Incorporating external controls in the design of randomized clinical trials: a case study in solid tumors
Abstract Background The use of historical external control data in clinical trials has grown in interest and needs when considering the design of future trials. Hybrid control designs can be more efficient to achieve the same power with fewer patients and limited resources. The literature is sparse...
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| Language: | English |
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BMC
2024-11-01
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| Series: | BMC Medical Research Methodology |
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| Online Access: | https://doi.org/10.1186/s12874-024-02383-3 |
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| author | Emily M. Damone Jiawen Zhu Herbert Pang Xiao Li Yinqi Zhao Evan Kwiatkowski Lisa A. Carey Joseph G. Ibrahim |
| author_facet | Emily M. Damone Jiawen Zhu Herbert Pang Xiao Li Yinqi Zhao Evan Kwiatkowski Lisa A. Carey Joseph G. Ibrahim |
| author_sort | Emily M. Damone |
| collection | DOAJ |
| description | Abstract Background The use of historical external control data in clinical trials has grown in interest and needs when considering the design of future trials. Hybrid control designs can be more efficient to achieve the same power with fewer patients and limited resources. The literature is sparse on appropriate statistical methods which can account for the differences between historical external controls and the control patients in a study. In this article, we illustrate the analysis framework of a clinical trial if a hybrid control design was used after determining an RCT may not be feasible. Methods We utilize two previously completed RCTs in nonsquamous NSCLC and a nationwide electronic health record derived de-identified database as examples and compare 5 analysis methods on each trial, as well as a set of simulations to determine operating characteristics of such designs. Results In single trial estimation, the Case Weighted Adaptive Power Prior provided estimated treatment hazard ratios consistent with the original trial’s conclusions with narrower confidence intervals. The simulation studies showed that the Case Weighted Adaptive Power Prior achieved the highest power (and well controlled type-1 error) across all 5 methods with consistent study sample size. Conclusions By following the proposed hybrid control framework, one can design a hybrid control trial transparently and accounting for differences between control groups while controlling type-1 error and still achieving efficiency gains from the additional contribution from external controls. |
| format | Article |
| id | doaj-art-6c68a2c8c1394e53b40271a7af99da10 |
| institution | OA Journals |
| issn | 1471-2288 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Research Methodology |
| spelling | doaj-art-6c68a2c8c1394e53b40271a7af99da102025-08-20T02:18:25ZengBMCBMC Medical Research Methodology1471-22882024-11-012411910.1186/s12874-024-02383-3Incorporating external controls in the design of randomized clinical trials: a case study in solid tumorsEmily M. Damone0Jiawen Zhu1Herbert Pang2Xiao Li3Yinqi Zhao4Evan Kwiatkowski5Lisa A. Carey6Joseph G. Ibrahim7Department of Biostatistics, University of North CarolinaDepartment of Data Science, Product Development, Genentech, IncDepartment of Data Science, Product Development, Genentech, IncDepartment of Personalized Healthcare, Product Development, Genentech, IncDepartment of Data Science, Product Development, Genentech, IncDepartment of Biostatistics, University of Texas MD Anderson Cancer CenterDivision of Oncology, University of North CarolinaDepartment of Biostatistics, University of North CarolinaAbstract Background The use of historical external control data in clinical trials has grown in interest and needs when considering the design of future trials. Hybrid control designs can be more efficient to achieve the same power with fewer patients and limited resources. The literature is sparse on appropriate statistical methods which can account for the differences between historical external controls and the control patients in a study. In this article, we illustrate the analysis framework of a clinical trial if a hybrid control design was used after determining an RCT may not be feasible. Methods We utilize two previously completed RCTs in nonsquamous NSCLC and a nationwide electronic health record derived de-identified database as examples and compare 5 analysis methods on each trial, as well as a set of simulations to determine operating characteristics of such designs. Results In single trial estimation, the Case Weighted Adaptive Power Prior provided estimated treatment hazard ratios consistent with the original trial’s conclusions with narrower confidence intervals. The simulation studies showed that the Case Weighted Adaptive Power Prior achieved the highest power (and well controlled type-1 error) across all 5 methods with consistent study sample size. Conclusions By following the proposed hybrid control framework, one can design a hybrid control trial transparently and accounting for differences between control groups while controlling type-1 error and still achieving efficiency gains from the additional contribution from external controls.https://doi.org/10.1186/s12874-024-02383-3Hybrid clinical trialsHistorical controlsReal world dataClinical trials |
| spellingShingle | Emily M. Damone Jiawen Zhu Herbert Pang Xiao Li Yinqi Zhao Evan Kwiatkowski Lisa A. Carey Joseph G. Ibrahim Incorporating external controls in the design of randomized clinical trials: a case study in solid tumors BMC Medical Research Methodology Hybrid clinical trials Historical controls Real world data Clinical trials |
| title | Incorporating external controls in the design of randomized clinical trials: a case study in solid tumors |
| title_full | Incorporating external controls in the design of randomized clinical trials: a case study in solid tumors |
| title_fullStr | Incorporating external controls in the design of randomized clinical trials: a case study in solid tumors |
| title_full_unstemmed | Incorporating external controls in the design of randomized clinical trials: a case study in solid tumors |
| title_short | Incorporating external controls in the design of randomized clinical trials: a case study in solid tumors |
| title_sort | incorporating external controls in the design of randomized clinical trials a case study in solid tumors |
| topic | Hybrid clinical trials Historical controls Real world data Clinical trials |
| url | https://doi.org/10.1186/s12874-024-02383-3 |
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