Biosimilars: Design and Analysis of Follow-on Biologics, 1st Edition (Hardback) book cover


Design and Analysis of Follow-on Biologics, 1st Edition

By Shein-Chung Chow

Chapman and Hall/CRC

444 pages | 34 B/W Illus.

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Hardback: 9781466579699
pub: 2013-07-29
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pub: 2013-07-29
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As many biological products face losing their patents in the next decade, the pharmaceutical industry needs an abbreviated regulatory pathway for approval of biosimilar drug products, which are cost-effective, follow-on/subsequent versions of the innovator’s biologic products. But scientific challenges remain due to the complexity of both the manufacturing process and the structures of biosimilar products.

Written by a top biostatistics researcher, Biosimilars: Design and Analysis of Follow-on Biologics is the first book entirely devoted to the statistical design and analysis of biosimilarity and interchangeability of biosimilar products. It includes comparability tests of important quality attributes at critical stages of the manufacturing processes of biologic products.

Connecting the pharmaceutical/biotechnology industry, government regulatory agencies, and academia, this state-of-the-art book focuses on the scientific factors and practical issues related to the design and analysis of biosimilar studies. It covers most of the statistical questions encountered in various study designs at different stages of research and development of biological products.


"This book extensively covers both statistical and regulatory considerations from design to analysis of biosimilarity. … it is well presented and comprehensively covers fundamental issues and some of the newly developed methods for biosimilarity studies. The book is very balanced between scientific aspects and regulatory requirements. In addition, the reference lists give readers helpful information. … a valuable resource for anyone interested and involved in biosimilarity studies."

Biometrics, September 2014

"[Professor] Chow’s book Biosimilars: Design and Analysis of Follow-On Biologics … is the first book ever written on this topic. I commend Professor Chow for his effort to introduce the topic … Overall, this is a worthwhile reference book for statisticians interested in understanding biosimilar product development and evaluation."

—Yi Tsong, PhD, Center for Drug Evaluation and Research, US Food and Drug Administration, USA, in Journal of Biopharmaceutical Statistics

Table of Contents



Fundamental Differences

Regulatory Requirements


Interchangeability of Biological Drug Products

Scientific Factors

Aim and Scope of the Book

Bioequivalence Experience for Small-Molecule Drug Products


Process for Bioequivalence Assessment

Issue of Drug Interchangeability

Highly Variable Drugs

Practical Issues

Frequently Asked Questions

Regulatory Requirements for Assessing Follow-On Biologics


Definitions and Interpretations of Biosimilar Products

Regulatory Requirements

Review of the FDA Draft Guidances

Global Harmonization

Criteria for Similarity


Criteria for Bioequivalence

Similarity Factor for Dissolution Profile Comparison

Measures of Consistency

Comparison of Moment-Based and Probability-Based Criteria

Alternative Criteria

Statistical Methods for Assessing Average Biosimilarity


Classic Methods for Assessing Biosimilarity

Bayesian Methods

Wilcoxon–Mann–Whitney Two One-Sided Tests Procedure

Three-Arm Parallel Design

General Approach for Assessing Biosimilarity


Reproducibility Probability

Development of the Biosimilarity Index

Relationship of the Biosimilarity Criterion versus Variability

Biosimilarity Index Based on the Bayesian Approach

Consistency Approach

Non-Inferiority versus Equivalence/Similarity


Testing for Equality

Testing for Noninferiority

Testing for Superiority

Testing for Equivalence

Relationship among Testing for Noninferiority, Superiority, and Equivalence

Determination of the Noninferiority Margin

Sample Size Requirement When There Is a Switch in Hypothesis Testing

Statistical Test for Biosimilarity in Variability


Pitman–Morgan’s Adjusted Test for Comparing Variabilities

F-Type Test under Parallel Design

Non-Parametrics Methods

Alternative Methods

Sample Size for Comparing Variabilities


Comparing Intra-Subject Variability

Comparing Inter-Subject Variability

Comparing Total Variability

Comparing Intra-Subject CVs

Impact of Variability on Biosimilarity Limits for Assessing Follow-On Biologics


Relationship between Variability and Biosimilarity Limits

Scaled Biosimilarity Margins



Drug Interchangeability


Population and Individual Bioequivalence

Interchangeability for Biosimilar Products

Study Designs for Interchangeability

Statistical Methods

Issues on Immunogenicity Studies


Regulatory Requirements

Assay Development/Validation

Design for Immunogenicity Studies

Sample Size for Immunogenicity Studies

CMC Requirements for Biological Products


CMC Development

Product Characterization and Specification

Manufacture and Process Validation

Quality Control/Assurance

Reference Standards, Container Closure System, and Stability

Test for Comparability in Manufacturing Process


Biologic Manufacturing Process

Consistency Index

Test for Comparability

Other Comparability Tests

Stability Analysis of Biosimilar Products


Regulatory Stability Guidelines on Biologicals

Stability Indicating Profile and Expiration Dating Period

Stability Designs

Statistical Analysis

Assessing Biosimilarity Using Biomarker Data


Assessment of Biosimilarity

Statistical Test for Biosimilarity Using Biomarker Data

Numerical Study

Current Issues in Biosimilar Studies


Scientific Factors

Current Issues



About the Author

Shein-Chung Chow is a professor in the Department of Biostatistics and Bioinformatics at Duke University School of Medicine. Dr. Chow is also a professor of clinical sciences at Duke–National University of Singapore Graduate Medical School. He is the editor-in-chief of the Journal of Biopharmaceutical Statistics and editor-in-chief of the Chapman & Hall/CRC Biostatistics Series. He has authored or co-authored over 230 papers and 22 books, including Adaptive Design Methods in Clinical Trials, Second Edition, Handbook of Adaptive Designs in Pharmaceutical and Clinical Development, and Controversial Statistical Issues in Clinical Trials. A fellow of the ASA and member of the ISI, Dr. Chow has received the ASA Chapter Service Recognition Award, the DIA Outstanding Service Award, and the ICSA Extraordinary Achievement Award.

About the Series

Chapman & Hall/CRC Biostatistics Series

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Subject Categories

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