CHAPTER 1 EXECUTIVE SUMMARY 4
Scope of the report 4
Key findings 4
Key definitions 5

CHAPTER 2 OVERVIEW OF BIOSIMILARS AND HOW REGULATORY ISSUES IMPACT THE MARKET 10
The potential for cost savings drives the development of a biosimilars regulatory approval pathway 11
Recombinant proteins are the key target for biosimilar developers 12
The complexity of the biosimilars regulatory environment is a key factor restricting biosimilars developers 13

CHAPTER 3 THE POWER BALANCE BETWEEN PRO-BIOSIMILARS AND ANTI-BIOSIMILARS SHAPES MARKET EVOLUTION 17
The current situation: the US lags further behind as the issue becomes more politically charged 17
Currently, the European environment is more pro-biosimilars than the US 17
The stronger position for innovator biologics companies in the US means that greater political pressure is required to support the development of a biosimilars regulatory approval pathway 18
Whoever wins the battle between the pro-biosimilars faction and the anti-biosimilars faction will significantly impact the way that the biosimilars market evolves in the US and Europe 19
There are significant difficulties with demonstrating comparability 19
Why is comparability such a problem? 19
Comparability is therefore a key issue for biosimilars, and stringent requirements boost development costs 21
The importance of choosing the right reference product to demonstrate comparability 21
Although there are extensive comparability requirements, it is important that biosimilar developers seek guidance from European and US regulatory bodies 22
Problems with establishing 'sameness' means that generic substitution is unlikely to be relevant for biosimilars 22
Does the process make the product? And if so, are biosimilar developers asking regulatory bodies to act illegally? 23
In the past, innovator drug companies have been happy to support the argument that biologics manufactured in entirely different ways are the same as the innovator drug 24
It is becoming easier to demonstrate comparability 25
Safety remains the key to determining comparability 25

CHAPTER 4 THE REGULATORY ENVIRONMENT FOR BIOSIMILARS IN THE US 26
Introduction to the approval process for generics in the US and how biosimilar approvals fit into this process 27
Key events shaping the development of a biosimilars approval pathway: the FDA changes tack in 2004, delaying biosimilars market entry 29
From 2001 to 2004, the FDA prioritized developing guidance for biosimilars, despite attacks from innovator developers 29
The resignation of McClellan in 2004 led to delays in the development of guidance for biosimilars 31
FDA workshops do little to accelerate progress, while the development of a regulatory pathway stalls 32
Biosimilar developers turn to the USP to help find a way to accelerate the development of a regulatory pathway for biosimilars of NDA biologics by characterizing comparability between biosimilars and innovator biologics 33
Innovator biologics companies retaliate by issuing a white paper, hoping to stall the process further 34
Despite significant resistance from innovator biologics companies, some progress in the development of a biosimilar regulatory process is now being made in the US 35
Hatch and Waxman urge the FDA to provide guidelines on approvals of biosimilars of NDA biologics 36
Citizen petition lobbies the FDA to provide requirements for the approval of biosimilar versions of NDA biologics 36
The 'Access to Life-Saving Medicine' Act represents the largest stride in developing a biosimilars approval pathway 37
While progress in developing a biosimilars regulatory pathway stalls, biosimilar developers are using the full submission pathway 40
The battle to get Omnitrope approved: the biosimilar submission and approval record at the FDA 41
Is Omnitrope really the first follow-on biologic to be approved? 41
Omnitrope's approval in the US: it may not have been the first follow-on biologic approved under Section 505(b)(2) but it has created the greatest interest 42

CHAPTER 5 THE REGULATORY ENVIRONMENT FOR BIOSIMILARS IN EUROPE 44
A range of directives and guidelines are used to shape the biosimilar regulatory environment in Europe 45
Overarching directives and guidelines shaping biosimilar approvals 48
The Pharma Review 2001 kicks off biosimilar approval pathway discussion 48
Product class guidelines help to guide biosimilar approvals for the major recombinant protein classes 50
Comparability guidelines provide essential information on how to demonstrate comparability between biosimilars and innovator biologics 52
Quality guidelines developed to help innovator drugs companies get around inter-batch variability can be used by biosimilar developers to show comparability 53
Non-clinical and clinical issues help shape what type of data is included in the biosimilar submission dossier 53
Additional legislation impacting biosimilars: Directive 2004/27/EC redefines exclusivity and affirms the Bolar provision 54
Biosimilar submission and approval record at the EMEA: Europe has been a more favorable environment for biosimilar approvals 55

CHAPTER 6 BIBLIOGRAPHY 56
Publications and online articles 56
Datamonitor resources 58

CHAPTER 7 GLOSSARY 59
Glossary of terms 59

List of Tables 
Table 1: Differences in the development and regulatory approval pathway between biosimilars and small molecule generics 14
Table 2: Adopted guidelines for European biosimilars, by submission/adoption date, 2003-06 (the most recent are first) 45
Table 3: Different product classes have different efficacy and safety requirements 51

List of Figures 
Figure 1: The biologics market has grown at a stronger rate than the overall market 11
Figure 2: Biosimilar development could take six to nine years 15
Figure 3: A range of situations require comparability testing 20
Figure 4: The FDA were pro-biosimilar development in the five-year period, from 1999 to 2004 31
Figure 5: The FDA became anti-biosimilar development in the two-year period from 2004 to 2005 35
Figure 6: The Access to Life-Saving Medicine Act rewards biosimilar development using three key incentives 39
Figure 7: Key biosimilar regulatory guidelines 47