Clinical Trial Strategies in Biosimilar Drug Development

CONTENTS

8 EXECUTIVE SUMMARY
8 The volume of biosimilar clinical trials initiated globally is growing
8 Autoimmune/inflammation is the top targeted area for biosimilar development
9 Oncology biosimilars come as a second choice for biosimilar developers
9 Biosimilars in endocrinology/nephrology are progressing through the pipeline
9 Some biosimilar sponsors also target therapy areas such as ophthalmology, reproductive health, and multiple sclerosis
10 Biosimilar sponsors may employ switching designs in their Phase III trials to demonstrate interchangeability

11 OVERVIEW OF CLINICAL TRIAL STRATEGIES
11 Biosimilar development is associated with many risks, but potential high returns
11 Comparison of biosimilar approval pathways
17 Views on indication extrapolation differ among regulatory authorities
22 The FDA outlined requirements for biosimilar sponsors seeking interchangeability status
27 Bibliography

30 GLOBAL TRENDS IN BIOSIMILAR CLINICAL TRIALS
30 The total number of clinical trials for biosimilar candidates has been incrementally increasing
31 The growth in biosimilar clinical trial volume is driven by the expiration of branded drug patents
34 A higher proportion of bioisimilar development projects is targeted towards regulated markets
35 A diverse range of industry sponsors are involved in biosimilar clinical development
37 Biosimilar sponsors carefully choose trial location regions
40 The top three therapy areas for the development of biosimilars are autoimmune and inflammation, oncology, and endocrinology/nephrology
44 Biosimilar sponsors carefully choose which disease indications to study in clinical trials
47 Bibliography

49 AUTOIMMUNE/INFLAMMATION BIOSIMILAR TRIAL TRENDS
49 Autoimmune/inflammation is the therapeutic area most often targeted by biosimilar developers
50 The most often targeted molecules in regulated markets are anti-TNF therapies
53 Biosimilar sponsors initiating trials in A/I indications are joining a highly competitive space
62 Analysis of tested A/I indications for biosimilars
67 Europe is the most active clinical trial hub for A/I biosimilar clinical development
69 Bibliography

72 ONCOLOGY BIOSIMILAR TRIAL TRENDS
72 Oncology is the second most often targeted therapeutic area by biosimilar developers
73 Sponsors developing biosimilars in oncology are targeting three blockbuster MAbs
76 Analysis of biosimilar sponsors conducting clinical trials in oncology indications
85 Choosing an appropriate target population for oncology biosimilar trials is essential
88 Europe has the highest number of clinical trial sites for oncology biosimilars
90 Bibliography

93 ENDOCRINOLOGY/NEPHROLOGY BIOSIMILAR TRIAL TRENDS
93 Endocrinology/nephrology is the third most often targeted therapeutic area by biosimilar developers
95 Insulin products and erythropoetin stimulating agents are among the top reference choices for developers of biosimilars in
endocrinology/nephrology
98 Analysis of biosimilar sponsors conducting clinical trials in endocrinology/nephrology indications
104 The US is the most active region chosen for the clinical development of endocrinology/nephrology biosimilars
105 Bibliography

108 BIOSIMILAR TRIAL TRENDS IN OTHER THERAPEUTIC AREAS
108 A key biosimilar target in ophthalmology is the monoclonal antibody ranibizumab
110 A key biosimilar target in reproductive health is follitropin alfa
112 Biosimilar sponsors also develop biosimilars in hematology, hepatitis C, and multiple sclerosis
119 Bibliography

120 PHASE III SWITCHING STUDY DESIGNS AND BIOSIMILAR INTERCHANGEABILITY
120 There is a need for data from switching studies
120 The FDA has issued draft interchangeability guidelines to shed some light on the issue of interchangeability
120 Biosimilar sponsors may conduct switching studies to assess safety and effectiveness of switching between the brand and
the biosimilar
146 Bibliography

148 APPENDIX
148 Scope
148 Methodology

LIST OF FIGURES
30 Figure 1: Clinical trial volume over time, per trial phase, 2011–17
31 Figure 2: Volume of biosimilar clinical trial starts by geographic market type, all therapeutic areas, 2011–17
33 Figure 3: Volume of biosimilar trials per wave in all regions, 2011–17
34 Figure 4: Volume of biosimilar trials per wave, in regulated markets and ROW, 2011–17
35 Figure 5: Biosimilar clinical trial starts, all therapeutic areas, 2011–17, by trial phase
36 Figure 6: Clinical trials in the regulated markets and in ROW regions: top 10 sponsors by total number, 2011–17
37 Figure 7: Volume of biosimilar clinical trials by sponsor and phase: top 15 sponsors, all regions, 2011–17
38 Figure 8: Volume of biosimilar clinical trials in the regulated markets and ROW, by country
39 Figure 9: Biosimilar clinical trial location by sponsor in the regulated markets: top 15 sponsors, by trial volume
40 Figure 10: Biosimilar clinical trial location by sponsor in ROW: top 15 sponsors, by trial volume
41 Figure 11: Volume of biosimilar clinical trials, by therapeutic area
42 Figure 12: Volume of clinical trial starts by therapeutic area in the regulated markets and ROW
43 Figure 13: Proportion of clinical trial volume within a specific therapeutic area, regulated markets, 2011–17
44 Figure 14: Overall biosimilar clinical trial volume by choice of reference product (top 10 products)
45 Figure 15: Volume of clinical trials targeting a specific disease indication: top 10 indications
46 Figure 16: Volume of Phase I and Phase III biosimilar clinical trials targeting a specific disease indication, regardless of region: top 5 indications per phase
47 Figure 17: Volume of Phase IV biosimilar clinical trials targeting a specific disease indication, regardless of region: top 10 indications
49 Figure 18: Volume of biosimilar clinical trial starts by geographic market type, A/I indications, 2011–17
50 Figure 19: Volume of biosimilar clinical trial starts by geographic market type, A/I indications
51 Figure 20: Choice of reference product for A/I biosimilar clinical trials, all regions and phases
52 Figure 21: Number of biosimilar trials in A/I indications, per reference product and phase
53 Figure 22: Clinical trial volume of biosimilar programs in A/I diseases, by start year, 2011–17
55 Figure 23: Top biosimilar sponsors in A/I indications, per phase
56 Figure 24: Map of the pipeline progress of the top 10 biosimilar developers in the A/I space in the EU, US, and Japan
58 Figure 25: Volume of A/I clinical trial starts per sponsor, per reference molecule: top sponsors
60 Figure 26: Status and sponsors of multinational Phase III A/I biosimilars programs
61 Figure 27: Volume of Phase III trials for biosimilars of each A/I reference product in the regulated markets
62 Figure 28: Status of Phase III A/I biosimilar trials for the top 10 sponsors in the regulated markets
66 Figure 29: Disease indications for Phase III trials of A/I biosimilars in the regulated markets, by reference product an sponsor
67 Figure 30: Indications studied in post-marketing trials of infliximab biosimilars for the regulated markets
68 Figure 31: Volume of biosimilar A/I clinical trial sites in the regulated markets and in ROW
69 Figure 32: Clinical trial locations for A/I biosimilar candidates per region
72 Figure 33: Volume of biosimilar clinical trial starts by geographic market type, oncology indications, 2011–17
73 Figure 34: Volume of biosimilar clinical trial starts by geographic market type, oncology indications
74 Figure 35: Choice of reference product for oncology biosimilar clinical trials, all regions and phases
75 Figure 36: Number of biosimilar trials in oncology indications, per reference product and phase
76 Figure 37: Clinical trial volume of biosimilar programs in oncology, by start year, 2011–17
77 Figure 38: Top biosimilar sponsors in oncology indications, per phase
79 Figure 39: Map of the pipeline progress of the top biosimilar developers in the oncology space in EU, US, and Japan: top four reference molecules
82 Figure 40: Volume of oncology clinical trial starts per sponsor, per reference molecule: top sponsors
84 Figure 41: Status and sponsors of oncology Phase III biosimilars programs targeting the regulated markets
85 Figure 42: Volume of Phase III trials for biosimilars of each oncology reference product in the regulated markets
88 Figure 43: Disease indications for Phase III trials of oncology biosimilars in the regulated markets, by reference product and sponsor
89 Figure 44: Volume of biosimilar oncology clinical trial sites in the regulated markets and in ROW
90 Figure 45: Clinical trial locations for oncology biosimilar candidates per region
94 Figure 46: Volume of biosimilar clinical trial starts by geographic market type, endocrinology/nephrology indications, 2011–17
95 Figure 47: Volume of biosimilar clinical trial starts by geographic market type, endocrinology/nephrology indications
96 Figure 48: Choice of reference product for endocrinology/nephrology biosimilar clinical trials, all regions and phases
97 Figure 49: Number of biosimilar trials in endocrinology/nephrology indications, per reference product and phase
98 Figure 50: Clinical trial volume of biosimilar programs in endocrinology/nephrology indications, by start year, 2011–17
100 Figure 51: Top biosimilar sponsors in endocrinology/nephrology indications, per phase
101 Figure 52: Map of the pipeline progress of the top biosimilar developers in the endocrinology/nephrology space in the EU, US or Japan
104 Figure 53: Volume of endocrinology/nephrology clinical trial starts per sponsor, per reference molecule (top sponsors)
105 Figure 54: Volume of biosimilar endocrinology/nephrology clinical trial sites in the regulated markets and in ROW
121 Figure 55: Volume of biosimilar Phase III trials in A/I which have or do not have a switching component
123 Figure 56: Detailed outline of different types of switching designs used by sponsors in Phase III trials of A/I biosimilar products
124 Figure 57: Volume of clinical trials per switching design (A/I biosimilars)
125 Figure 58: Presence of switch elements in adalimumab biosimilar Phase III trials in regulated markets
129 Figure 59: Indications studied in adalimumab Phase III trials
130 Figure 60: Volume of switching trials per switch type, Phase III adalimumab biosimilar trials
131 Figure 61: Presence of switch elements in etanercept biosimilar Phase III trials in regulated markets
134 Figure 62: Indications studied in etanercept Phase III trials
135 Figure 63: Volume of switching trials per switch type, Phase III etanercept biosimilar trials
136 Figure 64: Presence of switch elements in infliximab biosimilar Phase III trials in regulated markets
139 Figure 65: Indications studied in infliximab Phase III trials
140 Figure 66: Volume of switching trials per switch type, Phase III infliximab biosimilar trials
142 Figure 67: Presence of switch elements in rituximab biosimilar Phase III trials in regulated markets
145 Figure 68: Indications studied in rituximab Phase III trials
146 Figure 69: Volume of switching trials per switch type, Phase III rituximab biosimilar trials

LIST OF TABLES
12 Table 1: Comparison of biosimilar approval pathways
18 Table 2: Indications in which Remicade and infliximab biosimilars have obtained approval in from the regulatory authorities in EU, US and Canada
20 Table 3: Indications in which Enbrel and etanercept biosimilars have obtained approval in from the regulatory authorities in EU, US and Canada
22 Table 4: Indications in which Rituxan/MabThera and rituximab biosimilars have obtained approval in from the regulatory authorities in EU, US and Canada
24 Table 5: Overview of FDA interchangeability guidelines
32 Table 6: Waves of biosimilar development
63 Table 7: Number of Phase I trials conducted by sponsors in the regulated regions, per indication studied
64 Table 8: Number of Phase III trials conducted by sponsors in the regulated regions, per indication studied
86 Table 9: Number of Phase I trials conducted by sponsors in the regulated regions, per indication studied
87 Table 10: Phase III trials of biosimilar trastuzumab in metastatic or early HER2-positive breast cancer patients
109 Table 11: Competitive landscape of biosimilar ranibizumab, 2011–17
111 Table 12: Competitive landscape of biosimilar follitropin alfa, 2011–17
113 Table 13: Competitive landscape of clinical-stage biosimilars in hematology, 2011–17
115 Table 14: Competitive landscape of clinical-stage biosimilars of peginterferon alfa for the treatment of hepatitis, 2011–17
117 Table 15: Competitive landscape of clinical-stage biosimilars in multiple sclerosis, 2011–17
126 Table 16: Adalimumab biosimilar Phase III trials in regulated markets: trial design
132 Table 17: Etanercept biosimilar Phase III trials in regulated markets: trial design
137 Table 18: Infliximab biosimilar Phase III trials in regulated markets: trial design
143 Table 19: Rituximab biosimilar Phase III trials in regulated markets: trial design