After the New York Times publication of Steve Nissen’s secret tape recording meetings with pharmaceutical executives the Journal of the American Medical Association (JAMA), gave him some space to “Set the Record Straight.” Despite his laundry list of pharmaceutical companies he consults for, his comments call for new procedures in medical journals regarding published clinical data. Ironically, the inside flap, and back cover of the same issue of JAMA has advertisements for diabetes drugs.
Nissen Commentary
Dr. Nissen noted that the Food and Drug Administration (FDA) will be holding another Advisory Panel scheduled to meet in July 2010 to consider whether or not to remove rosiglitazone from the market. At this panel, members will discuss the results of a recently published cardiovascular outcomes trial that randomized patients to receive rosiglitazone or alternative diabetes therapies, known as the RECORD trial.
Overall, his remarks assert that the trial is flawed, using evidence from his own experience and from the February 20, 2010, US Senate Finance Committee investigation. The 334-page report included internal company e-mails, which discuss the industry sponsored clinical trial of rosiglitazone and drug maker GlaxoSmithKline (GSK). Nissen uses this singular case to declare that it will “have profound consequences for academic oversight of commercially sponsored clinical trials.”
Consequently, Nissen goes on to discuss his 2007 meta-analysis of 42 randomized rosiglitazone clinical trials, and certain events that followed, including a secretly taped interview with GSK officials. All of his accounts point to his belief that GSK “responded to his study by deciding to publish the ongoing RECORD trial as a way to “preserve the company’s market share.” He called the RECORD trial “an extremely unusual procedure that would seriously undermine the statistical validity and credibility of the final trial results.”
Although he calls into question GSK’s practices, Nissen totally ignores the fact that his infamous meta-analysis of rosiglitazone was potentially flawed because the selection of studies, and the exclusion of trials with no CVD events in either group, was blatantly biased. It was only accepted and editorialized so that the FDA would put pressure on the company.
Regardless of this lapse, his criticism of the RECORD trial begins with GSK’s appointment of an academic steering committee to oversee the study, which did not know that the company had “already unblended the study two weeks earlier.” Then he cites the issue of how GSK handled the manuscript, citing his secretly taped interview as a reason to call into question the “integrity of the data for the RECORD trial.”
Due to his concerns, Nissen recommends two general approaches to academic governance and one for Medical Journals.
Steering committees should be composed of academic investigators who have full access to all of the study data and reports.
The steering committee is appointed by the company, but the clinical trial database is exclusively controlled by the committee and “access” provided to the investigators. Although Nissen believes that the depth of confirmatory analysis remains uncertain, the RECORD trial final study reported using external statistical confirmation, an approach he recommends.
Medical journals to require independent outside statistical confirmation of trial results to significantly improve the quality of reporting of industry-sponsored clinical trials.
JAMA Editorial
In response to Dr. Nissen’s comments, Catherine D. DeAngelis, MD, MPH and Phil B. Fontanaros, MD, MBA, wrote an editorial focusing on ways to “Ensure Integrity in Industry-Sponsored Research.” They use the phrase “primum non nocere” or physicians must do no harm, as an emotional appeal to readers that industry-sponsored research does harm. In fact, they call Nissen’s commentary on the RECORD trial, “a disturbing example of inappropriate conduct surrounding an industry-sponsored clinical trial of rosiglitazone.”
The authors even go as far as saying that this kind of industry-sponsored research, which involves misleading reporting and possible misrepresentation has “become too common,” although they fail to cite other examples for this supposedly “too common event”.
They also criticize the study for what appears to be “physicians functioning at several levels who failed to put the well-being of patients first.” Again providing no specific examples.
In response to these “flaws”, they ask “several important questions” regarding the story Nissen tells. The answers, of which they cite, are not “reassuring” because the Senate investigation found that GSK was aware of the possible cardiac risks associated with Avandia years before such evidence became public. To address these concerns, the authors suggest a few recommendations.
Recommendations
Citing JAMA’s own ten-year old policy, they call for all studies to report at least 1 author who must indicate that she or he “had full access to all of the original data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, regardless of funding source, with.”
For industry-sponsored studies, this statement must be provided by an academic investigator or government researcher (preferably the principal investigator) who is not employed by any commercial funding source. Again providing no evidence of misconduct by private CRO’s (the study in question had an academic steering committee), JAMA editors like their friends in academia.
Industry-sponsored studies must also collect and manage primarily or solely by the academic investigators independently of the study sponsor or other for-profit research organization, and with additional monitoring and oversight, such as under the auspices of an academic independent data and safety monitoring committee.
Industry-sponsored studies must also use an independent statistician at an academic institution to analyze data, and should preferably be a faculty member at a medical school or academic medical center or an employee of a government research institute, with adequate oversight. The independent statistician would also be responsible for clearly describing his or her involvement as well as other criteria. Like Nissen, the editorial also calls on journals to adopt the formal policies listed above.
The authors also want to create a committee to investigate cases regarding concerns about data integrity or completeness of reporting, or about data manipulation or misrepresentation. This kind of ‘red tape’ seems to only slow the clinical trial and research and development process, which may ultimately harm patients.
Conclusion
While these authors believe that “the experience with RECORD raises important questions about the conduct of industry-sponsored clinical trials,” we cannot let this case overshadow the importance of industry funded clinical trials. Specifically, commentary should not stereotype all corporate motives based on this case as a way to say that companies paying physicians to do industry-sponsored clinical trials are harming patients.
This is especially true because DeAngelis and Fontanaros recognize that their recommendations for an independent statistical analysis of industry-sponsored studies “entail additional effort, time, and cost.”
Such limitations need to be studied regarding their impact on preventing treatments from reaching patients in a timely manner and so far for JAMA submitted studies to my knowledge there has never been a discrepancy from the original data and the “independent analysis”.
In addition, not all harm is being done by industry-sponsored trials. The authors recognize that industry is taking on “efforts at reporting details regarding data management, statistical analysis, and sponsor involvement in clinical trials,” making important progress in achieving more transparent reporting of industry-sponsored studies.
Ultimately, with 31 million more people about to enter the health care system, do we really need a new “requirement that provides an additional layer of institutional oversight?” Regardless of its “intent to help reduce the ability of the sponsoring company to interfere,” most likely companies will just stop sponsoring clinical trials in America, taking their funding, jobs and breakthroughs elsewhere. This will leave more patients without treatments and access to trials for new drugs. If that becomes the case, this requirement may be doing more harm than good.