Sequential multiple assignment randomized trial based on adaptive treatment strategy and its application in clinical trials_Chinese Journal of Evidence-Based Medicine

Authors：

ZHOU Sha ¹ , SHAN Zejun ² , SHUAI Yuxing ² , JI Mengmeng ³ , QIAN Zhenzhen ⁴ , JIANG Yanhua ⁵ , JING Zhiwei ⁵ , LI Hongyi ⁶ , LIU Chi ⁶ , XUAN Guowei ⁶ ,  CHEN Xinlin ² , GU Jing ⁷

1. Second Affiliated Clinical School, Guangzhou University of Chinese Medicine, Guangzhou 510403, P. R. China;
2. Basic Medical College, Guangzhou University of Chinese Medicine, Guangzhou 510006, P. R. China;
3. Ningxia Medical University, Yinchuan 750021, P. R. China;
4. Postdoctoral Station of China Academy of Chinese Medical Sciences, Beijing 100700, P. R. China;
5. Institute of Clinical Basic Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, P. R. China;
6. Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, P. R. China;
7. School of Public Health, Sun Yat-sen University, Guangzhou 510080, P. R. China;

Corresponding author：

CHEN Xinlin, Email: chenxlsums@126.com

Keywords：

Chronic disease management; Clinical trial design; Sequential multiple assignment randomized trial (SMART); Adaptive treatment strategy (ATS); Precision medicine

DOI：

10.7507/1672-2531.202404031

Video：

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The 14th Five-Year Plan for National Health explicitly proposes elevating the comprehensive prevention and control strategy for chronic diseases to a national strategy, aiming to address the growing demand for long-term management and individualized treatment of chronic diseases. In this context, the adaptive treatment strategy (ATS), as an innovative treatment model, offers new ideas and methods for the management and treatment of chronic diseases through its flexible, personalized, and scientific characteristics. To construct ATS, the sequential multiple assignment randomized trial (SMART) has emerged as a research method for multi-stage randomized controlled trials. The SMART design has been widely used in international clinical research, but there is a lack of systematic reports and studies in China. This paper first introduces the basic principles of ATS and SMART design, and then focuses on two key elements of the SMART design: re-randomization and intermediate outcomes. Based on these two elements, four major types of SMART designs are summarized, including: (1) SMART designs in which the intermediate outcome corresponds to a single re-randomization scheme (the classical type), (2) SMART designs in which no intermediate outcome is embedded, (3) SMART designs in which the intermediate outcome corresponds to a different re-randomization scheme, and (4) SMART designs in which the intermediate outcome and the previous interventions jointly determine the re-randomization. These different types of SMART designs are suited for solving different types of scientific problems. Using specific examples, this paper also analyzes the conditions under which SMART designs are applicable in clinical trials and predicts that the mainstream analysis methods for SMART designs in the future will combine frequentist statistics and Bayesian statistics. It is expected that the introduction and analysis in this paper will provide valuable references for researchers and promote the widespread application and innovative development of SMART design in the field of chronic disease prevention, control, and treatment strategies in China.

1.	Glasgow MS, Engel BT, D'Lugoff BC. A controlled study of a standardized behavioral stepped treatment for hypertension. Psychosom Med, 1989, 51(1): 10-26.
2.	Kreuter MW, Strecher VJ. Do tailored behavior change messages enhance the effectiveness of health risk appraisal. Results from a randomized trial. Health Educ Res, 1996, 11(1): 97-105.
3.	Breslin FC, Sobell MB, Sobell LC, et al. Problem drinkers: evaluation of a stepped-care approach. J Subst Abuse, 1998, 10(3): 217-232.
4.	Unützer J, Katon W, Williams JW, et al. Improving primary care for depression in late life: the design of a multicenter randomized trial. Med Care, 2001, 39(8): 785-799.
5.	Nahum-Shani I, Qian M, Almirall D, et al. Experimental design and primary data analysis methods for comparing adaptive interventions. Psychol Methods, 2012, 17(4): 457-477.
6.	Shortreed SM, Laber E, Scott Stroup T, et al. A multiple imputation strategy for sequential multiple assignment randomized trials. Stat Med, 2014, 33(24): 4202-4214.
7.	Artman WJ, Nahum-Shani I, Wu T, et al. Power analysis in a SMART design: sample size estimation for determining the best embedded dynamic treatment regime. Biostatistics, 2020, 21(3): 432-448.
8.	卜志军, 张雨欢, 孙源, 等. 序贯多分配随机试验设计样本量估算方法及应用. 现代中医临床, 2024, 31(4): 39-43.
9.	孙源, 鞠传兰, 郑薇, 等. 中医药序列多重分配随机试验设计分析思路及统计方法应用. 现代中医临床, 2024, 31(5): 86-91.
10.	周莎. 金匮泽泻汤辨治痰湿型良性阵发性位置性眩晕的SMART设计探索研究. 北京: 中国中医科学院, 2022.
11.	Murphy SA. Optimal dynamic treatment regimes. J R Stat Soc Series B Stat Methodol. 2003;65(2): 331-366.
12.	Moodie EE, Richardson TS, Stephens DA. Demystifying optimal dynamic treatment regimes. Biometrics, 2007, 63(2): 447-455.
13.	Wahed AS, Tsiatis AA. Optimal estimator for the survival distribution and related quantities for treatment policies in two-stage randomization designs in clinical trials. Biometrics, 2004, 60(1): 124-133.
14.	Collins LM, Murphy SA, Bierman KL. A conceptual framework for adaptive preventive interventions. Prev Sci, 2004, 5(3): 185-196.
15.	Dawson R, Lavori PW. Placebo-free designs for evaluating new mental health treatments: the use of adaptive treatment strategies. Stat Med, 2004, 23(21): 3249-3262.
16.	Murphy SA, McKay JR. Adaptive treatment strategies: an emerging approach for improving treatment effectiveness. Clin Sci (Lond), 2004, 12(1): 7-13.
17.	Bierman KL, Nix RL, Maples JJ, et al. Examining clinical judgment in an adaptive intervention design: the fast track program. J Consult Clin Psychol, 2006, 74(3): 468-481.
18.	Marlowe DB, Festinger DS, Arabia PL, et al. Adaptive interventions in drug court: a pilot experiment. Crim Justice Rev, 2008, 33(3): 343-360.
19.	McKay JR. Is there a case for extended interventions for alcohol and drug use disorders. Addiction, 2005, 100(11): 1594-1610.
20.	Lei H, Nahum-Shani I, Lynch K, et al. A "SMART" design for building individualized treatment sequences. Annu Rev Clin Psychol, 2012, 8: 21-48.
21.	Murphy SA. An experimental design for the development of adaptive treatment strategies. Stat Med, 2005, 24(10): 1455-1481.
22.	Lavori PW, Dawson R, Rush AJ. Flexible treatment strategies in chronic disease: clinical and research implications. Biol Psychiatry, 2000, 48(6): 605-614.
23.	Oslin DW, Sayers S, Ross J, et al. Disease management for depression and at-risk drinking via telephone in an older population of veterans. Psychosom Med, 2003, 65(6): 931-937.
24.	Wallace MP, Moodie EEM, Stephens DA. SMART thinking: a review of recent developments in sequential multiple assignment randomized trials. Curr Epidemiol Rep, 2016, 3(3): 225-232.
25.	Collins LM, Nahum-Shani I, Almirall D. Optimization of behavioral dynamic treatment regimens based on the sequential, multiple assignment, randomized trial (SMART). Clin Trials, 2014, 11(4): 426-434.
26.	Gunter L, Zhu J, Murphy S. Variable selection for qualitative interactions in personalized medicine while controlling the family-wise error rate. J Biopharm Stat, 2011, 21(6): 1063-1078.
27.	Pelham WE Jr, Hoza J, Pillow DR, et al. Effects of methylphenidate and expectancy on children with ADHD: behavior, academic performance, and attributions in a summer treatment program and regular classroom setting. J Consult Clin Psychol, 2002, 70(2): 320-335.
28.	Schoenfelder EN, Chronis-Tuscano A, Strickland J, et al. Piloting a sequential, multiple assignment, randomized trial for mothers with attention-deficit/hyperactivity disorder and their at-risk young children. J Child Adolesc Psychopharmacol, 2019, 29(4): 256-267.
29.	Horiguchi M, Tian L, Uno H, et al. Quantification of long-term survival benefit in a comparative oncology clinical study. JAMA Oncol, 2018, 4(6): 881-882.
30.	Chen TT. Statistical issues and challenges in immuno-oncology. J Immunother Cancer, 2013, 1: 18.
31.	Xu Z, Zhen B, Park Y, et al. Designing therapeutic cancer vaccine trials with delayed treatment effect. Stat Med, 2017, 36(4): 592-605.
32.	Ruppert AS, Yin J, Davidian M, et al. Application of a sequential multiple assignment randomized trial (SMART) design in older patients with chronic lymphocytic leukemia. Ann Oncol, 2019, 30(4): 542-550.
33.	Stone RM, Berg DT, George SL, et al. Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Engl J Med, 1995, 332(25): 1671-1677.
34.	Tummarello D, Mari D, Graziano F, et al. A randomized, controlled phase III study of cyclophosphamide, doxorubicin, and vincristine with etoposide (CAV-E) or teniposide (CAV-T), followed by recombinant interferon-alpha maintenance therapy or observation, in small cell lung carcinoma patients with complete responses. Cancer, 1997, 80(12): 2222-2229.
35.	Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med, 1999, 341(16): 1165-1173.
36.	Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol, 2009, 27(7): 1007-1013.
37.	Thall PF, Logothetis C, Pagliaro LC, et al. Adaptive therapy for androgen-independent prostate cancer: a randomized selection trial of four regimens. J Natl Cancer Inst, 2007, 99(21): 1613-1622.
38.	Kelleher SA, Dorfman CS, Plumb Vilardaga JC, et al. Optimizing delivery of a behavioral pain intervention in cancer patients using a sequential multiple assignment randomized trial SMART. Contemp Clin Trials, 2017, 57: 51-57.
39.	Kasari C, Kaiser A, Goods K, et al. Communication interventions for minimally verbal children with autism: a sequential multiple assignment randomized trial. J Am Acad Child Adolesc Psychiatry, 2014, 53(6): 635-646.
40.	Chevret S. Bayesian adaptive clinical trials: a dream for statisticians only. Stat Med, 2012, 31(11-12): 1002-1013.
41.	Lavori PW, Dawson R. Adaptive treatment strategies in chronic disease. Annu Rev Med, 2008, 59: 443-453.

1. Glasgow MS, Engel BT, D'Lugoff BC. A controlled study of a standardized behavioral stepped treatment for hypertension. Psychosom Med, 1989, 51(1): 10-26.
2. Kreuter MW, Strecher VJ. Do tailored behavior change messages enhance the effectiveness of health risk appraisal. Results from a randomized trial. Health Educ Res, 1996, 11(1): 97-105.
3. Breslin FC, Sobell MB, Sobell LC, et al. Problem drinkers: evaluation of a stepped-care approach. J Subst Abuse, 1998, 10(3): 217-232.
4. Unützer J, Katon W, Williams JW, et al. Improving primary care for depression in late life: the design of a multicenter randomized trial. Med Care, 2001, 39(8): 785-799.
5. Nahum-Shani I, Qian M, Almirall D, et al. Experimental design and primary data analysis methods for comparing adaptive interventions. Psychol Methods, 2012, 17(4): 457-477.
6. Shortreed SM, Laber E, Scott Stroup T, et al. A multiple imputation strategy for sequential multiple assignment randomized trials. Stat Med, 2014, 33(24): 4202-4214.
7. Artman WJ, Nahum-Shani I, Wu T, et al. Power analysis in a SMART design: sample size estimation for determining the best embedded dynamic treatment regime. Biostatistics, 2020, 21(3): 432-448.
8. 卜志军, 张雨欢, 孙源, 等. 序贯多分配随机试验设计样本量估算方法及应用. 现代中医临床, 2024, 31(4): 39-43.
9. 孙源, 鞠传兰, 郑薇, 等. 中医药序列多重分配随机试验设计分析思路及统计方法应用. 现代中医临床, 2024, 31(5): 86-91.
10. 周莎. 金匮泽泻汤辨治痰湿型良性阵发性位置性眩晕的SMART设计探索研究. 北京: 中国中医科学院, 2022.
11. Murphy SA. Optimal dynamic treatment regimes. J R Stat Soc Series B Stat Methodol. 2003;65(2): 331-366.
12. Moodie EE, Richardson TS, Stephens DA. Demystifying optimal dynamic treatment regimes. Biometrics, 2007, 63(2): 447-455.
13. Wahed AS, Tsiatis AA. Optimal estimator for the survival distribution and related quantities for treatment policies in two-stage randomization designs in clinical trials. Biometrics, 2004, 60(1): 124-133.
14. Collins LM, Murphy SA, Bierman KL. A conceptual framework for adaptive preventive interventions. Prev Sci, 2004, 5(3): 185-196.
15. Dawson R, Lavori PW. Placebo-free designs for evaluating new mental health treatments: the use of adaptive treatment strategies. Stat Med, 2004, 23(21): 3249-3262.
16. Murphy SA, McKay JR. Adaptive treatment strategies: an emerging approach for improving treatment effectiveness. Clin Sci (Lond), 2004, 12(1): 7-13.
17. Bierman KL, Nix RL, Maples JJ, et al. Examining clinical judgment in an adaptive intervention design: the fast track program. J Consult Clin Psychol, 2006, 74(3): 468-481.
18. Marlowe DB, Festinger DS, Arabia PL, et al. Adaptive interventions in drug court: a pilot experiment. Crim Justice Rev, 2008, 33(3): 343-360.
19. McKay JR. Is there a case for extended interventions for alcohol and drug use disorders. Addiction, 2005, 100(11): 1594-1610.
20. Lei H, Nahum-Shani I, Lynch K, et al. A "SMART" design for building individualized treatment sequences. Annu Rev Clin Psychol, 2012, 8: 21-48.
21. Murphy SA. An experimental design for the development of adaptive treatment strategies. Stat Med, 2005, 24(10): 1455-1481.
22. Lavori PW, Dawson R, Rush AJ. Flexible treatment strategies in chronic disease: clinical and research implications. Biol Psychiatry, 2000, 48(6): 605-614.
23. Oslin DW, Sayers S, Ross J, et al. Disease management for depression and at-risk drinking via telephone in an older population of veterans. Psychosom Med, 2003, 65(6): 931-937.
24. Wallace MP, Moodie EEM, Stephens DA. SMART thinking: a review of recent developments in sequential multiple assignment randomized trials. Curr Epidemiol Rep, 2016, 3(3): 225-232.
25. Collins LM, Nahum-Shani I, Almirall D. Optimization of behavioral dynamic treatment regimens based on the sequential, multiple assignment, randomized trial (SMART). Clin Trials, 2014, 11(4): 426-434.
26. Gunter L, Zhu J, Murphy S. Variable selection for qualitative interactions in personalized medicine while controlling the family-wise error rate. J Biopharm Stat, 2011, 21(6): 1063-1078.
27. Pelham WE Jr, Hoza J, Pillow DR, et al. Effects of methylphenidate and expectancy on children with ADHD: behavior, academic performance, and attributions in a summer treatment program and regular classroom setting. J Consult Clin Psychol, 2002, 70(2): 320-335.
28. Schoenfelder EN, Chronis-Tuscano A, Strickland J, et al. Piloting a sequential, multiple assignment, randomized trial for mothers with attention-deficit/hyperactivity disorder and their at-risk young children. J Child Adolesc Psychopharmacol, 2019, 29(4): 256-267.
29. Horiguchi M, Tian L, Uno H, et al. Quantification of long-term survival benefit in a comparative oncology clinical study. JAMA Oncol, 2018, 4(6): 881-882.
30. Chen TT. Statistical issues and challenges in immuno-oncology. J Immunother Cancer, 2013, 1: 18.
31. Xu Z, Zhen B, Park Y, et al. Designing therapeutic cancer vaccine trials with delayed treatment effect. Stat Med, 2017, 36(4): 592-605.
32. Ruppert AS, Yin J, Davidian M, et al. Application of a sequential multiple assignment randomized trial (SMART) design in older patients with chronic lymphocytic leukemia. Ann Oncol, 2019, 30(4): 542-550.
33. Stone RM, Berg DT, George SL, et al. Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Engl J Med, 1995, 332(25): 1671-1677.
34. Tummarello D, Mari D, Graziano F, et al. A randomized, controlled phase III study of cyclophosphamide, doxorubicin, and vincristine with etoposide (CAV-E) or teniposide (CAV-T), followed by recombinant interferon-alpha maintenance therapy or observation, in small cell lung carcinoma patients with complete responses. Cancer, 1997, 80(12): 2222-2229.
35. Matthay KK, Villablanca JG, Seeger RC, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med, 1999, 341(16): 1165-1173.
36. Matthay KK, Reynolds CP, Seeger RC, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol, 2009, 27(7): 1007-1013.
37. Thall PF, Logothetis C, Pagliaro LC, et al. Adaptive therapy for androgen-independent prostate cancer: a randomized selection trial of four regimens. J Natl Cancer Inst, 2007, 99(21): 1613-1622.
38. Kelleher SA, Dorfman CS, Plumb Vilardaga JC, et al. Optimizing delivery of a behavioral pain intervention in cancer patients using a sequential multiple assignment randomized trial SMART. Contemp Clin Trials, 2017, 57: 51-57.
39. Kasari C, Kaiser A, Goods K, et al. Communication interventions for minimally verbal children with autism: a sequential multiple assignment randomized trial. J Am Acad Child Adolesc Psychiatry, 2014, 53(6): 635-646.
40. Chevret S. Bayesian adaptive clinical trials: a dream for statisticians only. Stat Med, 2012, 31(11-12): 1002-1013.
41. Lavori PW, Dawson R. Adaptive treatment strategies in chronic disease. Annu Rev Med, 2008, 59: 443-453.

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