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September 19, 2008

Ezetimibe Congressional Investigation: SEAS of Discontent

If you are one of the world’s premier biostatisticians and have a Sir before your name you can pretty much tell Congress thanks but no, thanks.  This is exactly what Sir Richard Peto, professor of medical statistics and epidemiology at Oxford UK did in a Letter to Congress  from The Clinical Trial Services Unit and Epidemiology Studies Unit at Oxford University in the UK.

This was in a response to a series of letters from Congressmen John Dingell and Bart Stupak, Chairman of the Committee on Energy and Commerce, Subcommittee on Oversight and Investigations on August 21, 2008 and September 2, 2008 to the Presidents of Merck and Schering Plough.

In the response letter Dr. Peto outlines the methodology and independence in which he conducted the meta analysis of the clinical trials of SHARP, IMPROVE-IT to review whether the findings of the SEAS trial on increased cancer rates in ezetimibe patients was an anomaly or a trend.

The analysis conducted in seven weeks and published in the New England Journal of Medicine main conclusion was that there was “no credible evidence” that ezetimibe affects cancer.

Congress wanted to know what influence the sponsors of the original trials had on the meta-analysis.

The CTSU outlined how all relevant conflicts of interest were declared, but are of no material relevance to the reliability of this conclusion, for any competent trial statistician would indorse it (the study results).

This is not to say that the analysis is without question, Thomas Fleming, PhD one of America’s top biostatistician pointed out the potential limitations of Dr Peto’s analysis also in the New England Journal of Medicine.

The companies (Merck and Schering Plough) were told that the meta analysis was being undertaken, but did not know the results or receive any draft of his report before it was finalized and sent out by email to the FDA and the European Regulatory Agency on Monday July 21, 2008.

In a response to how the doctors were compensated: Their salaries are not directly or indirectly paid for by industry or industry-sponsored projects.  Moreover, the CTSU has staff policy of not accepting any honoraria, consultancy fees or other payments directly or indirectly from industry.

When requested to turn over all their communications with the supporters since 1998, they replied that it would involve an unreasonably vast amount of effort as CTSU has conducted clinical trials for over ten years involving 60,000 patients each involving extensive correspondence.  And they made clear that: “Such requests seem to constitute inappropriate harassment, if the term “records” is defined as widely as in the attachment.

The congressional staff kept referring to the study as a “consultants study”, at which Professor Peto stated “this is not a consultant’s study”.  Sir Peto kept coming back to the fact that what they conducted, was an independent analysis.

When asked that they make Dr. Peto available for a staff interview as soon as possible, the response was straight forward:  the companies are not in a position to make Professor Peto available since he is a tenured professor at Oxford University and companies have no control over him (though he is available to review data statistical data sets at their request).

The pièce de résistance to the letter was the P.S.

PS: Request that your subcommittee declare its own potential conflict of interest:

Twenty academic coauthors published a careful critique of your subcommittee’s investigation of the breast cancer researcher Dr. Bernard Fisher in the 1990s. (Peto R et al. The Trials of Dr Bernard Fisher: A European perspective on an American episode.

Controlled Clinical Trials 1997; 18: 113; one of the sections is entitled “Inappropriate congressional subcommittee procedures”, see attached article.)

 

Given this, it might well be appropriate for you and any of your subcommittee members or staff to describe this potential conflict of interest when commenting directly or indirectly on the CTSU’s work.

 

Apparently, the same subcommittee in 1994 helped destroy the carrier of perhaps our most successful breast cancer researcher at the time Bernard Fisher, MD over what amounted to no scientific or ethical reason and caused many patients to question their cancer therapy at the time.

 

If you are unfamiliar with Dr. Fisher’s case I encourage you to read the article, it will remind us how a rush to judgment can have catastrophic results.

Dr. Peto reminded congress that independence works both ways.

Relevant documents:

Response to Congressional letters about CTSU work on ezetimibe: September 16, 2008

Attachment to CTSU response: 1997 article entitled The Trials of Dr. Bernard Fisher: A European Perspective on an American Episode

Letters about CTSU from Congressmen Dingell and Stupak

Letter 1: August 21, 2008 

Letter 2: September 2, 2008

Attachment to Letter 2: CTSU 21 July report to the FDA

Attachment to Letter 2 (Tables)

Other relevant links

 CTSU guidelines for honoraria, etc

Peto R et al “Analyses of Cancer Data from Three Ezetimibe Trials.” NEJM 2008: 359 (10.1056/NEJMsa0806603). Available from www.nejm.org

Fleming T  Identifying and Addressing Safety Signals in Clinical Trials” NEJM 2008 (10.1056/NEJMe0807372) Available from www.nejm.org

Forbes: Sir Peto Defends Vytorin Analysis

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