Propensity score matched augmented controls in randomized clinical trials: A case study.

Abstract

Existing statutes in the United States and Europe require manufacturers to demonstrate evidence of effectiveness through the conduct of adequate and well-controlled studies to obtain marketing approval of a therapeutic product. What constitutes adequate and well-controlled studies is usually interpreted as randomized controlled trials (RCTs). However, these trials are sometimes unfeasible because of their size, duration, cost, patient preference, or in some cases, ethical concerns. For example, RCTs may not be fully powered in rare diseases or in infections caused by multidrug resistant pathogens because of the low number of enrollable patients. In this case, data available from external controls (including historical controls and observational studies or data registries) can complement information provided by RCT. Propensity score matching methods can be used to select or "borrow" additional patients from the external controls, for maintaining a one-to-one randomization between the treatment arm and active control, by matching the new treatment and control units based on a set of measured covariates, ie, model-based pairing of treatment and control units that are similar in terms of their observable pretreatment characteristics. To this end, 2 matching schemes based on propensity scores are explored and applied to a real clinical data example with the objective of using historical or external observations to augment data in a trial where the randomization is disproportionate or asymmetric.