Friday, November 30, 2007

"The Intimidation of Dr. John Buse"--Some Further Lessons

The recent report by the staff of the Senate Finance Committee on how GlaxoSmithKline tried to silence an early critic of Avandia who called attention to the drug's cardiovascular risk in 1999 has received some play in the press and among my esteemed fellow bloggers. I'm grateful to have had my attention called to the complete text of the Finance Committee report, as it raises some issues that may not have been fully exposed:

The basic story mirrors a previous case, Dr. Gurkirpal Singh of Stanford University, whom Merck tried to warn off from making critical statements about Vioxx's heart risks. Dr. John Buse is a distinguished research endocrinologist at the University of North Carolina. In 1999, Dr. Buse gave several talks at national conferences in which he warned of increased heart risks from the diabetes drug, Avandia--risks that this year led to the FDA requiring a black box warning, though it seems only fair to say that the case has not been definitively proven. GSK (back then, SmithKline Beecham) went into frenzied activity to shut him up. The consultations on how to manage the Buse problem went all the way to the CEO. Dr. Tachi Yamada, the company's research director (and now research head of the Gates Foundation) was directly involved in talking both with Dr. Buse and with his department chair. The end result was that the company drafted a letter which Buse referred to as a "clarification" and the company internal memos call a "retraction," and Buse effectively was silenced from making any more claims in public, though he continued to express his reservations in private.

So now we have the standard melodrama--GSK is the dastardly villain and Dr. Buse, plus all the patients who may have sufered from heart disease from taking Avandia, are the innocent victims. Or does this script hold water? Specifically, what made GSK so outraged that Buse had spoken up; and what made them think that they could succeed in reining him in?

A close reading of the documentary record that the Senate Committee staff compiled yields a number of facts. Dr. Buse was a consultant (presumably paid) for both SmithKline Beecham who made Avandia, and its competitor, Takeda-Lilly, that makes the closely related diabetes drug, Actos. (Actos seems to be sufficiently different in its chemical mechanism that it does not create the same heart risk that is seen with Avandia.) When for example SmithKline Beecham executives labeled Buse, in a series of internal e-mails, the "Avandia Renegade," were they referring to an independent academic stating his scientific views--or were they referring to the fact that one of their paid agents seemed to be turning on them? Or suggesting that Buse was a double agent who was now in the pay of their rivals and therefore tearing down Avandia to boost Actos sales?

In 2000, Buse seemed to be doing all he could to be conciliatory to the company. He even proposed to GSK that they give him money to sponsor a continuing medical education program about the use of all drugs in the same class, and that he had similarly approached Takeda for their financial support. He argued in his message that it would be a good thing for both company's marketing of their drugs that they were seen publicly as burying the hatchet, and that such a joint CME program had the potential to "grow interest in the class [of drugs] as a whole"--that is, that more doctors would prescribe both Avandia and Actos. An interesting posture, it now seems, for a doctor who is supposedly a hero for trying to call early attention to the risk of heart disease among patients taking Avandia.

In 2002 the internal GSK memos are singing a different tune. The company is worried because he was becoming the "most powerful Endocrinologist in the Carolinas," so that extending more olive branches (and money) in his direction would be a good move. GSK was trying to launch a new combination drug that combined Avandia with metformin, an old standby generic diabetes drug. In one memo a GSK official asks another, "It looks like marketing would like us to move forward using Dr. Buse as an investigator in the Avandamet program. Are you OK with this?" (That is truly an interesting question. Why is marketing, not research, deciding who should be an investigator in what is supposedly a research program? Say goodbye to any pretense that these firms are about science and not about sales.) The Senate Committee documents do not say if Buse became an Avandamet investigator and how much more he might have received in research grants or consulting fees.

I agree that it is bad when companies try to intimidate scientists to keep quiet about potential drug risks. But what about the academic physician-scientists, who think that they can ride the tiger and still stay in control? Dr. Buse, it appears, thought that on the one hand he could pocket his consulting fees (and perhaps speaker fees as well; we are not told) from these drug companies; and on the other hand could freely speak his mind as an academic scientist. His new owners told him in no uncertain terms that once the business deal had gone through, he had better remember who was calling the shots. Buse himself seems to have gotten the message as to who owns his opinion--when the press approached him recently to say something nasty about GSK, he refused, saying that the matter was over years ago, that they had apologized to him, and he was eager to let bygones be bygones.

My central message in HOOKED is: when we physicians are lacking in our own professional integrity, pointing fingers at the bad drug companies is hardly an adequate ethical response.

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