A Regulatory Perspective on Essential Considerations in Design and Analysis of Subgroups When Correctly Classified

Abstract

This regulatory research provides possible approaches for improvement to conventional subgroup analysis in a fixed design setting. The interaction-to-overall effects ratio is recommended in the planning stage for potential predictors whose prevalence is at most 50% and its observed ratio is recommended in the analysis stage for proper subgroup interpretation if sample size is only planned to target the overall effect size. We illustrate using regulatory examples and underscore the importance of striving for balance between safety and efficacy when considering a regulatory recommendation of a label restricted to a subgroup. A set of decision rules gives guidance for rigorous subgroup-specific conclusions.

Key Words:

• Biomarker
• Formation of subgroup
• Interaction-to-overall effects ratio
• Predictive of treatment effect
• Subgroup-specific treatment effect hypothesis

ACKNOWLEDGMENTS

We thank Dr. Lisa LaVange for her helpful comments. We also thank two anonymous referees for their insightful comments that led to a much improved article.

Notes

Note. Δ₊ = 0.3, Δ₋ = 0, n ₊ = 175 per arm based on Δ₊ only or 212 per arm with Bonferroni adjustment.

*Does not require consistent treatment effects across subgroups, Δ₊ > Δ₋ > 0 or Δ₊ = Δ₋ > 0.

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Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lbps.