Evaluating the impact of stratification on the power and cross-arm balance of randomized phase 2 clinical trials

Abstract

Background/aims

Randomized clinical trials often use stratification to ensure balance between arms. Analysis of primary endpoints of these trials typically uses a “stratified analysis,” in which analyses are performed separately in each subgroup defined by the stratification factors, and those separate analyses are weighted and combined. In the phase 3 setting, stratified analyses based on a small number of stratification factors can provide a small increase in power. The impact on power and type-1 error of stratification in the setting of smaller sample sizes as in randomized phase 2 trials has not been well characterized.

Methods

We performed computational studies to characterize the power and cross-arm balance of modestly sized clinical trials (less than 170 patients) with varying numbers of stratification factors (0–6), sample sizes, randomization ratios (1:1 vs 2:1), and randomization methods (dynamic balancing vs stratified block).

Results

We found that the power of unstratified analyses was minimally impacted by the number of stratification factors used in randomization. Analyses stratified by 1–3 factors maintained power over 80%, while power dropped below 80% when four or more stratification factors were used. These trends held regardless of sample size, randomization ratio, and randomization method. For a given randomization ratio and sample size, increasing the number of factors used in randomization had an adverse impact on cross-arm balance. Stratified block randomization performed worse than dynamic balancing with respect to cross-arm balance when three or more stratification factors were used.

Conclusion

Stratified analyses can decrease power in the setting of phase 2 trials when the number of patients in a stratification subgroup is small.