RE: Trial optimization across multiple endpoints
Dear Dr. Corrigan,
Could you kindly elaborate what is the other co-primary end-point? I can
understand that you may not be able to share this additional
information. I will therefore try to illustrate my concern with this
secondary end-point optimization assuming that your drug of interest is
an anti-amyloid therapy (maybe a bad assumption given the recent fate of
semagacestat).
In mild to moderate AD ADAS-cog shows clear worsening of disease state
as you have illustrated in your A&D publications and abstracts. However,
recent publications1,2 from ADNI suggest that biomarkers such as Ab (PIB
measurements or CSF) plateau out by the time the subjects reach mild to
moderate AD. Therefore, I wonder how you are going to optimize on a
biomarker that has plateaued out in your patient population of interest.
Thank-you,
Mahesh
References:
1. Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner
MW, Petersen RC, Trojanowski JQ. Hypothetical model of dynamic
biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010
Jan;9(1):119-28.
2. Beckett LA, Harvey DJ, Gamst A, Donohue M, Kornak J, Zhang H,
Kuo JH; Alzheimer's Disease Neuroimaging Initiative. The Alzheimer's
Disease Neuroimaging Initiative: Annual change in biomarkers and
clinical outcomes. Alzheimers Dement. 2010 May;6(3):257-64.
Quoted reply history
From: [email protected] [mailto:[email protected]]
On Behalf Of Corrigan, Brian (Clin Pharm)
Sent: Saturday, August 28, 2010 8:56 PM
To: nmusers
Subject: [NMusers] Trial optimization across multiple endpoints
Folks:
I knew that 15 plus years of NMUSER messages in my inbox would pay-off
someday.................
I am asking for you help with a question from a non-US health authority
for an upcoming meeting.....not really a NONMEM question, but more of a
general modelng question.
We have proposed some trial design and optimization work (comparing
various trial durations, designs, etc) based on a primary endpoint
(ADAS-cog) used universally in the longitudinal disease progression
trials for this indication (mild to moderate AD). The health authority
opinion is that the trial optimization results could be misleading, as
they are based only on one endpoint, and other endpoints (including a
co-primary) would need to be taken into account in the overall
assesment.
My questions are
1) Does anybody else want to go to the meeting in my place?
2) Assuming I get no positive responses to question 1 above, is anyone
aware of any model base trial simulations and optimization activities
that have utilized more than one endpoint simultaneously? Any that look
at two endpoints and weight them in some sort of utility index, or any
that just even look at two endpoints and compare the trial simulation
results at the end?
Much thanks,
Brian Corrigan, PhD
Pfizer Global Research and Development
50 Pequot Avenue
New London, CT
06320
860-732-9189