RE: Validation

From: "BRUNO, Rene" <Rene.BRUNO@RP-RORER.FR> Subject: RE: Validation Date: Thu, 4 Feb 1999 15:03:03 +0100 Hi everybody, I am not sure I agree with Mats that the purpose of the model is seldom clear ... I believe that one of the objectives of pop PK in premarketing trials is drug labeling and the purpose is the identification of subpopulations at risk because of altered PK. The risk of course depends on both the magnitude of PK (CL) change and the consequences of such a change on effect (PK/PD). Lets focus on PK. In this context what matter is to validate a predicted decrease of CL in a subpopulation with some (often extreme) covariate value (say in older patients, patients with liver disease ...) and this is what we tried to do in the reference quoted in the draft guidance (ref 44, JPB, 24(2), 153, 1996) under the heading validation through parameters. The approach is based on the assessment of the performance of the (index set) model in predicting CL in the particular subpopulation (taken in the validation set). I agree with Vladimir that the issue here is the estimation of 'true' individual parameters of the validation set patients based on sparse data. It is my experience that, provided that the design is informative enough in individual patients, the performance of empirical Bayesian estimation is quite robust to the priors. At the extreme, if the 'true' value estimates would strongly be biased toward the mean of priors (which is the risk), then the model would appear as non valid even if it is, which is conservative. I don't think the model could appear as valid if it is not. Note that this approach requires as many patients in the validation set than in the index set (just to have enough patients in subpopulations with extreme covariate values). An alternative would be to independently re-built the model from the validation set and I would bet that you would come to a very similar final model (if it was valid) with similar parameter estimates and similar inferences regarding the subpopulations that matter (i.e. those with a change in CL with sufficient magnitude to be clinically relevant) ... this approach would not rely on the estimation of individual parameters ... unless if you are using them for model buiding. Best, Rene. Rene BRUNO, PhD Drug Metabolism and Pharmacokinetics Pharmacometry Unit - Box 58 Rhône-Poulenc Rorer Recherche-Developement 20, Av. Raymond Aron 921645 Antony cedex - France Tel : 33.1.55.71.73.17 Fax : 33.1.55.71.63.22 email : rene.bruno@rp-rorer.fr