Re: Placebo-corrected PD models

From:Nick Holford Subject:Re: [NMusers] Placebo-corrected PD models Date:Sat, 18 May 2002 09:09:31 +1200 Daren, Leonid, Chuanpu and Lewis have commented on the statistical aspects of your model but I would like to expand on a comment made by Lewis which relates to the structural form of the model. The time course of a response (e.g. biomarker or clinical outcome) in a clinical trial can be thought of as: R(t) = DP(t) + D(t) + P(t) where DP is a disease progress model for the time course of the response in the absence of a drug (D) or placebo effect (P). The additive form of the model shown above is just indicative and more complex models should be considered e.g. if the DP model is linear (DP(0)=R0) and the drug affects the slope: R(t) = R0 + (D(t) + slope) * t + P(t) DP(t) and P(t) may appear to be confounded but if you are prepared to make some reasonable assumption about the shapes of each component eg. DP is linear and P rises to a peak then fades away, then they can be disentangled. I would encourage you to consider plausible, biologically reasonable models for each of these three components and use the observed response data to test hypotheses about the structural form that best describes the data e.g. Does D(t) affect the slope of DP(t) or is the effect simply additive? Is P(t) the same in placebo treated and drug treated groups? Some examples can be found in the following references. Nick Chan PLS, Holford NHG. Drug treatment effects on disease progression. Annual Review of Pharmacology and Toxicology 2001;41:625-659 Holford NHG, Mould DR, Peck CC. Disease Progress Models. In: Atkinson A, editor. Principles of Clinical Pharmacology. San Diego: Academic Press; 2001. p. 253-262.