Biosimilars : design and analysis of follow-on biologics

444 Pages·2014·10.097 MB·English

by  Shein-Chung Chow

Biosimilars
Design and Analysis
of Follow-on Biologics
Editor-in-Chief
Shein-Chung Chow, Ph.D.
Professor
Department of Biostatistics and Bioinformatics
Duke University School of Medicine
Durham, North Carolina
Series Editors
Byron Jones Jen-pei Liu
Biometrical Fellow Professor
Statistical Methodology Division of Biometry
Department of Agronomy
Integrated Information Sciences
National Taiwan University
Novartis Pharma AG
Taipei, Taiwan
Basel, Switzerland

Karl E. Peace Bruce W. Turnbull
Georgia Cancer Coalition Professor
Distinguished Cancer Scholar School of Operations Research
Senior Research Scientist and and Industrial Engineering
Professor of Biostatistics Cornell University
Jiann-Ping Hsu College of Public Health Ithaca, New York
Georgia Southern University
Statesboro, Georgia
Adaptive Design Methods in Causal Analysis in Biomedicine and
Clinical Trials, Second Edition Epidemiology: Based on Minimal
Shein-Chung Chow and Mark Chang Sufficient Causation
Mikel Aickin
Adaptive Design Theory and
Implementation Using SAS and R Clinical Trial Data Analysis using R
Mark Chang Ding-Geng (Din) Chen and Karl E. Peace
Advanced Bayesian Methods for Medical Clinical Trial Methodology
Test Accuracy Karl E. Peace and Ding-Geng (Din) Chen
Lyle D. Broemeling
Computational Methods in Biomedical
Advances in Clinical Trial Biostatistics Research
Nancy L. Geller Ravindra Khattree and Dayanand N. Naik
Applied Meta-Analysis with R Computational Pharmacokinetics
Ding-Geng (Din) Chen and Karl E. Peace Anders Källén
Basic Statistics and Pharmaceutical Confidence Intervals for Proportions and
Statistical Applications, Second Edition Related Measures of Effect Size
James E. De Muth Robert G. Newcombe
Bayesian Adaptive Methods for Controversial Statistical Issues in
Clinical Trials Clinical Trials
Scott M. Berry, Bradley P. Carlin, Shein-Chung Chow
J. Jack Lee, and Peter Muller
Data and Safety Monitoring Committees
Bayesian Analysis Made Simple: An Excel in Clinical Trials
GUI for WinBUGS Jay Herson
Phil Woodward
Design and Analysis of Animal Studies in
Bayesian Methods for Measures of Pharmaceutical Development
Agreement Shein-Chung Chow and Jen-pei Liu
Lyle D. Broemeling
Design and Analysis of Bioavailability and
Bayesian Methods in Health Economics Bioequivalence Studies, Third Edition
Gianluca Baio Shein-Chung Chow and Jen-pei Liu
Bayesian Missing Data Problems: EM, Design and Analysis of Bridging Studies
Data Augmentation and Noniterative Jen-pei Liu, Shein-Chung Chow,
Computation and Chin-Fu Hsiao
Ming T. Tan, Guo-Liang Tian,
Design and Analysis of Clinical Trials with
and Kai Wang Ng
Time-to-Event Endpoints
Bayesian Modeling in Bioinformatics Karl E. Peace
Dipak K. Dey, Samiran Ghosh,
Design and Analysis of Non-Inferiority
and Bani K. Mallick
Trials
Biosimilars: Design and Analysis of Mark D. Rothmann, Brian L. Wiens,
Follow-on Biologics and Ivan S. F. Chan
Shein-Chung Chow
Difference Equations with Public Health
Biostatistics: A Computing Approach Applications
Stewart J. Anderson Lemuel A. Moyé and Asha Seth Kapadia
DNA Methylation Microarrays: Multiple Testing Problems in
Experimental Design and Statistical Pharmaceutical Statistics
Analysis Alex Dmitrienko, Ajit C. Tamhane,
Sun-Chong Wang and Arturas Petronis and Frank Bretz
DNA Microarrays and Related Genomics Optimal Design for Nonlinear Response
Techniques: Design, Analysis, and Models
Interpretation of Experiments Valerii V. Fedorov and Sergei L. Leonov
David B. Allison, Grier P. Page,
Randomized Clinical Trials of
T. Mark Beasley, and Jode W. Edwards
Nonpharmacological Treatments
Dose Finding by the Continual Isabelle Boutron, Philippe Ravaud, and
Reassessment Method David Moher
Ying Kuen Cheung
Randomized Phase II Cancer Clinical
Elementary Bayesian Biostatistics Trials
Lemuel A. Moyé Sin-Ho Jung
Frailty Models in Survival Analysis Sample Size Calculations in Clinical
Andreas Wienke Research, Second Edition
Shein-Chung Chow, Jun Shao
Generalized Linear Models: A Bayesian
and Hansheng Wang
Perspective
Dipak K. Dey, Sujit K. Ghosh, Statistical Design and Analysis of
and Bani K. Mallick Stability Studies
Shein-Chung Chow
Handbook of Regression and Modeling:
Applications for the Clinical and Statistical Evaluation of Diagnostic
Pharmaceutical Industries Performance: Topics in ROC Analysis
Daryl S. Paulson Kelly H. Zou, Aiyi Liu, Andriy Bandos,
Lucila Ohno-Machado, and Howard Rockette
Interval-Censored Time-to-Event Data:
Methods and Applications Statistical Methods for Clinical Trials
Ding-Geng (Din) Chen, Jianguo Sun, Mark X. Norleans
and Karl E. Peace
Statistics in Drug Research:
Joint Models for Longitudinal and Time- Methodologies and Recent
to-Event Data: With Applications in R Developments
Dimitris Rizopoulos Shein-Chung Chow and Jun Shao
Measures of Interobserver Agreement Statistics in the Pharmaceutical Industry,
and Reliability, Second Edition Third Edition
Mohamed M. Shoukri Ralph Buncher and Jia-Yeong Tsay
Medical Biostatistics, Third Edition Survival Analysis in Medicine and
A. Indrayan Genetics
Jialiang Li and Shuangge Ma
Meta-Analysis in Medicine and Health
Policy Translational Medicine: Strategies and
Dalene Stangl and Donald A. Berry Statistical Methods
Dennis Cosmatos and Shein-Chung Chow
Monte Carlo Simulation for the
Pharmaceutical Industry: Concepts,
Algorithms, and Case Studies
Mark Chang
Biosimilars
Design and Analysis
of Follow-on Biologics
Shein-Chung Chow
Duke University School of Medicine
Durham, North Carolina, USA
Chow, Shein-Chung, 1955-
Biosimilars : design and analysis of follow-on biologics / Shein-Chung Chow.
pages cm. -- (Chapman & Hall/CRC biostatistics series ; 60)
Includes bibliographical references and index.
ISBN 978-1-4665-7969-9 (hardback) 1. Pharmaceutical biotechnology. 2. Pharmaceutical biotechnology industry. 3. Drugs-
-Generic substitution. 4. Pharmaceutical policy. 5. Biological products. I. Title.
RS380.C45 2014
615.1’9--dc23
2013012926
CRC Press
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Version Date: 20130625
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Contents
Preface ..................................................................................................................xvii
1. Introduction .....................................................................................................1
1.1 Background ............................................................................................1
1.2 Fundamental Differences.....................................................................4
1.3 Regulatory Requirements ....................................................................5
1.4 Biosimilarity ..........................................................................................8
1.4.1 Definition and Basic Principles ..............................................8
1.4.2 Criteria for Bioequivalence/Biosimilarity ............................9
1.4.2.1 Absolute Change versus Relative Change ..........10
1.4.2.2 Aggregated versus Disaggregated Criteria ........10
1.4.2.3 Moment-Based versus Probability-Based
Criteria .....................................................................12
1.4.2.4 Scaled versus Unscaled Criteria ...........................13
1.4.2.5 Weighted versus Unweighted Criteria ................13
1.4.3 Biosimilarity versus Non-inferiority...................................14
1.4.4 Practical Issues .......................................................................15
1.5 Interchangeability of Biological Drug Products .............................18
1.5.1 Definition and Basic Concepts .............................................18
1.5.2 Switching and Alternating ...................................................18
1.5.3 Study Design ..........................................................................19
1.5.4 Remarks ...................................................................................19
1.6 Scientific Factors ..................................................................................20
1.6.1 Fundamental Biosimilarity Assumption ............................20
1.6.2 Consistency in Manufacturing Process/Quality Control ....20
1.6.3 Biosimilarity in Biological Activity .....................................21
1.6.4 Similarity in Size and Structure ..........................................22
1.6.5 Issues of Immunogenicity ....................................................22
1.6.6 Comparability/Consistency of Manufacturing
Processes .................................................................................23
1.6.7 Other Practical Issues ............................................................23
1.7 Aim and Scope of the Book ...............................................................25
2. Bioequivalence Experience for Small-Molecule Drug Products ........27
2.1 Background ..........................................................................................27
2.2 Process for Bioequivalence Assessment ..........................................28
2.2.1 Fundamental Bioequivalence Assumption ........................28
2.2.2 Study Design ..........................................................................29
2.2.3 Power Analysis for Sample Size Calculation .....................30
vii
viii Contents
2.2.4 Statistical Methods ................................................................32
2.2.5 Remarks ...................................................................................33
2.3 Issue of Drug Interchangeability ......................................................34
2.3.1 Population Bioequivalence for Drug Prescribability ........34
2.3.2 Individual Bioequivalence for Drug Switchability ...........36
2.3.3 Remarks ...................................................................................37
2.4 Highly Variable Drugs .......................................................................37
2.4.1 Scaled Average Bioequivalence ............................................38
2.4.2 Recent Considerations by Regulatory Agencies ................38
2.4.3 Other Rules for Assessment of Bioequivalence .................39
2.4.4 Remarks ...................................................................................40
2.5 Practical Issues ....................................................................................41
2.5.1 Fundamental Bioequivalence Assumption ........................41
2.5.2 One-Size-Fits-All Criterion ...................................................43
2.5.3 Log-Transformation ...............................................................44
2.6 Frequently Asked Questions .............................................................46
2.6.1 What if We Pass the Raw Data Model but Fail the
Log-Transformed Data Model? ............................................46
2.6.2 What if We Pass AUC but Fail C ? ...................................47
max
2.6.3 What if We Fail by a Small Margin? ...................................47
2.6.4 Can We Still Assess Bioequivalence if There
Is a Significant Sequence Effect? ..........................................48
2.6.5 What Should We Do When We Have Almost
Identical Means but Still Fail to Meet the
Bioequivalence Criterion? .....................................................48
2.6.6 Power and Sample Size Calculations Based on Raw-
Data Model and Log-Transformed Model Are Different .......49
2.6.7 Multiplicity and Transitivity ................................................49
2.7 Concluding Remarks ..........................................................................50
3. Regulatory Requirements for Assessing Follow-on Biologics ............53
3.1 Background ..........................................................................................53
3.2 Definitions and Interpretations of Biosimilar Products ................54
3.3 Regulatory Requirements ..................................................................56
3.3.1 World Health Organization ..................................................56
3.3.1.1 Key Principles and Basic Concepts ......................56
3.3.1.2 Reference Biotherapeutic Product ........................57
3.3.1.3 Quality .....................................................................57
3.3.1.4 Nonclinical and Clinical Studies .........................58
3.3.2 European Union .....................................................................58
3.3.2.1 Key Principles and Basic Concepts ......................59
3.3.2.2 Reference Biotherapeutic Product ........................59
3.3.2.3 Quality .....................................................................60
3.3.2.4 Nonclinical and Clinical Evaluation ...................60
3.3.2.5 Product Class–Specific Guidelines ......................61
Contents ix
3.3.2.6 European Experience .............................................61
3.3.2.7 Remarks ...................................................................61
3.3.3 North America (the United States and Canada) ................62
3.3.3.1 United States (FDA) ................................................62
3.3.3.2 Canada (Health Canada) .......................................64
3.3.4 Asian Pacific Region (Japan and South Korea) ..................65
3.3.4.1 Japan (MHLW) ........................................................65
3.3.4.2 South Korea (KFDA) ..............................................65
3.4 Review of the FDA Draft Guidances ................................................66
3.4.1 Statistical Scientific Advisory Board ...................................66
3.4.2 FDA Draft Guidance on Scientific Considerations ...........67
3.4.3 Comments on the FDA Draft Guidance .............................67
3.4.3.1 Definition of Biosimilarity ....................................67
3.4.3.2 Criteria of Biosimilarity .........................................68
3.4.3.3 Biosimilar Studies ..................................................69
3.4.3.4 Study Design ...........................................................69
3.4.3.5 Statistical Methods .................................................69
3.4.3.6 Stepwise Approach ................................................70
3.4.3.7 Totality-of-the-Evidence ........................................70
3.4.3.8 Manufacturing Process Validation and
Tests for Comparability .........................................71
3.4.3.9 U.S.-Licensed Reference Product versus
Other Comparators ................................................71
3.4.3.10 Non-inferiority versus Similarity ........................72
3.4.3.11 Consultation with FDA .........................................72
3.4.3.12 Remarks ...................................................................72
3.5 Global Harmonization........................................................................73
3.6 Concluding Remarks ..........................................................................75
4. Criteria for Similarity ..................................................................................77
4.1 Introduction .........................................................................................77
4.2 Criteria for Bioequivalence ................................................................78
4.2.1 Average Bioequivalence ........................................................79
4.2.2 Population/Individual Bioequivalence ..............................80
4.2.3 Profile Analysis for In Vitro Bioequivalence Testing ........81
4.3 Similarity Factor for Dissolution Profile Comparison ...................82
4.4 Measures of Consistency ...................................................................84
4.4.1 Moment-Based Method .........................................................84
4.4.2 Probability-Based Approach ................................................85
4.5 Comparison of Moment-Based and Probability-Based
Criteria ..........................................................................................87
4.6 Alternative Criteria .............................................................................97
4.6.1 Probability-Based Relative Distance ...................................97
4.6.2 Reproducibility Probability ..................................................98
4.7 Concluding Remarks ..........................................................................99
x Contents
5. Statistical Methods for Assessing Average Biosimilarity ..................101
5.1 Introduction .......................................................................................101
5.2 Classic Methods for Assessing Biosimilarity ................................103
5.2.1 Confidence Interval Approach ...........................................103
5.2.2 Schuirmann’s Two One-Sided Tests Procedure ...............104
5.3 Bayesian Methods .............................................................................106
5.4 Wilcoxon–Mann–Whitney Two One-Sided Tests Procedure......109
5.5 Three-Arm Parallel Design ..............................................................113
5.5.1 Criteria for Biosimilarity .....................................................113
5.5.2 Statistical Tests for Biosimilarity .......................................115
5.5.2.1 Statistical Test Based on the Ratio Estimator ...115
5.5.2.2 Linearization Method ..........................................117
5.5.2.3 Power Functions ...................................................119
5.5.2.4 Numerical Results ................................................121
5.6 Concluding Remarks ........................................................................124
6. General Approach for Assessing Biosimilarity ...................................127
6.1 Background ........................................................................................127
6.2 Reproducibility Probability .............................................................128
6.2.1 Two Samples with Equal Variances ..................................130
6.2.2 Two Samples with Unequal Variances..............................132
6.2.3 Parallel-Group Designs .......................................................134
6.3 Development of the Biosimilarity Index ........................................135
6.4 Relationship of the Biosimilarity Criterion
versus Variability. ......................................................................139
6.5 Biosimilarity Index Based on the Bayesian Approach ................141
6.5.1 μ , μ Is Random and the Variance Is Fixed .....................142
T R
6.5.2 Both (μ , μ ) and the Variance Are Random ....................143
T R
6.6 Consistency Approach .....................................................................145
6.6.1 Response for Therapeutic Efficacy ....................................145
6.6.2 Response for Adverse Effects .............................................148
6.6.3 Sample Size Determination ................................................150
6.7 Concluding Remarks ........................................................................151
7. Non-Inferiority versus Equivalence/Similarity ...................................155
7.1 Background ........................................................................................155
7.2 Testing for Equality ..........................................................................156
7.3 Testing for Non-Inferiority ..............................................................157
7.4 Testing for Superiority ......................................................................158
7.5 Testing for Equivalence ....................................................................159
7.6 Relationship among Testing for Non-Inferiority, Superiority,
and Equivalence ................................................................................160
7.7 Determination of the Non-Inferiority Margin ..............................162