On fixed and uncertain mixture prior weights

This paper focuses on the specification of the weights for the components of mixture priors

Identifying Treatment Effects using Trimmed Means when Data are Missing Not at Random

Patients often discontinue treatment in a clinical trial because their health condition is not improving. Consequently, the patients still in the study at the end of the trial have better health outcomes on average than the initial patient population would have had if every patient had completed the trial. If we only analyze the patients who complete the trial, then this missing data problem biases the estimator of a medication's efficacy because study outcomes are missing not at random (MNAR). One way to overcome this problem - the trimmed means approach for missing data - sets missing values as slightly worse than the worst observed outcome and then trims away a fraction of the distribution from each treatment arm before calculating differences in treatment efficacy (Permutt 2017, Pharmaceutical statistics 16.1:20-28). In this paper we derive sufficient and necessary conditions for when this approach can identify the average population treatment effect in the presence of MNAR data. Numerical studies show the trimmed means approach's ability to effectively estimate treatment efficacy when data are MNAR and missingness is strongly associated with an unfavorable outcome, but trimmed means fail when data are missing at random (MAR) when the better approach would be to multiply impute the missing values. If the reasons for discontinuation in a clinical trial are known analysts can improve estimates with a combination of multiple imputation (MI) and the trimmed means approach when the assumptions of each missing data mechanism hold. When the assumptions are justifiable, using trimmed means can help identify treatment effects notwithstanding MNAR data

Applying Meta-Analytic-Predictive Priors with the R Bayesian Evidence Synthesis Tools

Use of historical data in clinical trial design and analysis has shown various advantages such as reduction of number of subjects and increase of study power. The metaanalytic-predictive (MAP) approach accounts with a hierarchical model for between-trial heterogeneity in order to derive an informative prior from historical data. In this paper, we introduce the package RBesT (R Bayesian evidence synthesis tools) which implements the MAP approach with normal (known sampling standard deviation), binomial and Poisson endpoints. The hierarchical MAP model is evaluated by Markov chain Monte Carlo (MCMC). The MCMC samples representing the MAP prior are approximated with parametric mixture densities which are obtained with the expectation maximization algorithm. The parametric mixture density representation facilitates easy communication of the MAP prior and enables fast and accurate analytical procedures to evaluate properties of trial designs with informative MAP priors. The paper first introduces the framework of robust Bayesian evidence synthesis in this setting and then explains how RBesT facilitates the derivation and evaluation of an informative MAP prior from historical control data. In addition we describe how the meta-analytic framework relates to further applications including probability of success calculations

Principal Stratum Strategy: Potential Role in Drug Development

A randomized trial allows estimation of the causal effect of an intervention compared to a control in the overall population and in subpopulations defined by baseline characteristics. Often, however, clinical questions also arise regarding the treatment effect in subpopulations of patients, which would experience clinical or disease related events post-randomization. Events that occur after treatment initiation and potentially affect the interpretation or the existence of the measurements are called {\it intercurrent events} in the ICH E9(R1) guideline. If the intercurrent event is a consequence of treatment, randomization alone is no longer sufficient to meaningfully estimate the treatment effect. Analyses comparing the subgroups of patients without the intercurrent events for intervention and control will not estimate a causal effect. This is well known, but post-hoc analyses of this kind are commonly performed in drug development. An alternative approach is the principal stratum strategy, which classifies subjects according to their potential occurrence of an intercurrent event on both study arms. We illustrate with examples that questions formulated through principal strata occur naturally in drug development and argue that approaching these questions with the ICH E9(R1) estimand framework has the potential to lead to more transparent assumptions as well as more adequate analyses and conclusions. In addition, we provide an overview of assumptions required for estimation of effects in principal strata. Most of these assumptions are unverifiable and should hence be based on solid scientific understanding. Sensitivity analyses are needed to assess robustness of conclusions

On weakly informative prior distributions for the heterogeneity parameter in Bayesian random-effects meta-analysis

The normal-normal hierarchical model (NNHM) constitutes a simple and widely used framework for meta-analysis. In the common case of only few studies contributing to the meta-analysis, standard approaches to inference tend to perform poorly, and Bayesian meta-analysis has been suggested as a potential solution. The Bayesian approach, however, requires the sensible specification of prior distributions. While non-informative priors are commonly used for the overall mean effect, the use of weakly informative priors has been suggested for the heterogeneity parameter, in particular in the setting of (very) few studies. To date, however, a consensus on how to generally specify a weakly informative heterogeneity prior is lacking. Here we investigate the problem more closely and provide some guidance on prior specification.Comment: 42 pages, 10 figures, 20 table