Table Of ContentMethodologies in
B iosimilar Product
D evelopment
Chapman & Hall/CRC
Biostatistics Series
Series Editors
Shein-Chung Chow
Duke University School of Medicine, USA
Byron Jones
Novartis Pharma AG, Switzerland
Jen-pei Liu
National Taiwan University, Taiwan
Karl E. Peace
Georgia Southern University, USA
Bruce W. Turnbull
Cornell University, USA
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For more information about this series, please visit: https://www.routledge.
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Methodologies in
B iosimilar Product
D evelopment
Edited by
Sang Joon Lee
Shein-Chung Chow
First edition published 2022
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Library of Congress Cataloging-in-Publication Data
Names: Lee, Sang Joon, editor. | Chow, Shein-Chung, 1955- editor.
Title: Methodologies in biosimilar product development / edited by Sang Joon Lee,
Shein-Chung Chow, Celltrion, Inc., Incheon, Republic of Korea,
Duke University School of Medicine, Durham, North Carolina, USA.
Description: First edition. | Boca Raton : CRC Press, 2022. | Series:
Chapman & Hall/CRC biostatistics series | Includes bibliographical
references and index.
Identifers: LCCN 2021021525 (print) | LCCN 2021021526 (ebook) |
ISBN 9780367896348 (hardback) | ISBN 9781032071800 (paperback) |
ISBN 9781003205807 (ebook)
Subjects: LCSH: Drug development. | Biologicals.
Classifcation: LCC RM301.25 .M46 2022 (print) | LCC RM301.25 (ebook) |
DDC 615.1/9—dc23
LC record available at https://lccn.loc.gov/2021021525
LC ebook record available at https://lccn.loc.gov/2021021526
ISBN: 9780367896348 (hbk)
ISBN: 9781032071800 (pbk)
ISBN: 9781003205807 (ebk)
DOI: 10.1201/9781003205807
Typeset in Palatino
by codeMantra
Contents
Preface.................................................................................................................... vii
Authors....................................................................................................................ix
Contributors............................................................................................................xi
1. Biosimilar Product Development ................................................................1
Sang Joon Lee and Shein-Chung Chow
2. CMC Considerations for Quality ..............................................................23
Shein-Chung Chow, Sanghee Kim, and Wei Zhang
3. Quality by Design ........................................................................................43
Min Joo Choo, Ji Youn Kim, Shein-Chung Chow, and Sang Joon Lee
4. Stability Studies............................................................................................77
Mo Liu, Yuqing Liu, and Shein-Chung Chow
5. Two One-Sided Tests Versus Confdence Interval Approach .............97
Jingyu Julia Luan, Weijia Mai, and Shein-Chung Chow
6. Equivalence Test with Flexible Margin ................................................. 115
Sang Joon Lee, Minkyung Oh, and Shein-Chung Chow
7. Modifed Quality Range Method for Analytical
Similarity Evaluation................................................................................. 135
Sung Taek Son, Min Kyung Oh, Min Joo Choo, Shein-Chung Chow,
and Sang Joon Lee
8. PK/PD Bridging Studies ........................................................................... 159
Fuyu Song, Xin Zheng, and Shein-Chung Chow
9. Non-inferiority/Similarity Margin......................................................... 173
Jingyu Julia Luan, Wenyue Zhuo, and Shein-Chung Chow
10. Design and Analysis of Biosimilar Switching Studies ......................205
Shein-Chung Chow, and Sang Joon Lee
11. Detecting Reference Product Change in Biosimilar Studies ............227
Jiayin Zheng, Peijin Wang, Yixin Wang, and Shein-Chung Chow
v
vi Contents
12. Sensitivity Analysis for Assessment of Extrapolation .......................253
Junheng Gao, Chenxuan Zang, Ying Lyu, and Shein-Chung Chow
13. Non-Medical Switch ..................................................................................277
Fuyu Song, He Bai, Peijin Wang, and Shein-Chung Chow
14. Case Studies..................................................................................................291
Ilsung Chang, Ti Na Pyo, Seul Gi Lee, Sin Hye Kim, Min Joo Choo,
and Sang Joon Lee
Index ......................................................................................................................371
Preface
Biologic drug products are therapeutic moieties that are manufactured using a
living system or an organism, which are important life-saving drug p roducts
for patients with unmet medical needs. Biosimilars are similars that are made
after the patent expiration of innovative biological products. To assist sponsors
in developing biosimilar products, regulatory agencies such as the United States
(US) Food and Drug Administration (FDA) have published several guidance
since the BPCI Act was passed by the US Congress in 2009. Following the regu-
latory guidance, several methodologies for assessment of analytical similarity,
pharmacokinetic and pharmacodynamic (PK/PD) similarity, and clinical simi-
larity have been developed in the literature. However, due to the complexity
of the structures of biosimilar products and the nature of the manufacturing
process, the development of biosimilar products is very different from that of
traditional small molecule (chemical) drug products. Thus, some practical and
challenging issues such as the selection of similarity margin, drug interchange-
ability, non-medical switch, possible reference product change, extrapolation
across different indications, etc. inevitably occur during the development of bio-
similar products. Methodology development for addressing these practical and
challenging issues is necessary for assuring an unbiased and reliable assessment
of the treatment effect of the proposed biosimilar product under investigation.
This book is intended to deal with some practical and challenging issues
that are commonly encountered during the development, review, and
approval of a proposed biosimilar product. These practical and challenging
issues include, but are not limited to, (1) the mix-up use of interval hypoth-
eses testing (i.e., the use of TOST) and confdence interval approach, (2) the
detection of possible reference product change over time, (3) design and anal-
ysis of biosimilar switching studies, (4) the assessment of sensitivity index
for assessment of extrapolation across indications without collecting data
from those indications not under study, and (5) the feasibility and valida-
tion of non-medical switch post-approval. We hope that this book can serve
as a bridge among the pharmaceutical/biotechnology industry, government
regulatory agencies, and academia.
The scope of this book is not only to cover scientifc factors and practical
issues that are commonly encountered in biosimilar studies, but also to focus
on recent development in research and development. This book contains 14
chapters. Chapter 1 provides an overview of biosimilar product research and
development. Also included in this chapter is a brief instruction of some com-
monly seen scientifc factors/practical issues and recent methodology devel-
opment in biosimilar product research and development. Chapter 2 reviews
chemistry, manufacturing, and control (CMC) requirements including man-
ufacturing process validation, quality control and assurance, and stability
vii
viii Preface
analysis for a biosimilar product. Chapter 3 introduces the concept and the
use of quality by design in biosimilar product development. Statistical design
and analysis of stability studies for drug shelf-life estimation are discussed in
Chapter 4. Chapter 5 discusses the relationship between the method of inter-
val hypotheses testing and the confdence interval approach for similarity
assessment in biosimilar studies. An effcient equivalence test with a fexible
margin for analytical similarity assessment is proposed in Chapter 6 followed
by an evaluation of the FDA recommended method of quality range (QR) for
analytical similarity assessment in Chapter 7. Also included in Chapter 7 is a
proposed method of modifed QR (mQR) for analytical similarity assessment.
Chapter 8 reviews various statistical designs for pharmacokinetic and phar-
macodynamic (PK/PD) bridging studies with multiple reference products
from different regions such as European Union and the United States. Chapter
9 proposes a method based on the evaluation of relative risk/beneft for selec-
tion of similarity margin for similarity assessment when there is a disagree-
ment between the sponsors and regulatory agencies. Chapter 10 provides an
overview of switching studies for addressing drug interchangeability in terms
of the assessment of risk with/without switching and alternation. The issue
of a potential reference product change in b iosimilar studies is discussed in
Chapter 11. Chapter 12 studies the issue of extrapolation across indications (the
conditions of use) and proposes statistical methods for assessment of extrapo-
lation in terms of sensitivity index for generalizability between patient popula-
tions (related to conditions of use). Chapter 13 provides statistical considerations
for the assessment of no-medical switch in biosimilar studies. Chapter 14 dis-
cusses some case studies concerning recent regulatory submissions.
We are indebted to many people for the completion of this book. From
Taylor & Francis, we offer our thanks to Mr. David Grubbs for providing us
with the opportunity to work on this book project. We also thank colleagues
from Celltrion, Inc. and Duke University School of Medicine and many
friends from the academia, the pharmaceutical industry, and, regulatory agen-
cies including US FDA, EU EMA, CDE/NMPA of China, and MFDS of the
Republic of Korea for their support, encouragement, and discussions during
the preparation of this book. The frst editor would like to express his appre-
ciation to Mr. Woo-Sung Kee, the CEO of Celltrion for his encouragement and
friendship since his frst day at Celltrion, and Dr. Jung-Jin Seo, the founder and
the honorary chairman of Celltrion, for his perspicacity and leadership of bio-
similar product development. Lastly, the frst editor also would like to thank
his loving wife, Sun-Ah, and his lovely daughters Alicia Kayoung and Sophia
Jooyoung for their support during the preparation of this book manuscript.
Finally, the views expressed are those of the editors and not necessarily
those of Celltrion and Duke University School of Medicine. We are solely
responsible for the contents and errors of this book. Any comments and
suggestions for future editions of this book are very much appreciated.
Sang Joon Lee, PhD
Shein-Chung Chow, PhD
Authors
Sang Joon Lee, Ph.D., is a Senior Executive Vice President at Celltrion. Dr. Lee
was previously a biostatistician at academia including the University of New
Mexico School of Medicine and The University of Texas, M.D. Anderson
Cancer Center. He received a Ph.D. degree in Statistics from Texas A&M
University. Dr. Lee has authored or co-authored over 100 research papers
and invited papers.
Shein-Chung Chow, Ph.D., is a Professor at the Duke University School of
Medicine. Dr. Chow was previously the Associate Director at the Offce of
Biostatistics, Center for Drug Evaluation and Research, United States Food
and Drug Administration (FDA). Dr. Chow was also at Millennium, Covance,
and Bristol-Myers Squibb. He received a Ph.D. degree in Statistics from the
University of Wisconsin-Madison. Dr. Chow has authored or co-authored
over 310 methodology papers and 31 books.
ix
