Noninferiority Testing in Clinical Trials: Issues and Challenges, 1st Edition (Hardback) book cover

Noninferiority Testing in Clinical Trials

Issues and Challenges, 1st Edition

By Tie-Hua Ng

Chapman and Hall/CRC

208 pages | 24 B/W Illus.

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pub: 2014-12-01
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Take Your NI Trial to the Next Level

Reflecting the vast research on noninferiority (NI) designs from the past 15 years, Noninferiority Testing in Clinical Trials: Issues and Challenges explains how to choose the NI margin as a small fraction of the therapeutic effect of the active control in a clinical trial. Requiring no prior knowledge of NI testing, the book is easily accessible to both statisticians and nonstatisticians involved in drug development.

With over 20 years of experience in this area, the author introduces the basic elements of the NI trials one at a time in a logical order. He discusses issues with estimating the effect size based on historical placebo control trials of the active control. The book covers fundamental concepts related to NI trials, such as assay sensitivity, constancy assumption, discounting, and preservation. It also describes patient populations, three-arm trials, and the equivalence of three or more groups.


"The author gives interesting examples and discusses all issues critically with respect to existing literature. Furthermore, striking and convincing motivation is given as well as discussions at the ends of most chapters. Many diagrams and graphs clearly illustrate the respective content and statistical issues. The book allows readers from different fields to understand the concept of NI testing as well as issues and challenges related to NI testing."

~Biometrics, 2017

"This book is intended for statisticians and non-statisticians working in the area of drug development, and it is written to be easily understood by a broad audience without any prior knowledge of non-inferiority testing. It covers important aspects of non-inferiority testing, including onesided and two-sided hypotheses, equivalence/non-inferiority margins, fixed-margin and the synthesis methods, controversial issues with switching between superiority and non-inferiority testing, tests with binary, continuous and time-to-event endpoints, multiple historical studies and meta-analysis, regulatory guidances, and issues and challenges in these tests."

~Lili Zhao, University of Michigan

Table of Contents


Equivalence and Noninferiority Testing

One-Sided and Two-Sided Hypotheses

Equivalence Margin δ

Choice of δ

Ethical Issues and Declaration of Helsinki

Conventional Approach versus Role-Reversal Approach

Notations and Noninferiority Hypotheses

Choice of Noninferiority Margin for the Mean Difference


Proposed δ


Choice of ε and Interpretation

How Do You Know the Effect Size?

Assay Sensitivity

Constancy Assumption versus Assay Sensitivity


Choice of Noninferiority Margin for the Mean Ratio and Hazard Ratio


Why Mean Ratio?

Mean Ratio for Continuous Endpoints

Hazard Ratio for Survival Endpoints


Noninferiority Hypotheses with Binary Endpoints


Noninferiority Hypothesis Based on the Difference or Ratio of Two Proportions

NI Hypothesis Based on the Odds Ratio


Two Statistical Approaches for Testing the Noninferiority Hypothesis


One-Sided versus Two-Sided

Fixed-Margin Method

Synthesis Method

Fixed-Margin Method versus Synthesis Method


Preservation versus Discounting

Control of Type I Error Rates

Switching between Superiority and Noninferiority



Statistical Issues with Simultaneous Testing

Decision-Theoretic Views

Conditional Type I Error Rate in Superiority Testing

Discussion and Concluding Remarks

Multiple Historical Studies and Meta-Analysis


Meta-Analysis and Systematic Review

Fixed-Effect Model

Random-Effects Model

Constancy Assumption in the Context of Meta-Analysis

Discounting-and-then-Pooling Approach


Three Treatment Groups


Gold-Standard Design

Two Test Treatments versus an Active Control

Equivalence of Three Test Groups

Regulatory Guidances


Guidelines in the Anti-Infective Area with a Binary Endpoint

EMEA/CPMP Document

FDA Draft Guidance

Intention-to-Treat versus Per-Protocol



Analyses of Randomized Control Trials

Intention-to-Treat Analysis versus Per-Protocol Analysis in Superiority Trials

Intention-to-Treat Analysis versus Per-Protocol Analysis in Noninferiority Trials

Implementation of an Intention-to-Treat Analysis in Randomized Control Trials

Thrombolytic Example



CBER Criteria in the Assessment of New Thrombotics in June 1999


Issues and Challenges


Fundamental Issues

Advances in Noninferiority Trials

Current Controversial Issues

Issues and Challenges


References appear at the end of each chapter.

About the Series

Chapman & Hall/CRC Biostatistics Series

Learn more…

Subject Categories

BISAC Subject Codes/Headings:
MATHEMATICS / Probability & Statistics / General
MEDICAL / Pharmacology
MEDICAL / Biostatistics