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Published on: September 20, 2019
On the use of external controls in clinical trials
Michelle M Nuño1,2, Stephanie L Pugh3, Lingyun Ji1,2
1Children's Oncology Group, Monrovia, CA 91016, United States.
Abstract:
Externally controlled trials have commonly been used when conducting a randomized controlled trial (RCT) is not feasible or ethical. By allowing the study of new treatments, use of external controls can lead to accelerated advances in the management of rare diseases. The use of external controls, however, introduces new challenges due to potential differences between the population the external controls are enrolled from and the population the patients on the new trial are enrolled from. Some differences include, but are not limited to, differences in how patients are diagnosed and treated, differences in the case mix of the underlying populations, differences in the ability to measure outcomes, and differences in data collection. We discuss the potential benefits and challenges of externally controlled trials, as well as strategies to mitigate bias, including the estimand and target-trial emulation framework. We also provide a brief overview of statistical methodology commonly used in these settings. We note that although the strategies presented may help mitigate some of these challenges, they cannot replace an RCT framework, and investigators should be aware of the potential limitations of externally controlled trials.
Insights
Externally controlled trials accelerate rare disease research but pose challenges. Strategies can mitigate bias, though they don't fully replace randomized controlled trials (RCTs).
Area of Science:
- Clinical Trials
- Epidemiology
- Medical Research
Background:
- Randomized controlled trials (RCTs) are not always feasible or ethical.
- Externally controlled trials (ECTs) offer a way to study new treatments, especially for rare diseases.
- ECTs present unique challenges due to population and data differences.
Purpose of the Study:
- To discuss the benefits and challenges of externally controlled trials.
- To explore strategies for mitigating bias in ECTs.
- To provide an overview of statistical methods for ECTs.
Main Methods:
- Discussion of potential benefits and challenges of externally controlled trials.
- Exploration of bias mitigation strategies, including estimand and target-trial emulation.
- Overview of common statistical methodologies used in externally controlled trials.
Main Results:
- Externally controlled trials can accelerate rare disease research.
- Differences in patient populations, diagnosis, treatment, and data collection introduce bias.
- The estimand and target-trial emulation framework can help mitigate bias.
Conclusions:
- Externally controlled trials offer significant benefits for rare disease research.
- Careful consideration of potential biases and implementation of mitigation strategies are crucial.
- While valuable, externally controlled trials have limitations and cannot fully replace randomized controlled trials.
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