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Exploring the Potential of External Control Arms created from Patient Level Data: A case study in non-small cell lung
Xiang Yin1, Pallavi S Mishra-Kalyan2, Rajeshwari Sridhara2
1Integrated Evidence, Acorn AL, a Medidata Company, New York, NY, USA.
Abstract:
Randomized controlled trials (RCTs) are the gold standard for evaluation of new medical products. However, RCTs may not always be ethical or feasible. In cases where the investigational product is available outside the trial (e.g., through accelerated approval), patients may fail to enroll in clinical trials or drop out early to take the investigational product. These challenges to enrolling or maintaining a concurrent control arm may compromise timely recruitment, retention, or compliance. This can threaten the study's integrity, including the validity of results. External control arms (ECAs) may be a promising augmentation to RCTs when encountered with challenges that threaten the feasibility and reliability of a randomized controlled clinical trial. Here, we propose the use of ECAs created from patient-level data from previously conducted clinical trials or real-world data in the same indication. Propensity score methods are used to balance observed disease characteristics and demographics in the previous clinical trial or real-world data with those of present-day trial participants assigned to receive the investigational product. These methods are explored in a case study in non-small cell lung cancer (NSCLC) derived from multiple previously conducted open label or blinded phase 2 and 3 multinational clinical trials initiated between 2004 and 2013. The case study indicated that when balanced for baseline characteristics, the overall survival estimates from the ECA were very similar to those of the target randomized control, based on Kaplan-Meier curves and hazard ratio and confidence interval estimates. This suggests that in the future, a randomized control may be able to be augmented by an ECA without compromising the understanding of the treatment effect, assuming sufficient knowledge, measurement, and availability of all or most of the important prognostic variables.
Insights
External control arms (ECAs) can augment randomized controlled trials (RCTs) when enrollment is challenging. Using patient data and propensity scores, ECAs showed similar survival estimates to RCT controls in a non-small cell lung cancer study.
Area of Science:
- Clinical Trials Methodology
- Biostatistics
- Oncology Research
Background:
- Randomized controlled trials (RCTs) are the standard for medical product evaluation but face ethical and feasibility challenges.
- Patient enrollment and retention in RCTs can be compromised by early access to investigational products, threatening study integrity.
- External control arms (ECAs) offer a potential solution to maintain RCT feasibility and reliability.
Purpose of the Study:
- To propose and evaluate the use of ECAs created from historical clinical trial or real-world data.
- To assess the feasibility of augmenting RCTs with ECAs when concurrent control arms are compromised.
- To determine if ECAs can provide reliable estimates comparable to traditional RCT controls.
Main Methods:
- Developed ECAs using patient-level data from prior clinical trials or real-world data within the same indication.
- Employed propensity score methods to balance baseline disease characteristics and demographics between historical data and current trial participants.
- Applied methods to a case study in non-small cell lung cancer (NSCLC) using data from multinational Phase 2 and 3 trials (2004-2013).
Main Results:
- Overall survival estimates derived from the ECA were highly similar to those of the target randomized control in the NSCLC case study.
- Comparisons based on Kaplan-Meier curves, hazard ratios, and confidence intervals demonstrated strong concordance between ECA and RCT control outcomes.
- Propensity score balancing effectively aligned baseline characteristics, supporting the validity of the ECA approach.
Conclusions:
- External control arms (ECAs) augmented with propensity score methods can reliably supplement randomized controlled trials (RCTs).
- ECAs show potential to maintain study integrity and provide valid treatment effect estimates when RCT enrollment or retention is challenging.
- Future RCTs may be augmented by ECAs, provided sufficient prognostic variables are known, measured, and available, without compromising treatment effect understanding.
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