Re: Plcebo Corrected PK/PD

From: "Nick Holford" n.holford@auckland.ac.nz Subject: Re: [NMusers] Plcebo Corrected PK/PD Date: Sat, March 5, 2005 4:43 pm Joga, >"Gobburu, Jogarao V" wrote: > > 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. ----- I am afraid I dont think I agree with you on this. Non-progressive responses are just a special case of progression where alpha=0. I think it is a simple matter to estimate the variability in drug effect in this case -- under the model of no disease progression then any systematic change in response with time must be attributed to drug effect. The parallel design with a non-progressing placbeo group would let you estimate the residual error and thus be able to distinguish true drug effect from noise. ----- > 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? ----- The situation when the drug affects the rate of progression is harder to identify (this is the case that Mats also thought was problematic). With sufficient variation in Ce within a subject then I think one can identify the protective drug effect on rate of progression. As Mats has pointed out the variation in Ce acts as a form of natural cross over within the treatment period although the basic design does not demand a formal crossover of treatment. In the special case where there is no variation in Ce within a subject then I agree one cannot separate drug effect from disease progression. ---- Nick -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/