FDA Guidance about Considerations for the Design and Conduct of Externally Controlled Studies for Drugs and Biologics

Content Overview

This FDA guidance describes recommendations for sponsors and monitors of clinical trials to demonstrate the effectiveness and safety of a drug. An externally controlled trial is a type of clinical trial that compares the results of participants receiving an investigational treatment with the results of a comparison group that did not receive the same treatment. This comparison group may be drawn from previous treated or untreated subjects (historical control) or from treated or untreated subjects from the same time period but from a different setting (concurrent control).

The guide addresses considerations for the design and analysis of external controlled trials and discusses potential biases that may lead to invalid study results. It will focus primarily on the use of patient data from other clinical trials or real-world data sources such as registries, electronic health records, and medical billing. The guidance also addresses considerations for communicating with FDA and ensuring FDA access to data from an external controlled trial.

It does not discuss considerations for using summary-level estimates, using external control data to supplement a control arm in a traditional randomized controlled trial, or the reliability and relevance of different sources of real-world data. The FDA guidance merely describes the agency's current thinking and should be considered recommendations only, unless specific regulatory or statutory requirements are listed.

Background

Clinical trials are conducted to investigate the effect of a drug on a target disease and to separate it from other influences such as placebo effects or spontaneous changes in disease progression. To allow a valid conclusion about the effectiveness of the drug, participants are usually randomly assigned to either a treatment group or a placebo group. However, there are other types of controls, such as historical controls, that may be considered adequate and well-controlled in some cases. Before conducting such a study, sponsors and investigators must assess the similarity of the study populations in terms of factors that may affect the outcome being measured. The appropriateness of an external control arm depends on factors such as disease heterogeneity, preliminary knowledge of the drug being studied, and the objective of the study. Historical information can be used as a control arm when the natural history of the disease is well known and the disease does not improve without intervention.

Further information, e.g. on the design and analysis of external controlled trials, can be found directly in the FDA Guidance for Industry "Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products".