Re: NONMEM

From: Mark Sale - Next Level Solutions mark@nextlevelsolns.com Subject: Re: [NMusers] NONMEM Date: Thu, 14 Sep 2006 09:50:09 -0700 Andy, There are several practical obstacles to this. The first reason that no one uses a formal optimization (based on a pop pk model) to optimize NCA, or other study endpoints it that it is pretty hard. We estimated saving about 10% of sample assay costs (maybe 100 samples per study, ~$10,000 dollars in a $500,000 study), and the sample assay budget came from a different group than the people designing the study, so the study designers didn't lose a lot of sleep over assay costs, prefering the CYA approach. It took me several of weeks of work to do the optimization, another downside. The second study optimization would obviously go a lot faster, but it isn't clear that there is a business case for it, until someone writes a general application to do it. Hence my offer of any code I have to anyone who wants to pursue it. It also is very computationally intensive, running Monte Carlo simualtion on 1000's of designs, doing the pk and statistics for each design (ANOVA for NCA) etc. Probably the pay off for BE studies is marginal. The payoff for large, expensive, difficult to recruit studies may be significant, and they wouldn't be much harder to optimize. Another practical issue is that the stats groups were skeptical - because we basically would control the SE of the AUC - finding an "optimal" SE - not a minimal value- by controling sample number and times. They told us that stats was responsible for estimating the SE of the parameters, not clin pharm. They prefered to use historical values for SE of AUC (and worst case scenario at that), and so the formal power analysis, which was done by stats, didn't reflect the optimization, only the SE of the NCA quantities from an historical study. These are all reasons why I gave up on this a while ago. But, I think in theory it is a very practical way to formally optimize study designs - much more powerful than just doing some simulations in Trial Simulator and manually tweaking some study parameters. Mark Sale MD Next Level Solutions, LLC www.NextLevelSolns.com