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Multidimensional Coculture System to Model Lung Squamous Carcinoma Progression
Published on: March 17, 2020
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Using Regression Discontinuity in Time to Strengthen Real-World Evidence: A Case Study in Lung Cancer.
Nai-Chia Chen1, Antal T Zemplenyi1, Blythe Adamson2
1Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.
Summary
The regression discontinuity in time (RDiT) method offers more reliable real-world evidence for cancer drug effectiveness by addressing unmeasured confounders. This approach aligns better with clinical trial results than traditional methods, improving causal inference for treatments like pembrolizumab in advanced non-small-cell lung cancer.
Area of Science:
- Real-world evidence in oncology
- Causal inference methodologies
- Comparative effectiveness research
Background:
- Real-world evidence (RWE) is vital for assessing treatment effectiveness but faces challenges from unmeasured confounders and missing data, especially with historical controls.
- Traditional methods like time-stratified inverse probability treatment weighting (ts-IPTW) struggle with evolving prognostic factors in historical data.
Purpose of the Study:
- To apply the regression discontinuity in time (RDiT) design, a quasi-experimental method, to a real-world study of second-line pembrolizumab versus docetaxel for advanced non-small-cell lung cancer (aNSCLC).
- To compare RDiT results with ts-IPTW and benchmark against long-term clinical trial data to evaluate RDiT's ability to mitigate confounding.
Main Methods:
- A retrospective cohort study using the Flatiron Health Research Database (2011-2023) of 1,975 patients receiving second-line pembrolizumab or docetaxel post-chemotherapy.
- The introduction of pembrolizumab in Q2 2016 served as the RDiT discontinuity threshold, with treatment probabilities estimated via logistic regression.
- Survival outcomes (median overall survival, hazard ratios, restricted mean survival time) were compared across RDiT, ts-IPTW, and reconstructed trial estimates.
Main Results:
- RDiT estimated median survival of 11.5 months for pembrolizumab vs. 6.9 months for docetaxel (HR 0.65), showing better alignment with trial data (HR 0.70) than ts-IPTW (HR 0.52).
- RDiT yielded smaller survival gains compared to ts-IPTW, indicating a potential reduction in unmeasured confounding.
- The study demonstrated RDiT's utility in strengthening causal inference from real-world data.
Conclusions:
- The RDiT method may provide more credible effect estimates consistent with clinical trial findings, especially when unmeasured confounding is a concern.
- RDiT accommodates both historical and concurrent controls and reduces reliance on comprehensive confounder measurement.
- Further research is warranted to explore RDiT's performance in diverse real-world evidence applications.
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