RE: Describing variability

From:"Diane R Mould" Subject: RE: [NMusers] Describing variability Date:Tue, 1 Apr 2003 11:43:26 -0500 Hi again While I think that most of us would agree with Ken's comments that failing to obtain a covariance step is an indication of a problem with the model (yes, over parameterization is typically the culprit), I also think some attention should be paid to the intended use of the model and the stage of development that one is in when this happens. Perhaps the 'learning versus confirming' aspect should be applied here as well. If the drug is in the final stages of development and one is attempting to assure that proposed dose regimens will provide safe and efficacious coverage then I would be very unhappy to accept a PK model that had these sorts of problems. however, if I were in Phase II and the model was intended as a guideline for possible dose adjustments (which presumably would be tested in a protocol) then minor issues would be of slightly less concern. I think that tests such as altering the initial estimate to evaluate the effect on the results is something that all of us try and that gross instabilities such as are mentioned below are of course even greater cause for concern. In addition, the type of model one is dealing with has to be considered as well. Its rare that I cant get a $COV step with a PK model, but conversely it is often difficult to get this with PKPD models - particularly complex ones involving disease progression. Long run times further complicate the matter and the relative importance of obtaining standard errors for such a model may be quite minor. its difficult to formulate suggestions based on such broad generalities but we do need to keep the use of the model in mind when making such decisions. However, I do agree with Bill that throwing out a potentially useful model when a $COV step fails seems inappropriate. I don't think its reasonable to ignore what has been learned by model development simply because the $COV step fails although I would always be happier if it succeeded. thanks Diane