Negotiating the Emerging Biosimilars Landscape: Key developments in the regulatory environment

Negotiating the Emerging Biosimilars Landscape: Key developments in the regulatory environment

Negotiating the Emerging Biosimilars Landscape
Key developments in the regulatory environment

As regulatory obstacles to biosimilars development have become increasingly resolved, a growing number of opportunities have been created for generics companies in the biopharmaceutical market, which according to IMS data was valued at $85.9 billion in 2007. Conservative projections estimate that sales of biopharmaceutical products will exceed $135 billion by 2011. With some of the earliest biopharmaceuticals having already lost patent protection, the originators of biopharmaceutical products are facing intense competition from generics developers. In response, originators are resorting to a range of defensive tactics, including the reformulation of existing products to improve efficacy, the implementation of more efficient delivery systems and the pursuit of high-level intellectual property (IP) battles.

‘Negotiating the Emerging Biosimilars Landscape’ is a new report published by Business Insights that examines the structure of the biopharmaceutical industry and the strategic approaches taken to alleviate the threat posed by the biosimilar market. The key factors affecting market access within the biosimilars market are assessed and the latest issues surrounding bioequivalence are examined. This report also provides a comprehensive review of the current legislative and regulatory positions of key geographic regions in addition to evaluating their anticipated future legislative changes and outcomes.

Key Findings

European Union guidelines have been prepared which authorise the use of specific therapeutic biopharmaceutical medicines as biosimilars. However, despite the range of current European guidelines produced by the EMEA, many European governments have issued laws prohibiting the automatic substitution of original products.

No approval pathway for biosimilars (FOB) exists in the USA, and one is unlikely to exist before 2010. A complex range of Acts and Bills have failed to resolve a number of outstanding legal and regulatory issues.

India’s biopharmaceutical industry is projected to grow to almost $5 billion by the end of 2010, representing annual growth in excess of 30%. However, despite WTO membership and recent advances in compliance with international regulatory/intellectual property laws, there remains no formal regulatory framework for biosimilars in India or China.

Health Canada has not yet publicly announced a legal or regulatory framework for biosimilar approval, and no legal framework for biosimilars currently exists in Japan. New regulatory frameworks and biosimilar guidelines are currently under development in both countries.

Use this report to...

• Identify and respond to the challenges and threats posed by the emergence of the biosimilars industry with this report’s examination of key trends and strategic approaches used by the biopharmaceutical industry to protect market share and intellectual property.
• Examine details of expired patents or impending patent expiries for first-gen biopharmaceuticals derived from recombinant DNA such as interferons, human insulin and insulin analogs, monoclonal antibodies (Mab) growth hormone and epoietins.
• Evaluate the legislative and regulatory requirements for biosimilars across key geographic regions including Europe, the US, Japan, Australia, Canada as well as the strategically important emerging markets of China and India.
• Assess the factors affecting biosimilar market access with this report’s analysis of the drivers and restraints to biosimilar approval, use and uptake, in addition to an investigation of the problems associated with determining bioequivalence.

Explore issues including...

Impending patent expiries. The critical challenge facing the biopharmaceutical industry is the expiry or pending expiry of patents for first generation biopharmaceuticals derived from recombinant DNA such as interferons, growth hormone and epoietins.

Defensive strategies. As part of efforts to protect the market share of products with impending patent expiries, originator biopharmaceutical companies have begun to protect intellectual property and engage in strategic alliances, joint ventures and mergers between themselves and major pharma companies.

Geographical disparities in biosimilar legislation. Different geographic regions have varying legislative approaches to the regulation and/or approval of biosimilars. Such discrepancies often lead to misunderstandings and can result in complexity and complication during the approval process.

Discover...

• Which biopharmaceutical companies are at risk from product patent expires?
• What is the status of the analytical techniques used for determining bioequivalence?
• What tactics prove most effective for originator biopharmaceutical companies who wish to protect their market position?
• What effect the market entry of second generation biopharmaceuticals by originator companies have on the biosimilars market?
• What are the growth drivers and restraints of the biosimilars market?
• How are global healthcare costs influenced by biosimilar market entry prospects?
• What is the current legislative and regulatory status of biosimilars in Europe and the US?
• How will China and India influence the biopharmaceutical and biosimilars market in the future?

Table of Contents
Negotiating the Emerging Biosimilars Landscape Executive Summary 10
Chapter 1: Biosimilars and the biosimilars industry 10
Chapter 2: Factors affecting market access for biosimilars 11
Chapter 3: The European position on biosimilars 12
Chapter 4: The United States’ position on biosimilars 13
Chapter 5: Position on biosimilars: China and India 13
Chapter 5: Position on biosimilars: other geographic regions 15
Chapter 1 Biosimilars and the biosimilars industry 18
Summary 18
Introduction and Overview 19
Biotechnology in Healthcare and the Biotechnology Industry 19
Biosimilars: terminology, definitions and nomenclature 20
Biosimilars definitions and terminology 22
Structure of the healthcare based Biotechnology Industry 25
The pharmaceutical-biopharmaceutical relationship 25
Emergence of the biopharmaceutical sector 27
Biopharmaceutical sales by therapeutic area and leading companies 32
Biopharmaceutical sales by therapeutic area 32
Leading biopharmaceutical companies 33
Characteristics and strategy of the biopharmaceutical industry 36
Strategic alliances, joint ventures and mergers 36
High technology and intellectual property issues 37
High venture capital investment 38
High risk and costs associated with drug development 38
Challenges and major Issues 40
The threat from biosimilars 40
Erythropoietins (EPOs). 41
Interferons 44
Human Insulin and Insulins Analogues 49
Monoclonal antibodies (MAb) 51
Lack of regulatory guidelines and legislation controlling biosimilars 53
Product complexity of biopharmaceuticals 53
Differences in immunogenicity 55
Differences in processing and manufacturing 57
Chapter 2 Factors affecting market access for biosimilars 60
Summary 60
Introduction 61
Market dynamics 61
Market drivers influencing biosimilars approval, use and uptake 61
Emergence of biosimilars as patents of leading biopharmaceuticals expire 61
Biosimilars predicted to reduce global healthcare costs 62
Advances in manufacturing and proving equivalence provide new impetus to manufacturers 63
Lower priced biosimilars enable greater patient coverage and market penetration 65
EMEA legislation relating to biosimilars sets standard for market development of biosimilars in Europe 66
Market restraints influencing biosimilars approval, use and uptake 68
Political lobbying by branded companies 68
Resistance to substitution of products from pharmacists, physicians and patients 68
R&D and commercialization of second generation biopharmaceuticals by innovator companies 69
Manufacturing issues related to bioequivalence and substitutability of branded biopharmaceuticals 70
Biosimilars: The cost and complexity of development 71
Lack of legislation restricts growth of biosimilars in the United States 71
Determining the bioequivalence or essential similarity of biosimilars 73
Proving equivalence of therapeutic proteins 74
Glycosylation 75
Mammalian cell culture processes 76
Glyco-engineered yeast cell lines 77
Proving equivalence of the end product 78
Opinions from originator companies and supporting associations 80
Opinions from generic manufacturers and supporting associations 82
Demonstrating therapeutic equivalence 84
Assays for confirming the presence of antibodies 87
Assays for dissecting the specificity of antibodies 88
Neutralization assays 88
Chapter 3 European position on biosimilars 92
Summary 92
European regulation on biosimilars 93
EU legal and regulatory framework for biosimilar products 94
Creation of the European Agency for the Evaluation of Medicinal Products (EMEA) 94
Directive 2001/83/EC 97
Directive 2003/63/EC 98
Directive 2004/27/EC 99
Regulatory framework for biosimilars in Europe 101
Principle European guidelines 102
EU specific guidelines on biosimilars (quality & clinical and non clinical issues) 106
EU product specific guidelines on biosimilars 111
Concerns over regulatory, clinical and marketing issues 119
Prohibition of automatic substitution of biosimilars in European countries 119
National interpretations and implementation of the “Bolar Clause” 122
Patient, pharmacist and physician acceptability of biosimilars 124
Reimbursement of biosimilars in Europe 124
Chapter 4 United States position on biosimilars 129
Summary 129
Regulation and legislation affecting follow-on biologics in the US 130
Historical background and current legislation in the US 130
Historic legislative developments for biosimilars in the US 133
Recent congressional legislation 141
Access to Life-Saving Medicine Act (H.R. 1038/S.623) 142
Patient Protection and Innovative Biologic Medicines Act (H.R. 1956) 145
S.1695 The Biologics Price Competition and Innovation Act of 2007 147
The Pathways for Biosimilars Act (H.R. 5629) 147
The Federal Trade Commission reviews biosimilars and competition
(Notice Billing Code: 6750-01-S) 149
The future outlook for biosimilars in the USA 150
Chapter 5 Position on biosimilars: China and India 154
Summary 154
China 155
Healthcare regulation and legislation in China 155
The Chinese biopharmaceutical and biosimilar industry 157
Regulation and legislation of biologicals in China 166
India 172
Healthcare regulation and legislation in India 172
Establishment of the Central Drug Authority (CDA) 172
Improvements to the administration of biotechnologies in India 173
The biopharmaceutical and biosimilar industry in India 175
Regulation and legislation of biologicals in India 177
Chapter 6 Position on biosimilars: other geographic regions 182
Summary 182
Australia 183
Regulation and legislation affecting biopharmaceuticals in Australia 183
Regulatory approval process for medicines in Australia 184
Regulatory approval process for biosimilars in Australia 186
Canada 188
Regulation and legislation affecting biopharmaceuticals in Canada 188
Regulatory approval process for medicines in Canada 188
Current position on subsequent entry biologics in Canada 189
Interim regulatory status of sebs in Canada 191
Japan 192
Healthcare regulation and legislation in Japan 192
Restructuring of principle regulatory agencies in Japan 192
Major changes to pharmaceutical laws enacted April 2005 194
The biopharmaceutical and biosimilar industry in Japan. 197
Current position on follow-on biologicals (fobs) or biosimilars 198
Chapter 7 Appendix 199
Methodology statement 199
Primary Data and Information Gathering 199
Secondary data and information gathering 199
Market share analysis and market forecast predictions 201
Definitions of Product-Life Cycle stages 202
Glossary of abbreviations and acronyms 203
Glossary of Terms 211
Index 223
List of Figures
Figure 1.1: Evolution of the biopharmaceutical corporation 28
Figure 1.2: Comparison of global sales by biopharmaceutical class 2007 34
Figure 1.3: Challenges and Issues Affecting the Biopharmaceutical Industry 42
Figure 1.4: Predicted market share of multiple sclerosis drugs (2007-2017) 49
Figure 1.5: Estimated last patent expiry dates of selected proteins 52
Figure 2.6: Impact of second generation biopharmaceuticals on erythropoietin market development (2000-2006) 70
Figure 2.7: The process of determining therapeutic equivalence 85
Figure 2.8: Analytical techniques used to physicochemically characterize complex glycoproteins 89
Figure 3.9: Structure of the EMEA 96
Figure 3.10: Timeline of EU guidelines on biosimilars 104
Figure 4.11: Timeline of US guidelines on follow-on-biologics 141
Figure 5.12: Biopharmaceutical and pharmaceutical sales revenue in China (2005) 168
List of Tables
Table 1.1: Terminology used to describe generic biopharmaceuticals 23
Table 1.2: Top 20 Pharmaceutical companies ranked by revenue (2007) 30
Table 1.3: Top 10 Biopharmaceutical companies ranked by revenues (2007) 31
Table 1.4: Biopharmaceutical sales by therapeutic area, 2007 33
Table 1.5: Top 10 biopharmaceutical companies biopharmaceutical sales $m (2003-2007) by ATC3, therapeutic products 35
Table 1.6: Top 10 biopharmaceutical companies sales $m (2003-2007) by ATC3, therapeutic products 43
Table 1.7: Interferons on the market and patent expiries 45
Table 1.8: Multiple sclerosis drugs on the market and patent expiries 47
Table 1.9: Recombinant insulin products on the market and patent expiries 51
Table 1.10: Summary of key structural data for selected therapeutic protein products 54
Table 1.11: Comparison of biopharmaceuticals versus chemical low molecular weight drugs 55
Table 2.12: Approved biosimilars EMEA and recommended authorizations 67
Table 2.13: Productivity increases over the last 20 years in mammalian cell culture 78
Table 2.14: Physicochemical characterization methodology of non-glycosylated proteins 86
Table 3.15: Summary of biosimilar overarching guideline (EMEA/CHMP/437/04) 103
Table 3.16: General EU guidelines on biosimilars 104
Table 3.17: Summary of Biosimilar Quality Guideline (EMEA/CHMP/49348/05) 108
Table 3.18: Summary of Biosimilar Non Clinical Guideline (EMEA/CHMP/42832/05) 109
Table 3.19: Summary of Biosimilars (non) Clinical Guideline Principles for EMEA/CHMP/42832/05 110
Table 3.20: EU product specific guidelines on biosimilars 115
Table 3.21: EU revisions to product specific guidelines on biosimilars 115
Table 5.22: Major biosimilars in China 160
Table 5.23: Major biosimilar manufacturers in China 161
Table 5.24: Top 60 Chinese-Owned Biopharmaceutical Companies (Part 1) 164
Table 5.25: Top 60 Chinese-Owned Biopharmaceutical Companies (Part 2) 164
Table 5.26: Top 60 Chinese-Owned Biopharmaceutical Companies (Part 3) 165
Table 5.27: Major biosimilar manufactures based in India 176
Table 5.28: Major Biosimilars and Manufacturers in India 177