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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
Generalized Linear Models: A Bayesian Shein-Chung Chow, Jun Shao
Perspective and Hansheng Wang
Dipak K. Dey, Sujit K. Ghosh, Statistical Design and Analysis of
and Bani K. Mallick Stability Studies
Handbook of Regression and Modeling: Shein-Chung Chow
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,
Interval-Censored Time-to-Event Data: Lucila Ohno-Machado, and Howard Rockette
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
Meta-Analysis in Medicine and Health Jialiang Li and Shuangge Ma
Policy Translational Medicine: Strategies and
Dalene Stangl and Donald A. Berry Statistical Methods
Monte Carlo Simulation for the Dennis Cosmatos and Shein-Chung Chow
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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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 Cmax?.................................... 47
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 μT, μR Is Random and the Variance Is Fixed...................... 142
6.5.2 Both (μT, μR) and the Variance Are Random..................... 143
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
Contents xi

7.8 Sample Size Requirement When There Is a Switch

in Hypothesis Testing........................................................................ 167
7.8.1 Switch from Equivalence Hypotheses
to Non-Inferiority/Superiority Hypotheses...................... 167
7.8.2 Example.................................................................................. 168
7.8.3 Remarks.................................................................................. 169
7.9 Concluding Remarks......................................................................... 169

8. Statistical Test for Biosimilarity in Variability..................................... 171

8.1 Introduction........................................................................................ 171
8.2 Pitman–Morgan’s Adjusted Test for Comparing Variabilities......172
8.3 F-Type Test under Parallel Design................................................... 174
8.4 Non-Parametrics Methods................................................................ 175
8.4.1 Conover’s Squared Rank Test............................................. 175
8.4.2 Levene’s Type of Test............................................................ 177
8.4.3 Simulation Studies................................................................ 178
8.4.4 Remarks.................................................................................. 186
8.5 Alternative Methods.......................................................................... 187
8.5.1 Probability-Based Criterion and Statistical
Hypothesis.......................................................................... 187
8.5.2 Statistical Testing Procedure............................................... 188
8.5.3 Probability-Based Criteria versus nX, nY, and δ................. 191
8.5.4 Simulation Study................................................................... 194
8.5.5 Numerical Example.............................................................. 199
8.6 Concluding Remarks......................................................................... 200

9. Sample Size for Comparing Variabilities............................................... 203

9.1 Introduction........................................................................................ 203
9.2 Comparing Intra-subject Variability............................................... 204
9.2.1 Parallel Design with Replicates.......................................... 204
9.2.1.1 Example.................................................................. 207
9.2.2 Replicated Crossover Design.............................................. 208
9.3 Comparing Inter-subject Variability............................................... 210
9.3.1 Parallel Design with Replicates.......................................... 210
9.3.1.1 Example.................................................................. 212
9.3.2 Replicated Crossover Design.............................................. 213
9.4 Comparing Total Variability............................................................. 214
9.4.1 Parallel Design without Replicates..................................... 214
9.4.2 Parallel Design with Replicates.......................................... 215
9.4.3 Standard 2 × 2 Crossover Design....................................... 216
9.4.4 Replicated 2 × 2m Crossover Design.................................. 218
9.5 Comparing Intra-subject CVs........................................................... 219
9.6 Concluding Remarks......................................................................... 221
xii Contents

10. Impact of Variability on Biosimilarity Limits for Assessing

Follow-on Biologics..................................................................................... 223
10.1 Introduction........................................................................................223
10.2 Relationship between Variability and Biosimilarity Limits........ 224
10.3 Scaled Biosimilarity Margins........................................................... 230
10.3.1 Fixed Cutoff Linear Scaled Margin.................................... 230
10.3.2 Fixed Cutoff Square Root Scaled Margin.......................... 232
10.3.3 Dynamic Cutoff Scaled Margin.......................................... 232
10.3.4 Dynamic Cutoff with Factor Scaled Margin..................... 233
10.3.5 Dynamic Cutoff with Slope Scaled Margin...................... 233
10.4 Simulations.........................................................................................234
10.5 Discussions......................................................................................... 243

11. Drug Interchangeability............................................................................ 245

11.1 Introduction........................................................................................ 245
11.2 Population and Individual Bioequivalence.................................... 246
11.2.1 Population Bioequivalence.................................................. 246
11.2.2 Individual Bioequivalence................................................... 249
11.2.3 Remarks.................................................................................. 252
11.3 Interchangeability for Biosimilar Products.................................... 253
11.3.1 Definition and Basic Concepts............................................ 253
11.3.2 Switching and Alternating.................................................. 253
11.3.3 Remarks.................................................................................. 255
11.4 Study Designs for Interchangeability............................................. 255
11.4.1 Designs for Switching.......................................................... 256
11.4.1.1 Balaam Design....................................................... 256
11.4.1.2 Two-Stage Design.................................................. 257
11.4.2 Designs for Alternating....................................................... 258
11.4.2.1 Two-Sequence Dual Design................................. 258
11.4.2.2 Williams’ Design................................................... 259
11.4.3 Designs for Switching/Alternating.................................... 259
11.4.3.1 Modified Balaam Design...................................... 260
11.4.3.2 Complete Design................................................... 260
11.4.3.3 Alternative Designs.............................................. 262
11.4.3.4 Adaptive Designs.................................................. 262
11.4.4 Bridging Studies.................................................................... 262
11.4.5 Remarks.................................................................................. 263
11.5 Statistical Methods............................................................................. 263
11.5.1 Totality Biosimilarity Index................................................ 263
11.5.2 Switching Index.................................................................... 264
11.5.3 Alternating Index.................................................................. 266
11.5.4 Remarks.................................................................................. 267
11.6 Concluding Remarks......................................................................... 268
Contents xiii

12. Issues on Immunogenicity Studies.......................................................... 269

12.1 Introduction........................................................................................ 269
12.2 Regulatory Requirements................................................................. 270
12.2.1 European Medicines Agency.............................................. 270
12.2.2 United States Food and Drug Administration................. 271
12.2.3 International Conference on Harmonization................... 272
12.3 Assay Development/Validation....................................................... 273
12.3.1 Assay Development.............................................................. 273
12.3.1.1 Screening Assays................................................... 274
12.3.1.2 Assays for Confirming the Presence
of Antibodies.......................................................... 274
12.3.1.3 Assays for Dissecting the Specificity
of Antibodies.......................................................... 274
12.3.1.4 Neutralization Assays.......................................... 274
12.3.2 Assay Validation................................................................... 274
12.4 Design for Immunogenicity Studies............................................... 275
12.4.1 Basic Design Considerations............................................... 276
12.4.1.1 Patient Population................................................. 276
12.4.1.2 Randomization...................................................... 276
12.4.1.3 Washout.................................................................. 276
12.4.1.4 Variability in Antibody Response...................... 276
12.4.1.5 Sample Size............................................................ 277
12.4.1.6 Surrogate Endpoints............................................. 277
12.4.2 Risk Factors............................................................................ 277
12.4.3 Selection/Assessment of Assays......................................... 278
12.4.4 Data Collection and Analysis.............................................. 278
12.4.5 Interpretation of Results...................................................... 279
12.5 Sample Size for Immunogenicity Studies...................................... 279
12.5.1 Sample Size Determination................................................. 279
12.5.1.1 Power Analysis...................................................... 279
12.5.1.2 Precision Analysis................................................. 280
12.5.1.3 Sensitivity Analysis.............................................. 281
12.5.1.4 Procedure for Sample Size Determination........ 283
12.5.1.5 Example..................................................................284
12.5.2 Strategy for Data Safety Monitoring Procedure............... 287
12.5.3 Bayesian Approach............................................................... 287
12.5.4 Remarks.................................................................................. 295
12.6 Concluding Remarks......................................................................... 296

13. CMC Requirements for Biological Products.......................................... 297

13.1 Introduction........................................................................................ 297
13.2 CMC Development............................................................................ 298
13.3 Product Characterization and Specification..................................300
13.3.1 General Description..............................................................300
xiv Contents

13.3.2 Drug Substance Characterization...................................... 301

13.3.3 Product Characterization..................................................... 302
13.3.4 Practical Issues...................................................................... 302
13.4 Manufacture and Process Validation.............................................. 303
13.4.1 Manufacturing Process........................................................ 303
13.4.2 Process Validation................................................................. 303
13.4.3 Commonly Encountered Issues.......................................... 307
13.5 Quality Control/Assurance.............................................................. 307
13.5.1 General Principles................................................................. 307
13.5.2 Starting Materials.................................................................308
13.5.3 Seed Lot and Cell Bank System..........................................308
13.5.4 Operating Principles............................................................309
13.5.5 Premises and Equipment..................................................... 309
13.5.6 Practical Issues...................................................................... 311
13.6 Reference Standards, Container Closure System, and Stability........311
13.6.1 Reference Standards............................................................. 311
13.6.2 Container Closure System................................................... 312
13.6.3 Stability................................................................................... 313
13.7 Concluding Remarks......................................................................... 313

14. Test for Comparability in Manufacturing Process............................... 315

14.1 Introduction........................................................................................ 315
14.2 Biologic Manufacturing Process...................................................... 317
14.3 Consistency Index.............................................................................. 318
14.4 Test for Comparability....................................................................... 322
14.4.1 Acceptance Criteria.............................................................. 322
14.4.2 Sampling Plan....................................................................... 323
14.4.3 Testing Procedure................................................................. 324
14.4.4 Strategy for Statistical Quality Control............................. 326
14.5 Other Comparability Tests................................................................ 328
14.5.1 PK Comparability Test......................................................... 329
14.5.2 PD Comparability Index...................................................... 330
14.5.3 Clinical Efficacy Comparability Study.............................. 330
14.6 Concluding Remarks......................................................................... 331

15. Stability Analysis of Biosimilar Products.............................................. 333

15.1 Introduction........................................................................................ 333
15.2 Regulatory Stability Guidelines on Biologicals.............................334
15.2.1 ICH/EMA Guidelines on Stability.....................................334
15.2.2 ICH Q5C Stability Guideline............................................... 335
15.2.2.1 Scope....................................................................... 335
15.2.2.2 Batch Selection....................................................... 335
15.2.2.3 Study Design.......................................................... 337
15.2.2.4 Storage Conditions................................................ 337
Contents xv

15.2.2.5 Testing Frequency................................................. 339

15.2.2.6 General Principles................................................. 339
15.3 Stability Indicating Profile and Expiration Dating Period...........340
15.3.1 Stability Indicating Assay....................................................340
15.3.2 Expiration Dating Period.....................................................340
15.4 Stability Designs................................................................................ 341
15.4.1 Basic Matrix 2/3 on Time Design.......................................342
15.4.2 Matrix 2/3 on Time Design with Multiple Packages.......342
15.4.3 Matrix 2/3 on Time Design with Multiple Packages
and Multiple Strengths........................................................343
15.4.4 Matrix 1/3 on Time Design.................................................344
15.4.5 Matrix on Batch × Strength × Package Combinations...... 344
15.4.6 Uniform Matrix Design.......................................................345
15.4.7 Comparison of Designs........................................................345
15.4.8 Factors Acceptable to Matrix...............................................345
15.4.9 General Rules........................................................................ 347
15.5 Statistical Analysis............................................................................. 347
15.5.1 Separate Analysis Approach...............................................348
15.5.2 One Analysis Approach without Testing Poolability........ 348
15.5.3 One Analysis Testing Poolability.......................................348
15.6 Concluding Remarks......................................................................... 349

16. Assessing Biosimilarity Using Biomarker Data................................... 353

16.1 Introduction........................................................................................ 353
16.2 Assessment of Biosimilarity............................................................. 354
16.2.1 Moment- and Probability-Based Criteria..........................354
16.2.1.1 Moment-Based Criterion...................................... 355
16.2.1.2 Probability-Based Criterion................................. 355
16.2.2 Assessing Biosimilarity Using Genomic Data.................. 355
16.3 Statistical Test for Biosimilarity Using Biomarker Data............... 358
16.3.1 General Idea........................................................................... 358
16.3.2 Moment-Based Criterion for Assessing Biosimilarity....... 358
16.3.2.1 Confidence Interval Estimation.......................... 359
16.3.2.2 Type I Error Rate and Power................................ 360
16.3.3 Probability-Based Criterion for Assessing Biosimilarity..... 362
16.3.3.1 Estimation.............................................................. 362
16.3.3.2 Power and Sample Size......................................... 363
16.4 Numerical Study................................................................................ 366
16.5 Concluding Remarks......................................................................... 370

17. Current Issues in Biosimilar Studies...................................................... 375

17.1 Introduction........................................................................................ 375
17.2 Scientific Factors................................................................................. 376
17.2.1 Endpoint Selection................................................................ 376
17.2.2 One-Size-Fits-All Criterion.................................................. 378
xvi Contents

17.2.3 How Similar Is Similar?....................................................... 378

17.2.4 Study Design......................................................................... 379
17.2.5 Test for Comparability in Critical Quality Attributes....... 380
17.3 Current Issues..................................................................................... 381
17.3.1 Reference Standards............................................................. 382
17.3.2 Criteria for Biosimilarity...................................................... 382
17.3.3 Criteria for Interchangeability............................................ 385
17.3.4 Criteria for Comparability................................................... 385
17.3.5 Determination of Non-Inferiority Margin........................ 386
17.3.6 Bridging Bioequivalence Studies........................................ 387
17.3.7 Assessing Biosimilarity Using Biomarker........................ 389
17.3.8 Stepwise Approach and Totality-of-the-Evidence........... 389
17.3.9 Contamination in a Manufacturing Process..................... 390
17.3.10 Meta-Analysis for Biosimilarity Review........................... 391
17.3.11 Profile Analysis..................................................................... 393
17.4 Concluding Remarks......................................................................... 394

References............................................................................................................ 397
Preface

Biologic drug products are therapeutic moieties that are manufactured using
a living system or organism. These are important life-saving drug products
for patients with unmet medical needs. They also comprise a growing seg-
ment in the pharmaceutical industry. In 2007, for instance, worldwide sales
of biological products reached $94 billion, accounting for about 15% of the
pharmaceutical industry’s gross revenue. Meanwhile, many biological prod-
ucts face losing their patents in the next decade. Attempts have been made
therefore to establish an abbreviated regulatory pathway for approval of
biosimilar drug products, that is, follow-on (or subsequent entered) biologics
of the innovator’s biological products in order to reduce cost. However, due
to the complexity of the structures of biosimilar products and the nature of
the manufacturing process, biological products differ from traditional small-
molecule (chemical) drug products. Although the concepts and principles for
bioequivalence and interchangeability could be the same for both chemical
generics and biosimilar products, scientific challenges remain for establish-
ing an abbreviated regulatory pathway for approval of biosimilar products
due to their unique characteristics.
This book is intended to be the first book entirely devoted to the design and
analysis of biosimilarity and drug interchangeability and includes tests for
comparability in important quality attributes at critical stages of manufactur-
ing processes of biological products. It covers most of the statistical issues that
one may encounter in biosimilar studies under various study designs at dif-
ferent stages of research and development of biological products. The goal of
this book is to provide a useful desk reference and describe the state of the art
to (1) scientists and researchers engaged in pharmaceutical/clinical research
and development of biological products, (2) those in government regulatory
agencies who have to make decisions in the review and approval process of
biological regulatory submissions, and (3) biostatisticians who provide statis-
tical support to the assessment of biosimilarity and drug interchangeability
of biosimilar products. I 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 restricted to scientific factors and practical
issues related to the design and analysis of biosimilar studies that are
commonly seen in biosimilar research and development. Also, since reg-
ulatory requirements for assessment of biosimilar products between the
European Medicines Agency (EMA) and the United States Food and Drug
Administration (FDA) are similar but slightly different, this book primar-
ily focuses on regulatory requirements from FDA. The book contains 17
chapters. Chapter 1 provides a background of pharmaceutical/clinical

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