Sequential designs were originally based on industrial quality control, to monitor whether a process resulted in an abnormally high proportion of defects1. They focus on decision making rather than estimation. The simplest sequential trial designs involve assessing each person as their outcome becomes available, although they can be modified to analyse at regular intervals2-4. These modified designs can be used in a similar way as those based on the alpha-spending group sequential approach5, although the two approaches are based on different philosophies.
One of the simpler sequential designs is the triangular test for a single proportion. This is illustrated in the following figure which is from a non-comparative trial of three treatments for visceral leishmaniasis in East Africa6.
The outcome of interest is the number of patients who recovered, which is captured on the vertical axis. The horizontal axis (V) is proportional to the number of people recruited to the trial so far. The trial continues while the findings fall in the triangular region, which is calculated based on the acceptable cure rate and error probabilities. Findings above the upper boundary (as in the case here for the three treatments at the third time-point), indicate a favourable conclusion, while region below the triangle indicate an unfavourable conclusion.
Aspects of sequential designs being researched by members of the CSM and their collaborators include analysis methods for time points subsequent to assessment of the primary endpoint, and development of asymmetrical stopping boundaries e.g. the imposition of a minimum sample size7,8.
- Wald, A. Sequential Analysis. (Wiley, 1947).
- Whitehead, J. The Design and Analysis of Sequential Clinical Trials. 1st edn, (Ellis Horwood, 1983).
- Bellissant, E., Benichou, J. & Chastang, C. Application of the triangular test to phase II cancer clinical trials. Stat Med 9, 907-917 (1990).
- Ranque, S., Badiaga, S., Delmont, J. & Brouqui, P. Triangular test applied to the clinical trial of azithromycin against relapses in Plasmodium vivax infections. Malar J 1, 13 (2002).
- Lan, K. K. G. & DeMets, D. L. Discrete sequential boundaries for clinical trials. Biometrika 70, 659-663 (1983).
- Wasunna, M. et al. Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial. PLoS Negl Trop Dis 10, e0004880.
- Omollo, R. et al. Safety and efficacy of miltefosine alone and in combination with sodium stibogluconate and liposomal amphotericin B for the treatment of primary visceral leishmaniasis in East Africa: study protocol for a randomized controlled trial. Trials 12, 166 (2011).
- Allison, A. et al. Generalizing boundaries for triangular designs, and efficacy estimation at extended follow-ups. Trials 16, 522, doi:10.1186/s13063-015-1018-1 (2015).