Reinterpretation of the results of randomized clinical trials.

BACKGROUND

Randomized clinical trials (RCTs) shape our clinical practice. Several studies report a mediocre replicability rate of the studied RCTs. Many researchers believe that the relatively low replication rate of RCTs is attributed to the high p value significance threshold. To solve this problem, some researchers proposed using a lower threshold, which is inevitably associated with a decrease in the study power.

METHODS

The results of 22 500 RCTs retrieved from the Cochrane Database of Systematic Reviews (CDSR) were reinterpreted using 2 fixed p significance threshold (0.05 and 0.005), and a recently proposed flexible threshold that minimizes the weighted sum of errors in statistical inference.

RESULTS

With p < 0.05 criterion, 28.5% of RCTs were significant; p < 0.005, 14.2%; and p < flexible threshold, 9.9% (2/3 of significant RCTs based on p < 0.05 criterion, were found not significant). Lowering the p cut-off, although decreases the false-positive rate, is not generally associated with a lower weighted sum of errors; the false-negative rate increases (the study power decreases); important treatments may be left undiscovered. Accurate calculation of the optimal p value thresholds needs knowledge of the variance in each study arm, a posteriori.

CONCLUSIONS

Lowering the p value threshold, as it is proposed by some researchers, is not reasonable as it might be associated with an increase in false-negative rate. Using a flexible p significance threshold approach, although results in a minimum error in statistical inference, might not be good enough too because only a rough estimation may be calculated a priori; the data necessary for the precise computation of the most appropriate p significance threshold are only available a posteriori. Frequentist statistical framework has an inherent conflict. Alternative methods, say Bayesian methods, although not perfect, would be more appropriate for the data analysis of RCTs.