Methodological progress and challenges of oncology drug umbrella clinical trials in the context of precision medicine_Chinese Journal of Evidence-Based Medicine

Authors：

XU Caihua ¹ , ZHOU Yongjia ¹ , CUI Yating ¹ , WANG Junfei ¹ , ZHU Yonghong ² ,  TIAN Jinhui ^1,3,4 ,  ZHANG Junhua ⁵

1. Center for Evidence-based Medicine, School of Basic Medicine, Lanzhou University, Lanzhou 730000, P. R. China;
2. Gansu Pharmaceutical Group Science and Technology Innovation Research Institute Co., Lanzhou 730102, P. R. China;
3. Key Laboratory of Evidence-based Medicine of Gansu Province, School of Basic Medicine, Lanzhou University, Lanzhou 730000, P. R. China;
4. Research Unit of Evidence-Based Evaluation and Guidelines, Chinese Academy of Medical Sciences, School of Basic Medicine, Lanzhou University, Lanzhou 730000, P. R. China;
5. Evidence-based Medicine Center, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, P. R. China;

Corresponding author：

TIAN Jinhui, Email: tjh996@163.com; ZHANG Junhua, Email: zjhtcm@foxmail.com

Keywords：

Umbrella trials; Methodology; Research progress; Challenges

DOI：

10.7507/1672-2531.202506019

Video：

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This paper explores the methodological characteristics and key considerations of umbrella trials. By allocating different treatment strategies based on patients' molecular features, umbrella trials significantly enhance screening efficiency and can quickly identify ineffective therapies. Through the analysis of patient allocation strategies, statistical model selection, and error control methods, we can better utilize this design to accelerate drug development and achieve more efficient personalized treatment. However, despite significant progress in methodology and practice, umbrella trials still face multiple challenges during implementation, including trial design, sample size calculation, patient recruitment, informed consent, and resource allocation. Addressing these challenges in the future will help further optimize the application of umbrella trials. This study aims to provide thoughts and inspirations for researchers conducting umbrella trials and promote the steady development of this field.

Citation： XU Caihua, ZHOU Yongjia, CUI Yating, WANG Junfei, ZHU Yonghong, TIAN Jinhui, ZHANG Junhua. Methodological progress and challenges of oncology drug umbrella clinical trials in the context of precision medicine. Chinese Journal of Evidence-Based Medicine, 2025, 25(10): 1197-1203. doi: 10.7507/1672-2531.202506019 Copy

1.	吴涵, 姜德春. 新型抗肿瘤药物的个体化治疗基础与临床研究新进展. 中国临床药学杂志, 2025, 34(4): 315-320.
2.	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.
3.	孙荣国, 贾晓蓉. 我国精准医学的探讨. 华西医学, 2016, 31(12): 2076-2078.
4.	孙源, 张玲. 主方案设计的研究方法在精准医学中的应用. 中国循证医学杂志, 2023, 23(4): 465-470.
5.	Redman MW, Allegra CJ. The master protocol concept. Semin Oncol, 2015, 42(5): 724-730.
6.	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): 1145-1115.
7.	Arteaga CL, Adamson PC, Engelman JA, et al. AACR cancer progress report 2014. Clin Cancer Res, 2014, 20(19 Suppl): S1-S112.
8.	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.
9.	Zhou T, Zhang J. Types and progress of clinical trial design for breast cancer: a narrative review. Transl Breast Cancer Res, 2023, 4: 20.
10.	张怡君, 田雪, 胥芹, 等. 篮式研究和伞式研究及案例分析. 中国卒中杂志, 2023, 18(2): 240-243.
11.	Yin J, Shen S, Shi Q. Challenges, opportunities, and innovative statistical designs for precision oncology trials. Ann Transl Med, 2022, 10(18): 1038.
12.	Ouma LO, Wason JMS, Zheng H, et al. Design and analysis of umbrella trials: where do we stand. Front Med (Lausanne), 2022, 9: 1037439.
13.	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.
14.	Kesselmeier M, Benda N, Scherag A. Effect size estimates from umbrella designs: handling patients with a positive test result for multiple biomarkers using random or pragmatic subtrial allocation. PLoS One, 2020, 15(8): e0237441.
15.	Wason JMS, Brocklehurst P, Yap C. When to keep it simple - adaptive designs are not always useful. BMC Med, 2019, 17(1): 152.
16.	Wason JM, Abraham JE, Baird RD, et al. A Bayesian adaptive design for biomarker trials with linked treatments. Br J Cancer, 2015, 113(5): 699-705.
17.	Liu Q, Yu W, Gao L, et al. A Bayesian adaptive umbrella trial design with robust information borrowing for screening multiple combination therapies. Stat Biopharm Res, 2023, 16(2): 171-180.
18.	Kang D, Coffey CS, Smith BJ, et al. Hierarchical Bayesian clustering design of multiple biomarker subgroups (HCOMBS). Stat Med, 2021, 40(12): 2893-2921.
19.	Wang X, Ji X. Sample size estimation in clinical research: from randomized controlled trials to observational studies. Chest, 2020, 158(1S): S12-S20.
20.	周小芹, 刘慧珍, 王婷, 等. 肿瘤药物临床试验设计之伞式试验. 中国胸心血管外科临床杂志, 2023, 30(9): 1228-1233.
21.	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.
22.	Simon R. Optimal two-stage designs for phase Ⅱ clinical trials. Control Clin Trials, 1989, 10(1): 1-10.
23.	Mander AP, Thompson SG. Two-stage designs optimal under the alternative hypothesis for phase Ⅱ cancer clinical trials. Contemp Clin Trials, 2010, 31(6): 572-578.
24.	Yi C, Bian D, Wang J, et al. Anti-PD1 based precision induction therapy in unresectable stage Ⅲ non-small cell lung cancer: a phase II umbrella clinical trial. Nat Commun, 2025, 16(1): 1932.
25.	Lee SY. Using Bayesian statistics in confirmatory clinical trials in the regulatory setting: a tutorial review. BMC Med Res Methodol, 2024, 24(1): 110.
26.	Matsuyama Y, Sakamoto J, Ohashi Y. A Bayesian hierarchical survival model for the institutional effects in a multi-centre cancer clinical trial. Stat Med, 1998, 17(17): 1893-1908.
27.	Yada S, Hamada C. A Bayesian hierarchal modeling approach to shortening phase Ⅰ/Ⅱ trials of anticancer drug combinations. Pharm Stat, 2018, 17(6): 750-760.
28.	Berry SM, Broglio KR, Groshen S, et al. Bayesian hierarchical modeling of patient subpopulations: efficient designs of Phase Ⅱ oncology clinical trials. Clin Trials, 2013, 10(5): 720-734.
29.	Lee JJ, Xuemin Gu, Suyu Liu. Bayesian adaptive randomization designs for targeted agent development. Clin Trials, 2010, 7(5): 584-596.
30.	熊海燕, 罗剑锋, 王伟炳. 药物临床试验的设计创新和技术创新. 复旦学报(医学版), 2025, 52(1): 153-158.
31.	Liu Y, Xu H. Sample size re-estimation for pivotal clinical trials. Contemp Clin Trials, 2021, 102: 106215.
32.	Hade EM, Young GS, Love RR. Follow up after sample size re-estimation in a breast cancer randomized trial for disease-free survival. Trials, 2019, 20(1): 527.
33.	Kim S, Wong WK. Spatial two-stage designs for phase Ⅱ clinical trials. Comput Stat Data Anal, 2022, 169: 107420.
34.	Stallard N, Todd S, Parashar D, et al. On the need to adjust for multiplicity in confirmatory clinical trials with master protocols. Ann Oncol, 2019, 30(4): 506-509.
35.	Ren Y, Li X, Chen C. Statistical considerations of phase 3 umbrella trials allowing adding one treatment arm mid-trial. Contemp Clin Trials, 2021, 109: 106538.
36.	Ballarini NM, Burnett T, Jaki T, et al. Optimizing subgroup selection in two-stage adaptive enrichment and umbrella designs. Stat Med, 2021, 40(12): 2939-2956.
37.	Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov, 2011, 1(1): 44-53.

1. 吴涵, 姜德春. 新型抗肿瘤药物的个体化治疗基础与临床研究新进展. 中国临床药学杂志, 2025, 34(4): 315-320.
2. 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.
3. 孙荣国, 贾晓蓉. 我国精准医学的探讨. 华西医学, 2016, 31(12): 2076-2078.
4. 孙源, 张玲. 主方案设计的研究方法在精准医学中的应用. 中国循证医学杂志, 2023, 23(4): 465-470.
5. Redman MW, Allegra CJ. The master protocol concept. Semin Oncol, 2015, 42(5): 724-730.
6. 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): 1145-1115.
7. Arteaga CL, Adamson PC, Engelman JA, et al. AACR cancer progress report 2014. Clin Cancer Res, 2014, 20(19 Suppl): S1-S112.
8. 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.
9. Zhou T, Zhang J. Types and progress of clinical trial design for breast cancer: a narrative review. Transl Breast Cancer Res, 2023, 4: 20.
10. 张怡君, 田雪, 胥芹, 等. 篮式研究和伞式研究及案例分析. 中国卒中杂志, 2023, 18(2): 240-243.
11. Yin J, Shen S, Shi Q. Challenges, opportunities, and innovative statistical designs for precision oncology trials. Ann Transl Med, 2022, 10(18): 1038.
12. Ouma LO, Wason JMS, Zheng H, et al. Design and analysis of umbrella trials: where do we stand. Front Med (Lausanne), 2022, 9: 1037439.
13. 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.
14. Kesselmeier M, Benda N, Scherag A. Effect size estimates from umbrella designs: handling patients with a positive test result for multiple biomarkers using random or pragmatic subtrial allocation. PLoS One, 2020, 15(8): e0237441.
15. Wason JMS, Brocklehurst P, Yap C. When to keep it simple - adaptive designs are not always useful. BMC Med, 2019, 17(1): 152.
16. Wason JM, Abraham JE, Baird RD, et al. A Bayesian adaptive design for biomarker trials with linked treatments. Br J Cancer, 2015, 113(5): 699-705.
17. Liu Q, Yu W, Gao L, et al. A Bayesian adaptive umbrella trial design with robust information borrowing for screening multiple combination therapies. Stat Biopharm Res, 2023, 16(2): 171-180.
18. Kang D, Coffey CS, Smith BJ, et al. Hierarchical Bayesian clustering design of multiple biomarker subgroups (HCOMBS). Stat Med, 2021, 40(12): 2893-2921.
19. Wang X, Ji X. Sample size estimation in clinical research: from randomized controlled trials to observational studies. Chest, 2020, 158(1S): S12-S20.
20. 周小芹, 刘慧珍, 王婷, 等. 肿瘤药物临床试验设计之伞式试验. 中国胸心血管外科临床杂志, 2023, 30(9): 1228-1233.
21. 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.
22. Simon R. Optimal two-stage designs for phase Ⅱ clinical trials. Control Clin Trials, 1989, 10(1): 1-10.
23. Mander AP, Thompson SG. Two-stage designs optimal under the alternative hypothesis for phase Ⅱ cancer clinical trials. Contemp Clin Trials, 2010, 31(6): 572-578.
24. Yi C, Bian D, Wang J, et al. Anti-PD1 based precision induction therapy in unresectable stage Ⅲ non-small cell lung cancer: a phase II umbrella clinical trial. Nat Commun, 2025, 16(1): 1932.
25. Lee SY. Using Bayesian statistics in confirmatory clinical trials in the regulatory setting: a tutorial review. BMC Med Res Methodol, 2024, 24(1): 110.
26. Matsuyama Y, Sakamoto J, Ohashi Y. A Bayesian hierarchical survival model for the institutional effects in a multi-centre cancer clinical trial. Stat Med, 1998, 17(17): 1893-1908.
27. Yada S, Hamada C. A Bayesian hierarchal modeling approach to shortening phase Ⅰ/Ⅱ trials of anticancer drug combinations. Pharm Stat, 2018, 17(6): 750-760.
28. Berry SM, Broglio KR, Groshen S, et al. Bayesian hierarchical modeling of patient subpopulations: efficient designs of Phase Ⅱ oncology clinical trials. Clin Trials, 2013, 10(5): 720-734.
29. Lee JJ, Xuemin Gu, Suyu Liu. Bayesian adaptive randomization designs for targeted agent development. Clin Trials, 2010, 7(5): 584-596.
30. 熊海燕, 罗剑锋, 王伟炳. 药物临床试验的设计创新和技术创新. 复旦学报(医学版), 2025, 52(1): 153-158.
31. Liu Y, Xu H. Sample size re-estimation for pivotal clinical trials. Contemp Clin Trials, 2021, 102: 106215.
32. Hade EM, Young GS, Love RR. Follow up after sample size re-estimation in a breast cancer randomized trial for disease-free survival. Trials, 2019, 20(1): 527.
33. Kim S, Wong WK. Spatial two-stage designs for phase Ⅱ clinical trials. Comput Stat Data Anal, 2022, 169: 107420.
34. Stallard N, Todd S, Parashar D, et al. On the need to adjust for multiplicity in confirmatory clinical trials with master protocols. Ann Oncol, 2019, 30(4): 506-509.
35. Ren Y, Li X, Chen C. Statistical considerations of phase 3 umbrella trials allowing adding one treatment arm mid-trial. Contemp Clin Trials, 2021, 109: 106538.
36. Ballarini NM, Burnett T, Jaki T, et al. Optimizing subgroup selection in two-stage adaptive enrichment and umbrella designs. Stat Med, 2021, 40(12): 2939-2956.
37. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov, 2011, 1(1): 44-53.

Chinese Journal of Evidence-Based Medicine

Methodological progress and challenges of oncology drug umbrella clinical trials in the context of precision medicine

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