Market Report Source

Overview

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

Table of Contents

CHAPTER 1 EXECUTIVE SUMMARY

Scope of the report

Key findings

Key definitions

CHAPTER 2 INTRODUCTION TO THE BIOSIMILARS MARKET

Drivers and resistors of the biosimilars market growth

Drivers of growth in the biosimilars market

Biologics are the fastest growing segment of the pharmaceuticals market

Patent expiry on first-generation biologics

Increasing pressures of cost-containment

Advances in analytical techniques

Resistors of growth in the biosimilars market

Opposition from the innovator companies

Lack of biosimilars regulatory approval pathway in the US is stalling the entry of biosimilars into the US market

Cost and complexity of development

Lack of time on market hinders physician uptake

CHAPTER 3 BIOSIMILARS REGULATORY ISSUES

Europe is leading the way in biosimilars legislation and approval

Guideline on quality issues for biosimilars is based on analysis of comparability after process change

Guidelines on pre-clinical and clinical issues are vague

Results of clinical trials could be extrapolated to other indications in some cases

Product-class specific annexes provide more details

Route of administration used in clinical trials is critical

Five biosimilars have been approved in the EU

Omnitrope’s approval forced a change of law to allow approval of biosimilars

BioPartners’s Valtropin received approval but Alpheon failed on quality issues

Three biosimilar Epoetins have been approved in Europe

Further guidance is expected

Other regulatory issues in Europe remain

The Bolar provision – a safe harbor for development of biosimilars

Use of trade secret data

Innovators insist that biosimilars should have unique INNs

Others will follow where EU leads

Opposing interests hinder progress in the US

The FDA has delayed issuing guidance for approval of biosimilars

The FDA has already approved follow-on protein products

Avonex marks approval of a first biosimilar

Follow-on hyaluronidase approval

Glucagon and Fortical (salmon calcitonin nasal spray) follow-on protein products

Sandoz’s Omnitrope

The FDA’s decision to use the abbreviated approval pathway for Omnitrope was met with criticism

Recent activity in the US Senate and Congress suggests legislation on biosimilars approval might be issued in the near future

The Access to Life-Saving Medicine Act is pro-biosimilar and was not accepted by the pro-innovator faction

The Patent Protection and Innovative Biologic Medicines Act of 2007 is pro-innovator

The Biologics Price Competition and Innovation Act of 2007 proposes a middle-of-the road solution

Impact of future legislation on the FDA’s biosimilars approval pathway

What happens before legislation is passed?

Abbreviated or full submission routes?

Strategies for innovators to minimize the effect of biosimilar competition

Naming of biosimilars remains an issue in the US

Automatic substitution with biosimilars or not – an unresolved issue

Automatic substitution in the US is unlikely

Substitution policies are defined by individual member states in the EU

Will reimbursement incentives drive biosimilar substitution?

CHAPTER 4 BIOSIMILARS DEVELOPMENT ISSUES

Biosimilars producers have to develop their own manufacturing process

Development of a manufacturing process for biosimilars involves many steps

Process knowledge is key

Choice of cell line is important

Patent protection of biologics is complex

Demonstration of comparability and similarity employs the same techniques

Product knowledge is critical for designing analytical testing strategy

Advice from regulators is invaluable

Lack of experience and data makes defining acceptance margins difficult

Analytical testing of biosimilars

Limitations of analytical testing

Primary sequence analysis

Misfolding can have a serious impact on clinical performance

Different processes result in different heterogeneity profiles – critical factor to explore

Post-translational modifications are a major cause of heterogeneity

Differences in glycosylation patterns need to be investigated

Presence of aggregates can have negative effects on a protein’s clinical profile

Differences in hydrophobicity and charge need to be investigated

Stability testing of biosimilars

Comparability after process change

Choice of reference product is important

Some originator products exhibit great inter-batch variability

Pre-clinical testing of biosimilars

Biological activity assays are used in pre-clinical testing of biosimilars

Animal studies have limited value

Pre-clinical safety studies

Immunogenicity testing is critical for approval

Factors influencing the potential of a protein product to elicit an immune response

Immunogenicity considerations are especially important for therapeutic antibodies.

Pre-clinical immunogenicity testing

In vitro methods used in clinical immunogenicity testing

Aggregates have the capacity to trigger immune response

Differences in glycosylation can lead to enhanced immunogenicity

PRCA associated with Eprex led to increased focus on immunogenicity

Final formulation and packaging

Formulation can impact the clinical profile

Differences in packaging can have an effect on safety

Second-generation biosimilars have different formulation and packaging

Clinical trials are necessary for approval of biosimilars

Clinical trials are the longest and most expensive part of the comparability demonstration

Comparative PK studies of biosimilars

Comparative PD studies of biosimilars

Comparative efficacy studies of biosimilars

Clinical safety studies of biosimilars

Clinical immunogenicity testing of biosimilars

Risk management plans are important

Pharmacovigilance plans are necessary for approval of biosimilars

Scientific advice from regulatory bodies

Comparable or interchangeable?

Can a biosimilar be better than the originator’s product?

The EMEA has been flexible in its approval of biosimilars to date

Omnitrope was approved by the EMEA despite changes in the purification procedure of the final product

Approval of Valtropin demonstrates the importance of using the correct reference product

BioPartners’s Alpheon was rejected on grounds of quality issues

Three biosimilars of Eprex were approved by the EMEA

Finding information about previous approvals is not straightforward

Development strategies for biosimilar manufacturers

A detailed development plan can help avoid pitfalls

Third party advice

Strategic collaborations are used to gain access to complementary competencies

Acquisitions are used to acquire biosimilar pipelines or production facilities

CHAPTER 5 FUTURE DEVELOPMENTS

The EMEA will issue further guidelines

Which biosimilars will be approved next?

The future of biosimilars in the US depends on whether a consensus can be reached in Congress

If the Senate bill is accepted the US will be a more lucrative market

What about other markets?

Biosimilars of monoclonal antibodies

Monoclonal antibodies will not be open to biosimilar competition for several years

Manufacturing and comparability of biosimilar mAbs

New technologies allowing controlled glycosylation are emerging

Regulatory approval of mAbs

The big players are most likely to enter this market

BIBLIOGRAPHY

Publications and online articles

Websites

Conference literature

Datamonitor resources

Suggested reading

GLOSSARY

List of Tables

Table 1: Patent expiries of selected key biologics

Table 2: Safety and efficacy study duration and extrapolation to other indications for different classes of biosimilars

Table 3: Statutory pathways for the approval of small molecule drug generics in the US

Table 4: Three bills regarding biosimilars were introduced in 2007

List of Figures

Figure 1: Drivers and resistors of the biosimilars market growth

Figure 2: The EMEA has published several guideline documents on biosimilars

Figure 3: The Access to Life-Saving Medicines Act is pro-biosimilar

Figure 4: The Patent Protection and Innovative Biologic Medicines Act is pro-innovator

Figure 5: The Biologic Price Competition and Innovation Act balances the interests of the public, biosimilar manufacturers and innovators

Figure 6: Manufacturing of biosimilars involves many steps

Figure 7: Relevance of different tests and studies used to characterize biosimilar products

Figure 8: EMEA’s recommendations for the detection and characterization of antibodies in patients’ sera