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Trials
Published in: Trials 1/2020

Open Access 01-12-2020 | Methodology

Overrunning in clinical trials: some thoughts from a methodological review

Authors: Ileana Baldi, Danila Azzolina, Nicola Soriani, Beatrice Barbetta, Paola Vaghi, Giampaolo Giacovelli, Paola Berchialla, Dario Gregori

Published in: Trials | Issue 1/2020

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Abstract

Background

In sequential and adaptive trials, the delay that happens after the trial is stopped, by a predetermined stopping criterion, takes the name of overrunning. Overrunning consists of extra data, collected by investigators while awaiting results of the interim analysis (IA). The inclusion of such extra data in the analyses is scientifically appropriate and follows regulatory advice. Nevertheless, its effect from a broader perspective is unclear.

Methods

This article aims at clarifying the overall impact of including such overrunning data, providing first a revision, and then a comparison of the several approaches proposed in the literature for treating such data. A simulation study is performed based on two real-life examples.

Results

The paper shows that overrunning inclusion could seriously change the decision of an early conclusion of the study. It also shows that some of the methods proposed in the literature to include overrunning data are more conservative than others.

Conclusion

The choice of a more or a less conservative method could be considered more appropriate depending on the endpoint type or the design type.
Appendix
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Literature
1.
Lai TL, Lavori PW, Shih M. Sequential design of phase II–III cancer trials. Stat Med. 2012;31:1944–60.CrossRef
2.
Hamilton C, Lu M, Lewis S, Anderson W. Sequential design for clinical trials evaluating a prosthetic heart valve. Ann Thorac Surg. 2012;93:1162–6.CrossRef
3.
4.
Bartroff J, Lai TL, Shih M-C. Group sequential design of phase II and III trials. In: Sequential experimentation in clinical trials. New York: Springer; 2013. p. 77–100.
5.
Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika. 1977;64:191–9.CrossRef
6.
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549–56.
7.
Fleming TR, Harrington DP, O’Brien PC. Designs for group sequential tests. Control Clin Trials. 1984;5:348–61.CrossRef
8.
Kairalla JA, Coffey CS, Thomann MA, Muller KE. Adaptive trial designs: a review of barriers and opportunities. Trials. 2012;13:1.CrossRef
9.
Kumar A, Chakraborty B. Interim analysis: a rational approach of decision making in clinical trial. J Adv Pharm Technol Res. 2016;7:118.CrossRef
10.
Salkind NJ, editor. Encyclopedia of research design. Thousand Oaks, Calif: SAGE Publications; 2010.
11.
Pritchett YL, Menon S, Marchenko O, Antonijevic Z, Miller E, Sanchez-Kam M, et al. Sample size re-estimation designs in confirmatory clinical trials—current state, statistical considerations, and practical guidance. Stat Biopharm Res. 2015;7:309–21.CrossRef
12.
Whitehead J. Overrunning and underrunning in sequential clinical trials. Control Clin Trials. 1992;13:106–21.CrossRef
13.
Schmidt R, Burkhardt B, Faldum A. Adaptive designs with discrete test statistics and consideration of overrunning. Methods Inf Med. 2015;54:434–46.CrossRef
14.
Committee for Medicinal Products for Human Use. Reflection paper on methodological issues in confirmatory clinical trials planned with an adaptive design. London: EMEA; 2007.
15.
Committee for Medicinal Products for Human Use. Reflection paper on methodological issues in confirmatory clinical trials with flexible design and analysis plan. London: European Medicines Agency (EMEA); 2006.
16.
ICH E9 Expert Working Group. Statistical principles for clinical trials. Stat Med. 1999;18:1905–42.
17.
Hall W, Ding K. Sequential tests and estimates after overrunning based on p-value combination. In: Pushing the Limits of Contemporary Statistics: Contributions in Honor of Jayanta K. Ghosh: Institute of Mathematical Statistics, Beachwood; 2008. p. 33–45.
18.
Jennison C, Turnbull BW. Interim analyses: the repeated confidence interval approach. J R Stat Soc Ser B (Methodological). 1989;51:305–61.
19.
Sooriyarachchi MR, Whitehead J, Matsushita T, Bolland K, Whitehead A. Incorporating data received after a sequential trial has stopped into the final analysis: implementation and comparison of methods. Biometrics. 2003;59:701–9.CrossRef
20.
Whitehead J. Application of sequential methods to a phase III clinical trial in stroke. Drug Inform J. 1993;27:733–40.CrossRef
21.
Fairbanks K, Madsen R. P values for tests using a repeated significance test design. Biometrika. 1982;69:69–74.
22.
Whitehead J. The design and analysis of sequential clinical trials. New York: Wiley; 1997.
23.
Jennison C, Turnbull B. Group sequential tests and repeated confidence intervals. New York: Cornell University Operations Research and Industrial Engineering; 1988.
24.
Mahoney FI, Barthel DW. Functional evaluation: the Barthel index: a simple index of independence useful in scoring improvement in the rehabilitation of the chronically ill. Maryland State Med J. 1965;14:61–5.
25.
Wang SK, Tsiatis AA. Approximately optimal one-parameter boundaries for group sequential trials. Biometrics. 1987;43(1):193–9.
26.
Food and Drug Administration. E9: statistical principles for clinical trials. Federal Register. 1998;63:49583–98.
27.
Food and Drug Administration. Non-inferiority clinical trials to establish effectiveness: guidance for industry 2016; 2017. p. 6.
28.
29.
Snapinn SM. Noninferiority trials. Curr Control Trials Cardiovasc Med. 2000;1:19–21.CrossRef
30.
Aberegg SK, Hersh AM, Samore MH. Empirical consequences of current recommendations for the design and interpretation of noninferiority trials. J Gen Intern Med. 2018;33:88–96.CrossRef
31.
Turgeon RD, Reid EK, Rainkie DC. Design and interpretation of noninferiority trials. J Gen Intern Med. 2018;33:1215.CrossRef
32.
Greene CJ, Morland LA, Durkalski VL, Frueh BC. Noninferiority and equivalence designs: issues and implications for mental health research. J Trauma Stress. 2008;21:433–9.CrossRef
33.
Zhou W, Yuan A, Thieu T, Fang H, Tan T. Phase II basket group sequential clinical trial with binary responses. Austin Biom Biostat. 2017;4:1033.
34.
Schüler S, Kieser M, Rauch G. Choice of futility boundaries for group sequential designs with two endpoints. BMC Med Res Methodol. 2017;17:119.CrossRef
35.
Bhandari M, Lochner H, Tornetta P. Effect of continuous versus dichotomous outcome variables on study power when sample sizes of orthopaedic randomized trials are small. Arch Orthop Trauma Surg. 2002;122:96–8.CrossRef
Metadata
Title
Overrunning in clinical trials: some thoughts from a methodological review
Authors
Ileana Baldi
Danila Azzolina
Nicola Soriani
Beatrice Barbetta
Paola Vaghi
Giampaolo Giacovelli
Paola Berchialla
Dario Gregori
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Trials / Issue 1/2020
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-020-04526-5

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