Umbrella trial for clinical trial design of oncology drugs_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZHOU Xiaoqin ^1,2 , LIU Huizhen ¹ , WANG Ting ¹ , LI Xu ¹ , SHI Fanfan ¹ ,  KANG Deying ^1,2

1. Center of Biostatistics, Design, Measurement and Evaluation (CBDME), Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China;
2. Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu, 610041, P. R. China;

Corresponding author：

KANG Deying, Email: deyingkang@126.com

Keywords：

Precision medicine; oncology drugs clinical trials; umbrella trial; same disease with different treatments

DOI：

10.7507/1007-4848.202303024

Video：

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The umbrella trial has received increasing attention in the design of clinical trials for oncology drugs in recent years. This trial design categorizes a single disease into multiple sub-types based on predictive biomarkers or other predictive factors, and simultaneously evaluates the efficacy of multiple targeted therapies. When compared with the traditional drug development model of phase Ⅰ, phaseⅡ, and phase Ⅲ randomized controlled trials, umbrella trials are a more scientifically rigorous trial design that can speed up drug evaluation to address the conflict between numerous untested drugs and diseases with a lack of effective treatment options. This article will focus on the concept, main characteristics, eligibility criteria, design and statistical considerations, ethical considerations, and future directions of umbrella trials, with the aim of providing methodological guidance for the design of clinical trials for oncology drugs.

Citation： ZHOU Xiaoqin, LIU Huizhen, WANG Ting, LI Xu, SHI Fanfan, KANG Deying. Umbrella trial for clinical trial design of oncology drugs. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2023, 30(9): 1228-1234. doi: 10.7507/1007-4848.202303024 Copy

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2.	Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med, 2017, 377(1): 62-70.
3.	高珺, 苏丽文, 袁鹰, 等. 抗肿瘤药物主方案试验设计进展及统计考量. 中国卫生统计, 2021, 38(6): 950-955.
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5.	Arteaga CL, Adamson PC, Engelman JA, et al. AACR Cancer Progress Report 2014. Clin Cancer Res, 2014, 20 (19_Suppl): S1–S112.
6.	眭瑞卿, 朱超林. 从肿瘤精准医疗创新性临床试验探讨中医辨证论治科学性. 中国中医药信息杂志, 2019, 26(4): 4.
7.	Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: Personalizing therapy for lung cancer. Cancer Discov, 2011, 1(1): 44-53.
8.	West HJ. Novel precision medicine trial designs: Umbrellas and baskets. JAMA Oncol, 2017, 3(3): 423.
9.	Mittmann N, Chan K KW, Cheung M, et al. Platform, basket, and umbrella trial designs: Stakeholder perspectives of novel therapeutics. URL: https://canjhealthtechnol.ca/index.php/cjht/article/view/nm003/786. Accessed on 2023-01-07.
10.	Renfro LA, Sargent DJ. Statistical controversies in clinical research: Basket trials, umbrella trials, and other master protocols: A review and examples. Ann Oncol, 2017, 28(1): 34-43.
11.	Biankin AV, Piantadosi S, Hollingsworth SJ. Patient-centric trials for therapeutic development in precision oncology. Nature, 2015, 526(7573): 361-370.
12.	Janiaud P, Serghiou S, Ioannidis JPA. New clinical trial designs in the era of precision medicine: An overview of definitions, strengths, weaknesses, and current use in oncology. Cancer Treat Rev, 2019, 73: 20-30.
13.	Park JJH, Siden E, Zoratti MJ, et al. Systematic review of basket trials, umbrella trials, and platform trials: A landscape analysis of master protocols. Trials, 2019, 20(1): 572.
14.	Haslam A, Olivier T, Tuia J, et al. A systematic review of basket and umbrella trials in oncology: The importance of tissue of origin and molecular target. Eur J Cancer, 2023, 178: 227-233.
15.	Menis J, Hasan B, Besse B. New clinical research strategies in thoracic oncology: Clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response. Eur Respir Rev, 2014, 23(133): 367-378.
16.	Lu CC, Li XN, Broglio K, et al. Practical considerations and recommendations for master protocol framework: Basket, umbrella and platform trials. Ther Innov Regul Sci, 2021, 55(6): 1145-1154.
17.	Bauer P, Köhne K. Evaluation of experiments with adaptive interim analyses. Biometrics, 1994, 50(4): 1029-1041.
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19.	Yee LM, McShane LM, Freidlin B, et al. Biostatistical and logistical considerations in the development of basket and umbrella clinical trials. Cancer J, 2019, 25(4): 254-263.
20.	国家药品监督管理局药品审评中心. 药物临床试验多重性问题指导原则(试行). URL: https://www.cqn.com.cn/ms/att/2021-02/09/c357919b-b8ca-4c30-a8d0-8e5d2c70fb93.pdf. Accessed on 2020-12-31.
21.	国家药品监督管理局药品审评中心. 抗肿瘤药物临床试验统计学设计指导原则(试行). URL: https://www.cde.org.cn/main/news/viewInfoCommon/b8a33e6df753b13e091b83b8d5a412f8. Accessed on 2020-12-31.
22.	Collignon O, Gartner C, Haidich AB, et al. Current statistical considerations and regulatory perspectives on the planning of confirmatory basket, umbrella, and platform trials. Clin Pharmacol Ther, 2020, 107(5): 1059-1067.
23.	Parker RA, Weir CJ. Non-adjustment for multiple testing in multi-arm trials of distinct treatments: Rationale and justification. Clin Trials, 2020, 17(5): 562-566.
24.	Bretz F, Koenig F. Commentary on parker and weir. Clin Trials, 2020, 17(5): 567-569.
25.	Bai X, Deng Q, Liu D. Multiplicity issues for platform trials with a shared control arm. J Biopharm Stat, 2020, 30(6): 1077-1090.
26.	Dmitrienko A, D'Agostino RB Sr. Multiplicity considerations in clinical trials. N Engl J Med, 2018, 378(22): 2115-2122.
27.	Gutjahr G, Posch M, Brannath W. Familywise error control in multi-armed response-adaptive two-stage designs. J Biopharm Stat, 2011, 21(4): 818-830.
28.	Robertson DS, Wason JMS. Familywise error control in multi-armed response-adaptive trials. Biometrics, 2019, 75(3): 885-894.
29.	Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA, 2000, 283(20): 2701-2711.
30.	Strzebonska K, Waligora M. Umbrella and basket trials in oncology: Ethical challenges. BMC Med Ethics, 2019, 20(1): 58.
31.	Flaherty KT, Gray RJ, Chen AP, et al. Molecular landscape and actionable alterations in a genomically guided cancer clinical trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH). J Clin Oncol, 2020, 38(33): 3883-3894.
32.	Rasheed AA, Koyyala VPB. Newer trial designs. Ind J Med Paediatr Oncol, 2021, 42: 96-98.
33.	Jung SH. Statistical issues for design and analysis of single-arm multi-stage phase Ⅱ cancer clinical trials. Contemp Clin Trials, 2015, 42: 9-17.
34.	Ouma LO, Wason JMS, Zheng H, et al. Design and analysis of umbrella trials: Where do we stand? Front Med (Lausanne), 2022, 9: 1037439.
35.	Kang D, Coffey CS, Smith BJ, et al. Hierarchical Bayesian clustering design of multiple biomarker subgroups (HCOMBS). Stat Med, 2021, 40(12): 2893-2921.
36.	Zang Y, Guo B, Han Y, et al. A Bayesian adaptive marker-stratified design for molecularly targeted agents with customized hierarchical modeling. Stat Med, 2019, 38(15): 2883-2896.
37.	Tarride JE, Cheung M, Hanna TP, et al. Platform, basket, and umbrella trial designs: Issues around health technology assessment of novel therapeutics. Can J Health Technol, 2022, 2(7): 1-21.
38.	Strzebonska K, Blukacz M, Wasylewski MT, et al. Risk and benefit for umbrella trials in oncology: A systematic review and meta-analysis. BMC Med, 2022, 20(1): 219.

1. Park JJH, Hsu G, Siden EG, et al. An overview of precision oncology basket and umbrella trials for clinicians. CA Cancer J Clin, 2020, 70(2): 125-137.
2. Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med, 2017, 377(1): 62-70.
3. 高珺, 苏丽文, 袁鹰, 等. 抗肿瘤药物主方案试验设计进展及统计考量. 中国卫生统计, 2021, 38(6): 950-955.
4. 于亚南, 杜培艳, 刘骏, 等. 精准医学创新性临床试验设计“主方案”研究的概念、设计与案例. 中国新药杂志, 2020, 29(23): 2712-2717.
5. Arteaga CL, Adamson PC, Engelman JA, et al. AACR Cancer Progress Report 2014. Clin Cancer Res, 2014, 20 (19_Suppl): S1–S112.
6. 眭瑞卿, 朱超林. 从肿瘤精准医疗创新性临床试验探讨中医辨证论治科学性. 中国中医药信息杂志, 2019, 26(4): 4.
7. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: Personalizing therapy for lung cancer. Cancer Discov, 2011, 1(1): 44-53.
8. West HJ. Novel precision medicine trial designs: Umbrellas and baskets. JAMA Oncol, 2017, 3(3): 423.
9. Mittmann N, Chan K KW, Cheung M, et al. Platform, basket, and umbrella trial designs: Stakeholder perspectives of novel therapeutics. URL: https://canjhealthtechnol.ca/index.php/cjht/article/view/nm003/786. Accessed on 2023-01-07.
10. Renfro LA, Sargent DJ. Statistical controversies in clinical research: Basket trials, umbrella trials, and other master protocols: A review and examples. Ann Oncol, 2017, 28(1): 34-43.
11. Biankin AV, Piantadosi S, Hollingsworth SJ. Patient-centric trials for therapeutic development in precision oncology. Nature, 2015, 526(7573): 361-370.
12. Janiaud P, Serghiou S, Ioannidis JPA. New clinical trial designs in the era of precision medicine: An overview of definitions, strengths, weaknesses, and current use in oncology. Cancer Treat Rev, 2019, 73: 20-30.
13. Park JJH, Siden E, Zoratti MJ, et al. Systematic review of basket trials, umbrella trials, and platform trials: A landscape analysis of master protocols. Trials, 2019, 20(1): 572.
14. Haslam A, Olivier T, Tuia J, et al. A systematic review of basket and umbrella trials in oncology: The importance of tissue of origin and molecular target. Eur J Cancer, 2023, 178: 227-233.
15. Menis J, Hasan B, Besse B. New clinical research strategies in thoracic oncology: Clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response. Eur Respir Rev, 2014, 23(133): 367-378.
16. Lu CC, Li XN, Broglio K, et al. Practical considerations and recommendations for master protocol framework: Basket, umbrella and platform trials. Ther Innov Regul Sci, 2021, 55(6): 1145-1154.
17. Bauer P, Köhne K. Evaluation of experiments with adaptive interim analyses. Biometrics, 1994, 50(4): 1029-1041.
18. 国家食品药品监督管理总局. 药物临床试验的生物统计学指导原则. URL: https://www.nmpa.gov.cn/directory/web/nmpa/xxgk/ggtg/qtggtg/201606031612.01857.html. Accessed on 2016-06-03.
19. Yee LM, McShane LM, Freidlin B, et al. Biostatistical and logistical considerations in the development of basket and umbrella clinical trials. Cancer J, 2019, 25(4): 254-263.
20. 国家药品监督管理局药品审评中心. 药物临床试验多重性问题指导原则(试行). URL: https://www.cqn.com.cn/ms/att/2021-02/09/c357919b-b8ca-4c30-a8d0-8e5d2c70fb93.pdf. Accessed on 2020-12-31.
21. 国家药品监督管理局药品审评中心. 抗肿瘤药物临床试验统计学设计指导原则(试行). URL: https://www.cde.org.cn/main/news/viewInfoCommon/b8a33e6df753b13e091b83b8d5a412f8. Accessed on 2020-12-31.
22. Collignon O, Gartner C, Haidich AB, et al. Current statistical considerations and regulatory perspectives on the planning of confirmatory basket, umbrella, and platform trials. Clin Pharmacol Ther, 2020, 107(5): 1059-1067.
23. Parker RA, Weir CJ. Non-adjustment for multiple testing in multi-arm trials of distinct treatments: Rationale and justification. Clin Trials, 2020, 17(5): 562-566.
24. Bretz F, Koenig F. Commentary on parker and weir. Clin Trials, 2020, 17(5): 567-569.
25. Bai X, Deng Q, Liu D. Multiplicity issues for platform trials with a shared control arm. J Biopharm Stat, 2020, 30(6): 1077-1090.
26. Dmitrienko A, D'Agostino RB Sr. Multiplicity considerations in clinical trials. N Engl J Med, 2018, 378(22): 2115-2122.
27. Gutjahr G, Posch M, Brannath W. Familywise error control in multi-armed response-adaptive two-stage designs. J Biopharm Stat, 2011, 21(4): 818-830.
28. Robertson DS, Wason JMS. Familywise error control in multi-armed response-adaptive trials. Biometrics, 2019, 75(3): 885-894.
29. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA, 2000, 283(20): 2701-2711.
30. Strzebonska K, Waligora M. Umbrella and basket trials in oncology: Ethical challenges. BMC Med Ethics, 2019, 20(1): 58.
31. Flaherty KT, Gray RJ, Chen AP, et al. Molecular landscape and actionable alterations in a genomically guided cancer clinical trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH). J Clin Oncol, 2020, 38(33): 3883-3894.
32. Rasheed AA, Koyyala VPB. Newer trial designs. Ind J Med Paediatr Oncol, 2021, 42: 96-98.
33. Jung SH. Statistical issues for design and analysis of single-arm multi-stage phase Ⅱ cancer clinical trials. Contemp Clin Trials, 2015, 42: 9-17.
34. Ouma LO, Wason JMS, Zheng H, et al. Design and analysis of umbrella trials: Where do we stand? Front Med (Lausanne), 2022, 9: 1037439.
35. Kang D, Coffey CS, Smith BJ, et al. Hierarchical Bayesian clustering design of multiple biomarker subgroups (HCOMBS). Stat Med, 2021, 40(12): 2893-2921.
36. Zang Y, Guo B, Han Y, et al. A Bayesian adaptive marker-stratified design for molecularly targeted agents with customized hierarchical modeling. Stat Med, 2019, 38(15): 2883-2896.
37. Tarride JE, Cheung M, Hanna TP, et al. Platform, basket, and umbrella trial designs: Issues around health technology assessment of novel therapeutics. Can J Health Technol, 2022, 2(7): 1-21.
38. Strzebonska K, Blukacz M, Wasylewski MT, et al. Risk and benefit for umbrella trials in oncology: A systematic review and meta-analysis. BMC Med, 2022, 20(1): 219.

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