TY - JOUR
T1 - Hybrid Controlled Clinical Trials Using Concurrent Registries in Amyotrophic Lateral Sclerosis
T2 - A Feasibility Study
AU - van Eijk, Ruben P A
AU - van den Berg, Leonard H
AU - Roes, Kit C B
AU - Tian, Lu
AU - Lai, Tze L
AU - Nelson, Lorene M
AU - Li, Chenyu
AU - Scowcroft, Anna
AU - Garcia-Segovia, Jesus
AU - Lu, Ying
N1 - Funding Information:
This work was funded by the UCB‐Stanford Digital Health Research Collaborative. The Sponsor of this study was not involved in the study design; in the collection and analysis; nor in the decision to submit the paper for publication. Scientific employees of the Sponsor contributed to the interpretation of study findings and writing the report.
Funding Information:
This work was funded by the UCB-Stanford Digital Health Research Collaborative. The Sponsor of this study was not involved in the study design; in the collection and analysis; nor in the decision to submit the paper for publication. Scientific employees of the Sponsor contributed to the interpretation of study findings and writing the report. The authors thank Brenda Vollers-King for assistance with language editing.
Publisher Copyright:
© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PY - 2023/10
Y1 - 2023/10
N2 - Hybrid designs with both randomized arms and an external control cohort preserve key features of randomization and utilize external information to augment clinical trials. In this study, we propose to leverage high-quality, patient-level concurrent registries to enhance clinical trials and illustrate the impact on trial design for amyotrophic lateral sclerosis. The proposed methodology was evaluated in a randomized, placebo-controlled clinical trial. We used patient-level information from a well-defined, population-based registry, that was running parallel to the randomized clinical trial, to identify concurrently nonparticipating, eligible patients who could be matched with trial participants, and integrate them into the statistical analysis. We assessed the impact of the addition of the external controls on the treatment effect estimate, precision, and time to reach a conclusion. During the runtime of the trial, a total of 1,141 registry patients were alive; 473 (41.5%) of them fulfilled the eligibility criteria and 133 (11.7%) were enrolled in the study. A matched control population could be identified among the nonparticipating patients. Augmenting the randomized controls with matched external controls could have avoided unnecessary randomization of 17 patients (-12.8%) as well as reducing the study duration from 30.1 months to 22.6 months (-25.0%). Matching eligible external controls from a different calendar period led to bias in the treatment effect estimate. Hybrid trial designs utilizing a concurrent registry with rigorous matching can minimize bias due to a mismatch in calendar time and differences in standard of care, and may accelerate the development of new treatments.
AB - Hybrid designs with both randomized arms and an external control cohort preserve key features of randomization and utilize external information to augment clinical trials. In this study, we propose to leverage high-quality, patient-level concurrent registries to enhance clinical trials and illustrate the impact on trial design for amyotrophic lateral sclerosis. The proposed methodology was evaluated in a randomized, placebo-controlled clinical trial. We used patient-level information from a well-defined, population-based registry, that was running parallel to the randomized clinical trial, to identify concurrently nonparticipating, eligible patients who could be matched with trial participants, and integrate them into the statistical analysis. We assessed the impact of the addition of the external controls on the treatment effect estimate, precision, and time to reach a conclusion. During the runtime of the trial, a total of 1,141 registry patients were alive; 473 (41.5%) of them fulfilled the eligibility criteria and 133 (11.7%) were enrolled in the study. A matched control population could be identified among the nonparticipating patients. Augmenting the randomized controls with matched external controls could have avoided unnecessary randomization of 17 patients (-12.8%) as well as reducing the study duration from 30.1 months to 22.6 months (-25.0%). Matching eligible external controls from a different calendar period led to bias in the treatment effect estimate. Hybrid trial designs utilizing a concurrent registry with rigorous matching can minimize bias due to a mismatch in calendar time and differences in standard of care, and may accelerate the development of new treatments.
UR - https://www.scopus.com/pages/publications/85165273769
U2 - 10.1002/cpt.2994
DO - 10.1002/cpt.2994
M3 - Article
C2 - 37422655
SN - 0009-9236
VL - 114
SP - 883
EP - 892
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 4
ER -