RE: covariate selection question

From: "Gobburu, Jogarao V" GOBBURUJ@cder.fda.gov Subject: RE: [NMusers] covariate selection question Date: Wed, 18 Jan 2006 14:34:41 -0500 Dear Mats, I (and others in our pharmacometrics team) could not help but notice your following remark: "(ii) it is perceived that regulatory authorities want to have information even about relations that don't make sense (to e.g. to confirm expected non-interactions)." The following are my personal comments: In my experience, this perception is unfounded. But then perception is reality, as they say. The exposure-response guidance clearly encourages mechanism-based modeling. In fact, I am unaware of any label where the dosing is based on a prognostic factor that does not make biological sense (and derived using mixed-effects modeling). Statistical inference can (only) provide supportive evidence for mechanism-based covariates. I presume you have had an experience with that type of issue and hence your statement. Unless, the specifics of your experience are known, a meaningful discussion cannot occur. Now, there are cases when modeling found covariates that did not make biological sense - no party involved with the drug wanted dose adjustments based on that covariate. There are cases when the opposite (ie., mechanistic not included, but then included after subsequent discussions) also occurred. On the other hand, there is empirical evidence in few cases where the strong prior beliefs do not hold good - so your 'don't make sense' becomes subjective and depends on prior experience one might have had. All decisions will have some risk (false negatives/positives), the only way I can think of increasing comfort in taking this 'risk' is by adhering to biology. The alternative is prohibitively costly. Joga