Thanks, Ash I will try to find time to have a look. This is the case of the FDA taking the NEJM to task. You might find it interesting.
Powers, J. H., C. A. Dixon, et al. (2002). "Voriconazole versus liposomal amphotericin B in patients with neutropenia and persistent fever." N Engl J Med 346(4): 289-290.
http://www.nejm.org/doi/full/10.1056/NEJM200201243460414
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
University of Glasgow
15 University Gardens
Glasgow G12 8QW
The University of Glasgow, charity number SC004401
________________________________________
From: Evidence based health (EBH) [[log in to unmask]] On Behalf Of Ash Paul [[log in to unmask]]
Sent: 21 August 2011 12:28
To: [log in to unmask]
Subject: Re: Ezetimibe/Simvastatin
Dear Stephen,
Please have a read of the article 'The Vytorin Letters' published by Forbes on 4th November 2008; it makes a fascinating read:
http://www.forbes.com/2008/04/11/vytorin-congress-schering-biz-healthcare-cx_mh_0411vytorin.html
Also have a read of another Forbes article published earlier on 25th March 2008, again by Forbes 'More Questions on the Vytorin Panel':
http://www.forbes.com/2008/03/25/vytorin-pharmaceuticals-congress-biz-healthcare-cx_mh_0325vytorin.html
And, if you have the patience to read through all this, here's the 2008 news material on Vytorin from the US Congress:
http://democrats.energycommerce.house.gov/Press_110/110nr183.shtml
http://democrats.energycommerce.house.gov/Press_110/110nr182.shtml
http://democrats.energycommerce.house.gov/Press_110/110nr183.shtml
http://democrats.energycommerce.house.gov/index.php?q=archive/110th-congress/dingell-stupak-question-merckschering-ploughs-sponsorship-of-american-college
Regards,
Ash
From: Stephen Senn <[log in to unmask]>
To: [log in to unmask]
Sent: Sunday, 21 August 2011, 11:37
Subject: Re: Ezetimibe/Simvastatin
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.
For a third party I don't see much difference between 1 and 2 except perhaps that 2 is indicative of some thinking by those who conducted the trial that may be useful as secondary information. (However one may have to be very careful in case 1 to avoid falling into the trap of only paying attention to the most significant measure.) Case 3 I think is a shame because one would like to know about the other measures but it is not biasing. Case 4 is biasing and is outlawed in the regulatory framework. In fact there is at least one case where the FDA has rapped the knuckles of the NEJM for publishing a type 4 analysis.
So which was the case here?
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
University of Glasgow
15 University Gardens
Glasgow G12 8QW
The University of Glasgow, charity number SC004401
________________________________________
From: Piersante Sestini [[log in to unmask]<mailto:[log in to unmask]>]
Sent: 21 August 2011 03:36
To: Stephen Senn
Cc: [log in to unmask]<mailto:[log in to unmask]>
Subject: Re: Ezetimibe/Simvastatin
On 20/08/2011 10.35, Stephen Senn wrote:
> Does anybody know if the endpoint was changed before or after unblinding of the data?
> Stephen
This is an excellent point.
I don't believe in the mystic of a priori primary outcomes. As Ludwik
Fleck pointed out more than 70 years ago, we then shouldn't accept the
discovery of America, because Colombo's declared primary outcome was to
get to India. Thus, there is nothing wrong in reinterpreting the data to
accept the conclusions that they logically support, once they are fairly
reported.
But here the point is different: it is that of a possible casuistic (in
its popular negative meaning) choice of an outcome based not on logic,
but possibly on reaching statistic "significance", which by itself does
not provide logic strength to the interpretation of the data, or on some
other untold reason.
The argument that to analyze the results from a single carotid site is
faster than from three which were already measured and recorded is
ridiculous, and I think that should have been rejected. The two more
likely explanations that I see are a)results from that analysis "look
better", and/or b)a form of auto-plagiarism: an attempt to maximize
the number of papers "produced" by the study (by publishing the other
results in a separate paper).
Both reasons are appealing both to the sponsor (to amplify the selling
points) and to the participating scientists (fattening the CV), and are
a consequence of a "pathological" mechanism of how the scientific
literature is evaluated and used.
I maintain that it is the journal editors that should guard about these
ethical misconducts. It makes no sense to require that clinical trials
have been pre-registered if their report is accepted without questioning
whether they are have been conducted and reported accordingly.
The problem is that journals have also an interest in publishing more
papers, particularly when they have a good chance of rise interest (and
sponsors do help with this), to be cited afterwards (increasing the IF
of the journal), or to raise income by selling reprints to drug companies.
Thus, with due exceptions, drug companies, clinical scientists
(including reviewers) and journals are largely in bed together, and
breaking these pathological mechanisms seems difficult. Open disclosure
(in this case of the reasons for the change in primary outcome, and when
it occurred), could help. Of course, your proposal of moving the
publication of results of clinical trials out of this business could
also help, although with the danger of creating one more dumb
bureaucracy caring more about rules than about logic. Nevertheless,
while promoting a new journal that enforces stricter rules for
publication of clinical trials could be successful, forbidding authors
to submit to other journals is not simple.
The worst thing is that many call this process "evidence-based
medicine", and any effort to explain to the practitioners and the
community that EBM is a different thing that suffers, rather than cause,
these problems would be valuable.
regards,
Piersante Sestini
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