Washington, DC - The US Senate Committee on Finance has released a report describing what it terms the "intimidation" of Dr John Buse (University of North Carolina [UNC], Chapel Hill) by GlaxoSmithKline (GSK) over his concerns about the cardiovascular risks associated with the company's antidiabetes drug rosiglitazone (Avandia). The report is the product of months of review by the committee, which has been wading through documents since the spring of this year.
"According to documents provided to the committee by, among others, GSK and the University of North Carolina, it is apparent that the original allegations regarding Dr Buse and GSK's attempts at silencing him are true," the committee report concludes. "According to relevant emails, GSK executives labeled Dr Buse a 'renegade' and silenced his concerns about Avandia by complaining to his superiors and threatening a lawsuit."
Buse, commenting on the report to heart wire , says he bears the company no ill will.Intimidation questions raised at Avandia hearing
The committee first voiced concerns over whether Buse had been bullied into retracting public statements he'd made about the CV risks associated with rosiglitazone in the run-up to the rosiglitazone hearing held by the committee in June 2007. That hearing was prompted by the now-famous Nissen and Wolski meta-analysis examining the ischemic adverse events associated with rosiglitazone use. Two weeks earlier, the committee had sent a letter to GSK querying alleged intimidation; the company had responded with a press release calling allegations "absolutely false."
Buse, testifying at the committee's rosiglitazone hearing in June, described some of the events now detailed in the committee's report, including suggestions that his comments about Avandia in a letter to the FDA and during two presentations at professional society meetings, were responsible for a $4-billion plunge in the company's stock value. The company elsewhere allegedly characterized him as a "liar" and as being "for sale," he said.
But Moncef Slaoui, GSK's chair of research and development, also called to testify at the June 2007 hearing, said then that while the company expressed "regret" that Buse felt pressured in any way, their aim had been to correct "mistakes" in his presentation and that "there was a lot of passion at the time on both sides." Slaoui himself was not with GSK at the time (when the company was still SmithKline Beecham) but rather replaced Dr Tadataka Yamada, who, along with CEO Jean-Pierre Garnier, is named in the report as being involved in the intimidation tactics.
Buse, contacted by heart wire to comment on the committee's report, said he does not "have much to say," about their conclusions. "Other than the intense interest of reporters and the emails and phone calls that ensue, this has had little impact on me personally or professionally. I certainly hold no ill will toward GSK or Dr Yamada."
Dr Steve Nissen (Cleveland Clinic, OH), also commenting on the committee report, called it "disturbing."
"Dr Buse was a very early critic of the cardiovascular safety of Avandia, and, as I think is very clear now from the sequence of events, he was really forced to agree not to speak out about the safety of the drug at a very early time," Nissen told heart wire . "Obviously, in retrospect, his concerns seem very prescient."Intimidation dating back to 1999
As detailed in the Senate Finance Committee report, Buse sent a letter to the FDA in 1999 noting that the toxicity and safety of rosiglitazone and pioglitazone (Actos, Takeda Pharmaceutical Co) were "not yet known"; he also mentioned a possible increased cardiovascular risk of rosiglitazone during presentations at the Endocrine Society and American Diabetes Association meetings.
Later that year, GSK emails describe Buse as an "Avandia renegade" who had "repeatedly and intentionally misrepresented Avandia data from the speaker's dais" and who should be sent "a firm letter that would warn him about doing this again . . . with the punishment being that we will complain up his academic line and to the CME-granting bodies that accredit his activities."
According the report, GSK's Yamada did call Buse's department chair, presumably prompting a letter sent by Buse to Yamada three days later stating that he wished to "set the record straight" but also telling Yamada to "please call off the dogs. I cannot remain civilized much longer under this kind of heat."
But Buse also sent a second letter that GSK later dubbed his "retraction letter," in which he attempted to clarify the remarks he'd made publicly about rosiglitazone. Subsequent GSK emails, however, indicate that the "clarification letter" was in fact prepared by GSK and that Buse had reproduced it on new letterhead and signed it without making any changes. Further email discussions between GSK executives apparently debated the level of trust now felt for Buse. Yet another email cited in the report describes GSK executives' reaction to the letter Buse had sent to the FDA: "We need to address this as a company. . . . Looks like Dr Buse doesn't buy into our lipid or cardiovascular story."
And later: "I am getting messages that [Buse] is really coming around to the [SmithKline Beecham] side of things. He has stopped his outright bashing and is now more [thiazolidinedione] TZD positive, with kind comments on Avandia.""Embarrassed to have caved"
The Senate Finance Committee report describes a two-year period of silence about Buse's rosiglitazone concerns, broken by an email to Nissen in 2005 in response to a paper by Nissen, Wolski, and Topol describing cardiovascular side effects of the dual-peroxisome proliferator-activated receptor (PPAR) agonist muraglitazar, published in the Journal of the American Medical Association. In that email, Buse describes his experiences following the GSK call to his chair as "a short and ugly set of interchanges [that] occurred over a period of about a week, ending in my having to sign some legal document in which I agreed not to discuss this issue further in public." In the same email, Buse congratulates Nissen and his coauthors, adding, "I was certainly intimidated by [GSK] but frankly did not have the granularity of data that you had and decided that it was not worth it. . . . It makes me embarrassed to have caved in several years ago."
Indeed, the committee suggests in its report that the price of suppressing Buse's rosiglitazone concerns has been paid in human lives: "The effect of silencing this criticism is, in our opinion, extremely serious. . . . Had GSK considered Avandia's increased cardiovascular risk more seriously when the issue was first raised in 1999 by Dr Buse, instead of trying to smother an independent medical opinion, some of these heart attacks may have been avoided."
GSK spokesperson Nancy Pekarek explained to heart wire that while the "tone" of GSK's interactions with Buse back in 1999 may have become heated, the company was motivated primarily to correct inaccuracies and omissions made by Buse in a Takeda-sponsored CME presentation in which he implied that the Takeda drug pioglitazone was safer and more effective than rosiglitazone. A formal statement from GSK notes: "In hindsight, we agree that perhaps we could have handled interactions with Dr Buse better."
But Pekarek also emphasized to heart wire that the letter Buse signed was not legally binding, nor was he forced to sign it. It also did not in any way prevent him from speaking publicly about Avandia. "This was eight years ago," she said. "GSK apologized, he accepted the apology. . . . Even Dr Buse has said, this is, in his mind, done and dusted a long time ago."
Nissen, for his part, is not so sure and said he hoped physicians and researchers read the report. "Hopefully people who read this will decide for themselves that they simply will not allow themselves to be intimidated on issues where patient care is involved," he told heart wire .
This is easier said than done for many investigators earlier in their careers, he acknowledged. "Frankly, at a younger stage in my career, I might have been more vulnerable, too, but I'm kind of at the point where I feel I can stand the heat. It's very hard for younger physician-scientists to stand up to the pressure, and Dr Buse, at the time, was somewhat younger and more vulnerable, he wasn't a section head [of the endocrinology division at UNC] at the time. . . . One of the lessons from this is that we need to create an environment where dissent is tolerated, accepted, and in fact encouraged."
The Senate Finance Committee report was released just days after the FDA announced that rosiglitazone could stay on the market in the US, but with new warnings about ischemic events.
|Buse has previously disclosed receiving grants from and/or acting as an advisor or consultant to Eli Lilly, Takeda, Pfizer, Aventis, Novartis, Bristol-Myers Squibb, and GlaxoSmithKline.|
Heartwire from Medscape © 2007
Cite this: US Senate Committee releases report on GSK's "intimidation" of John Buse over rosiglitazone - Medscape - Nov 20, 2007.