Analytical Similarity Assessment in Biosimilar Product Development

Author Shein-Chung Chow, Ph.D, is currently an Associate Director at Office of Biostatistics, Center for Drug Evaluation and Research, United States Food and Drug Administration (FDA). Prior to joining FDA, Dr. Chow was a Professor at Duke University School of Medicine, Durham, NC. He was also a special government employee (SGE) appointed by the FDA as an Advisory Committee member and statistical advisor to the FDA. Prior to that, Dr. Chow also held various positions in the pharmaceutical industry such as Vice President at Millennium, Cambridge, MA, Executive Director at Covance, Princeton, NJ, and Director and Department Head at Bristol-Myers Squibb, Plainsboro, NJ. Dr. Chow is the Editor-in-Chief of the Journal of Biopharmaceutical Statistics and the Editor-in-Chief of the Biostatistics Book Series at Chapman and Hall/CRC Press, Taylor & Francis Group. He was elected Fellow of the American Statistical Association and an elected member of the ISI (International Statistical Institute). Dr. Chow is the author or co-author of over 300 methodology papers and 29 books including Designs and Analysis of Bioavailability and Bioequivalence Studies, Sample Size Calculations in Clinical Research, Adaptive Design Methods in Clinical Trials, Translational Medicine, Design and Analysis of Clinical Trials, and Quantitative Methods for Traditional Chinese Medicine Development.

Contents

Preface.......................................................................................................................xi

Author.................................................................................................................... xiii

1. Introduction......................................................................................................1

1.1 Background.............................................................................................1

1.2 Past Experience for In Vitro Bioequivalence Testing.........................4

1.2.1 Study Design and Data Collection.........................................5

1.2.2 Bioequivalence Limit................................................................7

1.2.3 Statistical Methods...................................................................8

1.2.4 Sample Size Requirement...................................................... 12

1.3 Analytical Similarity Assessment..................................................... 13

1.3.1 Tier 1 Equivalence Test........................................................... 13

1.3.2 Tier 2 Quality Range Approach............................................ 14

1.3.3 Tier 3 Raw Data and Graphical Comparison...................... 16

1.4 Scientific Factors and Practical Issues............................................... 16

1.4.1 Fundamental Similarity Assumption.................................. 16

1.4.2 Primary Assumptions for Tiered Approach....................... 18

1.4.3 Fixed Approach for Margin Selection.................................. 19

1.4.4 Inconsistent Test Results between Tiered Approaches.....20

1.4.5 Sample Size Requirement...................................................... 21

1.4.6 Relationship between Similarity Limit and Variability.... 21

1.4.7 Regulator’s Current Thinking on Scientific Input.............22

1.4.8 A Proposed Unified Tiered Approach.................................23

1.4.9 Practical Issues........................................................................25

1.4.10 Remarks....................................................................................26

1.5 Aim and Scope of the Book................................................................27

2. Regulatory Approval Pathway of Biosimilar Products.........................29

2.1 Introduction..........................................................................................29

2.2 Regulatory Requirements................................................................... 31

2.2.1 World Health Organization (WHO)..................................... 32

2.2.2 European Union (EU).............................................................34

2.2.3 North America (United States of America and Canada)...... 37

2.2.4 Asian Pacific Region (Japan, South Korea, and China)..... 39

2.2.5 Debatable Issues in Regulatory Requirements...................40

2.3 Analytical Studies for Structural/Functional Characteristics......45

2.4 Global Harmonization........................................................................48

2.5 Conclusion Remarks............................................................................ 51

3. CMC Requirements for Biological Products............................................53

3.1 Introduction..........................................................................................53

3.2 CMC Development..............................................................................54

3.2.1 Fermentation and Purification Process................................54

3.2.2 Drug Substance and Product Characterization..................55

3.2.3 Reference Standards and Container Closure System........ 57

3.2.4 Practical Issues........................................................................58

3.3 Manufacturing Process Validation....................................................58

3.3.1 Manufacturing Process..........................................................58

3.3.2 Process Validation................................................................... 61

3.3.3 Practical Issues........................................................................ 62

3.4 Quality Control and Assurance.........................................................63

3.4.1 General Principles...................................................................63

3.4.2 Quality by Design...................................................................64

3.5 Stability Analysis................................................................................. 69

3.6 Concluding Remarks...........................................................................75

4. Analytical Method Validation....................................................................77

4.1 Introduction..........................................................................................77

4.2 Regulatory Requirements................................................................... 78

4.2.1 FDA Guidance on Analytical Procedures

and Methods Validation........................................................ 78

4.2.2 ICH Guidance on Assay Validation.....................................80

4.2.3 United States Pharmacopeia and National

Formulary (USP/NF).............................................................. 81

4.3 Analytical Method Validation............................................................82

4.3.1 Validation Performance Characteristics..............................82

4.3.2 Study Design...........................................................................82

4.3.3 Choice of Validation Performance Characteristics............84

4.3.4 Acceptance Criteria................................................................85

4.4 Analysis of Validation Data................................................................86

4.4.1 Assessment of Accuracy, Linearity, and Specificity..........86

4.4.2 The Assessment of Assay Parameters Related

to Variability............................................................................ 91

4.5 Evaluation of Reliability, Repeatability, and Reproducibility.......95

4.5.1 Study Design and Statistical Model.....................................96

4.5.2 Variability Monitoring...........................................................98

4.5.3 Sample Size for Comparing Variabilities............................98

4.5.4 An Example........................................................................... 100

4.6 Concluding Remarks......................................................................... 102

5. Critical Quality Attributes........................................................................ 105

5.1 Background......................................................................................... 105

5.2 Identification of CQAs....................................................................... 106

5.2.1 Link between CQAs and Clinical Outcomes.................... 106

5.2.2 Statistical Design and Methods.......................................... 107

5.3 Stepwise Approach for Demonstrating Biosimilarity.................. 112

5.4 Tier Assignment for Critical Quality Attributes........................... 114

5.4.1 Criticality or Risk Ranking.................................................. 114

5.4.2 Statistical Model.................................................................... 116

5.4.3 Validity of the Translational Model...................................122

5.4.4 Two-Way Translational Process.......................................... 123

5.4.5 Remarks.................................................................................. 124

5.5 Concluding Remarks......................................................................... 125

6. FDA Tiered Approach for Analytical Similarity Assessment........... 127

6.1 Background......................................................................................... 127

6.2 Stepwise Approach for Demonstrating Biosimilarity.................. 128

6.3 Tier 1 Equivalence Test...................................................................... 129

6.4 Other Tiered Approaches................................................................. 136

6.4.1 Quality Range Approach for Tier 2.................................... 136

6.4.2 Raw Data and Graphical Comparison for Tier 3.............. 139

6.5 Some Practical Considerations......................................................... 141

6.6 Concluding Remarks......................................................................... 145

7. Sample Size Requirement.......................................................................... 147

7.1 Introduction........................................................................................ 147

7.2 Traditional Approach........................................................................ 148

7.2.1 Power Calculation................................................................. 148

7.2.2 Alternative Criteria for Sample Size Calculation............. 150

7.3 FDA’s Current Thinking and Recommendation............................ 150

7.3.1 FDA’s Current Thinking...................................................... 150

7.3.2 FDA’s Recommendation....................................................... 152

7.4 Sample Size Requirement................................................................. 156

7.4.1 Chow et al.’s Proposal for Test/Reference Lots

Selection................................................................................. 156

7.4.2 Recent Development............................................................. 159

7.5 Numerical Studies............................................................................. 163

7.6 Concluding Remarks......................................................................... 163

Appendix....................................................................................................... 167

8. Analytical Studies with Multiple References....................................... 173

8.1 Background......................................................................................... 173

8.2 Method of Pairwise Comparisons................................................... 174

8.2.1 Equivalence Test for Tier 1 CQAs....................................... 174

8.2.2 Pairwise Comparisons with Multiple References............ 176

8.2.3 An Example........................................................................... 177

8.3 Simultaneous Confidence Approach............................................... 179

8.3.1 Assumptions and Statistical Framework.......................... 179

8.3.2 Simultaneous Confidence Interval with

the Assumption that T R R 1 2................................... 181

8.3.3 Simultaneous Confidence Interval without

the Assumption of T R R 1 2...................................... 185

8.3.4 An Example........................................................................... 192

8.4 Reference Product Change............................................................... 193

8.4.1 Kang and Chow’s Approach............................................... 194

8.4.2 Criteria for Biosimilarity...................................................... 195

8.4.3 Statistical Tests for Biosimilarity........................................ 196

8.4.4 Remarks..................................................................................200

8.5 Concluding Remarks......................................................................... 202

9. Extrapolation across Indications..............................................................203

9.1 Introduction........................................................................................203

9.2 An Example.........................................................................................204

9.3 Development of Sensitivity Index................................................... 207

9.4 Assessment of Sensitivity Index......................................................209

9.4.1 The Case Where ε Is Random and C Is Fixed...................209

9.4.2 The Case Where ε Is Fixed and C Is Random................... 211

9.4.3 The Case Where Both ε and C Are Random..................... 214

9.5 Statistical Inference of Extrapolation.............................................. 217

9.5.1 The Case Where ε Is Random and C Is Fixed................... 218

9.5.2 The Case Where ε Is Fixed and C Is Random...................220

9.5.3 The Case Where ε and C Are Random.............................. 221

9.5.4 The Confidence Interval of the Effect Size

in Original Population.........................................................222

9.5.5 An Example...........................................................................223

9.6 Concluding Remarks.........................................................................225

Appendix.......................................................................................................225

10. Case Studies – Recent FDA Biosimilar Submissions...........................229

10.1 FDA Abbreviated Licensure Pathway.............................................229

10.2 Sponsor’s Strategy for Regulatory Submission.............................. 231

10.3 Avastin Biosimilar Regulatory Submission...................................233

10.4 Herceptin Biosimilar......................................................................... 241

10.5 Concluding Remarks......................................................................... 246

11. Practical and Challenging Issues............................................................. 249

11.1 Introduction........................................................................................ 249

11.2 Hypotheses Testing versus Confidence Interval Approach........250

11.2.1 Interval Hypotheses Testing...............................................250

11.2.2 Confidence Interval Approach............................................ 251

11.2.3 Remarks.................................................................................. 252

11.3 Totality-of-the-Evidence....................................................................253

11.3.1 Primary Assumptions of Stepwise Approach..................253

11.3.2 Relationships among Analytical, PK/PD,

and Clinical Similarity.........................................................254

11.3.3 Practical Issues......................................................................256

11.3.4 Examples................................................................................ 257

11.3.5 Remarks..................................................................................258

11.4 Inconsistencies between Tiered Approaches................................. 259

11.4.1 In Vitro Bioequivalence Testing versus Analytical

Testing.................................................................................... 259

11.4.2 Primary Assumptions for Tiered Approach.....................260

11.4.3 Inconsistencies between Different Tiered Tests...............260

11.5 Individual Bioequivalence................................................................ 261

11.6 Commonly Asked Questions from the Sponsors..........................263

11.7 Concluding Remarks......................................................................... 270

12. Recent Development................................................................................... 273

12.1 Introduction........................................................................................ 273

12.2 Comparing Means versus Comparing Variances......................... 274

12.2.1 Generally Similar versus Highly Similar.......................... 275

12.2.2 Similarity Test in Variability............................................... 275

12.2.3 Remarks..................................................................................277

12.3 Switching Design...............................................................................277

12.3.1 Introduction...........................................................................277

12.3.2 Concept and Criteria for Drug Interchangeability.......... 278

12.3.3 Hybrid Parallel-Crossover Design..................................... 279

12.3.4 Statistical Model and Analysis........................................... 282

12.3.5 Sample Size Requirement.................................................... 287

12.4 Non-Medical Switching.................................................................... 294

12.4.1 Introduction........................................................................... 295

12.4.2 Approaches for Evaluation of Non-Medical Switch........ 296

12.4.3 Clinical Studies.....................................................................299

12.4.4 Scientific Factors and Statistical Considerations..............302

12.4.4.1 Scientific Factors....................................................302

12.4.4.2 Statistical Considerations.....................................303

12.4.5 Design and Analysis of Switching Studies.......................305

12.5 FDA Draft Guidance on Analytical Similarity Assessment........306

12.6 Concluding Remarks.........................................................................309

References and Further Reading..................................................................... 311

Index...................................................................................................................... 321