Dear Ash,
Agreed that there is a lot to read. Has anybody done an analysis of the other endpoint (the one that was initially primary) to see if the message is different. My opinion is that if the two differ but medical opinion is divided as to which is important then it is more or less irrelevant as to which was pre-specified. There is a problem with the trial.
Regards
Stephen
Stephen Senn
Professor of Statistics
School of Mathematics and Statistics
Direct line: +44 (0)141 330 5141
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From: Evidence based health (EBH) [[log in to unmask]] On Behalf Of Ash Paul [[log in to unmask]]
Sent: 21 August 2011 19:28
To: [log in to unmask]
Subject: Re: Ezetimibe/Simvastatin
Dear Piersante,
Sorry for yet another email on the subject, but I forgot to include the links to the 70 page US Congress documentation on the ENHANCE Trial which was released on 11th April 2008, which are also a very important read on the subject:
April 11, 2008
After Review of ENHANCE Trial Documents, Dingell, Stupak Express “Serious Concerns”<http://uk.mg1.mail.yahoo.com/dc/110nr248.shtml>
Read the Letter »<http://uk.mg1.mail.yahoo.com/dc/110-ltr.041108.MerckScheringPlough.pdf>
Read the Attachments »<http://uk.mg1.mail.yahoo.com/dc/110-ltr.041108.MerckScheringPlough.ENHANCE_Attachments.pdf>
Which busy clinician has time to read all these documents?
It's only dumb healthcare commissioners around the world like myself who are condemned to reading these voluminous documents, because at the end of the day, we have to provide value for money for the taxpayers monies that are handed over to us by our respective parliaments in order to provide a safe, quality assured and affordable health service for our local populations, and we have to stay within our allocated annual budgets as well.
Regards,
Ash
From: Ash Paul <[log in to unmask]>
To: Evidenced-Based Health <[log in to unmask]>
Sent: Sunday, 21 August 2011, 19:09
Subject: Re: Ezetimibe/Simvastatin
Dear Piersante,
I know many critics keep seeing conspiracy theories when, in reality, there might be none, but how does one explain that the minutes of the meeting held by the expert advisory panel in November 2007 to change the study aim (and whose members have never been disclosed), were written up one month after the panel met?
If you read the two Forbes articles which I referred to earlier in another email, more details are given there.
Regards,
Ash
From: Piersante Sestini <[log in to unmask]>
To: [log in to unmask]
Sent: Sunday, 21 August 2011, 18:43
Subject: Re: Ezetimibe/Simvastatin
On 21/08/2011 12.37, Stephen Senn wrote:
> Multiplicity is tricky issue. I too do not believe in the mystic value of pre-specification. Nevertheless evidentially there are some different scenarios one can imagine.
> 1. Several outcomes were measured all were analysed and presented.
> 2. Several outcomes were measured all were analysed and presented and one was prespecified.
> 3. Several outcomes were measured but only the pres-specified one was presented and it was always known that this would be the case.
> 4. Several outcomes were measured and analysed but one that was not pre-specified was presented.
It seems to be case 2.
The report on the NEJM reads: "The predefined primary outcome was the change from baseline in ultrasonographic measurement of the mean carotid-artery intima–media thickness, which was defined as the average of the means of the far-wall intima–media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries in the two study groups.". What seems to have been the previous primary outcome (Change in ultrasound-determined average carotid artery plus average common femoral artery intima-media thickness) is then presented as a secondary outcome.
This is the same information present on clinicaltrials.gov: however the trial was registered on clinicaltrials.gov only in october 2007, while it had been carried out between June 2002 and April 2006. Furthermore, the panel that allegendly suggested to change the study aim was held one month later than that, in November 2007. The data were last changed on June 19, 2008 (two months after the publication of the results. Surprisingly, clinicaltrials.gov doesn't keep trace of changes, and unfortunately the wayback machine on web.archive.org has no captures of that page before January 2008.
The problem, though, is that no account is given of the fact that what constitute the "predefined primary outcome" was actually changed before registering the trial. Thus, the sentence published on the registry is ambiguous (it does not say whether it was predefined) and that published on the NEJM is false, as it reports it as "predefined" without mentioning the change. It is like having a history book saying that Colombo left Palos to find America.
It seems that all this has little effect on the interpretation of the results (negative anyway), still it denotes a disregard for giving a fair account of what happened which mines the thrust also on other aspects of the story, including the reasons for delaying its publication.
For example, to come to your question on whether the data were still blinded, it seems unlikely that in November 2007 there were still 40,000 images to be manually processed, as reported to support the view that they were, when the paper (online 30 March 2008, in print 4 April, no information on when it was submitted or accepted) could not have been reasonably submitted later than January 2008.
regards,
Piersante Sestini
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