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
Trial optimization across multiple endpoints
Brian,
1) Why not?
2) I am not sure what is the difficulty here. It is quite usual to optimize efficacy with the restriction on safety (for example, to select doses to provide maximum effect with the restriction on maximum allowable measure of adverse events). It is also quite usual to select sampling scheme to achieve the desired estimation precision for several parameters (similar to many-endpoints problem). If we are talking about p-value of the effect, it could be a study design that allows to get a desired p-value for several (primary and secondary) end points. What is exactly the problem in your particular case?
Thanks
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
Quoted reply history
On 8/28/2010 8:55 PM, Corrigan, Brian (Clin Pharm) wrote:
> 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
Title: Block versus diagonal omega
Brian, Let me risk ridicule and mention my favorite algorithm, Genetic algorithm. We've actually done some work in this area (just a little, not published anything). But, it is pretty easy to set up an optimization with constraints. Basically, you simulate (100's of times) whatever scenario you want (we've just done sampling times for pk models), run nonmem (or whatever analysis you want) and look at the expected outcome (as I recall, probability of convergence, probability of covariance step and bias of parameters). Then you also can add a penalty for failing to meet some criteria (in out case, missing Cmax). Very computer intensive (100's-1000's of scenarios, 100's of simulations for each, each with NONMEM run), but can be made as realistic as you want, whatever stats you want, constraints of max exposure, constraints of sample scenarios [not after 1 AM not before 7 AM etc etc) There also is an area of multi objective Genetic algorithm, which might work as well, but that's another story. Mark Mark Sale MD Next Level Solutions, LLC www.NextLevelSolns.com 919-846-9185 A carbon-neutral company See our real time solar energy production at: http://enlighten.enphaseenergy.com/public/systems/aSDz2458
Quoted reply history
-------- Original Message --------
Subject: [NMusers] Trial optimization across multiple endpoints
From: "Corrigan, Brian (Clin Pharm)" < [email protected] >
Date: Sat, August 28, 2010 8:55 pm
To: "nmusers" < [email protected] >
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
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
Hello Brian,
1) Is the meeting in New Jersey? If not, you got a deal ;-)
2) Did the HA specifically request optimization of a weighted score/utility
index? Sounds to me as if they are merely asking you to assess probability
distributions (alpha level, power to reject null hypothesis or the like) for
the other relevant endpoints while you are allowed to optimize for the primary
only. It is of course possible to optimize for a weighted composite score of
multiple endpoints, for sure you can simulate different designs and compute
such a score for each. But I would think you can get it down to the simpler
task of the secondaries meeting some specified restrictions while you optimize
for the primary. Whether you simulate with NONMEM, Pharsigt Trial Simulator or
whatever it should certainly be possible to output values of multiple variables
in your model.
Well, this is assuming that the HA agree with your choice of primary. Could it
be the case they are actually suggesting you change that?
Good luck,
Andreas
Quoted reply history
________________________________________
From: [email protected] [[email protected]] On Behalf Of
Leonid Gibiansky [[email protected]]
Sent: Sunday, August 29, 2010 7:12 AM
To: Corrigan, Brian (Clin Pharm)
Cc: nmusers
Subject: Re: [NMusers] Trial optimization across multiple endpoints
Brian,
1) Why not?
2) I am not sure what is the difficulty here. It is quite usual to
optimize efficacy with the restriction on safety (for example, to select
doses to provide maximum effect with the restriction on maximum
allowable measure of adverse events). It is also quite usual to select
sampling scheme to achieve the desired estimation precision for several
parameters (similar to many-endpoints problem). If we are talking about
p-value of the effect, it could be a study design that allows to get a
desired p-value for several (primary and secondary) end points. What is
exactly the problem in your particular case?
Thanks
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
On 8/28/2010 8:55 PM, Corrigan, Brian (Clin Pharm) wrote:
> 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
>