The use of external controls: To what extent can it currently be recommended?

With more and better clinical data being captured outside of clinical studies and greater data sharing of clinical studies, external controls may become a more attractive alternative to randomized clinical trials (RCTs). Both industry and regulators recognize that in situations where a randomized study cannot be performed, external controls can provide the needed contextualization to allow a better interpretation of studies without a randomized control. It is also agreed that external controls will not fully replace RCTs as the gold standard for formal proof of efficacy in drug development and the yardstick of clinical research. However, it remains unclear in which situations conclusions about efficacy and a positive benefit/risk can reliably be based on the use of an external control. This paper will provide an overview on types of external control, their applications and the different sources of bias their use may incur, and discuss potential mitigation steps. It will also give recommendations on how the use of external controls can be justified.     

On the use of between–within models to adjust for confounding due to unmeasured cluster-level covariates

Between–within models are generalized linear mixed models (GLMMs) for clustered data that incorporate a random intercept together with fixed effects for within-cluster and between-cluster covariates; the between-cluster covariates represent the cluster means of the within-cluster covariates. One popular use of these models is to adjust for confounding of the effect of within-cluster covariates due to unmeasured between-cluster covariates. Previous research has shown via simulations that using this approach can yield inconsistent estimators. We present theory and simulations as evidence that a primary cause of the inconsistency is heteroscedasticity of the linearized version of the GLMM used for estimation.