would be conducted as part of the study.

The success of the STEPS trial in increasing prescriptions was reported in a June 12, 1996, Parke-Davis memo from its "Epilepsy Marketing Team" titled the "Neurontin Situation Analysis," which described how investigators were "increasing their [Neurontin] shares... and their use of 400 mg capsules."

Ross and colleagues noted that these analyses were conducted prior to the dissemination of any clinical trial results. The STEPS trial did result in two published articles, one in Epilepsia describing the efficacy analysis and one in Seizure describing the safety and tolerability analyses, both generally supportive of the drug.

"The STEPS trial was a key component of gabapentin marketing strategy," said the researchers in their report. "Multiple strategic plans cite the STEPS trial itself, as opposed to the anticipated trial findings, as a key marketing tool for the promotion of gabapentin.... Although STEPS was conducted 15 years ago, the ethical issues illustrated by the trial's conduct, and the data gained from Parke-Davis's marketing analyses, have tremendous relevance in today's debates over the limits and consequences of pharmaceutical industry sponsorship of phase 4 postmarketing clinical trials."

In an accompanying editorial, G. Caleb Alexander, M.D., an assistant professor of medicine at the University of Chicago and affiliate faculty of the MacLean Center for Clinical Medical Ethics, expressed his concerns about the revelations of Ross and colleagues.

"The biomedical enterprise depends on good science for its foundation, and good science requires transparency of methods and integrity of purpose," Alexander said. "The very success of the (seeding) trial depends on 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."

He stressed that "perhaps the greatest cause for concern is that these trials deceive investigators, clinicians, and patients, subverting the scientific process and violating ethical norms."

This project was not supported by external grants or funds. Ross is supported by the National Institute on Aging and the American Federation of Aging Research through the Paul B. Beeson Career Development Award Program.

An abstract of "Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) Trial: A Narrative Account of a Gabapentin Seeding Trial" is posted at <http://archinte.ama-assn.org/cgi/content/short/171/12/1100>.