Setting the RECORD Straight.

THE FOOD AND DRUG ADMINISTRATION (FDA) REcently announced another Advisory Panel scheduled to meet in July 2010 to consider whether or not to remove rosiglitazone from the market. Central to the discussion will be the results of a recently published cardiovascular outcomes trial that randomized patients to receive rosiglitazone or alternative diabetes therapies, the RECORD trial. On February 20, 2010, the US Senate Finance Committee released a 334-page investigation of rosiglitazone and drug maker GlaxoSmithKline (GSK). The documents released by the Senate include internal company e-mails that provide an extraordinary window into the conduct of an industry-sponsored clinical trial. The implications of these e-mails and other documents released by the Senate have profound consequences for academic oversight of commercially sponsored clinical trials. On May 1, 2007, Wolski and I submitted for publication a meta-analysis of 42 randomized rosiglitazone clinical trials, showing a hazard ratio (HR) for myocardial infarction (MI) of 1.43 (95% confidence interval, 1.03-1.98, P=.03). On May 2, the journal sent the manuscript for review and on May 3, an academic reviewer faxed the draft manuscript (in violation of journal rules) to GSK with a cover page marked “confidential” and “urgent.” Rather than destroying the inappropriately obtained manuscript, GSK embarked on a comprehensive internal analysis of the study, circulating the manuscript among more than 40 scientists and executives at the highest levels of the company. footnote 30) Within a few days, company statisticians concluded that “there is no statistical reason for disregarding the findings as presented.” It is also apparent from internal e-mails that the company and FDA had already come to similar conclusions. The director of research at GSK commented, “FDA, Nissen, and GSK all come to comparable conclusions regarding increased risk for ischemic events, ranging from 30% to 43%!” Faced with the potential loss of revenue for a drug that had reached more than $3 billion in annual sales, company officials, in internal e-mails, proposed a strategy to preserve the company’s market share. GSK management decided to unblind and publish the ongoing RECORD trial, an extremely unusual procedure that would seriously undermine the statistical validity and credibility of the final trial results. In e-mails, the company officials extensively discussed unblinding the trial. One official wrote, “My personal view is that short pub of the planned safety interim is warranted (as is) followed in short order by what might be coined as an orderly close out of the main phase of the trial and that accompanying full publication (sic).” But the company faced a dilemma. Although the RECORD study was an industry-controlled clinical trial, the company had appointed an academic steering committee to oversee the study. It is always expected that such oversight includes authority over critical decisions about trial conduct and reporting of results. However, internal GSK e-mails proposed a strategy for handling the steering committee. On May 24, 2007, one official wrote, “if the SC believe that publishing interim data will fatally damage their ability to bring the study to a completion,” GSK will inform them “that a decision has been made, live with it.” Fortunately for GSK, the steering committee was convinced to publish an interim analysis, even though the analysis was so underpowered that no conclusions could be drawn about the safety of rosiglitazone. The steering committee never knew that GSK had actually already unblinded the study 2 weeks earlier. These physician-scientists apparently believed it was their decision (not the company’s) to unblind the study and publish the interim results. The company faced yet another dilemma: what to do about the pending meta-analysis manuscript. The company scheduled an appointment to visit me on May 10, 2007, in Cleveland, 11 days before our meta-analysis was published. The 4 GSK scientists and executives with whom I met had full knowledge of the content of our manuscript, although they never hinted that they had inappropriately obtained a copy of the confidential manuscript (as a result of the ethical breach by the peer reviewer who sent the manuscript to them). At the time, I was aware that the company had previously threatened