RE: truncation & simulation
Ron,
Truncation can also introduce bias so you should check for this in your
simulations as well. Also, if your model based on 100 patients results in
simulations of CL/F ranging from 1 300 L/hr but the post hoc estimates of
CL/F range from 5 30 L/hr then you may want to further assess the
appropriateness of your model before using it to conduct clinical trial
simulations. Sounds like you are over-estimating the variance. You might
want to look at a histogram of the ETAs for CL/F and look for departures
from normality.
Ken
Quoted reply history
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On
Behalf Of Nick Holford
Sent: Tuesday, April 22, 2008 4:04 PM
To: Ron Mathôt
Cc: [email protected]
Subject: Re: [NMusers] truncation & simulation
Ron,
When you truncate the simulated parameter distribution it can lead to a
major violation of the assumptions of maximum likelihood i.e. that all
random effects are normally distributed. This means that the likelihood
ratio test will have a larger Type 1 error than expected from using the
chi-2 distribution assumption. You should use a randomization test in order
to determine what change in OFV is needed in order to reject the null under
your desired hypothesis.
Nick
Ron Mathôt wrote:
Dear NONMEM users,
Currently I am working on the simulation of a bio-equavalence trial. For the
reference compound a population PK model has been derived on basis of data
from 100 patients. Values for between-and within-patient variability are
available for all PK parameters. The simulation comprises a randomized
cross-over study with 12 patients taking the test and reference compound.
Two-hunderd trials are simulated and summarized. During the simulations I
noticed that truncation of the simulated of PK parameters significantly
influences the power of the study to confirm bio-equivalence. For instance
truncation of simulated oral clearances of both compounds from a range of
1-300 L/hr to 5 - 30 L/hr doubled the number of positive trials (due to
decreased within- patient variability). Post-hoc estimates form the popPK
study indicated that clearance values of the reference compound are all
within the latter range of 5 to 30 L/hr. I expect that oral clearance of the
test compound will not differ more than 5% from the reference compound. In
my opinion simulation of trials with the smallest range will produce more
reliable estimates of the power to detect bio-equivalence.
I would greatly appreciate your comments on this subject.
Best regards,
Ron Mathôt
Department of Hospital Pharmacy and Clincal Pharmacology
Erasmus University Medical Center
Rotterdam
The Netherlands
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
[EMAIL PROTECTED] tel:+64(9)373-7599x86730 fax:+64(9)373-7090
www.health.auckland.ac.nz/pharmacology/staff/nholford