Applying the estimand and target trial frameworks to external control analyses using observational data: a case study in the solid tumor setting
Introduction: In causal inference, the correct formulation of the scientific question of interest is a crucial step. The purpose of this study was to apply causal inference principles to external control analysis using observational data and illustrate the process to define the estimand attributes.M...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1223858/full |
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| author | Letizia Polito Qixing Liang Navdeep Pal Philani Mpofu Ahmed Sawas Olivier Humblet Kaspar Rufibach Dominik Heinzmann |
| author_facet | Letizia Polito Qixing Liang Navdeep Pal Philani Mpofu Ahmed Sawas Olivier Humblet Kaspar Rufibach Dominik Heinzmann |
| author_sort | Letizia Polito |
| collection | DOAJ |
| description | Introduction: In causal inference, the correct formulation of the scientific question of interest is a crucial step. The purpose of this study was to apply causal inference principles to external control analysis using observational data and illustrate the process to define the estimand attributes.Methods: This study compared long-term survival outcomes of a pooled set of three previously reported randomized phase 3 trials studying patients with metastatic non-small cell lung cancer receiving front-line chemotherapy and similar patients treated with front-line chemotherapy as part of routine clinical care. Causal inference frameworks were applied to define the estimand aligned with the research question and select the estimator to estimate the estimand of interest.Results: The estimand attributes of the ideal trial were defined using the estimand framework. The target trial framework was used to address specific issues in defining the estimand attributes using observational data from a nationwide electronic health record-derived de-identified database. The two frameworks combined allow to clearly define the estimand and the aligned estimator while accounting for key baseline confounders, index date, and receipt of subsequent therapies. The hazard ratio estimate (point estimate with 95% confidence interval) comparing the randomized clinical trial pooled control arm with the external control was close to 1, which is indicative of similar survival between the two arms.Discussion: The proposed combined framework provides clarity on the causal contrast of interest and the estimator to adopt, and thus facilitates design and interpretation of the analyses. |
| first_indexed | 2024-03-08T09:43:56Z |
| format | Article |
| id | doaj.art-a939dfabf3ac4570bda25fd533323362 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-08T09:43:56Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-a939dfabf3ac4570bda25fd5333233622024-01-29T16:41:02ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-01-011510.3389/fphar.2024.12238581223858Applying the estimand and target trial frameworks to external control analyses using observational data: a case study in the solid tumor settingLetizia Polito0Qixing Liang1Navdeep Pal2Philani Mpofu3Ahmed Sawas4Olivier Humblet5Kaspar Rufibach6Dominik Heinzmann7Product Development Data Sciences, F Hoffmann-La Roche Ltd., Basel, SwitzerlandFlatiron Health, Inc., New York, NY, United StatesGenentech, Inc., San Francisco, CA, United StatesFlatiron Health, Inc., New York, NY, United StatesFlatiron Health, Inc., New York, NY, United StatesFlatiron Health, Inc., New York, NY, United StatesProduct Development Data Sciences, F Hoffmann-La Roche Ltd., Basel, SwitzerlandProduct Development Data Sciences, F Hoffmann-La Roche Ltd., Basel, SwitzerlandIntroduction: In causal inference, the correct formulation of the scientific question of interest is a crucial step. The purpose of this study was to apply causal inference principles to external control analysis using observational data and illustrate the process to define the estimand attributes.Methods: This study compared long-term survival outcomes of a pooled set of three previously reported randomized phase 3 trials studying patients with metastatic non-small cell lung cancer receiving front-line chemotherapy and similar patients treated with front-line chemotherapy as part of routine clinical care. Causal inference frameworks were applied to define the estimand aligned with the research question and select the estimator to estimate the estimand of interest.Results: The estimand attributes of the ideal trial were defined using the estimand framework. The target trial framework was used to address specific issues in defining the estimand attributes using observational data from a nationwide electronic health record-derived de-identified database. The two frameworks combined allow to clearly define the estimand and the aligned estimator while accounting for key baseline confounders, index date, and receipt of subsequent therapies. The hazard ratio estimate (point estimate with 95% confidence interval) comparing the randomized clinical trial pooled control arm with the external control was close to 1, which is indicative of similar survival between the two arms.Discussion: The proposed combined framework provides clarity on the causal contrast of interest and the estimator to adopt, and thus facilitates design and interpretation of the analyses.https://www.frontiersin.org/articles/10.3389/fphar.2024.1223858/fullcausal inferenceestimand frameworktarget trial emulation frameworkexternal controloncologyreal-world data |
| spellingShingle | Letizia Polito Qixing Liang Navdeep Pal Philani Mpofu Ahmed Sawas Olivier Humblet Kaspar Rufibach Dominik Heinzmann Applying the estimand and target trial frameworks to external control analyses using observational data: a case study in the solid tumor setting Frontiers in Pharmacology causal inference estimand framework target trial emulation framework external control oncology real-world data |
| title | Applying the estimand and target trial frameworks to external control analyses using observational data: a case study in the solid tumor setting |
| title_full | Applying the estimand and target trial frameworks to external control analyses using observational data: a case study in the solid tumor setting |
| title_fullStr | Applying the estimand and target trial frameworks to external control analyses using observational data: a case study in the solid tumor setting |
| title_full_unstemmed | Applying the estimand and target trial frameworks to external control analyses using observational data: a case study in the solid tumor setting |
| title_short | Applying the estimand and target trial frameworks to external control analyses using observational data: a case study in the solid tumor setting |
| title_sort | applying the estimand and target trial frameworks to external control analyses using observational data a case study in the solid tumor setting |
| topic | causal inference estimand framework target trial emulation framework external control oncology real-world data |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1223858/full |
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