Rift-lines within European regulatory framework for Biosimilars when taking heterogeneity and variation during lifecycle of the reference biologic and the biosimilar into account

Inhaltsverzeichnis (Table of Contents)

• Abstract
• Acknowledgements
• List of abbreviations
• Chapter 1: Introduction
• 1.0. Rationale on the selection of the topic (as guide for future students)
• 1.1 Definitions
• 1.1.1 Definition of biological medicine and major differences to "classical" chemical medicine
• 1.1.2 Definition of Biosimilar
• 1.2 Statement of the main problem, subsequent research questions and test-functions
• 1.2.1 Background aspects
• 1.2.2 Problem statement
• 1.3 Thesis "Within Scope" and "Out of Scope"
• 1.4 Description of the European Regulatory Environment with Regard to Biosimilars
• 1.5. Why are biosimilars interesting for the generic industry?
• 1.5.1 What is the market size? What are the growth estimates for biologics and biosimilars?
• 1.5.2 Patent protection and market exclusivity
• Chapter 2: Literature review
• 2.1. Re-presenting the current biosimilar legislation and regulatory requirements
• 2.1.1 The European biosimilar approval pathway and its regulatory framework
• 2.1.2 Regulatory guidance literature
• 2.1.3. Review of the state of regulation prior to the submission of questions and comments in relation to two draft biosimilar guidance documents
• 2.2 Life cycle in relation to heterogeneity and variation
• 2.2.1 Heterogeneity of biologics (proteins only)
• 2.2.2 Variation in the biotechnology processes
• 2.2.3 The biologics life cycle
• 2.2.4 Discussion
• 2.3 Screening the above presented literature related to current biosimilar regulation with regard to the research questions
• 2.3.1 Guideline on similar biological medicinal products CHMP/437/04 (49)
• 2.3.2 Guideline on comparability of medicinal products containing biotechnology derived proteins as active substance: Quality issues EMEA/CPMP/BWP/3207/00 (50)
• 2.3.3 Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues EMEA/CPMP/3097/02/Final (51)
• 2.3.4 Concept paper on the revision of the guideline on similar biological medicinal product EMA/CHMP/BMWP/572643/2011 (52)
• 2.3.5 Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Quality issues EMEA/CHMP/BWP/49348/2005 (53)
• 2.3.6 Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Quality issues (revision 1) Draft EMA/CHMP/BWP/247713/2012 (54)
• 2.3.7 Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues EMEA/CHMP/BMWP/42832/2005 (55)
• 2.3.8 Concept paper on the revision of the guideline on similar biological medicinal products containing biotechnology derived proteins as active substance: Non-clinical and clinical issues EMA/CHMP/BMWP/572828/2011 (56)
• 2.4. Reference to other biosimilar regulations (for informational purposes only)
• 2.4.1 The US
• 2.4.2 Japan
• 2.4.3 Canada
• 2.4.4 The WHO
• Chapter 3: Materials and Methods
• 3.1 Methods used and rational for choosing them
• 3.1.1 Questionnaires and submissions
• 3.1.2 Literature review
• 3.2 Rationale for using the employed research methodologies
• 3.2.1 General suitability of the research methods employed
• 3.3 Practical aspects
• 3.3.1 Practical aspects of the questionnaires and critical considerations
• 3.3.2 Practical aspects of the submissions and critical considerations
• 3.3.3 Practical aspects of the literature research and critical considerations
• Chapter 4.0: What are the implications of heterogeneity and variation through the life cycle of the biosimilar and the reference biologic, from a European perspective?
• 4.1 Introduction
• 4.1.1 Why is the dynamic of the Q-profile for biologics of relevance?

Zielsetzung und Themenschwerpunkte (Objectives and Key Themes)

This thesis examines the implications of heterogeneity and variation in the quality profile of biosimilars and reference biologics throughout their lifecycles, focusing on the European regulatory framework. It aims to address challenges and risks associated with biosimilar submissions, particularly for large and complex molecules like antibodies. The work also explores the scope of clinical trials for biosimilars and the controversial issue of extrapolation of indications. Key themes explored in the thesis include: * **Heterogeneity and variation in biosimilars and reference biologics:** The thesis investigates the dynamic of heterogeneity and variations in the quality profile of biosimilars and reference biologics. * **European regulatory framework for biosimilars:** The thesis explores the evolution of the European regulatory framework for biosimilars, focusing on the challenges and opportunities for biosimilar development. * **Scope of clinical trials for biosimilars:** The thesis examines the adequacy of non-inferiority trials for biosimilars and the need for equivalence studies. * **Extrapolation of indications for biosimilars:** The thesis discusses the challenges and controversies surrounding extrapolation of indications for biosimilars. * **Design space and biosimilar development:** The thesis explores the potential role of design space in addressing the challenges of heterogeneity and variation in biosimilars.

Zusammenfassung der Kapitel (Chapter Summaries)

Chapter 1 introduces the topic, defining biological medicine and biosimilars, and outlining the research questions. It describes the European regulatory environment for biosimilars and discusses the market size and potential for biosimilars. Chapter 2 reviews relevant literature, focusing on the current biosimilar legislation and regulatory requirements, the life cycle of biologics, and the heterogeneity and variation in these products. Chapter 4 delves into the implications of heterogeneity and variation through the life cycle of the biosimilar and the reference biologic, from a European perspective. This chapter analyzes the dynamic of the quality profile for biologics, its relevance, and the current regulatory oversight. The chapter also explores the potential for design space to address the challenges of heterogeneity and variation in biosimilars.

Schlüsselwörter (Keywords)

Biosimilars, reference biologics, heterogeneity, variation, regulatory framework, European Medicines Agency (EMA), clinical trials, non-inferiority, equivalence, extrapolation of indications, design space.