title: Practical considerations for using functional uniform prior distributions for dose-response estimation in clinical trials.
abstract: Estimating nonlinear dose-response relationships in the context of pharmaceutical clinical trials is often a challenging problem. The data in these trials are typically variable and sparse, making this a hard inference problem, despite sometimes seemingly large sample sizes. Maximum likelihood estimates often fail to exist in these situations, while for Bayesian methods, prior selection becomes a delicate issue when no carefully elicited prior is available, as the posterior distribution will often be sensitive to the priors chosen. This article provides guidance on the usage of functional uniform prior distributions in these situations. The essential idea of functional uniform priors is to employ a distribution that weights the functional shapes of the nonlinear regression function equally. By doing so one obtains a distribution that exhaustively and uniformly covers the underlying potential shapes of the nonlinear function. On the parameter scale these priors will often result in quite nonuniform prior distributions. This paper gives hints on how to implement these priors in practice and illustrates them in realistic trial examples in the context of Phase II dose-response trials as well as Phase I first-in-human studies.
authors.affiliation: Novartis Pharma AG, CH-4002, Basel, Switzerland.
authors.forename: Björn
authors.initials: B
authors.lastname: Bornkamp
mesh_terms: D001499:Bayes Theorem; D001699:Biometry / Q000379:methods*; D002986:Clinical Trials as Topic / Q000379:methods*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D012984:Software
keywords: Bayesian statistics; Dose-finding; Emax model; Functional uniform prior; Jeffreys prior