As far as I understand now the answer is no. First of all, the primary
outcome eventually was not changed. Second, I don't know which was the
single measurement that was proposed to be used in place of the original
composite index, but all the three single measurements were presented
and none was any better than the composite index itself. So, whatever
single measurement had been chosen it would not change the results.
So I don't think that the FDA will have anything to complain with the
NEJM about this paper. It could still have to complain with the sponsor
about the way they tried to avoid and/or delay the publication of the
results.
As for what the study shows, I'm not an expert in the field and won't
try to go in detail. Certainly, to me it showed that, at the doses
employed, ezetimbe+simvastatin, despite lowering LDL cholesterol levels
27% more than simvastatin alone, was no different in slowing the
progression of arterial thickening (as assessed by ultrasound imaging)
in patients with familial hypercholesterolemia, no matter what
ultrasound index one would consider as the primary outcome (that is, the
more relevant surrogate marker for progression of disease). Apparently,
the progression of arterial thickening was very slow in both groups,
possibly reflecting the effect of previous treatment with statins..
regards,
Piersante Sestini
On 22/08/2011 4.59, Stephen Senn wrote:
> Dear Piersente,
> I agree with you in that it seems to me that the key point is 'what should we believe the study showed'. This comes down to the analyses and ultimately the data. So what I would like to know is does changing the endpoint have an effect on the interpretation. In the NEJM study I gave as an example some posts back changing the analysis did change the interpretation. The FDA advisory panel unanimously rejected the analysis that was eventually published in the NEJM. In the very same issue the FDA published a letter saying (effectively) do not believe the results of this study. Whether the NEJM is right or the FDA is right (and I side with the latter) this is truly extraordinary.
> Regards
> Stephen
>
>
> Stephen Senn
>
> Professor of Statistics
> School of Mathematics and Statistics
> Direct line: +44 (0)141 330 5141
> Fax: +44 (0)141 330 4814
> Private Webpage: http://www.senns.demon.co.uk/home.html
>
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> 15 University Gardens
> Glasgow G12 8QW
>
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> ________________________________________
> From: Piersante Sestini [[log in to unmask]]
> Sent: 22 August 2011 02:40
> To: Stephen Senn
> Cc: [log in to unmask]
> Subject: Re: Ezetimibe/Simvastatin
>
> On 21/08/2011 20.39, Stephen Senn wrote:
>> 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.
>>
> As I wrote in a previous message (I am unsure whether it went through,
> since I had no confirmation from the listserv), my current understanding
> is that the change in "primary outcome" was proposed, but eventually
> dropped.
>
> Indeed the article on the NEJM reports the results of the "primary
> outcome" as the mean of several points as originally planned, and not as
> a single point as for the proposed change.
> Furthermore, the data are also presented separately for each of the
> points, and in none there is a noticeable effect, making it unlikely
> that the change had been proposed based on the knowledge of a better
> result.
>
> As I explained in the message, I don't think that this makes the sponsor
> freed from all the charges, though
>
> regards,
> Piersante Sestini
>
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