Re-Randomization

ASA Biopharmaceutical Working Group on Designs with

Re-Randomization

Utilizing Re-randomization Techniques in Clinical Trials: Application and Statistical Considerations for Enrichment Designs

Primary Goal

Enrichment designs such as sequential parallel comparison designs (SPCD) and sequential multiple assignment randomized trials (SMART) by means of re-randomization have been proposed and implemented in clinical trials recently to achieve trial success and efficiency. More research, however, is needed to explore the advantages of re-randomization in enrichment designs and promote its practical use. This project is intended to collect information from clinical trials that implement re-randomization, with the aim to gain a clear understanding of its utility and technical challenges. By weighing the pros and cons, we can formulate better strategies guided by evidence-based research and provide solutions to addressing foreseeable problems.

Members

Gheorghe Doros

Anastasia Ivanova

Roy Tamura

Kelley Kidwell

Neal Thomas

Qing Liu

James Hung

Helen Li

George Kordzakhia

Eiji Ishida

Feiran Jiao

Qing Xie

Jiashen Liu

Jialu Wang

Alex Sverdlov

Yeh-Fong Chen (Chair)

Detailed Introduction

We will study the following two-stage designs:

Sequential Parallel Design (SPD)

Two-Way Enriched Design (TED)

Sequential Enriched Design (SED)

Sequential multiple assignment randomized trial (SMART)

Project Objective and Updated Papers from Team Members

We plan to produce a white Paper as a tangible output - either a standalone document or a journal publication as an endpoint after 3 years. It will cover a review of literature, recommendations on usage, and open questions that still need addressed.

1. Ivanova, A., Qaqish, B. (2020). Power calculations for the sequential parallel comparison design with continuous outcomes. Journal of Biopharmaceutical Statistics 30(6) 1121-1129.

2. Wiener, L.E., Ivanova, A., Li, S., Silverman, R., Koch, G. (2019). Randomization-based analysis of covariance for inference in the sequential parallel comparison design. Journal of Biopharmaceutical Statistics 29(4), 696-713.

3. Silverman, R., Ivanova, A., Fine, J., Zink, R. (2019). Permutation and bootstrap tests for sequential parallel comparison design. Statistics in Biopharmaceutical Research 11, 44-51.

4. Silverman, R.K., Ivanova, A., Fine, J. (2018). Sequential parallel comparison design with binary and time to event outcomes. Statistics in Medicine, 37(9), 1454-1466.

5. Silverman, R.K., Ivanova, A (2017). Sequential parallel comparison design with sample size re-estimation. Journal of Biopharmaceutical Statistics, 27(3), 416-425.

6. Chao, Y.C.*, Tran, Q.*, Tsodikov, A., Kidwell, K.M. Joint modeling and multiple comparisons with the best for data from a SMART with survival outcomes. (In Press). Biostatistics.

7. Hartman, H., Tamura, R.T., Schipper, M.*, Kidwell, K.M.* Small n sequential multiple assignment trial with continuous intermediate and overall outcomes. (2021). Statistics in Medicine. 40(2): 312-326.

8. Fang, F.*, Hochstedler, K.A.*, Tamura, R.N., Braun, T.M., Kidwell, K.M. A Bayesian Analysis of small n, sequential, multiple assignment, randomized trial designs for the registration of a drug in rare diseases. (2021). Statistics in Medicine. 40(4): 963-977.

9. Wei, B., Braun, T., Tamura, R., Kidwell, K.M. Sample size considerations to find the optimal treatment in a small n sequential multiple assignment randomized trial in the setting of a rare disease. (2020). Journal of Biopharmaceutical Statistics. 30(6): 1109-1120.

10. Chao, Y.C., Braun, T.M., Tamura, R.N., Kidwell, K.M. A Bayesian two-step dropping rule for small n sequential multiple assignment randomized trials. (2020). Journal of the Royal Statistical Society Series C. 69: 663-680.

11. Chao, Y.C., Trachtman, H., Gipson, D., Spino, C., Braun, T.M., Kidwell, K.M. Dynamic Treatment Regimens in Small n, Sequential, Multiple Assignment, Randomized Trials: An Application in Focal Segmental Glomerulosclerosis. (2020). Contemporary Clinical Trials. 92:105989.

12. Seewald, N.J., Kidwell, K.M., Wu, T., Nahum-Shani, I., Almirall, D. Sample size considerations for the analysis of continuous repeated-measures outcomes in sequential multiple assignment randomized trials. (2019). Statistical Methods in Medical Research. 29(7): 1891-1912.

13. Jiao, F., Chen, Y.-F., Min, M., Jimenez, S.. Challenges and potential strategies utilizing external data for efficacy evaluation in small-sized clinical trials. (2022). Journal of Biopharmaceutical Statistics (in press).

Major References

[1] Murphy SA. An experimental design for the development of adaptive treatment strategies. Statistics in Medicine 2005; 24: 1455–1481.

[2] Tamura RN, Krischer JP, Pagnoux C, Micheletti R, Grayson PC, Chen Y, Merkel PA. A small n sequential multiple assignment randomized trial design for use in rare disease research. Contemporary Clinical Trials 2016; 46: 48–51.

[3] Fava M, Evins AE, Dorer DJ, Schoenfeld DA. The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychotherapy and Psychosomatics 2003; 72: 115–127.

[4] Chen YF, Zhang X, Tamura RN. A sequential enriched design for target patient population in psychiatric clinical trials. Statistics in Medicine 2014; 33: 2953–2967.

[5] Ivanova A, Tamura RN. A two-way enriched clinical trial design: combining advantages of placebo lead-in and randomized withdrawal. Statistical Methods in Medical Research 2015; 24: 871–890.

[6] US Food and Drug Administration. (2010). Guidance for industry: Adaptive Design Clinical Trials for Drugs and Biologics

[7] US Food and Drug Administration. (2014). Guidance for industry: Expedited programs for serious conditions—drugs and biologics.

[8] US Food and Drug Administration. (2001). Guidance for industry: E10 Choice of Control Group and Related Issues in Clinical Trials.

[9] Wei, B., Braun, T.M., Tamura, R.N., Kidwell, K.M. (2018). A Bayesian analysis of small n sequential multiple assignment randomized trials (snSMARTs). Statistics in Medicine. 37, 3723-3732.

[10] Liu, Q., Lim, P., Singh J., Lewin D., Schwab B., Kent J. (2012) Doubly randomized delayed-start design for enrichment studies with responders or nonresponders. J Biopharm Stat. 2012;22(4):737-57.

Questions?

Contact yehfong1@gmail.com to get more information on the project

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