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November 11, 2009

Off-Label Gabapentin Trial Outcome Reporting Examined, Inclusion of Protocols in Trial Registration Recommended

A study by researchers at the Johns Hopkins Bloomberg School of Public Health identified evidence of selective outcome reporting for clinical trials of off-label use of the seizure medication, gabapentin. The analysis compared study protocols for off-label use and the manufacturer’s internal research reporting with published reports of study findings. The results are published in the November 12 edition of the New England Journal of Medicine.

Gabapentin was originally approved as an adjunctive epilepsy treatment by the U.S. Food and Drug Administration. Off-label uses of gabapentin include use as a prophylaxis against migraines, treatment of bipolar disorders, neuropathic pain and nociceptive pain. In 2004, gabapentin manufacturer Pfizer settled litigation regarding marketing off-label use of the drug.

“We were concerned that the reporting practices observed in our analysis did not meet the ethical standards for clinical research or maintain the integrity of scientific knowledge,” said senior author Kay Dickersin, PhD, professor in the Bloomberg School’s Department of Epidemiology and director of the Center for Clinical Trials.

For the study, Dickersin, S. Swaroop Vedula, MD, MPH, lead author of the study, and colleagues, identified 20 clinical trials for gabapentin in which internal company documents were available from manufacturers Pfizer and Parke-Davis. Of those trials, 12 were published in research journals. For 8 of the 12 reported trials, the primary outcome defined in the published report differed from that described in the protocol.

Sources of disagreement included the introduction of a new primary outcome (in the case of 6 trials), failure to distinguish between primary and secondary outcomes (2 trials), relegation of primary outcomes to secondary outcomes (2 trials), and failure to report one or more protocol-defined primary outcomes (5 trials). The primary outcome was changed in of 5 of 8 published trials for which statistically significant differences favoring gabapentin were reported. Of the 21 primary outcomes described in the protocols of the published trials, 6 were not reported at all and 4 were reported as secondary outcomes. Of 28 primary outcomes described in the published reports, 12 were newly introduced.

“As our analysis shows, differences between primary and other outcomes specified in the protocol and those described in the published report are often subtle but may lead to different interpretations of an intervention’s effectiveness. We believe that existing registration systems need to go further than they currently do and should include registration of the full study protocol and amendments,” said Dickersin.

Additional authors of “Outcome Reporting in Industry-Sponsored Trials of Gabapentin for Off-Label Use” include Lisa Bero, PhD, of the University of California at San Francisco, and Roberta W. Scherer, PhD, of the Bloomberg School of Public Health.

Public Affairs media contact: Tim Parsons at 410-955-7619 or tmparson@jhsph.edu.