Inclusion of non-inferiority analysis in superiority-based clinical trials with single-arm, two-stage Simon's design

Javier Cortés,José Pérez-García,Javier Garde-Noguera,Elena Aguirre,Ángel L Guerrero-Zotano,Antonio Llombart-Cussac,David Páez,Xin Huang,Andrea Malfettone,Miguel Sampayo-Cordero,Elena López-Miranda,Esther Holgado,Bernat Miguel-Huguet

doi:10.1016/j.conctc.2020.100678

Abstract

IntroductionNon-inferiority (NI) analysis is not usually considered in the early phases of clinical development. In some negative phase II trials, a post-hoc NI analysis justified additional phase III trials that were successful. However, the risk of false positive achievements was not controlled in these early phase analyses. We propose to preplan NI analyses in superiority-based Simon's two-stage designs to control type I and II error rates. MethodsSimulations have been proposed to assess the control of type I and II errors rates with this method. A total of 12,768 two-stage Simon's design trials were constructed based on different assumptions of rejection response probability, desired response probability, type I and II errors, and NI margins. P-value and type II error were calculated with stochastic ordering using Uniformly Minimum Variance Unbiased Estimator. Type I and II errors were simulated using the Monte Carlo method. The agreement between calculated and simulated values was analyzed with Bland-Altman plots. ResultsWe observed the same level of agreement between calculated and simulated type I and II errors from both two-stage Simon's superiority designs and designs in which NI analysis was allowed. Different examples has been proposed to explain the utility of this method. ConclusionInclusion of NI analysis in superiority-based single-arm clinical trials may be useful for weighing additional factors such as safety, pharmacokinetics, pharmacodynamic, and biomarker data while assessing early efficacy. Implementation of this strategy can be achieved through simple adaptations to existing designs for one-arm phase II clinical trials.

Highlights

The non-inferiority (NI) hypothesis is not usually considered in the early phases of clinical development
The aim of the present study is to assess the validity of the Uniformly Minimum Variance Unbiased Estimator (UMVUE)-based calculation method is planning two-stage Simon’s design phase II trials, where switching to NI is allowed if the superiority criteria cannot be met
Higher levels of type I error related to greater absolute differences between the calculated p-values and simulated alpha errors

Summary

Introduction

The non-inferiority (NI) hypothesis is not usually considered in the early phases of clinical development. Methods A total of 12,768 two-stage Simon’s design trials were constructed based on different assumptions of rejection response probability, minimum desired response probability, type I and II errors, and NI margins. A single-arm phase II trial is the proof-of-concept stage in drug development, and focuses on the evaluation of new therapeutic hypothesis[1] and strategies[2] in a clinical setting. Two-stage designs are becoming increasingly more common, allowing for early trial termination in cases with low response rates (RRs) towards avoiding wasting time resources on ineffective treatments.[3] These trials aim to determine whether the new regimen is superior to a pre-specified RR (often 5%)[4] or experience with the standard of care, whereas the alternative hypothesis is that RR is somewhat higher, say 20%.4. A typical scenario is one in which an experimental treatment is potentially less toxic, less costly, easier to administer or with longer duration of benefit than a conventional treatment, but these do not represent a reduction of efficacy or in percentage of patient with clinical benefit. 6

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