Overrunning in Clinical Trials: Some Thoughts from a Methodological Review

Overview

Journal Trials

Publisher Biomed Central

Specialties General Medicine
Pharmacology

Date 2020 Jul 23

PMID 32693832

Citations 3

Authors

Ileana Baldi

Danila Azzolina

Nicola Soriani

Beatrice Barbetta

Paola Vaghi

Giampaolo Giacovelli

Paola Berchialla

Dario Gregori

Affiliations

Soon will be listed here.

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.

Citing Articles

Two-stage group-sequential designs with delayed responses - what is the point of applying corresponding methods?.

Schuurhuis S, Wassmer G, Kieser M, Pahlke F, Kunz C, Herrmann C BMC Med Res Methodol. 2024; 24(1):242.

PMID: 39420280 PMC: 11484224. DOI: 10.1186/s12874-024-02363-7.

Effects of duration of follow-up and lag in data collection on the performance of adaptive clinical trials.

Granholm A, Lange T, Harhay M, Jensen A, Perner A, Moller M Pharm Stat. 2023; 23(2):138-150.

PMID: 37837271 PMC: 10935606. DOI: 10.1002/pst.2342.

Group sequential designs in pragmatic trials: feasibility and assessment of utility using data from a number of recent surgical RCTs.

Parsons N, Stallard N, Parsons H, Haque A, Underwood M, Mason J BMC Med Res Methodol. 2022; 22(1):256.

PMID: 36183085 PMC: 9526271. DOI: 10.1186/s12874-022-01734-2.

References

Schuler S, Kieser M, Rauch G . Choice of futility boundaries for group sequential designs with two endpoints. BMC Med Res Methodol. 2017; 17(1):119. PMC: 5549398. DOI: 10.1186/s12874-017-0387-4. View

. ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. International Conference on Harmonisation E9 Expert Working Group. Stat Med. 1999; 18(15):1905-42. View

Kumar A, Chakraborty B . Interim analysis: A rational approach of decision making in clinical trial. J Adv Pharm Technol Res. 2016; 7(4):118-122. PMC: 5052936. DOI: 10.4103/2231-4040.191414. View

Aberegg S, Hersh A, Samore M . Empirical Consequences of Current Recommendations for the Design and Interpretation of Noninferiority Trials. J Gen Intern Med. 2017; 33(1):88-96. PMC: 5756156. DOI: 10.1007/s11606-017-4161-4. View

Wang S, Tsiatis A . Approximately optimal one-parameter boundaries for group sequential trials. Biometrics. 1987; 43(1):193-9. View

Fleming T, Harrington D, OBrien P . Designs for group sequential tests. Control Clin Trials. 1984; 5(4):348-61. DOI: 10.1016/s0197-2456(84)80014-8. View

Bhandari M, Lochner H, Tornetta 3rd 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(2):96-8. DOI: 10.1007/s004020100347. View

Schmidt R, Burkhardt B, Faldum A . Adaptive Designs with Discrete Test Statistics and Consideration of Overrunning. Methods Inf Med. 2015; 54(5):434-46. DOI: 10.3414/ME14-02-0023. View

Kairalla J, Coffey C, Thomann M, Muller K . Adaptive trial designs: a review of barriers and opportunities. Trials. 2012; 13:145. PMC: 3519822. DOI: 10.1186/1745-6215-13-145. View

10.

OBrien P, Fleming T . A multiple testing procedure for clinical trials. Biometrics. 1979; 35(3):549-56. View

11.

Whitehead J . Overrunning and underrunning in sequential clinical trials. Control Clin Trials. 1992; 13(2):106-21. DOI: 10.1016/0197-2456(92)90017-t. View

12.

Sooriyarachchi M, 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(3):701-9. DOI: 10.1111/1541-0420.00081. View

13.

MAHONEY F, BARTHEL D . FUNCTIONAL EVALUATION: THE BARTHEL INDEX. Md State Med J. 1965; 14:61-5. View

14.

Turgeon R, Reid E, Rainkie D . Design and Interpretation of Noninferiority Trials. J Gen Intern Med. 2018; 33(8):1215. PMC: 6082220. DOI: 10.1007/s11606-018-4504-9. View

15.

Lai T, Lavori P, Shih M . Sequential design of phase II-III cancer trials. Stat Med. 2012; 31(18):1944-60. PMC: 4532356. DOI: 10.1002/sim.5346. View

16.

Snapinn S . Noninferiority trials. Curr Control Trials Cardiovasc Med. 2001; 1(1):19-21. PMC: 59590. DOI: 10.1186/cvm-1-1-019. View

17.

Greene C, Morland L, Durkalski V, Frueh B . Noninferiority and equivalence designs: issues and implications for mental health research. J Trauma Stress. 2008; 21(5):433-9. PMC: 2696315. DOI: 10.1002/jts.20367. View

18.

. International conference on harmonisation; guidance on statistical principles for clinical trials; availability--FDA. Notice. Fed Regist. 1998; 63(179):49583-98. View

19.

Hamilton C, Lu M, Lewis S, Anderson W . Sequential design for clinical trials evaluating a prosthetic heart valve. Ann Thorac Surg. 2011; 93(4):1162-6. DOI: 10.1016/j.athoracsur.2011.07.091. View