RE: Plcebo Corrected PK/PD

From: "Gobburu, Jogarao V" GOBBURUJ@cder.fda.gov Subject: RE: [NMusers] Plcebo Corrected PK/PD Date: Fri, March 4, 2005 6:44 pm Dear Nick, 1. Let us first acknowledge what we agree on: For non-progressive responses one cannot estimate the true variability in drug effect reliably. You might be able to estimate the mean effects though. I would also like to make it clear that I am not advocating not-estimating the drug effect variance during modeling or other analysis. I simply want us to note the limitations. 2. Now, where you seem to be having a difference in opinion (along with others?) is when the disease is progressive. In my opinion, the disease progression sub-model is not going to change the consequences of interpreting parallel trial results. May be I am missing something. In any case, I would like to seek your opinion on a specific problem. Let us say, the disease is progressing linearly. All patients start with a zero intercept at randomization (randomized to either placebo or trt). This patient who received the drug had responses of 0, 0, 0 at 1, 3 and 6 months. Basically the drug froze the disease from progressing. Let us even make the analysis simpler by assuming no drop-outs, no missing observations, one dose level only, no effect delay, etc.. So, it does not matter if you used one or two-stage analysis. What reference control effect would you use to determine the drug (ONLY) effect for this patient? NB: Bill, there are cross-over studies for your 'teeth-pulling example' in the literature. Thanks. joga