SECRETS: Subject-efficient clinical randomized controlled trials using synthetic intervention
Background:: The parallel-group randomized controlled trial (RCT) is commonly used in Phase-3 clinical trials to establish treatment effectiveness but requires hundreds-to-thousands of subjects, making it difficult to implement, which leads to high Phase-3 trial failure rates. One approach to increa...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | Contemporary Clinical Trials Communications |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2451865424000127 |
| _version_ | 1797256376395759616 |
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| author | Sayeri Lala Niraj K. Jha |
| author_facet | Sayeri Lala Niraj K. Jha |
| author_sort | Sayeri Lala |
| collection | DOAJ |
| description | Background:: The parallel-group randomized controlled trial (RCT) is commonly used in Phase-3 clinical trials to establish treatment effectiveness but requires hundreds-to-thousands of subjects, making it difficult to implement, which leads to high Phase-3 trial failure rates. One approach to increasing power of a trial is to augment data collected from an RCT with external data from prospective studies or prior RCTs. However, this requires that external data be comparable to data from the study of interest, a condition that does not hold for new interventions or populations being studied. Another approach is to lower sample size requirements by using the cross-over design, which measures individual treatment effects (ITEs) to remove inter-subject variability; however, this design is only suitable for chronic conditions and interventions with effects that wash out rapidly. Method:: We propose a novel and practical framework called SECRETS (Subject-Efficient Clinical Randomized Controlled Trials using Synthetic Intervention) to increase power of any parallel-group RCT by simulating the cross-over design using only data collected from the study. SECRETS first estimates ITEs across all subjects recruited to the RCT by using a state-of-the-art counterfactual estimation algorithm called synthetic intervention (SI). Since SI induces dependencies among the ITEs, we introduce a novel hypothesis testing strategy to test for treatment effectiveness. Results:: We show that SECRETS can increase the power of an RCT while maintaining comparable significance levels; in particular, on three real-world clinical RCTs (Phase-3 trials), SECRETS increases power over the baseline method by 6 − 54% (average: 21.5%, standard deviation: 15.8%), thereby reducing the number of subjects needed to obtain a typically desired statistical operating point of 80% power and 5% significance level by 25 − 76% (10-3,957 fewer subjects per arm). Our analyses show that SECRETS increases power by consistently reducing the variance of the average treatment effect, thereby mimicking the effects of a cross-over design. Conclusion:: SECRETS increases subject efficiency of an RCT by simulating the cross-over design using only data collected from the RCT; therefore, it is a feasible solution for increasing the trial’s power, especially under settings where satisfying sample size requirements is difficult. |
| first_indexed | 2024-03-08T05:14:34Z |
| format | Article |
| id | doaj.art-dd0f39997ed34a12a254e8beedfd5837 |
| institution | Directory Open Access Journal |
| issn | 2451-8654 |
| language | English |
| last_indexed | 2024-04-24T22:20:46Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Contemporary Clinical Trials Communications |
| spelling | doaj.art-dd0f39997ed34a12a254e8beedfd58372024-03-20T06:10:50ZengElsevierContemporary Clinical Trials Communications2451-86542024-04-0138101265SECRETS: Subject-efficient clinical randomized controlled trials using synthetic interventionSayeri Lala0Niraj K. Jha1Corresponding author.; Department of Electrical and Computer Engineering, Princeton University, Princeton, 08544, NJ, USADepartment of Electrical and Computer Engineering, Princeton University, Princeton, 08544, NJ, USABackground:: The parallel-group randomized controlled trial (RCT) is commonly used in Phase-3 clinical trials to establish treatment effectiveness but requires hundreds-to-thousands of subjects, making it difficult to implement, which leads to high Phase-3 trial failure rates. One approach to increasing power of a trial is to augment data collected from an RCT with external data from prospective studies or prior RCTs. However, this requires that external data be comparable to data from the study of interest, a condition that does not hold for new interventions or populations being studied. Another approach is to lower sample size requirements by using the cross-over design, which measures individual treatment effects (ITEs) to remove inter-subject variability; however, this design is only suitable for chronic conditions and interventions with effects that wash out rapidly. Method:: We propose a novel and practical framework called SECRETS (Subject-Efficient Clinical Randomized Controlled Trials using Synthetic Intervention) to increase power of any parallel-group RCT by simulating the cross-over design using only data collected from the study. SECRETS first estimates ITEs across all subjects recruited to the RCT by using a state-of-the-art counterfactual estimation algorithm called synthetic intervention (SI). Since SI induces dependencies among the ITEs, we introduce a novel hypothesis testing strategy to test for treatment effectiveness. Results:: We show that SECRETS can increase the power of an RCT while maintaining comparable significance levels; in particular, on three real-world clinical RCTs (Phase-3 trials), SECRETS increases power over the baseline method by 6 − 54% (average: 21.5%, standard deviation: 15.8%), thereby reducing the number of subjects needed to obtain a typically desired statistical operating point of 80% power and 5% significance level by 25 − 76% (10-3,957 fewer subjects per arm). Our analyses show that SECRETS increases power by consistently reducing the variance of the average treatment effect, thereby mimicking the effects of a cross-over design. Conclusion:: SECRETS increases subject efficiency of an RCT by simulating the cross-over design using only data collected from the RCT; therefore, it is a feasible solution for increasing the trial’s power, especially under settings where satisfying sample size requirements is difficult.http://www.sciencedirect.com/science/article/pii/S2451865424000127Clinical randomized controlled trialsCounterfactual estimationHypothesis testingSample efficiencySynthetic intervention |
| spellingShingle | Sayeri Lala Niraj K. Jha SECRETS: Subject-efficient clinical randomized controlled trials using synthetic intervention Contemporary Clinical Trials Communications Clinical randomized controlled trials Counterfactual estimation Hypothesis testing Sample efficiency Synthetic intervention |
| title | SECRETS: Subject-efficient clinical randomized controlled trials using synthetic intervention |
| title_full | SECRETS: Subject-efficient clinical randomized controlled trials using synthetic intervention |
| title_fullStr | SECRETS: Subject-efficient clinical randomized controlled trials using synthetic intervention |
| title_full_unstemmed | SECRETS: Subject-efficient clinical randomized controlled trials using synthetic intervention |
| title_short | SECRETS: Subject-efficient clinical randomized controlled trials using synthetic intervention |
| title_sort | secrets subject efficient clinical randomized controlled trials using synthetic intervention |
| topic | Clinical randomized controlled trials Counterfactual estimation Hypothesis testing Sample efficiency Synthetic intervention |
| url | http://www.sciencedirect.com/science/article/pii/S2451865424000127 |
| work_keys_str_mv | AT sayerilala secretssubjectefficientclinicalrandomizedcontrolledtrialsusingsyntheticintervention AT nirajkjha secretssubjectefficientclinicalrandomizedcontrolledtrialsusingsyntheticintervention |