Physicians who enrolled their patients in the phase four "Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS)" trial thought they were participating in a clinical trial to assess the efficacy, safety, tolerability, and quality of life among gabapentin users.
Instead, they appear to have been unwitting participants in a "seeding trial," where the real objective was to market and promote use of gabapentin (Neurontin) and ultimately put more money in the pockets of its sponsor, Parke-Davis, according to a study published in the June 27 issue of Archives of Internal Medicine.
Indicators of an alternative purpose of the STEPS trial came to light as a result of litigation against Parke-Davis for illegally marketing gabapentin, which was approved by the US Food and Drug Administration (FDA) for the treatment of epilepsy, for a variety of off-label uses. Parke-Davis is owned by Pfizer.
Joseph S. Ross, MD, MHS, from Yale University School of Medicine, New Haven, Connecticut, and his colleagues were consultants to the plaintiffs and so had access to emails, memos, depositions, and other documents uncovered during the litigation. Perusing these materials, they came to the conclusion that the trial was really being used for marketing purposes.
"Once I began looking at the documents, it became very clear that this was a marketing ploy," Dr. Ross, the senior author of the study, told Medscape Medical News. "We found lots of memos, emails, and reports about how the trial was being used for marketing purposes, how they wanted to get as many investigators involved in the trial as possible so that they could promote gabapentin to as many doctors as possible."
Dr. Ross, whose expertise is in outcomes research and clinical trials conduct, said Parke-Davis identified the highest potential prescribers in various communities and then reached out to them to get them involved in STEPS. The company tracked prescribing patterns of gabapentin and found that physicians prescribed more gabapentin after they became STEPS investigators.
A typical clinical trial that is properly done will identify five or ten specific sites and then specify the number of patients who are to be enrolled so that there is a strict, standardized protocol used throughout. The trial will also be double-blind and randomized, Dr. Ross said.
"Instead, what they did in STEPS was identify as many investigators as possible to enroll approximately five patients. My inference is that they weren't interested in a standardized protocol, they were interested in reaching out to as many physicians as they could to tell them how great gabapentin is," he said.
In all, 2759 patients were enrolled by 772 investigators. The study results were published in separate analyses of efficacy and safety and tolerability in the journals Epilepsia and Seizure. "Both articles were generally supportive, describing gabapentin as effective, safe, and tolerable," the study authors note.
Dr. Ross said he and his colleagues were suspicious that STEPS was a seeding trial because the company already knew that the drug worked in epilepsy. "It's already been approved by the FDA, so why are they studying it again? And why are they studying it in a way that's sort of sloppy? They're studying it in a way where you have lots of physicians enrolling just a few patients, so you know that there's going to be a problem with data collection and standardization across the sites," he said.
Although two articles based on the results of the study were published, the study 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, they 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.
G. Caleb Alexander, MD, from the University of Chicago, Illinois, commented in an accompanying editorial that seeding trials threaten the integrity of phase four clinical trials.
"Clinicians and researchers and institutional policymakers have to more closely scrutinize phase four or postapproval studies of prescription drugs and medical devices and ask the question, 'Could this be a seeding trial?' he said in an interview with Medscape Medical News.
The study is important because so little is known about how these trials are conducted and even whether or not they take place, he said.
"These types of studies seldom see the light of day because, by their very nature, they involve deception — deception of the investigators who are participating but who are not aware that there may be a strong marketing motive for the trial and deception of the patients who are enrolled," Dr. Alexander said.
"Seeding trials may be grossly unethical, but they're not illegal, and I think this study serves an important purpose by raising awareness among the public and the scientific community that they do take place."
Tips to Avoid Unwitting Participation
To avoid becoming unwitting participants in seeding trials, clinicians should be on the lookout for the following characteristics, Dr. Alexander suggested.
"The first question to ask is, 'Does this study investigate a compelling scientific question?' If the answer is no, then a red flag should be raised. Another clue is if there are a very large number of investigators involved, with a small number of patients enrolled by a single investigator. Also, when the investigators themselves have limited or no clinical trial experience, that is a tipoff. A clinician might also ask what is the role of the marketing division in the conduct of the trial, and I think that the true intent of the trial would be more likely to be exposed," Dr. Alexander said.
Dr. Ross agrees. "If a company only wants you to enroll five to ten patients you should be wary that they're not actually interested in the drug, they're more interested in you, and it's worth being very critical of the trial design and what you are getting yourself into," he said.
Doing so is not illegal but is highly unethical, he added. "It clearly violates a number of ethical norms and clinical trial conduct rules because the patients are being exposed to some risk...but they are not doing so with the full understanding that the trial is a marketing trial."
Medscape Medical News asked Pfizer for its viewpoint and received this statement in reply: "Neurontin is an important FDA-approved medicine that physicians have prescribed to treat millions of patients safely and effectively. Neurontin has been widely studied for more than two decades, and there is an extensive body of publicly available literature on its safety and its use."
Dr. Ross disclosed that he was an unpaid consultant at the request of plaintiffs in the litigation against Pfizer Inc related to gabapentin and that he was a paid consultant in litigation against Merck related to Vioxx. Dr. Alexander reports that he is a consultant for IMS Health, a marketing research firm.
Arch Intern Med. 2011;171:1100-1107, 1107-1108. Abstract — Editorial
Fran Lowry • Medscape Medical News © 2011 WebMD, LLC