Frequentist rules for regulatory approval of subgroups in phase III trials: A fresh look at an old problem
Open Access
- 2 June 2021
- journal article
- research article
- Published by SAGE Publications in Statistical Methods in Medical Research
- Vol. 30 (7), 1725-1743
- https://doi.org/10.1177/09622802211017574
Abstract
Background: The number of Phase III trials that include a biomarker in design and analysis has increased due to interest in personalised medicine. For genetic mutations and other predictive biomarkers, the trial sample comprises two subgroups, one of which, say B+ is known or suspected to achieve a larger treatment effect than the other B-. Despite treatment effect heterogeneity, trials often draw patients from both subgroups, since the lower responding B- subgroup may also gain benefit from the intervention. In this case, regulators/commissioners must decide what constitutes sufficient evidence to approve the drug in the B- population. Methods and Results: Assuming trial analysis can be completed using generalised linear models, we define and evaluate three frequentist decision rules for approval. For rule one, the significance of the average treatment effect in B- should exceed a pre-defined minimum value, say Z(B-) > L . For rule two, the data from the low-responding group B- should increase statistical significance. For rule three, the subgroup-treatment interaction should be non-significant, using type I error chosen to ensure that estimated difference between the two subgroup effects is acceptable. Rules are evaluated based on conditional power, given that there is an overall significant treatment effect. We show how different rules perform according to the distribution of patients across the two subgroups and when analyses include additional (stratification) covariates in the analysis, thereby conferring correlation between subgroup effects. Conclusions When additional conditions are required for approval of a new treatment in a lower response subgroup, easily applied rules based on minimum effect sizes and relaxed interaction tests are available. Choice of rule is influenced by the proportion of patients sampled from the two subgroups but less so by the correlation between subgroup effects.Funding Information
- NIHR
This publication has 16 references indexed in Scilit:
- Evidence for Treatment-by-Biomarker interaction for FDA-approved Oncology Drugs with Required Pharmacogenomic Biomarker TestingScientific Reports, 2017
- Abiraterone for Prostate Cancer Not Previously Treated with Hormone TherapyThe New England Journal of Medicine, 2017
- The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trialAmerican Heart Journal, 2017
- Methods for identification and confirmation of targeted subgroups in clinical trials: A systematic reviewJournal of Biopharmaceutical Statistics, 2015
- Adaptive Designs for Confirmatory Clinical Trials with Subgroup SelectionJournal of Biopharmaceutical Statistics, 2014
- Adjusted significance levels for subgroup analyses in clinical trialsContemporary Clinical Trials, 2010
- A recycling framework for the construction of Bonferroni‐based multiple testsStatistics in Medicine, 2009
- Prognostic versus predictive value of biomarkers in oncologyEuropean Journal of Cancer, 2008
- The Abuse of PowerThe American Statistician, 2001
- Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negativesHealth Technology Assessment, 2001