Clinical study of epilepsy drug may have served primarily to promote drug and increase prescribing, review suggests

According to background information in the article, a seeding trial is a clinical trial conducted primarily for marketing purposes and intended to promote the drug and increase prescribing by exposing physician-investigators to it. "Although seeding trials are not illegal, they are unethical," write the authors, because of the promotional nature of the trials and because participants and physicians may not be told the true purpose of the studies.

Samuel D. Krumholz, B.A., from Never Again Consulting LLC, Attleboro, Mass., and colleagues sought to determine whether the Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) study was a seeding trial. They assessed documents relating to the marketing, sales practices, and product liability litigation of the drug Neurontin (gabapentin), a treatment for epilepsy. The authors were consultants to the plaintiffs in a lawsuit involving the drug, and had access to depositions and the document database, which included correspondence, clinical research reports and market research analyses.

According to the researchers, the trial's ostensible purpose was to study dose-titration of gabapentin among 2,759 patients who were enrolled by 772 investigators. Although two articles based on the results of the study appeared in journals, the authors note that the uncontrolled, unblinded study design was questioned by two outside sources and that "data quality during the study was often compromised." Further, the authors cite documents that appear to suggest that marketing personnel were involved in data collection, and that marketers viewed the trial (and not just the trial results) as a vehicle for promoting gabapentin.

This involvement of the marketing team and the failure to disclose the study's real purpose from participants and collaborators mark the STEPS study as a seeding trial, according to the authors. They urge institutional review boards (IRBs) to take a stronger stance in discouraging these types of trials. "Reform of the current IRB system," they write, "as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry."

Editor's Note: This project was not directly supported by any external grants or funds. Coauthors Samuel D. Krumholz, B.A., and David S. Egilman, M.D., M.P.H., are currently paid consultants at the request of plaintiffs in litigation against Pfizer Inc related to gabapentin in the United States, and coauthor Joseph S. Ross, M.D., M.H.S., is currently an unpaid consultant in the same litigation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Commentary: Understanding the Implications of Seeding Trials

"The biomedical enterprise depends on good science for its foundation, and good science requires transparency of methods and integrity of purpose," begins a commentary accompanying the article. G. Caleb Alexander, M.D., M.S., from the University of Chicago, notes that tactics such as seeding trials negatively affect scientific knowledge and clinical care. While the roles of Krumholz and colleagues as consultants to a lawsuit involving gabapentin may influence "their frame of reference and preconceptions," he asserts that the supporting evidence they gathered "strongly supports the conclusion that STEPS meets key criteria of seeding trials."

One of the consequences of seeding trials, Alexander states, is that they may detract from the legitimate value of well-designed and well-conducted phase 4 studies of pharmaceuticals. He urges stakeholders to become more vigilant and to more effectively preserve ethics in research. Citing steps that have been taken in the past decade to reduce bias and undue commercial influence in drug research, including mandatory reporting of trial results at ClinicalTrials.gov, Alexander concludes, "Although the road is long and the hill steep, these and other changes offer the promise of incrementally improving and safeguarding the integrity of the biomedical enterprise. One can only hope that the report by Krumholz et al will contribute to this evolution."

Editor's Note: The author is supported by the Agency for Healthcare Research and Quality. The funding source had no role in the preparation, review, or approval of the manuscript for publication. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.