During the course of this thesis evidence was presented and discussed related to the research questions. The fundamental question related to the heterogeneity and variation through the life cycle of the biosimilar and the reference biologic remains neglected, based on the results collected during this thesis, by the stakeholders, mainly because those issues where not addressed in any official regulatory guidance document.
As clear guidance from the EMA is lacking, with the only available guidance being that once a marketing authorization is issued it is accepted that the quality profiles of the reference biologic and the biosimilar will have different quality profiles.
Abstract:
Within the biosimilar development context, there are unaddressed questions by the European Medicines Agency (EMA) with regard to the impacts of shifts of the quality profile (purity- and impurity levels) of the reference biologic for the biosimilar development program. This dynamic is an open issues has potentially implications on the comparability exercise of the before mentioned.
Opinions from experts involved in the guidance drafting process of EMA and other were evaluated with regard to the issue.[...]
Table of Contents
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?
4.2 Experimental procedure (methods and materials) employed
4.2.1. Literature research
4.2.2. Questions and comments submitted to the EMA
4.2.3 Survey research questions
4.3 Results for main research questions 1.0 and directly associated research questions 1.1 and 1.2 that discus the impact of the dynamic to the quality profile
4.3.1 Results from the literature
4.3.2 Results from the questions and comments submitted to EMA
4.3.3 Results from the survey research method
4.4 Discussion
Chapter 5.0: What should be the scope of trials?
5.1 Introduction
5.1.1 Why is the dynamic of the Q-profile for biologics of relevance in clinical trials for biosimilars?
5.1.2 Meta analysis for biosimilar clinical trials?
5.2 Experimental procedure (methods and materials) employed
5.2.1. Literature research
5.2.2. Questions and comments submitted to EMA
5.2.3 Survey research
5.3 Results for the series 2 research questions
5.3.1 Results from the literature
5.3.2 Results for the questions and comments submitted to EMA
5.3.3 Results for the survey
5.4 Discussion
5.4.1 The trial size for biosimilars varies between 90 to ca. 500 subjects on average
5.4.2 The extent of the clinical trials depends on the extent of the similarity of the Q-profile
5.4.3 Possible meta analysis within the biosimilars context is disputed amongst experts
Chapter 6.0: Why is extrapolation of indications for biosimilar controversial?
6.1 Introduction
6.1.1 Hypothesis: Extrapolation of indication can only be allowed if the mechanism of action is identical, if the mechanism of action is different some limited trials should be required
6.2 Experimental procedure (methods and materials) employed
6.2.1. Literature research
6.2.2. Questions and comments submitted to EMA
6.2.3 Survey research
6.3 Results from why is extrapolation of indications for biosimilar controversial?
6.3.1 Results from the literature
6.3.2 Results from questions and comments submitted to EMA
6.3.3 Results from the survey
6.4 Discussion
Chapter 7.0 Integrated discussion
7.1 Part I: General Comments
7.2 Part II: Findings evaluation
7.3 Part III: Discussion of solutions (and outlook)
7.3.1 Solution for development strategy of biosimilars
7.3.2 Small trials
7.3.3 Extrapolation of Indications
Chapter 8.0 Integrated conclusion
Objectives and Research Themes
This thesis examines the regulatory challenges associated with the approval of biosimilars, specifically focusing on the implications of inherent heterogeneity and quality profile variations in both biosimilars and reference biologics. The primary research goal is to understand how these dynamic factors impact development strategies, clinical trial requirements, and the validity of extrapolating indications within the European regulatory framework.
- The impact of heterogeneity and process-related variability on the life cycle of biologics.
- Challenges in synchronizing a biosimilar's quality profile with the dynamic evolution of a reference biologic.
- Determination of the necessary scope and extent of clinical trials for biosimilar comparability.
- Scientific and regulatory controversies surrounding the extrapolation of indications.
- Evaluation of regulatory guidance documents and industry feedback through surveys and direct submissions to the EMA.
Excerpts from the Book
1.2.1 Background aspects
This section provides the basic information for understanding the research question.
The biologics life cycle includes changes to the production process, which are inevitably linked to changes to the quality profile of the biologic. As for a change in the manufacturing process, the biosimilar developer is required to show comparability to the reference medicinal product. However, heterogeneity of the biologics and variability of the process be it due to regulatory controlled changes or be it through unnoticed (and therefore uncontrolled) effects, result in challenges to successfully develop, conduct and accomplish a biosimilar development program.
Summary of Chapters
Chapter 1: Introduction: Outlines the rationale for selecting biosimilars as a thesis topic, establishes key definitions for biological and biosimilar medicines, and defines the scope of the research.
Chapter 2: Literature review: Provides an extensive review of existing European biosimilar legislation, regulatory guidance literature, and the scientific principles behind biologic heterogeneity and life cycle management.
Chapter 3: Materials and Methods: Details the qualitative research methodology, including the use of surveys and direct submissions to the EMA to gather industry and expert perspectives.
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?: Analyzes the core issue of quality profile dynamics, demonstrating that both biosimilars and reference products evolve over time.
Chapter 5.0: What should be the scope of trials?: Discusses the financial and scientific drivers behind clinical trial design, arguing that there is no standardized, one-size-fits-all approach for biosimilar trials.
Chapter 6.0: Why is extrapolation of indications for biosimilar controversial?: Explores the scientific complexities of extrapolating efficacy and safety data between different therapeutic indications, highlighting the risk of differing mechanisms of action.
Chapter 7.0 Integrated discussion: Integrates the findings from the research chapters, emphasizing the need for a development strategy that accounts for the dynamic nature of biologics.
Chapter 8.0 Integrated conclusion: Summarizes the thesis, highlighting that regulatory guidance remains insufficient to address the dynamic nature of quality profiles and suggesting a stepwise development approach.
Keywords
Biosimilars, European Medicines Agency (EMA), Quality Profile, Heterogeneity, Clinical Comparability, Extrapolation of Indications, Immunogenicity, Biologics Life Cycle, Comparability Exercise, Regulatory Framework, Monoclonal Antibodies (mAbs), Quality Target Product Profile (QTPP), Pharmacokinetics, Pharmacodynamics
Frequently Asked Questions
What is the core subject of this thesis?
The thesis explores the regulatory and development challenges of biosimilars in Europe, particularly how heterogeneity and dynamic changes in quality profiles affect safety, efficacy, and regulatory approval.
What are the primary themes discussed?
Key themes include the impact of biologic life cycles on quality, the necessity of head-to-head clinical comparability, the controversial nature of extrapolating indications, and the burden of proof for biosimilar manufacturers.
What is the main research objective?
The goal is to determine how biosimilar developers can synchronize their development processes with the dynamic, unpredictable changes in the quality profile of a reference biologic while meeting stringent regulatory expectations.
Which scientific methods were employed?
The research uses a qualitative approach, combining an extensive literature review of regulatory guidelines with expert-based questionnaires and direct formal comments submitted to the EMA regarding draft guidance.
What topics are covered in the main body?
The main sections cover the scientific basis of biologic heterogeneity, the requirements for comparability exercises, the scope of clinical trials for biosimilars, and the rationale for (and controversies of) extrapolating indications to secondary therapeutic uses.
Which terms characterize this research?
Essential terms include "quality profile," "comparability exercise," "dynamic life cycle," "extrapolation of indications," and "process-related variability."
Does the author suggest a design space?
Yes, the author proposes the use of a "design space" as a progressive solution for biosimilar developers to manage and adapt to sudden changes in the quality profile of a reference product without needing to restart clinical development.
What is the conclusion regarding extrapolation of indications?
The author concludes that extrapolation remains highly controversial, particularly for complex molecules like monoclonal antibodies, where different therapeutic indications may rely on entirely different mechanisms of action.
How does the author view the EMA’s current role?
The author characterizes the EMA as providing a necessary, albeit evolving, regulatory framework that currently lacks specific, clear guidance for the dynamic quality shifts that occur during a biosimilar's development life cycle.
- Quote paper
- Malik Osmane (Author), 2013, Rift-lines within European regulatory framework for Biosimilars when taking heterogeneity and variation during lifecycle of the reference biologic and the biosimilar into account, Munich, GRIN Verlag, https://www.grin.com/document/262089
