Commentary on Improving Precision and Power in Randomized Trials for COVID-19 Treatments Using Covariate Adjustment, for Binary, Ordinal, and Time-to-Event Outcomes

This is a commentary on the paper by Benkeser, Díaz, Luedtke, Segal, Scharfstein, and Rosenblum

Incorrect Covariate Adjustment May Be More Correct than Adjusted Marginal Estimates

This article provides a demonstration that the perceived non-robustness of nonlinear models for covariate adjustment in randomized trials may be less of an issue than the non-transportability of marginal so-called robust estimators.

Avoiding One-Number Summaries of Treatment Effects for RCTs with Binary Outcomes

This article presents an argument that for RCTs with a binary outcome the primary result should be a distribution and not any single number summary. The GUSTO-I study is used to exemplify risk difference distributions.

If You Like the Wilcoxon Test You Must Like the Proportional Odds Model

Since the Wilcoxon test is a special case of the proportional odds (PO) model, if one likes the Wilcoxon test, one must like the PO model. This is made more convincing by showing examples of how one may accurately compute the Wilcoxon statistic from the PO model's odds ratio.

Implementation of the PATH Statement

The recent PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement outlines principles, criteria, and key considerations for applying predictive approaches to clinical trials to provide patient-centered evidence in support of decision making. Here challenges in implementing the PATH Statement are addressed with the GUSTO-I trial as a case study.

Violation of Proportional Odds is Not Fatal

Many researchers worry about violations of the proportional hazards assumption when comparing treatments in a randomized study. Besides the fact that this frequently makes them turn to a much worse approach, the harm done by violations of the proportional odds assumption usually do not prevent the proportional odds model from providing a reasonable treatment effect assessment.

Unadjusted Odds Ratios are Conditional

This article discusses issues with unadjusted effect ratios such as odds ratios and hazard ratios, showing a simple example of non-generalizability of unadjusted odds ratios.

RCT Analyses With Covariate Adjustment

This article summarizes arguments for the claim that the primary analysis of treatment effect in a RCT should be with adjustment for baseline covariates. It reiterates some findings and statements from classic papers, with illustration on the GUSTO-I trial.

Bayesian Methods to Address Clinical Development Challenges for COVID-19 Drugs and Biologics

The COVID-19 pandemic has elevated the challenge for designing and executing clinical trials with vaccines and drug/device combinations within a substantially shortened time frame. Numerous challenges in designing COVID-19 trials include lack of prior data for candidate interventions / vaccines due to the novelty of the disease, evolving standard of care and sense of urgency to speed up development programmes. We propose sequential and adaptive Bayesian trial designs to help address the challenges inherent in COVID-19 trials. In the Bayesian framework, several methodologies can be implemented to address the complexity of the primary endpoint choice. Different options could be used for the primary analysis of the WHO Severity Scale, frequently used in COVID-19 trials. We propose the longitudinal proportional odds mixed effects model using the WHO Severity Scale ordinal scale. This enables efficient utilization of all clinical information to optimize sample sizes and maximize the rate of acquiring evidence about treatment effects and harms.

Implications of Interactions in Treatment Comparisons

This article explains how the generalizability of randomized trial findings depends primarily on whether and how patient characteristics modify (interact with) the treatment effect. For an observational study this will be related to overlap in the propensity to receive treatment.