In the Wake of Avandia Report, a Call for Change

Cleveland, OHIn February the Senate released a 334-page report chastising drugmaker GlaxoSmithKline (GSK) for failing to warn patients of the risk of liver failure and heart attacks linked to type 2 diabetes drug Avandia. Now, a noted cardiologist has published unsettling findings about the drug in the current issue of the Journal of the American Medical Association (JAMA).

Dr. Steven Nissen, whose 2007 meta-analysis of 42 randomized rosiglitazone (Avandia) clinical trials triggered the current controversy over Avandia, calls for independent access to all clinical trial data. An accompanying editorial in JAMA by Drs. Catherine DeAngelis and Phil Fontanarosa supports that stance and calls on scientific publications to enact stringent reforms to ensure integrity and to minimize the capacity for corporations to conceal scientific data.

The editorial describes the alleged behavior of Avandia manufacturer GlaxoSmithKline as troubling.

Nissen, who hails from the Department of Cardiovascular Medicine at the Cleveland Clinic Foundation, routinely discloses all potential conflicts in his paper submissions. He notes that while he serves as a consultant for "many pharmaceutical companies," he accepts no income or tax deduction for his efforts and requires that the companies donate all honoraria or consulting fees to charity.

Nissen writes in the current issue of JAMA that the day after submitting his meta-analysis for publication in 2007, his manuscript was submitted for peer review—a normal process. However, in violation of journal rules, an academic reviewer also faxed a copy of Nissen's manuscript to GlaxoSmithKline.

According to internal memoranda identified in Nissen's recent article, the manufacturer read his manuscript (prior to publication) and subsequently decided to unblind the then-current RECORD trial, allegedly in an effort to mitigate the fallout.

"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," Dr. Nissen writes.

"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.'"

Nissen reveals that GSK officials met with him on May 10 ,2007—ten days after he submitted his paper for publication, seven days after it landed on the desk of GSK and 11 days before it was due to be published.

"… During the meeting, a GSK executive said, 'let's suppose RECORD was done tomorrow and the hazard ratio was 1.12.' This comment was made 4 days before the company claims it unblinded the trial and 14 days before the steering committee was asked to approve unblinding. The actual hazard ratio reported in the published interim analysis was 1.11. This exchange raises the question of whether unblinding of the study by the company had compromised the integrity of the data for the RECORD trial," Nissen writes.

When the RECORD trial was published two years later, "there remained additional concerning inconsistencies."

In the accompanying JAMA editorial, Drs. DeAngelis and Fontanarosa reference the February 20, 2010 report by the US Senate Committee on Finance. Based on a two-year investigation that reviewed more than 250,000 pages of documents from GlaxoSmithKline, the US Food and Drug Administration (FDA), various universities and others decided that "the totality of evidence suggests that GSK was aware of the possible cardiac risks associated with Avandia years before such evidence became public.

"Several years prior to Nissen's study, it can be argued that GSK was on notice that Avandia may have problems," note the authors in the editorial. "Based on this knowledge, GSK had a duty to sufficiently warn patients and the FDA of its concerns in a timely manner. Instead, GSK executives intimidated independent physicians, focused on strategies to minimize findings that Avandia may increase cardiovascular risk, and sought ways to downplay findings that the rival drug Actos (pioglitazone) might reduce cardiovascular risk."

The authors conclude, "Given the circumstances surrounding rosiglitazone and the RECORD trial, and perhaps other industry-sponsored trials, it is now time for all editors to require that academic researchers have full access to all trial data and that all industry-sponsored trials include independent statistical analysis and assurance. This approach would add powerful support to the fundamental principle that physicians must first do no harm."