Exploring the application of Zelen design in real-world studies_Chinese Journal of Evidence-Based Medicine

Authors：

JIA Yulong ^1,2,3 , YAO Minghong ^1,2,3 , XU Jiayue ^1,2,3 , WANG Yuning ^1,2,3 , LIN Kai ^2,5 , LI Yaohua ⁴ , WEI Chunmin ⁴ , ZOU Kang ^1,2,3 ,  REN Yan ^1,2,3 ,  SUN Xin ^1,2,3

1. Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu 610041, P. R. China;
3. Sichuan Center of Technology Innovation for Real World Data, Chengdu 610041, P. R. China;
4. Hainan Provincial Drug and Medical Device Evaluation Service Center, Haikou 570216, P. R. China;
5. Center for Adverse Drug Reaction Monitoring of Boao Pilot Zone, Qionghai 571435, P. R. China;

Corresponding author：

REN Yan, Email: ren_yan87@163.com; SUN Xin, Email: sunxin@wchscu.cn

Keywords：

Clinical trial; Zelen design; Informed consent; Real-world study

DOI：

10.7507/1672-2531.202202025

Video：

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With the gradual standardization and improvement of the real-world study system, real-world evidence, as a supplement to evidence from classical randomized controlled trials, is increasingly used to evaluate the effectiveness and safety of pharmaceuticals and medical devices. High-quality real-world evidence is not only related to the quality of real-world data, but also depends on the type of study design. Therefore, as one of the important designs for pragmatic clinical trials, the Zelen design has received much attention from investigators in recent years. This paper discussed the implementation processes, subtypes of design, advantages, limitations, statistical concerns, and appropriate application scenarios of the Zelen design, on the basis of published papers, in order to clarify its application value, and to provide references for future research.

Citation： JIA Yulong, YAO Minghong, XU Jiayue, WANG Yuning, LIN Kai, LI Yaohua, WEI Chunmin, ZOU Kang, REN Yan, SUN Xin. Exploring the application of Zelen design in real-world studies. Chinese Journal of Evidence-Based Medicine, 2022, 22(5): 615-620. doi: 10.7507/1672-2531.202202025 Copy

1.	国家药品监督管理局药品审评中心. 真实世界证据支持药物研发与审评的指导原则(试行), 2020. Available at: https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20200107151901190.html.
2.	国家药品监督管理局. 真实世界数据用于医疗器械临床评价技术指导原则(试行), 2020. Available at: https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20201126090030150.html.
3.	Zelen M. A new design for randomized clinical trials. N Engl J Med, 1979, 300(22): 1242-1245.
4.	Kim SY, Flory J, Relton C. Ethics and practice of trials within cohorts: an emerging pragmatic trial design. Clin Trials, 2018, 15(1): 9-16.
5.	Simon GE, Shortreed SM, DeBar LL. Zelen design clinical trials: why, when, and how. Trials, 2021, 22(1): 541.
6.	周奋, 詹绍康. 随机化临床试验新的设计方案探讨. 数理医药学杂志, 1993, (3): 36-38.
7.	Kalkman S, van Thiel GJMW, Zuidgeest MGP, et al. Series: Pragmatic trials and real world evidence: Paper 4. Informed consent. J Clin Epidemiol, 2017, 89: 181-187.
8.	Horwitz RI, Feinstein AR. Advantages and drawbacks of the zelen design for randomized clinical trials. J Clin Pharmacol, 1980, 20(7): 425-427.
9.	Velthuis MJ, May AM, Monninkhof EM, et al. Alternatives for randomization in lifestyle intervention studies in cancer patients were not better than conventional randomization. J Clin Epidemiol, 2012, 65(3): 288-292.
10.	Touzet S, Occelli P, Schröder C, et al. Impact of the early start denver model on the cognitive level of children with autism spectrum disorder: study protocol for a randomised controlled trial using a two-stage Zelen design. BMJ Open, 2017, 7(3): e014730.
11.	Faden R, Kass N, Whicher D, et al. Ethics and informed consent for comparative effectiveness research with prospective electronic clinical data. Med Care, 2013, 51(Suppl 3): S53-S57.
12.	McHugh R. Validity and treatment dilution in Zelen's single consent design. Stat Med, 1984, 3(3): 215-218.
13.	Zelen M. Randomized consent designs for clinical trials: an update. Stat Med, 1990, 9(6): 645-656.
14.	Anbar D. The relative efficiency of zelen's prerandomization design for clinical trials. Biometrics, 1983, 39(3): 711-718.
15.	Altman DG, Whitehead J, Parmar MK, et al. Randomised consent designs in cancer clinical trials. Eur J Cancer, 1995, 31A(12): 1934-1944.
16.	Haynes B. Can it work. Does it work? Is it worth it? The testing of healthcareinterventions is evolving. BMJ, 1999, 319(7211): 652-653.
17.	Homer CS. Using the Zelen design in randomized controlled trials: debates and controversies. J Adv Nurs, 2002, 38(2): 200-207.
18.	Campbell R, Peters T, Grant C, et al. Adapting the randomized consent (Zelen) design for trials of behavioural interventions for chronic disease: feasibility study. J Health Serv Res Policy, 2005, 10(4): 220-225.
19.	Land J, McCourt O, Heinrich M, et al. The adapted Zelen was a feasible design to trial exercise in myeloma survivors. J Clin Epidemiol, 2020, 125: 76-83.
20.	王雯, 谭婧, 任燕, 等. 重新认识真实世界数据研究: 更新与展望. 中国循证医学杂志, 2020, 20(11): 1241-1246.
21.	Langan SM, Schmidt SA, Wing K, et al. The reporting of studies conducted using observational routinely collected health data statement for pharmacoepidemiology (RECORD-PE). BMJ, 2018, 363: k3532.
22.	Torgerson DJ, Roland M. What is Zelen's design. BMJ, 1998, 316(7131): 606.
23.	Koutoukidis DA, Land J, Hackshaw A, et al. Fatigue, quality of life and physical fitness following an exercise intervention in multiple myeloma survivors (MASCOT): an exploratory randomised Phase 2 trial utilising a modified Zelen design. Br J Cancer, 2020, 123(2): 187-195.
24.	Faseru B, Ellerbeck EF, Catley D, et al. Changing the default for tobacco-cessation treatment in an inpatient setting: study protocol of a randomized controlled trial. Trials, 2017, 18(1): 379.

1. 国家药品监督管理局药品审评中心. 真实世界证据支持药物研发与审评的指导原则(试行), 2020. Available at: https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20200107151901190.html.
2. 国家药品监督管理局. 真实世界数据用于医疗器械临床评价技术指导原则(试行), 2020. Available at: https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20201126090030150.html.
3. Zelen M. A new design for randomized clinical trials. N Engl J Med, 1979, 300(22): 1242-1245.
4. Kim SY, Flory J, Relton C. Ethics and practice of trials within cohorts: an emerging pragmatic trial design. Clin Trials, 2018, 15(1): 9-16.
5. Simon GE, Shortreed SM, DeBar LL. Zelen design clinical trials: why, when, and how. Trials, 2021, 22(1): 541.
6. 周奋, 詹绍康. 随机化临床试验新的设计方案探讨. 数理医药学杂志, 1993, (3): 36-38.
7. Kalkman S, van Thiel GJMW, Zuidgeest MGP, et al. Series: Pragmatic trials and real world evidence: Paper 4. Informed consent. J Clin Epidemiol, 2017, 89: 181-187.
8. Horwitz RI, Feinstein AR. Advantages and drawbacks of the zelen design for randomized clinical trials. J Clin Pharmacol, 1980, 20(7): 425-427.
9. Velthuis MJ, May AM, Monninkhof EM, et al. Alternatives for randomization in lifestyle intervention studies in cancer patients were not better than conventional randomization. J Clin Epidemiol, 2012, 65(3): 288-292.
10. Touzet S, Occelli P, Schröder C, et al. Impact of the early start denver model on the cognitive level of children with autism spectrum disorder: study protocol for a randomised controlled trial using a two-stage Zelen design. BMJ Open, 2017, 7(3): e014730.
11. Faden R, Kass N, Whicher D, et al. Ethics and informed consent for comparative effectiveness research with prospective electronic clinical data. Med Care, 2013, 51(Suppl 3): S53-S57.
12. McHugh R. Validity and treatment dilution in Zelen's single consent design. Stat Med, 1984, 3(3): 215-218.
13. Zelen M. Randomized consent designs for clinical trials: an update. Stat Med, 1990, 9(6): 645-656.
14. Anbar D. The relative efficiency of zelen's prerandomization design for clinical trials. Biometrics, 1983, 39(3): 711-718.
15. Altman DG, Whitehead J, Parmar MK, et al. Randomised consent designs in cancer clinical trials. Eur J Cancer, 1995, 31A(12): 1934-1944.
16. Haynes B. Can it work. Does it work? Is it worth it? The testing of healthcareinterventions is evolving. BMJ, 1999, 319(7211): 652-653.
17. Homer CS. Using the Zelen design in randomized controlled trials: debates and controversies. J Adv Nurs, 2002, 38(2): 200-207.
18. Campbell R, Peters T, Grant C, et al. Adapting the randomized consent (Zelen) design for trials of behavioural interventions for chronic disease: feasibility study. J Health Serv Res Policy, 2005, 10(4): 220-225.
19. Land J, McCourt O, Heinrich M, et al. The adapted Zelen was a feasible design to trial exercise in myeloma survivors. J Clin Epidemiol, 2020, 125: 76-83.
20. 王雯, 谭婧, 任燕, 等. 重新认识真实世界数据研究: 更新与展望. 中国循证医学杂志, 2020, 20(11): 1241-1246.
21. Langan SM, Schmidt SA, Wing K, et al. The reporting of studies conducted using observational routinely collected health data statement for pharmacoepidemiology (RECORD-PE). BMJ, 2018, 363: k3532.
22. Torgerson DJ, Roland M. What is Zelen's design. BMJ, 1998, 316(7131): 606.
23. Koutoukidis DA, Land J, Hackshaw A, et al. Fatigue, quality of life and physical fitness following an exercise intervention in multiple myeloma survivors (MASCOT): an exploratory randomised Phase 2 trial utilising a modified Zelen design. Br J Cancer, 2020, 123(2): 187-195.
24. Faseru B, Ellerbeck EF, Catley D, et al. Changing the default for tobacco-cessation treatment in an inpatient setting: study protocol of a randomized controlled trial. Trials, 2017, 18(1): 379.

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