ARTICLE IN BRIEF
An analysis of legal documents from a “seeding trial” of gabapentin, which had been sponsored by Parke-Davis more than 10 years ago, is relevant in current debates over the limits and consequences of drug industry sponsorship of post-marketing trials, experts told Neurology Today.
Results of a phase 4 post-marketing trial of the seizure drug gabapentin (Neurontin) published more than a decade ago were manipulated to reflect favorably on the drug, and then aggressively used by its manufacturers to promote and increase prescribing by physicians, a legal but questionably unethical practice known as “seeding,” according to a paper in the July Archives of Internal Medicine.
The analysis was performed by consultants to the plaintiffs in a 2002-2009 trial against Parke-Davis, which at the time was a division of Warner-Lambert Co., now a subsidiary of Pfizer Inc in New York City.
The findings are important even 10 years after the trial was conducted, experts told Neurology Today, because the “ethical breaches” of the sponsoring company and the data gained from its marketing analyses, have “tremendous relevance” in current debates over the limits and consequences of drug industry sponsorship of such post-marketing trials.
THE STEPS TRIAL
The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) trial resulted in two papers published in 1999. The trial's stated purpose was to evaluate dose-titration of the drug, as well its safety and tolerability at higher doses in 2,759 patients treated by some 770 participating physicians.
The lawsuits alleged that Parke-Davis failed to inform study investigators or clinical trial participants that the results would be used for marketing gabapentin. Because the authors of the Archives of Internal Medicine paper represented the plaintiffs in the case, they had unusual access to internal company documents, including marketing and sales memoranda, correspondence, individual depositions, and clinical research reports.
The internal documents “demonstrated that STEPS was a seeding trial posing as a legitimate scientific study,” according to lead author Samuel D. Krumholz, of Never Again Consulting LLC of Attleboro, MA, an independent consulting firm that specializes in promoting occupational and environmental health through scientific and historical research and analysis. “Documents consistently described the trial itself, not trial results, to be a tactic in the company's marketing plans.”
In the paper, the authors said the documents revealed that at least two external sources questioned the validity of the study before its execution, and that data quality during the study's course was often compromised.
Parke-Davis recruited site inves-tigators “with little or no clinical trial experience,” provided insufficient training, and failed to properly audit some study sites, the authors wrote. Perhaps most troubling, is that sales representatives were “directly involved” in the collecting and recording of subject data in some cases, the documents showed.
The paper was co-authored by David S. Egilman, MD, clinical associate professor in the department of family medicine at Brown University in Providence, RI, and Joseph S. Ross, MD, assistant professor of general internal medicine at Yale University School of Medicine and the Yale–New Haven Hospital Center for Outcomes Research and Evaluation in New Haven, CT, who were also consultants in the trial.
“STEPS and all seeding trials prevent patients from making informed consent decisions about participation because the true marketing objectives are not disclosed,” Dr. Ross wrote in an e-mail to Neurology Today. “Reform of the current institutional review board [IRB] system, as well as promoting better clinical trial practices in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry.”
WERE MDS IN THE DARK?
Martha J. Morrell, MD, clinical professor of neurology at Stanford University and chief medical officer for NeuroPace, Inc., in Stanford CA, was a senior author on the studies in question. She told Neurology Today that she had no idea that the research was to be used for marketing puposes.
“It appears that the authors never tried to contact any of the investigators, so I was surprised to see this paper. The authors should understand that STEPS was designed by the investigators and the contract research organization involved, and was developed to evaluate efficacy and tolerability of a new antiepileptic medication titrated to higher doses than used in the phase 3 trials. Also, the intent was to assess efficacy and tolerability in a large patient population more representative of the real world of patients likely to take gabapentin.”
Gababentin was the one of the first new treatments for epileptic seizures in many years, she noted, and it was important to determine whether patients who did not achieve full seizure control at the dosages used in the phase 3 trials might respond to higher doses. Dosages were to be gradually titrated up to 3600 mg/day, or until seizure control was achieved or the patients developed side effects, she said.
“What we did is representative of standard clinical care,” Dr. Morrell said. “In fact, trials in which doses are titrated upwards are common in Europe. Many European researchers consider our fixed dose trials to be less informative about how to actually use a medication.”
“One of the challenges with the study was that some of the investigators did not follow the upwards titration protocol; when patients achieved partial control at lower doses, the neurologists held the dose constant. For many neurologists at that time, partial control was good enough. Today we know we can achieve better results with higher doses, but at that time there was reluctance to use higher doses because the drug was new and not well understood by many physicians.”
Another issue, she said, is that large phase 4 studies often involve investigators who have little or no experience with clinical trials. Phase 3 trials are performed at experienced centers with trained clinical trials staff. However, the numbers of these centers are limited and the patient populations tend to be the most refractory. In order to gather information about a patient population more representative of the population of people with epilepsy, it is often necessary to move out of the academic centers and into community practices. Although this allows large numbers of less refractory patients to enroll, there are challenges to conducting a study in sites with no prior experience.
“Some of the investigators did not follow the protocol correctly. All patients were included in the safety analysis, but patients with protocol violations were excluded from the efficacy analysis. In retrospect there should have been more initial and ongoing training for these investigators,” Dr. Morrell said.
GREATER FDA ROLE?
“Industry seeding studies probably have not changed much, but how industry sponsors interact with academic institutions is very different today than it was ten years ago,” Nazem Atassi, MD, assistant in neurology at Massachusetts General Hospital and an instructor in neurology at Harvard Medical School, told Neurology Today in a telephone interview.
For example, he said the practice of providing enrollment-based rewards or incentives should not happen now.
“The responsibility for reviewing the ethics behind study protocols, both before and during trials, falls mainly on the local IRB at each institution; they, along with trial investigators, are the only safeguard to detect the marketing component of seeing trials,” he said. “It is clear from this instance that none of the local IRBs were notified when one IRB rejected the protocol, suggesting the need for a centralized protocol review process.”
Creating a central protocol review committee for multicenter clinical trials — as is currently done at the National Cancer Institute — and requiring the full study protocols to be posted at the agency's clinicaltrials.gov website for public review would enhance transparency and help to eliminate ethical concerns, he said.
One solution would be to divide the responsibilities between a national central IRB and the local institutional IRBs, so that they share joint responsibility, Dr. Atassi said.
“Leave monitoring and oversight of resources, enrollment, and research experience to local IRBs, and have an FDA or a NIH central IRB monitor and approve phase 3 and 4 protocol designs, with regular updated exchange of information between the agencies and the local IRBs. That's how NCI is doing it, and it's probably the way to go,” he said.
EDITORS' NOTE: LEARNING STEP BY STEP
Neurology Today Associate Editors Orly Avitzur, MD, MBA, FAAN, and Robert Holloway, MD, MPH, FAAN: The STEPS seeding trial, whose purpose was to encourage physicians to prescribe gabapentin at higher doses, is a painful exposition for us as neurologists. After all, we played a key role in facilitating this debacle. We participated in this “seeding” trial and profited from Parke-Davis' marketing practices. We were “thought leaders,” “consultants,” “trial participants/investigators,” speakers, and prescribers. And many of us were paid handsomely.
So what have we learned from this? Before we smugly lay the blame here, perhaps we should ask ourselves some tough questions. How many of us would behave differently today? In the face of lucrative industry contracts, would we be able to maintain the higher moral ground — holding firm to our social values and scientific standards? Certainly, the lure of big money can create some blind spots — if not lax ethical judgment. We can all unconsciously stumble into bad behavior when it is in our interest to do so — but that does not excuse it. Indeed, the behavior of both the investigators and the pharmaceutical company that funded them are not excusable.
Since most phase 4 post-marketing studies do not fall under the authority of the FDA, other mechanisms of oversight and vigilance are needed. At a minimum, we should recognize seeding trials for what they are — shoddy and unethical attempts to market products. We all — neurology investigators, institutional review boards, and editors alike — need to ask tough questions about the motives and methods behind post-marketing “studies.” Is there convincing evidence that the purpose is to better understand the long-term effects or to expand the labeling indications of an approved medication? Is the study overseen by a certified surveillance program to minimize bias and provide quality oversight?
Having a healthy dose of skepticism and refusing to accept questionable research practices can only serve to promulgate the highest ideals of our specialty. It will also make us more vigilant when we — and others — fall short of our own standards; standards that will ultimately cure and comfort patients with neurological disease.
LEGAL DOCUMENTS DETAIL OFF-LABEL MARKETING TACTICS
Among the practices detailed in the 152-page court document laying out the case against Pfizer and Parke-Davis by the federal government — available at http://bit.ly/qRB16b:
* Parke-Davis senior management described the STEPS trial as an ”aggressive campaign to convince doctors to push the dose of Neurontin up into the 2400 to 3600 mg range.”
* The STEPS protocol paid doctors for keeping their patients on gabapentin; they were paid an additional $50 for each patient who were taking the drug after one year.
* Parke-Davis paid thousands of dollars to physicians, many of whom were neurologists, who promoted the off-label use of gabapentin in presentations
SEEDING TRIALS: WHAT WOULD YOU HAVE DONE?
Can seeding trials be stopped? How can neurologists gain better awareness of seeding trials? What would you have done differently? We'd like to hear your input — to these questions and this story. Send your comments to email@example.com.
Krumholz SD, Egilman DS, Ross JS. Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) Trial: A narrative account of a gabapentin seeding trial. Arch Intern Med
Morrell MJ, McLean MJ, Willmore LJ, et al; STEPS Study Group. Efficacy of gabapentin as adjunctive therapy in a large, multicenter study. Seizure
McLean MJ, Morrell MJ, Willmore LJ, et al. Safety and tolerability of gabapentin as adjunctive therapy in a large, multicenter study. Epilepsia
©2011 American Academy of Neurology
Morrell MJ. Dosing to efficacy with Neurontin: The STEPS Trial. Epilepsia
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