Methods for external control groups for single arm trials or long-term uncontrolled extensions to randomized clinical trials

Abstract

Purpose: Clinical trials compare outcomes among patients receiving study treatment with comparators drawn from the same source. These internal controls are missing in single arm trials and from long-term extensions (LTE) of trials including only the treatment arm. An external control group derived from a different setting is then required to assess safety or effectiveness.

Methods: We present examples of external control groups that demonstrate some of the issues that arise and make recommendations to address them through careful assessment of the data source fitness for use, design, and analysis steps.

Results: Inclusion and exclusion criteria and context that produce a trial population may result in trial patients with different clinical characteristics than are present in an external comparison group. If these differences affect the risk of outcomes, then a comparison of outcome occurrence will be confounded. Further, patients who continue into LTE may differ from those initially entering the trial due to treatment effects. Application of appropriate methods is needed to make valid inferences when such treatment or selection effects are present. Outcome measures in a trial may be ascertained and defined differently from what can be obtained in an external comparison group. Differences in sensitivity and specificity for identification or measurement of study outcomes leads to information bias that can also invalidate inferences.

Conclusion: This review concentrates on threats to the valid use of external control groups both in the scenarios of single arm trials and LTE of randomized controlled trials, along with methodological approaches to mitigate them.

Keywords: external control; long-term extension (LTE); pharmacoepidemiology; real world data (RWD); single-arm RCT.

FIGURE 1

Treatment effects may vary according to time since start of treatment. The light blue line indicates a constant risk of adverse event following treatment start, while the orange line represents a gradually increasing risk with time since treatment start. The dark blue and pink lines correspond to risks that are high early after treatment start and decline over time [Colour figure can be viewed at wileyonlinelibrary.com]