Biosimilars Approval Pathways in the US and Europe -
Development and Approval of Biosimilar mABs
May Face Tough Regulatory Environment
Reference Code: GBIHC075MR Publication Date:April 2011
Escalating Healthcare Expenditures Increase the Need for Low Cost Biosimilars
GBI Research analysis finds that the proposals for the approval pathway of Biosimilars, also called
follow-on biologics (FOB) in the US, have the ability to shape the US biosimilar industry. Reduction
The global biosimilar
of healthcare expenditures is at the top of the agenda for many governments, so initiatives on
market is forecast to reach
introducing regulations governing Biosimilars seem to be of prime importance in developing
$4.7 billion in 2016 at a
nations. Since biologics are among the highest priced therapies in the world, controlling the
CAGR of 52.6% during
expenses of biologics is one of the key focus points and this has increased the expectations of a
the period 2009-2016. The
regulatory pathway among the Biosimilars industry participants.
growth is driven by need
to cut healthcare costs in
Biosimilars Approval Pathways in the US and Europe, Global, Market Forecasts, ($m),
developed nations and
2009–2016
expiry of patents for major
biologic drugs. 5,000
4,500
4,000
3,500
3,000
Revenue ($m)
CAGR (2009-2016): 52.6%
2,500
2,000
1,500
1,000
500
0
2009 2013 2016
Source: GBI Research
Europe leads the way in the Biosimilars market with 13 approved Biosimilars belonging to the
erythropoietin (EPO) and granulocyte colony stimulating factors (G-CSF) and human growth
hormones (hGH). In Japan, the first biosimilar was only launched in October 2009. However, the
market is expected to gather pace due to the establishment of a biosimilar approval pathway in the
US. The global market for Biosimilars was valued at $243.8m in 2009 and is expected to increase
to $4.7 billion in 2016 at a compound annual growth rate (CAGR) of 52.6%.
Biologics Price Competition and Innovation Act 2009 Opens the Gates for Approval of
Biosimilars in the US
The Biologics Price Competition and Innovation Act (BPCIA), signed into law by the US President
Barack Obama in March 2010, established a regulatory pathway for the approval of Biosimilars in
the US. The act empowers the FDA to develop standards to evaluate and approve Biosimilars. The
act also grants the FDA authority to develop comprehensive guidelines for the approval of
biosimilar products or product classes. The act grants a market exclusivity of 12 years and data
exclusivity of four years to innovator biologic drugs, which is considered favorable.
The act also puts forward a resolution process for biosimilar related patent disputes. The process of
patent resolution is very complex and not encouraging to the biosimilar manufacturers. This patent
resolution process is being considered as a major hurdle to the growth of Biosimilars in the US.
Biosimilars Approval Pathways in the US and Europe - GBIHC075MR /Published APR 2011
Development and Approval of Biosimilar mABs May
Face Tough Regulatory Environment Page 1
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Lack of Interchangeability between Biosimilars and Reference Products and Absence of
Automatic Substitution of Biologics Slows Down Uptake of Biosimilars
One of the main challenges facing the Biosimilars market is the intrinsic difficulty in replicating the
efficacy profile of the original product. Biosimilars have similar therapeutic properties but they are
not the same, hence the issue of interchangeability is a major hurdle for the rapid growth of the
Biosimilars market. Unlike generic versions of chemical drugs, Biosimilars require preclinical and
clinical studies to evaluate and compare efficacy and safety, if the Biosimilars manufacturer claims
interchangeability. Manufacturers of branded biologics are opposed to the idea of automatic
substitution at the pharmacy due to differing characteristics of Biosimilars and original drugs.
Europe has made significant progress in establishing a pathway for Biosimilars and has set an
example which no doubt other regions will follow. In Europe, all medicines are given an 11 year
data protection period and the choice of interchangeability or substitution is left to the member
states. However, GBI Research analysis finds that substitution for biologics is not a guaranteed
possibility in the future. Hence, rapid uptake of Biosimilars akin to generics of conventional drugs is
not possible due to lower price differential, lack of substitution and negative perception of generics
in markets which have traditionally been consuming branded products.
High Cost of Development and Manufacturing Coupled with the Need for Technical
Expertise in Biologics Act as Entry Barriers for Smaller Players and Favors Larger Players
The high costs of development and manufacturing favor the success of large pharmaceutical
companies with technical expertise, sales force strength and financial strength. Consequently,
smaller players are not able to compete on financial grounds or production capacity. The
Biosimilars market is unlike its chemical generics counterpart, where the development and
manufacturing costs are comparatively much lower. The expected price reduction for a biosimilar is
not more than 10–30% of the original biological. This marked difference between the Biosimilars
and traditional generic drugs, where the price reduction is more than 70%, is because only
Biosimilars require preclinical studies and clinical studies to prove biosimilarity and safety.
Costs of Development, Manufacturing and Approval of Biosimilars by Cell Culture Type
Total Cost (Mammalian) = $466m
11%
2%
2% 15%
26%
13%
Total Cost (Microbial) = $196m 20%
4%
4%
9%
63%
31%
Facility CMC Clinical Trials Regulatory Affairs IP and Litigation Initial Marketing
Source: GBI Research, Gal. R, Bernstein Research
The cost of constructing a biopharmaceutical manufacturing facility is nearly $40–300m and the
manufacturing process is complex, requiring technical personnel with expertise in
biopharmaceutical manufacturing. Biopharmaceutical drugs also need an experienced sales force,
which the smaller biosimilar companies lack. While companies with financial muscle can afford
these high costs and spend an average development time of six to eight years, smaller
manufacturers are discouraged from entering the Biosimilars market.
Biosimilars Approval Pathways in the US and Europe - GBIHC075MR /Published APR 2011
Development and Approval of Biosimilar mABs May
Face Tough Regulatory Environment Page 2
© GBI Research. This is a licensed product and is not to be photocopied
1 Table of Contents
1 Table of Contents ........................................................................................................................ 3
1.1 List of Tables..................................................................................................................... 6
1.2 List of Figures ................................................................................................................... 7
2 Biosimilars Approval Pathways in the US and Europe – Introduction ........................................ 10
2.1 GBI Research Report Guidance ..................................................................................... 10
3 Biosimilars Approval Pathways in the US and Europe – Market Overview ................................ 11
3.1 Overview of the Biopharmaceutical Industry ................................................................... 11
3.2 Biosimilars and their Significance ................................................................................... 19
3.3 Comparison of Biosimilars with Generics ........................................................................ 22
3.4 Biopharmaceutical Manufacturing Process ..................................................................... 24
4 Biosimilars Approval Pathways in the US and Europe – Market Characterization..................... 26
4.1 Global Biosimilar Market Size and Forecast ................................................................... 26
4.2 The US Biosimilars Market Size and Forecast ................................................................ 27
4.3 Europe Biosimilar Market Size and Forecast .................................................................. 28
4.4 Japan Biosimilars Market Size and Forecasts ................................................................ 30
4.5 Market Forecasts for Biosimilars ..................................................................................... 31
4.5.1 Human Growth Hormone (hGH) Biosimilars Markets .............................................. 31
4.5.2 Erythropoietin (EPO) Biosimilars Markets ............................................................... 33
4.5.3 Granulocyte – Colony Stimulating Factor (G-CSF) Biosimilars Markets .................. 35
4.6 Opportunity Analysis ....................................................................................................... 37
4.6.1 Interferon alfa Biosimilars ........................................................................................ 37
4.6.2 Interferon beta Biosimilars ....................................................................................... 38
4.6.3 Insulin and Insulin Analogs Biosimilars .................................................................... 40
4.6.4 TNF alfa Inhibitor Biosimilars ................................................................................... 42
4.6.5 Biosimilars for Monoclonal Antibodies against Cancer ............................................ 43
5 Biosimilars Approval Pathways in the US and Europe – Industry Dynamics ............................. 45
5.1 Key Success Factors in the Biosimilar Industry .............................................................. 45
5.1.1 Long Term Strategy ................................................................................................. 45
5.1.2 Sound Financial Structure ....................................................................................... 46
5.1.3 Comprehensive Competitive Intelligence ................................................................ 46
5.1.4 Biomanufacturing Competencies ............................................................................. 46
5.1.5 Clinical Development and Regulatory Expertise ...................................................... 46
5.1.6 Marketing, Sales and Distribution Capabilities......................................................... 46
5.2 Participants in the Biosimilar Industry ............................................................................. 47
5.3 Suppliers ......................................................................................................................... 48
5.3.1 Clinical Trial Capability Providers ............................................................................ 48
5.3.2 Manufacturing Capacity Providers ........................................................................... 48
5.3.3 Media and Reagents Providers ............................................................................... 48
5.4 Innovators ....................................................................................................................... 49
5.5 Stakeholders ................................................................................................................... 49
5.5.1 Regulators ............................................................................................................... 49
5.5.2 Payers ..................................................................................................................... 49
5.5.3 Physicians ............................................................................................................... 50
5.5.4 Patients and Patient Groups .................................................................................... 50
6 Biosimilars Approval Pathways in the US and Europe – Drivers and Restraints ....................... 51
6.1 Drivers ............................................................................................................................ 52
6.1.1 Need to Cut Healthcare Costs in Developed Economies ........................................ 52
6.1.2 Lower Development Costs and Regulatory Costs Compared to a New Biologic Drug
................................................................................................................................ 54
6.1.3 Lower Overall Cost of Treatment Using Biosimilar Drugs Compared to Biologics ... 55
6.1.4 Patent Expiry for Blockbuster Biologics ................................................................... 55
6.1.5 Increasing Uptake of Biologic Drugs ........................................................................ 56
6.1.6 More Profitable than Generic Drugs ........................................................................ 56
Biosimilars Approval Pathways in the US and Europe - GBIHC075MR /Published APR 2011
Development and Approval of Biosimilar mABs May
Face Tough Regulatory Environment Page 3
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6.2 Restraints ........................................................................................................................ 56
6.2.1 Absence of Automatic Substitution .......................................................................... 56
6.2.2 Higher Development and Manufacturing Costs Compared to Generics .................. 57
6.2.3 High Entry Barriers .................................................................................................. 58
6.2.4 Threat from Second Generation Biologic Drugs ...................................................... 58
6.2.5 Patent Protection Around Biologic Drugs ................................................................ 58
7 Biosimilars Approval Pathways in the US and Europe – Regulatory Landscape ....................... 59
7.1 Regulatory Landscape in the US .................................................................................... 60
7.1.1 Regulatory Framework for Biopharmaceutical Industry ........................................... 60
7.1.2 Evolution of Regulatory Pathways for Biosimilars.................................................... 62
7.1.3 BPCIA and the Pathway for Approval of Biosimilar Products .................................. 65
7.2 FDA’s Public Meeting on Biosimilars .............................................................................. 70
7.2.1 Data requirement to Demonstrate Biosimilarity ....................................................... 71
7.2.2 The Standard for Interchangeability ......................................................................... 71
7.2.3 Naming for Biosimilars ............................................................................................. 71
7.2.4 Extrapolation............................................................................................................ 71
7.2.5 Foreign Studies ....................................................................................................... 71
7.2.6 Other Issues ............................................................................................................ 71
7.2.7 Drivers and Barriers ................................................................................................. 72
7.3 Regulatory Landscape in Europe .................................................................................... 73
7.3.1 Regulatory Framework for Biopharmaceutical Industry ........................................... 73
7.3.2 Evolution of Regulatory Pathways for Biosimilars.................................................... 74
7.3.3 Current Position on Biosimilars................................................................................ 75
7.3.4 The Bolar Type Provision ........................................................................................ 80
7.3.5 The Comparability Exercise ..................................................................................... 81
7.3.6 Biosimilars Approvals and Applications ................................................................... 82
7.3.7 EMEA Guidelines for Biosimilar mAb ...................................................................... 84
7.3.8 Issues Facing the European Biosimilars Industry .................................................... 84
7.3.9 Drivers for the European Biosimilars Market ........................................................... 85
7.3.10 Barriers for the European Biosimilars Market .......................................................... 86
7.3.11 Country Analysis – The UK ..................................................................................... 87
7.3.12 Country Analysis – Germany ................................................................................... 88
7.3.13 Country Analysis – France ...................................................................................... 90
7.3.14 Country Analysis – Spain ........................................................................................ 91
7.3.15 Country Analysis – Italy ........................................................................................... 93
7.4 Regulatory Landscape in Japan...................................................................................... 94
7.4.1 Regulatory Framework for Biopharmaceutical Industry ........................................... 94
7.4.2 Evolution of Regulatory Pathways for Biosimilars.................................................... 94
7.4.3 Current Position on Biosimilars................................................................................ 95
7.4.4 Drivers and Barriers ................................................................................................. 96
8 Biosimilars Approval Pathways in the US and Europe – Competitive Landscape ..................... 97
8.1 Profiles of Major Biosimilar Players ................................................................................. 97
8.1.1 Sandoz .................................................................................................................... 97
8.1.2 Teva Pharmaceuticals Ltd ..................................................................................... 100
8.1.3 Hospira Inc ............................................................................................................ 102
8.1.4 Dr. Reddy’s Laboratories ....................................................................................... 104
8.1.5 Biocon Ltd ............................................................................................................. 106
8.1.6 Biopartners ............................................................................................................ 108
8.1.7 Watson Pharmaceuticals ....................................................................................... 110
8.1.8 STADA Arzneimittel AG ......................................................................................... 112
8.1.9 Reliance Life Sciences .......................................................................................... 114
8.1.10 Intas Biopharmaceuticals ...................................................................................... 116
8.1.11 Celltrion Inc............................................................................................................ 118
8.1.12 3SBio Inc. .............................................................................................................. 120
9 Biosimilars Approval Pathways in the US and Europe – Strategic Consolidations .................. 122
Biosimilars Approval Pathways in the US and Europe - GBIHC075MR /Published APR 2011
Development and Approval of Biosimilar mABs May
Face Tough Regulatory Environment Page 4
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9.1 M&A Deals .................................................................................................................... 122
9.1.1 Pfizer–Biocon Deal ................................................................................................ 122
9.1.2 Teva Acquired Ratiopharm .................................................................................... 122
9.1.3 Watson–Itero Deal ................................................................................................. 122
9.1.4 Biocon and Mylan Strategic Collaboration ............................................................. 122
9.1.5 Merck Acquired Insmed’s Follow-On Biologics for $130m ..................................... 122
9.1.6 Teva and Lonza JV Targets Biosimilars ................................................................ 123
9.1.7 GTC Enters Follow-On-Biologic Founder Development Collaboration with Ag
Research ............................................................................................................... 123
9.1.8 Apotex–Intas Deal ................................................................................................. 123
9.1.9 Teva Acquires CoGenesys .................................................................................... 123
9.2 R&D Licensing Deals .................................................................................................... 124
9.2.1 Innogene Seals Deal With CIMAB to Market Biosimilars ....................................... 124
9.2.2 Abraxis Licenses Rights to Biosimilar from Indian Firm Biocon ............................. 124
10 Biosimilars Approval Pathways in the US and Europe – Appendix.......................................... 125
10.1 Market Definitions ......................................................................................................... 125
10.2 Abbreviations ................................................................................................................ 126
10.3 Research Methodology ................................................................................................. 128
10.3.1 Coverage ............................................................................................................... 128
10.3.2 Secondary Research ............................................................................................. 128
10.3.3 Primary Research .................................................................................................. 129
10.3.4 Expert Panel Validation ......................................................................................... 129
10.4 Contact Us .................................................................................................................... 129
10.5 Sources ......................................................................................................................... 130
10.6 Disclaimer ..................................................................................................................... 130
Biosimilars Approval Pathways in the US and Europe - GBIHC075MR /Published APR 2011
Development and Approval of Biosimilar mABs May
Face Tough Regulatory Environment Page 5
© GBI Research. This is a licensed product and is not to be photocopied
1.1 List of Tables
Table 1: Biosimilars Approval Pathways in the US and Europe, Medicare Formulary Coverage for
Top-Selling Biologics ...................................................................................................... 20
Table 2: Biosimilars Approval Pathways in the US and Europe, Global, Market Forecasts, ($m),
2009–2016 ..................................................................................................................... 26
Table 3: Biosimilars Approval Pathways in the US and Europe, the US, Market Forecasts, ($m),
2009–2016 ..................................................................................................................... 28
Table 4: Biosimilars Approval Pathways in the US and Europe, Europe, Market Forecasts, ($m),
2009–2016 ..................................................................................................................... 29
Table 5: Biosimilars Approval Pathways in the US and Europe, Japan, Market Forecasts, ($m),
2009–2016 ..................................................................................................................... 30
Table 6: Biosimilars Approval Pathways in the US and Europe, Global, hGH Biosimilars Market
Forecasts, ($m), 2009–2016 .......................................................................................... 31
Table 7: Biosimilars Approval Pathways in the US and Europe, Global, EPO Biosimilars Market
Forecasts, ($m), 2009–2016 .......................................................................................... 33
Table 8: Biosimilars Approval Pathways in the US and Europe, Global, G-CSF Biosimilars Market
Forecasts, ($m), 2009–2016 .......................................................................................... 35
Table 9: Biosimilars Approval Pathways in the US and Europe, Global, Interferon alfa Biosimilar
Market Opportunity Analysis, ($m), 2009–2016 ............................................................. 37
Table 10: Biosimilars Approval Pathways in the US and Europe, Global, Interferon-beta Biosimilar
Market Opportunity Analysis, ($m), 2009–2016 ............................................................. 39
Table 11: Biosimilars Approval Pathways in the US and Europe, Global, Insulin and Insulin
Analogs Biosimilar Market Opportunity Analysis, ($m), 2009–2016 ............................... 40
Table 12: Biosimilars Approval Pathways in the US and Europe, Global, TNF alfa Inhibitor
Biosimilar Market Opportunity Analysis, ($m), 2009–2016 ............................................. 42
Table 13: Biosimilars Approval Pathways in the US and Europe, Global, Monoclonal Antibodies
Against Cancer Biosimilar Market Opportunity Analysis, ($m), 2009–2016 ................... 44
Table 14: Biosimilars Approval Pathways in the US and Europe, Cost-Sharing Practices by Health
Insurers in the US, 2009 ................................................................................................ 50
Table 15: Biosimilars Approval Pathways in the US and Europe, Comparison for a Biosimilar, 2010
....................................................................................................................................... 54
Table 16: Biosimilars Approval Pathways in the US and Europe, Patent Expiry for Major Biologic
Drugs, 2010–2016.......................................................................................................... 55
Table 17: Biosimilars Approval Pathways in the US and Europe, Costs of Development,
Manufacturing and Approval of Biosimilars By Cell Culture Type, ($m), 2010 ............... 57
Table 18: Biosimilars Approval Pathways in the US and Europe, Europe, Existing Guidelines for
Biosimilars, 2010 ............................................................................................................ 75
Table 19: Biosimilars Approval Pathways in the US and Europe, Biosimilar Approvals, 2010 ....... 82
Table 20: Biosimilars Approval Pathways in the US and Europe, Europe, Applications Rejected or
Withdrawn, 2010 ............................................................................................................ 83
Biosimilars Approval Pathways in the US and Europe - GBIHC075MR /Published APR 2011
Development and Approval of Biosimilar mABs May
Face Tough Regulatory Environment Page 6
© GBI Research. This is a licensed product and is not to be photocopied
1.2 List of Figures
Figure 1: Biosimilars Approval Pathways in the US and Europe, Global Biologics Market Forecast,
($bn), 2007–2016 ........................................................................................................... 11
Figure 2: Biosimilars Approval Pathways in the US and Europe, Share of Top 25 Biologics By
Therapeutic Class, 2009 ................................................................................................ 12
Figure 3: Biosimilars Approval Pathways in the US and Europe, Growth for Biologics, 2010 ....... 13
Figure 4: Biosimilars Approval Pathways in the US and Europe, Share of Top 25 Biologics By
Production System, 2008 ............................................................................................... 14
Figure 5: Biosimilars Approval Pathways in the US and Europe, Biologics Under Development by
Therapeutic Class, Global, 2008 .................................................................................... 15
Figure 6: Biosimilars Approval Pathways in the US and Europe, Biologics Under Development by
Disease Category, Global, 2008 .................................................................................... 16
Figure 7: Biosimilars Approval Pathways in the US and Europe, Comparison of Small Molecule
Drugs and Biologics ....................................................................................................... 17
Figure 8: Biosimilars Approval Pathways in the US and Europe, Difference Between the
Distribution Chains for Small Molecule and Biologic Drugs ............................................ 18
Figure 9: Biosimilars Approval Pathways in the US and Europe, Medicare Coverage for Biologic
Drugs, 2009 ................................................................................................................... 19
Figure 10: Biosimilars Approval Pathways in the US and Europe, Imminent Biosimilar
Opportunities, 2010 ........................................................................................................ 21
Figure 11: Biosimilars Approval Pathways in the US and Europe, Comparison of Biosimilars With
Generics, 2010 ............................................................................................................... 22
Figure 12: Biosimilars Approval Pathways in the US and Europe, Development Costs and
Timelines for a Biosimilar, 2010 ..................................................................................... 23
Figure 13: Biosimilars Approval Pathways in the US and Europe, Challenges and their Solutions in
Biopharmaceutical Manufacturing, 2010 ........................................................................ 24
Figure 14: Biosimilars Approval Pathways in the US and Europe, Global, Market Forecasts, ($m),
2009–2016 ..................................................................................................................... 26
Figure 15: Biosimilars Approval Pathways in the US and Europe, the US, Market Forecasts, ($m),
2009–2016 ..................................................................................................................... 27
Figure 16: Biosimilars Approval Pathways in the US and Europe, Europe, Market Forecasts, ($m),
2009–2016 ..................................................................................................................... 28
Figure 17: Biosimilars Approval Pathways in the US and Europe, Japan, Market Forecasts, ($m),
2009–2016 ..................................................................................................................... 30
Figure 18: Biosimilars Approval Pathways in the US and Europe, Global, hGH Biosimilars Market
Forecas