How fragile the positive results of Chinese herbal medicine randomized controlled trials on irritable bowel syndrome are?

Abstract

Objective: The fragility index (FI), which is the minimum number of changes in status from "event" to "non-event" resulting in a loss of statistical significance, serves as a significant supplementary indicator for clinical physicians in interpreting clinical trial results and aids in understanding the outcomes of randomized controlled trials (RCTs). In this systematic literature survey, we evaluated the FI for RCTs evaluating Chinese herbal medicine (CHM) for irritable bowel syndrome (IBS), and explored potential associations between study characteristics and the robustness of RCTs.

Methods: A comprehensive search was conducted in four databases in Chinese and four databases in English from their inception to January 1, 2023. RCTs encompassed 1:1 ratio into two parallel arms and reported at least one binary outcome that demonstrated statistical significance were included. FI was calculated by the iterative reduction of a target outcome event in the treatment group and concomitant subtraction of a non-target event from that group, until positive significance (defined as P < 0.05 by Fisher's exact test) is lost. The lower the FI (minimum 1) of a trial outcome, the more fragile the positive result of the outcome was. Linear regression models were adopted to explore influence factors of the value of FI.

Results: A total of 30 trials from 2 4118 potentially relevant citations were finally included. The median FI of total trials included was 1.5 (interquartile range [IQR], 1-5), and half of the trials (n = 15) had a FI equal to 1. In 12 trials (40%), the total number of participants lost to follow-up surpassed the respective FI. The study also identified that increased FI was significantly associated with no TCM syndrome differentiation for inclusion criteria of the patients, larger total sample size, low risk of bias, and larger numbers of events.

Conclusions: The majority of CHM IBS RCTs with positive results were found to be fragile. Ensuring adequate sample size, scientifically rigorous study design, proper control of confounding factors, and a quality control calibration for consistency of TCM diagnostic results among clinicians should be addressed to increase the robustness of the RCTs. We recommend reporting the FI as one of the components of sensitivity analysis in future RCTs to facilitate the assessment of the fragility of trials.