Estimation of sample size in randomized controlled trials in multiple sclerosis studying annualized relapse rates: A systematic review

Abstract

Background: In multiple sclerosis (MS) studies, the most appropriate model for the distribution of the number of relapses was shown to be the negative binomial (NB) distribution. Objective: To determine whether the sample-size estimation (SSE) and the analysis of annualized relapse rates (ARRs) in randomized controlled trials (RCTs) were aligned and compare the SSE between normal and NB distributions. Methods: Systematic review of phase 3 and 4 RCTs for which the primary endpoint was ARR in relapsing remitting MS published since 2008 in pre-selected major medical journals. A PubMed search was performed on 30 November 2020. We checked whether the SSE and ARR analyses were congruent. We also performed standardized (fixed α/β, number of arms and overdispersion) SSEs using data collected from the studies. Results: Twenty articles (22 studies) were selected. NB distribution (or quasi-Poisson) was used for SSE in only 7/22 studies, whereas 21/22 used it for ARR analyses. SSE relying on NB regression necessitated a smaller sample size in 21/22 of our calculations. Conclusion: SSE was rarely performed using the most appropriate model. However, the use of an NB model is recommended to optimize the number of included patients and to be congruent with the final analysis.

Real-world annualized relapse rates from contemporary multiple sclerosis clinics in the UK: a retrospective multicentre cohort study

“…Our study findings suggest that the previously noted trend of reducing ARRs in RRMS [ 4 , 6 , 7 , 9 , 10 ] continues. It is plausible that the recent increased availability of higher efficacy DMTs can explain the reduced ARRs for the RRMS patients.…”

“…The most robust estimation of relapse incidence originates from clinical trials. In most of the clinical phase-3 placebo-controlled trials in MS, relapse incidence, measured by the annualized relapse rate (ARR), is used as the primary or secondary efficacy outcome measure [ 4 – 10 ]. ARR is a critical component in calculating sample size estimation, and hence feasibility of clinical trials [ 9 , 10 ].…”

“…In most of the clinical phase-3 placebo-controlled trials in MS, relapse incidence, measured by the annualized relapse rate (ARR), is used as the primary or secondary efficacy outcome measure [ 4 – 10 ]. ARR is a critical component in calculating sample size estimation, and hence feasibility of clinical trials [ 9 , 10 ]. Between 1990 and 2012, a trend of lower ARR over time has been reported in previous studies [ 4 – 7 , 9 , 11 ].…”