Biosimilars Series Regulatory and development issues hurdles

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More information from http://www.researchandmarkets.com/reports/560287/




Biosimilars Series: Regulatory and development issues hurdles exist
but are surmountable

Description:    Introduction

                Europe serves as a model for other countries looking to define their own regulatory approval
                criteria. The US is on the brink of passing legislation to establish a statutory pathway for biosimilars
                approval but the opposing interests of biosimilar and innovative companies may result in further
                delays. Development of biosimilars presents many challenges and potential pitfalls.

                Scope

                Overview of the key drivers and resistors of the biosimilars market growth Analysis of the
                regulatory requirements for approval of biosimilars in Europe Overview of the progress the US has
                made in establishing its approval pathway In-depth analysis of the challenges of biosimilars
                development, including potential technical pitfalls and considerations

                Highlights

                Europe has shown a degree of flexibility in its approval of 5 biosimilars to date. Although guidance
                has been issued biosimilar developers are urged to communicate with the EMEA as approval
                remains on a case-by case basis. Naming of biosimilars remains a contentious and unresolved issue
                as it carries implications for substitution with biosimilars. The increasing expenditure on biologics is
                pressuring US lawmakers to formulate a statutory pathway for approval of biosimilars. The
                Biologics Price Competition and Innovation bill proposes a compromise attempting to satisfy both
                innovative and biosimilar companies. However its future is uncertain as it faces a slow progress in
                Congress. Design of the biosimilar manufacturing process is key process knowledge and
                understanding of potential risks and pitfalls are necessary to minimize the time and cost of
                development. Selection of analytical methods for assessing biosimilars quality is critical as each
                method answers a different question about the product.

                Reasons to Purchase

                Identify the key trends that are driving and resisting the growth of the biosimilars market
                Understand the regulatory requirements in Europe and how recent attempts to establish a
                regulatory pathway in the US might affect that market Gain insight into challenges and potential
                pitfalls in the development of biosimilars including biosimilars of monoclonal antibodies



Contents:       CHAPTER 1 EXECUTIVE SUMMARY 4
                Scope of the report 4
                Key findings 4
                Key definitions 6
                CHAPTER 2 INTRODUCTION TO THE BIOSIMILARS MARKET 9
                Drivers and resistors of the biosimilars market growth 9
                Drivers of growth in the biosimilars market 10
                Biologics are the fastest growing segment of the pharmaceuticals market 10
                Patent expiry on first-generation biologics 10
                Increasing pressures of cost-containment 12
                Advances in analytical techniques 12
                Resistors of growth in the biosimilars market 13
                Opposition from the innovator companies 13
                Lack of biosimilars regulatory approval pathway in the US is stalling the entry of biosimilars into the
                US market 14
                Cost and complexity of development 15
                Lack of time on market hinders physician uptake 15
                CHAPTER 3 BIOSIMILARS REGULATORY ISSUES 17
Europe is leading the way in biosimilars legislation and approval 19
Guideline on quality issues for biosimilars is based on analysis of comparability after process
change 21
Guidelines on pre-clinical and clinical issues are vague 21
Results of clinical trials could be extrapolated to other indications in some cases 23
Product-class specific annexes provide more details 23
Route of administration used in clinical trials is critical 24
Five biosimilars have been approved in the EU 25
Omnitropes approval forced a change of law to allow approval of biosimilars 25
BioPartnerss Valtropin received approval but Alpheon failed on quality issues 26
Three biosimilar Epoetins have been approved in Europe 27
Further guidance is expected 27
Other regulatory issues in Europe remain 27
The Bolar provision - a safe harbor for development of biosimilars 27
Use of trade secret data 28
Innovators insist that biosimilars should have unique INNs 28
Others will follow where EU leads 30
Opposing interests hinder progress in the US 30
The FDA has delayed issuing guidance for approval of biosimilars 32
The FDA has already approved follow-on protein products 33
Avonex marks approval of a first biosimilar 34
Follow-on hyaluronidase approval 35
Glucagon and Fortical (salmon calcitonin nasal spray) follow-on protein products 35
Sandozs Omnitrope 36
The FDAs decision to use the abbreviated approval pathway for Omnitrope was met with criticism
38
Recent activity in the US Senate and Congress suggests legislation on biosimilars approval might be
issued in the near future 39
The Access to Life-Saving Medicine Act is pro-biosimilar and was not accepted by the pro-innovator
faction 40
The Patent Protection and Innovative Biologic Medicines Act of 2007 is pro-innovator 42
The Biologics Price Competition and Innovation Act of 2007 proposes a middle-of-the road solution
44
Impact of future legislation on the FDAs biosimilars approval pathway 49
What happens before legislation is passed? 50
Abbreviated or full submission routes? 51
Strategies for innovators to minimize the effect of biosimilar competition 51
Naming of biosimilars remains an issue in the US 52
Automatic substitution with biosimilars or not - an unresolved issue 53
Automatic substitution in the US is unlikely 54
Substitution policies are defined by individual member states in the EU 55
Will reimbursement incentives drive biosimilar substitution? 55
CHAPTER 4 BIOSIMILARS DEVELOPMENT ISSUES 57
Biosimilars producers have to develop their own manufacturing process 58
Development of a manufacturing process for biosimilars involves many steps 58
Process knowledge is key 59
Choice of cell line is important 60
Patent protection of biologics is complex 60
Demonstration of comparability and similarity employs the same techniques 61
Product knowledge is critical for designing analytical testing strategy 63
Advice from regulators is invaluable 63
Lack of experience and data makes defining acceptance margins difficult 64
Analytical testing of biosimilars 64
Limitations of analytical testing 65
Primary sequence analysis 66
Misfolding can have a serious impact on clinical performance 67
Different processes result in different heterogeneity profiles - critical factor to explore 67
Post-translational modifications are a major cause of heterogeneity 69
Differences in glycosylation patterns need to be investigated 70
Presence of aggregates can have negative effects on a proteins clinical profile 72
Differences in hydrophobicity and charge need to be investigated 73
Stability testing of biosimilars 73
Comparability after process change 74
Choice of reference product is important 75
Some originator products exhibit great inter-batch variability 77
Pre-clinical testing of biosimilars 77
Biological activity assays are used in pre-clinical testing of biosimilars 77
Animal studies have limited value 78
Pre-clinical safety studies 78
Immunogenicity testing is critical for approval 78
Factors influencing the potential of a protein product to elicit an immune response 80
Immunogenicity considerations are especially important for therapeutic antibodies. 82
Pre-clinical immunogenicity testing 82
In vitro methods used in clinical immunogenicity testing 83
Aggregates have the capacity to trigger immune response 84
Differences in glycosylation can lead to enhanced immunogenicity 86
PRCA associated with Eprex led to increased focus on immunogenicity 86
Final formulation and packaging 88
Formulation can impact the clinical profile 88
Differences in packaging can have an effect on safety 88
Second-generation biosimilars have different formulation and packaging 89
Clinical trials are necessary for approval of biosimilars 89
Clinical trials are the longest and most expensive part of the comparability demonstration 91
Comparative PK studies of biosimilars 92
Comparative PD studies of biosimilars 93
Comparative efficacy studies of biosimilars 93
Clinical safety studies of biosimilars 94
Clinical immunogenicity testing of biosimilars 95
Risk management plans are important 98
Pharmacovigilance plans are necessary for approval of biosimilars 99
Scientific advice from regulatory bodies 100
Comparable or interchangeable? 101
Can a biosimilar be better than the originators product? 101
The EMEA has been flexible in its approval of biosimilars to date 102
Omnitrope was approved by the EMEA despite changes in the purification procedure of the final
product 102
Approval of Valtropin demonstrates the importance of using the correct reference product 103
BioPartnerss Alpheon was rejected on grounds of quality issues 105
Three biosimilars of Eprex were approved by the EMEA 105
Finding information about previous approvals is not straightforward 106
Development strategies for biosimilar manufacturers 107
A detailed development plan can help avoid pitfalls 107
Third party advice 107
Strategic collaborations are used to gain access to complementary competencies 107
Acquisitions are used to acquire biosimilar pipelines or production facilities 109
CHAPTER 5 FUTURE DEVELOPMENTS 110
The EMEA will issue further guidelines 111
Which biosimilars will be approved next? 111
The future of biosimilars in the US depends on whether a consensus can be reached in Congress
112
If the Senate bill is accepted the US will be a more lucrative market 112
What about other markets? 113
Biosimilars of monoclonal antibodies 114
Monoclonal antibodies will not be open to biosimilar competition for several years 114
Manufacturing and comparability of biosimilar mAbs 115
New technologies allowing controlled glycosylation are emerging 116
Regulatory approval of mAbs 117
The big players are most likely to enter this market 117
BIBLIOGRAPHY 119
Publications and online articles 119
Websites 126
Conference literature 126
Our resources 126
Suggested reading 127
GLOSSARY 128
List of Tables
            Table 1: Patent expiries of selected key biologics 11
            Table 2: Safety and efficacy study duration and extrapolation to other indications for different
            classes of biosimilars 24
            Table 3: Statutory pathways for the approval of small molecule drug generics in the US 31
            Table 4: Three bills regarding biosimilars were introduced in 2007 40
            List of Figures
            Figure 1: Drivers and resistors of the biosimilars market growth 9
            Figure 2: The EMEA has published several guideline documents on biosimilars 20
            Figure 3: The Access to Life-Saving Medicines Act is pro-biosimilar 41
            Figure 4: The Patent Protection and Innovative Biologic Medicines Act is pro-innovator 43
            Figure 5: The Biologic Price Competition and Innovation Act balances the interests of the public,
            biosimilar manufacturers and innovators 45
            Figure 6: Manufacturing of biosimilars involves many steps 59
            Figure 7: Relevance of different tests and studies used to characterize biosimilar products 62
            Figure 8: EMEAs recommendations for the detection and characterization of antibodies in patients
            sera 97



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