Table Of ContentBiosimilarity
The FDA Perspective
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Biosimilarity
The FDA Perspective
Sarfaraz K. Niazi, PhD, SI, FRSB, FPAMS, FACB
Adjunct Professor, Biopharmaceutical Sciences, University of
Illinois (U.S.), University of Houston (U.S.), HEJ Research
Institute (PK), and National University of Science and
Technology (PK), Founder, Karyo Biologics,
LLC (U.S.), Adello Biologics (U.S.), and
Pharmaceutical Scientist, INC (U.S.)
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Library of Congress Cataloging‑in‑Publication Data
Names: Niazi, Sarfaraz, 1949- , author.
Title: Biosimilarity : the FDA perspective / Sarfaraz K. Niazi.
Description: Boca Raton : Taylor & Francis, 2016. | Includes bibliographical references and index.
Identifiers: LCCN 2015043743 | ISBN 9781498750394 (hardcover : alk. paper)
Subjects: | MESH: United States. Food and Drug Administration. | Biosimilar Pharmaceuticals--United
States. | Drug Approval--United States. | Government Regulation--United States. | United States Government
Agencies--United States.
Classification: LCC RS67.U6 | NLM QV 241 | DDC 615.10973--dc23
LC record available at http://lccn.loc.gov/2015043743
Visit the Taylor & Francis Web site at
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To Dr. Janet Woodcock, Director, CDER, FDA, whose
passion for making biosimilars accessible is only
superseded by her determination to assure their safety.
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Contents
About the author . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xix
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxiii
Disclaimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxxvii
1 Understanding proteins . . . . . . . . . . . . . . . . . . 1
1.1 Background 1
1.1.1 Developing biosimilars 3
1.2 Protein structure 4
1.2.1 Building elements 4
1.2.2 Translation 7
1.2.3 Peptide bond 7
1.3 Motifs and domains 9
1.4 Association and aggregation 11
1.5 Posttranslational modification 14
1.5.1 Glycosylation 19
1.6 Protein expression variability 22
Bibliography 24
2 The biosimilar landscape . . . . . . . . . . . . . . . . 29
2.1 Background 29
2.2 The rise of biosimilars 31
2.2.1 Legislative history 31
2.2.2 Regulatory guidance 33
2.2.3 The 351(k) Route 33
2.2.3.1 What interchangeable or
interchangeability means 34
2.2.3.2 The totality-of-the-evidence
approach 34
2.2.4 The FDA stance 35
2.2.5 351(k) Terminology 35
2.2.5.1 Innovator versus originator 35
vii
Biosimilarity: The FDA Perspective
2.2.5.2 Authorized versus licensed 36
2.2.5.3 Medicines versus drugs 36
2.2.5.4 Similarity versus
comparability 36
2.2.5.5 Effectiveness versus
efficacy 36
2.2.5.6 One-size-fits-all versus
case-by-case 37
2.2.5.7 Totality of the evidence 37
2.2.5.8 No clinically meaningful
difference 37
2.2.5.9 Fingerprint-like similarity 38
2.2.5.10 Extrapolation 39
2.2.5.11 Label copy 39
2.2.5.12 Interchangeable
biosimilars 39
2.2.5.13 Pediatric waiver 39
2.3.2.14 Impurity versus attributes 40
2.3 Biosimilars in use 40
2.3.1 FDA-Approved biosimilar products 41
2.3.2 Future of biosimilars 41
2.3.2.1 Global mind-set 45
2.3.2.2 Immediate needs 45
Bibliography 46
3 The FDA regulatory guidance . . . . . . . . . . . . . 47
3.1 Background 47
3.2 Overview of the FDA guidance 50
3.3 Formal meetings 51
3.3.1 Biosimilar initial advisory meeting 51
3.3.2 Biosimilar biological product
development (BPD) Type 1 meeting 52
3.3.3 BPD Type 2 meeting 52
3.3.4 BPD Type 3 meeting 52
3.3.5 BPD Type 4 meeting 53
3.4 Scientific considerations 53
3.4.1 Background 53
3.4.2 Complexities of protein products 53
3.4.2.1 Nature of protein
products and related
scientific considerations 54
3.4.2.2 Manufacturing process
considerations 54
3.4.3 U.S.-licensed reference product
and other comparators 55
viii
Contents
3.4.4 Approaches to developing and
assessing evidence to demonstrate
biosimilarity 56
3.4.4.1 Using a stepwise approach
to demonstrate biosimilarity 56
3.4.4.2 Using a totality-of-the-
evidence approach to
assess a demonstration
of biosimilarity 57
3.4.5 Demonstrating biosimilarity 58
3.4.5.1 Structural analyses 58
3.4.5.2 Functional assays 59
3.4.5.3 Animal data 60
3.4.5.4 Clinical studies—General
considerations 62
3.5 Postmarketing safety monitoring
considerations 71
3.5.1 Consultation with the FDA 72
3.6 Quality considerations in demonstrating
biosimilarity 73
3.6.1 Background 73
3.6.2 Scope 75
3.6.3 General principles 75
3.7 Factors for consideration in assessing
whether products are highly similar 80
3.7.1 Expression system 80
3.7.2 Manufacturing process 81
3.7.3 Assessment of physicochemical
properties 82
3.7.4 Functional activities 83
3.7.5 Receptor-binding
and immunochemical properties 84
3.7.6 Impurities 84
3.7.7 Reference product and reference
standards 85
3.7.8 Finished drug product 86
3.7.9 Stability 87
3.7.10 Conclusion 87
3.8 Clinical pharmacology data to support
biosimilarity 88
3.8.1 Background 88
3.8.2 The role of clinical pharmacology
studies 88
3.8.3 Critical considerations in the use
of clinical pharmacology studies
to support biosimilarity 89
ix
