A Yale clinician ponders the ethics of a seeding trial masquerading as research

In the June 2011 issue of Archives of Internal Medicine, researchers described their discovery of a seeding trial for the epilepsy drug gabapentin, sold under the trade name Neurontin. The trial was conducted 15 years ago by Parke-Davis (bought by Pfizer in 2000). Under the guise of studying gabapentin’s dosing—which had already been clinically established—the company enlisted more than 2,000 patients and 700 investigators. The trial’s real goal was to increase prescriptions of the drug.

David A. Kessler, M.D., the commissioner of the Food and Drug Administration and later dean of the School of Medicine, sounded an alarm about the use of seeding trials in a 1994 article in The New England Journal of Medicine. The article described such trials as having little scientific value and as “thinly veiled attempts to entice doctors to prescribe a new drug being marketed ... .” Fourteen years later Harlan M. Krumholz, M.D., M.S., the Harold J. Hines Jr. Professor of Internal Medicine, reported in the Annals of Internal Medicine on a 1999 seeding trial by Merck to market its arthritis drug Vioxx.

Last summer Joseph S. Ross, M.D., M.H.S. ’06, assistant professor of medicine and co-author of the Vioxx report and senior author of the gabapentin report, met with Yale Medicine to discuss seeding, whistle-blowing, and the future of industry-sponsored trials.

How did you and your colleagues discover that a 15-year-old trial may have been a seeding trial?

Several years ago colleagues published in Annals of Internal Medicine an interesting review of a limited set of litigation documents that described Parke-Davis’ promotion of gabapentin. Marketing involvement in the Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) trial was briefly mentioned, but discussion was incomplete. The recent availability of the complete documents produced as part of the litigation provided a unique opportunity to examine the STEPS trial in more detail.

Can you describe the elements of STEPS that pointed to a seeding trial?

Seeding trials are challenging to identify, but the internal documents clearly demonstrated that STEPS was a seeding trial posing as a legitimate scientific study. For instance, the trial itself, not trial results, was part of a marketing strategy used to promote gabapentin and increase prescribing among investigators without informing trial patients or investigators. Investigators were selected for participation based on whether they were high prescribers in their area. After the trial, examination of rates and dosages of gabapentin prescribing showed that STEPS investigator participation in the trial was positively associated with greater gabapentin prescribing.

What are the risks of seeding trials?

Seeding trials pose several real dangers. First, they undermine the integrity of the clinical trial research process, exposing subjects to an experimental medication for marketing, rather than scientific purposes. Second, seeding trials unethically recruit patients to participate because they are not provided with full informed consent. Finally, seeding trials undermine the medical literature when they are published, because the trials are designed by marketing to show the product’s benefit, thus biasing the evidence available in the literature.

There is a whistleblower element to the article. Were you worried about offending fellow investigators and physicians?

My colleagues and I made the decision that it is more important to take a stand against these unethical trials in an effort to prevent them in the future. We expect that many companies have long conducted seeding trials as standard operating procedure. We are not interested in punishing acts from the past but hope that by exposing past practices, the public and professional outcry will prevent them in the future.

What’s your recommendation for staying ethical in pharma-sponsored Phase IV clinical trials?

Promoting the importance of ethical conduct is one step, so if evidence of other seeding trials is found in the future, the profession would frown ever more severely. Other steps that may prevent seeding trials include clinical trial registries. Similarly, steps to enhance the current institutional review board system could also be helpful. However, at the end of the day, physicians and the pharmaceutical industry need to make the decision not to participate in unethical clinical trial research and to keep the focus on science rather than on marketing.