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Methods for external control groups for single arm trials or long-term uncontrolled extensions to randomized clinical
John D Seeger1, Kourtney J Davis2, Michelle R Iannacone3
1Life Sciences Epidemiology, Optum, Boston, Massachusetts, USA.
Pharmacoepidemiology and Drug Safety
|September 23, 2020
Summary
External control groups are crucial for single-arm trials and long-term extensions when internal controls are absent. Careful assessment and methods are needed to mitigate bias and ensure valid inferences for safety and effectiveness.
Area of Science:
- Clinical Trials
- Biostatistics
- Pharmaceutical Research
Background:
- Internal controls are standard in clinical trials for comparing treatments.
- Single-arm trials and long-term extensions (LTE) often lack internal controls, necessitating external comparison groups.
- External control groups are essential for assessing safety and effectiveness in these scenarios.
Purpose of the Study:
- To review threats to the valid use of external control groups in clinical trials.
- To provide recommendations for addressing issues arising from external control group utilization.
- To focus on methodological approaches for mitigating bias in single-arm trials and LTE.
Main Methods:
- Review of potential issues with external control groups.
- Examples illustrating challenges in using external control data.
- Recommendations for data source assessment, trial design, and analysis.
Main Results:
- Differences in patient characteristics between trial and external groups can lead to confounding.
- Treatment effects or selection bias can alter patient populations in LTE.
- Discrepancies in outcome ascertainment and definition can cause information bias, invalidating inferences.
Conclusions:
- Valid use of external control groups requires careful consideration of potential biases.
- Methodological strategies are necessary to ensure reliable safety and effectiveness assessments.
- Addressing threats to validity is critical for single-arm trials and LTE.
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