The STEPS trial was a seeding trial, used to promote gabapentin and increase prescribing among investigators, despite its stated scientific objective to examine efficacy, safety, and tolerability of the drug. Although STEPS was conducted fifteen years ago, the ethical issues illustrated by the trial’s conduct, and the data gained from Parke-Davis’ marketing analyses, have tremendous relevance in today’s debates over the limits and consequences of pharmaceutical industry sponsorship of Phase IV post-marketing clinical trials. Our analysis is only the second comprehensive account of a seeding trial based on primary source documents and clearly demonstrates how a clinical trial was designed, conducted, and explicitly used to promote marketing objectives, not science, without providing full informed consent to the patients and physicians who participated in the study.
Seeding trials have been used in the pharmaceutical industry for at least twenty years.1
However, since they are designed to impact sales, they may never be published and remain difficult to identify even when published. The only previous documentary account of a seeding trial, published in 2007,2
identified three main characteristics of seeding trials: marketing involvement in study conception and design, marketing involvement in data collection and analysis, and non-disclosure of the study’s true purpose from institutional review boards, patients, and investigators. Similarly, Kessler et al. described seeding trials, without the use of source documents, as lacking scientifically rigorous design or purpose and using the trial itself, not its findings, for wider marketing campaigns.1
STEPS differed from these previous examples as it was designed and conducted by a contract research organization, not a company’s marketing department. However, STEPS was clearly intended to promote gabapentin. The study, independent of any results, was repeatedly described as a means to market gabapentin and increase prescribed dosages. Our findings both corroborate previous descriptions of seeding trials, while also providing new insights into their execution.
There has been little academic research on the effect of seeding trials on prescribing. Danish researchers examined the effect on prescribing of participation in a clinical trial as a site-investigator,35
finding participation was associated with increased prescribing of the trial sponsor’s drug. In both ADVANTAGE and STEPS, the sponsor companies internally measured prescribing among investigators and found positive effects.2
While these internal analyses are suggestive, caution is warranted as the data and reports were not peer-reviewed and there were strong incentives to demonstrate that these seeding trials, as investments, were successful, potentially biasing the data. Additionally, much of the STEPS prescription data was uncontrolled and limited to summary descriptions, not raw data. Rigorously conducted research examining the impact on prescribing of participating as a trial investigator, or attending clinical trial marketing events, is necessary.
There were several ethical breaches within the STEPS trial. Principally, STEPS and all seeding trials prevent patients from making informed consent decisions about participation because the true marketing objectives are not disclosed. Informed consent is an established cornerstone of research on human subjects, both internationally36
and in U.S. law.37
During STEPS, among 2759 patients, there were 11 deaths, 73 patients experienced serious adverse events, and 997 experienced less serious adverse effects,11
suggesting that patients were at more than minimal risk. Second, investigators were also not fully informed, which is clearly unethical because these physicians were the intended study subjects. Third, the promotional rewards used within STEPS were also unethical. Conventional wisdom suggests that providing a small gift after data collection is acceptable, but unacceptable when given before,38
particularly if potentially coercive or presents undue influence.39
Seeding trials are not illegal and generally do not fall under the authority of the FDA, which has oversight only over clinical trials conducted as part of new drug applications or intended to support other label or advertising changes.40
However, the U.S. clinical trial regulatory system, principally under the authority of the U.S. Office for Human Research Protections, includes registration of clinical trials and protection of human research subjects that is dependent upon individual IRBs. As such, IRBs likely have the strongest potential to prevent seeding trials, outside of appeals to professionalism and ethical practice. However, recent research on IRBs suggest problems with conflict-of-interest and lax regulation, among both commercial and academic IRBs.41
These findings were substantiated by the U.S. Government Accountability Office, which demonstrated the inability of some commercial IRBs to protect against obvious violations of subject’s rights and suggested that IRBs were not effective at denying approval of scientifically unsound studies.42
Several steps may strengthen IRBs’ ability to prevent seeding trials. First, IRBs require stricter government oversight. All IRBs should be registered, accredited, and evaluated, with penalties for the approval of trials that do not meet ethical standards. Second, commercial IRBs should not be accredited. There is an inherent conflict of interest when an organization responsible for protecting human subjects subsists on payments from trial sponsors, potentially leading to companies shopping protocols to find the most receptive IRB. Third, IRBs should utilize a publicly-available repository to circulate previous reviews and rejections. Although the FDA requires prior IRB reviews be submitted as part of subsequent applications,43
this is not always practiced. For the STEPS trial, the concerns raised by the Johns Hopkins IRB might have alerted others. Finally, posting of original protocols within a publicly-available repository may also help to identify seeding trials, post-hoc, so that investigators, sponsors, and the IRBs which approved them can be identified. Even published seeding trials are challenging to recognize. But if a study is never published, or published misleadingly, there is no way for patients, physicians, or regulators to know the true nature of the trial. While mandatory trial registration within ClinicalTrials.gov is an important first step to address selective publication of all types of clinical trials, at this time registration does not include posting of study protocols, which could identify marketing-focused studies.
Our analysis has several limitations. First, because our analysis is limited to only one pharmaceutical company and describes events that took place 10–15 years ago, our findings may not be generalizable to today’s marketplace. However, our findings are consistent with the practices identified during another seeding trial.2
Second, we did not communicate with any company representatives or scientific investigators involved with STEPS. We based our analysis entirely upon document review, although we did also have access to deposition testimony. Third, any qualitative assessment of documents (or historical work in general) is susceptible to misinterpretation and unconscious bias. This analysis amounts to the authors’ best effort to faithfully and accurately reconstruct the planning, implementation and execution of the STEPS trial. Finally, given the large size of the document database, we may have missed relevant documents in the course of our search, although we used comprehensive search strategies to minimize this possibility.
In conclusion, the STEPS trial was a seeding trial masquerading as a scientific study. Parke-Davis performed an in-depth marketing analysis to track the effect of attendance at the STEPS introductory briefing and participation as a study investigator on the rate and dosage of gabapentin prescribing. No study publications mentioned the internal data quality problems, tampering (representatives filling out study forms) or the study’s marketing goals. Our analysis provides critical evidence suggesting that seeding trials are used as a promotional strategy by pharmaceutical companies. Reform of the current IRB system, as well as promoting better clinical trial practice in the human subjects research community, are necessary to prevent continued conduct of seeding trials by the pharmaceutical industry.