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Increasing Government Oversight Of IRBs Could Help Prevent Seeding Trials

I thought I read the final chapter in the tale of Pfizer’s shady marketing practices for Neurontin years ago. Sadly, there’s at least one more chapter to go.

Recall that in 2008, leaked documents from a US District Court revealed that Pfizer had covered-up the results of a clinical trial which showed the drug didn’t work for chronic nerve pain, even as it promoted off-label use of the anti-seizure drug for that purpose. The next year, it was revealed that Parke-Davis (now a subsidiary of Pfizer) took advantage of lax disclosure policies by certain medical journals to publish 13 articles promoting off-label use of Neurontin that were ghostwritten and funded by the company without disclosing such arrangements.

isthatamisprint 300x200 Neurontin: Seeds of DiscontentNow, it has come to light that Parke Davis’ marketing department sponsored a Seeding Trial of Neurontin back in the day—that is, a trial portrayed deceptively as a patient study but whose real aim was to encourage prescribers to use the drug.

The trial was STEPS, the ‘Study of Neurontin: Titrate to Effect, Profile of Safety’ trial. More than 772 physician ‘investigators’ and 2800 patients participated in STEPS.

The stated objective of STEPS was to study the safety, efficacy and tolerability of Neurontin. However, after reviewing documents compiled for a pair of lawsuits against Pfizer and its subsidiaries, Joseph Ross and colleagues concluded that the actual objective was to increase prescribing rates by ‘investigators’ in the study. Neither the ‘investigators’ nor their patients were informed about the real purpose of STEPS.

The trial worked, from Parke-Davis’ point of view. Physician ‘investigators’ prescribed 38% more Neurontin as a result of their participation in the trial.

The drug company also leveraged the patient recruitment process to market Neurontin to ‘investigators,’ Ross’ group found. Company representatives asked ‘investigators’ to set-aside certain days on their schedule in which epilepsy patients comprised the bulk of the appointments, thereby permitting the reps to be present and promote Neurontin at the moment of truth. The reps even helped collect patient data for the trial.

The smoking gun though, was uncovered in the company’s marketing plans, which cited the trial itself, not its anticipated results, as central to the promotion of Neurontin. For example, a 1995 report listed STEPS as a deliverable under the strategy “Solidify Neurontin’s position with neurologists and select primary care physicians as the safe and easy add-on for refractory patients.” Another document stated that “the rapid growth of Neurontin depends on the ability to influence the large population of community neurologists that see the majority of nonrefractory seizure patients. The STEPS trial…was a strong start to this…”

To be clear, Parke-Davis’ marketing department, not its clinical research department designed and conducted STEPS.

What’s Wrong with Seeding Trials?
Seeding trials are not illegal, but they are profoundly unethical. They don’t permit patients to make informed decisions about participating, since the real (marketing) objectives are not disclosed. Ross’ group reports that 11 patients died and 73 more experienced serious adverse events during STEPS, so they were exposed to considerable risk. Physician ‘investigators’ were also not informed that they, in fact, were the real study subjects in STEPS. Indeed, the very success of STEPS relied on deception; few physicians or patients would participate in studies with primary marketing objectives and little scientific value.

Remarkably, no one knows how many seeding trials have been carried out over the years, since their results are often not published (after all, the goal is to impact prescribing, not to contribute to medical knowledge). Other than Ross’ account of STEPS, the only other seeding trial to have been exposed in detail was Merck’s ADVANTAGE trial, which was designed to increase prescribing for Vioxx, a drug that was later pulled from the market after being linked to cardiovascular disease. As was the case in STEPS, a review of documents obtained during litigation was required to expose the problem.

What Can Be Done?
The FDA is largely powerless to prevent seeding trials. It only oversees trials designed to support new drug applications or to support label or advertising change requests. That leaves things up to the institutional review boards at individual institutions, which is not comforting since only one IRB (at Johns Hopkins) spotted problems with STEPS and failed to approve it.

It may finally be time to ramp-up government oversight of IRBs, therefore. Why not require all IRBs to register and become accredited, for example? Why not penalize institutions whose IRBs approve trials that are unethical, as was the case in STEPS? Why not proscribe commercial (as opposed to institutional) IRBs altogether, since they have intolerable conflicts of interest? Why not require that all research protocols be posted in a publicly available repository? At a minimum, this would make it easier to identify seeding trials—at least retrospectively. We wouldn’t have to wait for a lawsuit.

Even if all these recommendations were implemented however, clinical investigators and physicians themselves must ultimately step-up and accept their roles as ‘the last line of defense’ (as I mentioned here). It comes down to asking yourself this question: does the post-marketing study in which you have been invited to participate seem to have marketing objectives or actual science in mind?

*This blog post was originally published at Pizaazz*


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