Loading...

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

Textbook 2014 282 Pages

Excerpt

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 Study “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

Bibliography or References

List of Appendices

Appendix:

Appendix:

Appendix:

Appendix:

Appendix:

Note:

The research chapter 4, chapter 5 and chapter 6 deal individually with dedicated topics. Thus for each of those chapters an individual introduction, method and material parts, results and discussion section was written. Based on that approach information obtained from questionnaires or feedback received from submissions to EMA was split based on its content into those research chapter 4, chapter 5 and chapter 6.

The chapters general aspects and literature research was carried out as part of chapter 1, chapter 2 and chapter 3.

An integrated discussions and conclusions were performed as part of chapter 7 and chapter 8.

For Yasmina

and Nouara

to my beloved daughters

Abstract

Introduction:

Biopharmaceutical medicinal products (biologics) represent a huge financial market. Thus upon patent protection expiry of the innovator (reference) biologic there is interest from industry to gain a portion of this market by launching a “similar” biologic at a reduced development cost, thus boosting potential gains.

The EMA responded to this desire and lead the guidance process with industry on the topic of biosimilars. This guidance process can be described as a responsive or accompanying process, which resulted in the successive development of three (hierarchical) layers of regulatory guidance documentation for biosimilars by the EMA. The lowest layer (product class specific) was until recently still being updated.

Based on the experience gained with biosimilars in the past, the EMA started to introduce a second generation series of guidance documents, which take into account the past, current and possibly future challenges of biosimilars. Those proposals were evaluated by EMA and partially incorporated into new guidance documents.

This work highlights the challenges and risks associated with biosimilar submissions for large and complex bio-molecules such antibodies. The following topics were analysed, related to the overall biosimilar concept and its implicated costs:

1) What are the implications of heterogeneity and variation through the life cycle of the biosimilar and the reference biologic, from a European perspective? - refer to chapter 4.
2) What should be the scope of trials for biosimilars? - refer to chapter 5.
3) Why is extrapolation of indications for biosimilar controversial? - refer to chapter 6.

Results:

1) As the tile of this study indicates, there are unaddressed questions for the regulator with regard to the unsolved dynamic of heterogeneity and variations of the quality profile, which have potential implications on safety and efficacy. This is neglected and not taken into account seriously enough by the stakeholders.

2) Non-inferiority trials just barely meet the biosimilarity requirements (in my view), and equivalence studies require that the quality profiles of the biosimilar falls within the quality profile of the reference biologic, to have enough confidence to accomplish successfully the clinical trial phase of the comparability exercise.

However, regardless of the trial design, the current approach that heterogeneity and variation of the reference biologic is controlled by the oversight of the EMA, and therefore as an extension changes in the quality profile of the reference biologic will result in the same safety and efficacy pattern as the pre-changed is lacking foresight of potential problems during the biosimilar development.

Thus during the course of this study proposals and clarifications were submitted to the EMA and partially adopted by the EMA.

3) A biosimilar that may have been matched to the pre-change quality profile of the reference biologic may struggle to show similarity in its clinical profile when compared to the post-change quality profile of the reference biologic. It is unreasonable to assume per se similar safety and efficacy from different quality profiles; thus, extrapolation of indication in those circumstances should not be allowed.

Solution:

Further, the only (in my view) progressive way to deal with such foreseeable situations from the biosimilar developer’s point of view is to incorporate a design space. To that, in fact to any “sudden” change of the quality profile of the reference biologic, the biosimilar developer can respond in due time, assuring that the material used for the clinical trial comparability exercise is in fact within the boundaries of the quality profile of the reference biologic.

For particular scenarios where the heterogeneity and variation of the reference biologic, even without a major change, results in a detectable difference in the clinical phase, two possible causes need to be investigated.

1. The quality profile of the reference biologic and the biosimilar are not similar enough.
2. Trials would also fail, when different batches of the biosimilar would be compared to itself.

The reasons for such failure could be manifold, such as selection of the margin of tolerance and related to the selection of the clinical endpoint, or that the reference biologic is in its performance not consistent, i.e. the efficacy margins are low compared to the placebo arm, for example.

For these anticipated scenarios more guidance is needed, which will possibly only be available once the EMA is confronted with such a situation. One can only hope that that information will be made public for further analysis.

Acknowledgements

I would like to cite the following people for their help in the review process of this study:

Joe Brady, PhD:

For the endless help guidance and motivation with his exceptionally pleasant and routined way of dealing with people.

For helping me to challenging my logic and train of thoughts.

Regina Martins:

For helping me to challenging my logic and train of thoughts.

Jolyon Dodgson, PhD:

For helping me to challenging my logic and train of thoughts.

For helping me formatting parts of the study.

Paul Declerck, PhD Professor:

For helping me to challenging my logic and train of thoughts.

All other experts who supported my work through providing literature free of charge, for commenting on and reviewing my questionnaires.

This study was carried out with no other means and input beside the ones cited in this study. M. Osmane is the genuine author of this study including all its concepts and ideas.

(In the case where those ideas were already voice by others, this did not happen intentionally and was not discovered as part of my literature review.)

List of abbreviations

Abbildung in dieser Leseprobe nicht enthalten

Chapter 1: Introduction

1.0. Rationale on the selection of the topic (as guide for future students)

I started this course in pharmaceutical QA being aware that I would not benefit from full sponsorship from my employer. Although my financial possibilities were limited at the time, I wanted to explore the opportunity to take a step forward in my career in a meaningful way, by improving and developing my knowledge. Now, when I am close to finishing my study, looking back I realized it was the right choice as it was the gateway to a better future not only from the point of view of my knowledge but also from a personal perspective.

My educational and scientific background is in immunology[1], as I graduated with a Diploma thesis at the Max Planck Institute for Immunology in Freiburg. I wanted to use this scientific background to find a proper topic for my study project. On the other hand, I also wanted to focus on a topic I am personally interested in and that will help me find better career opportunities.

The search for a proper study topic started very early. I was asked by my teachers where do I want to be in 5-years time and what topic really interested me, and yet would allow me to gain further competencies and scientific skills. Finding the answer to this question took some time, but going through this process was deeply revealing and gave me clarity about my future career path.

At the end of 2010, following a lecture and an article in TOPRA, I found what I was looking for: Biosimilars.

The Biosimilar topic represents a good symbiosis of the DIT course content, focused on EMA regulations, and in accordance with my background in immunology. It is an emerging top regulatory topic, as the generic biologics industry (the correct term is biosimilar industry) seeks to gain access to the highly profitable biologics[2] market.

There was a good likelihood of writing a meaningful research paper and conducting an interesting study. The regulatory framework within Europe (the leading regulatory region for biosimilars) continues to require clarification and is in need of further development, especially at the theoretical level.

By commenting on EMA regulations and directly interacting with the EMA, this study bears the potential to bring a new perspective to the European biosimilar regulations, overall an excellent strategic opportunity for the elaboration of this study.

1.1 Definitions

To understand the notion of biosimilar and differences to classical small molecules, it is first required to outline the term generic.

The term 'generic' medicinal product is used to describe chemicals, which are small molecules. They are structurally equivalent to an innovator medicinal product whose patent and/or data protection period has expired.

Bioequivalence of the generic medicine with a reference product is required, which usually does not include clinical trial, or in the case where it does they are minimal.

It is permissible for generic companies to apply for a M.A., due to the pharmacopeia data from the reference medical product outline specification and the ability to produce robustly the same molecular entity, through synthesis. This high chemical purity product is very much different to biotherapeutics/biologics which are relatively large and complex proteins that are difficult to characterize (1).[3]

1.1.1 Definition of biological medicine and major differences to “classical” chemical medicine

Biologics refers to naturally occurring substances generated by animals or microorganisms, or that can be created through biotechnology[4] — recombinant DNA technology[5].

Biological medicines are medicinal products, which are produced using a living system or organism. Typically modern biotechnology products are proteins, since almost all life on earth is based on proteins with its manifold functional groups, thus being an ideal basis for drug development. Proteins are produced in cells using recombinant DNA technology. From the European regulatory perspective, they are defined as medicinal products[6] that are developed based on biotechnological processes:

- Recombinant DNA technology
- Controlled expression of genes[7] coding for biologically active proteins in prokaryotes[8] and eukaryotes[9] including transformed mammalian cells
- Hybridoma[10] and monoclonal antibody[11] methods
Biological medicines differ from “classical” chemical medicines fundamentally through the following perspective:

1) Chemical medicines are usually small molecules, which are produced using a chemical synthesis process. Aspirin, for example, has a molecular weight of ca. 0.2 kDA. Biological medicines are usually much larger. Interferon alpha, for example, has a molecular size of ca. 19kDA and the IgG molecule has a molecular size of ca. 150kDA.

2) This direct molecular size/weight difference between biological medicines (later abbreviated as biologics) and chemical medicines, results also in a more complex three-dimensional structure of biologics.

3) The complex structures of biologics are more prone to vary compared to chemical medicines and poses inherent heterogeneity[12], refer to section: 2.2 Life cycle in relation to heterogeneity and variation for details on that heterogeneity and variation issue.

4) Chemical medicines are well defined and need to follow specific standards, which makes it relatively easy to reproduce them if required. On the other hand, biologics are more difficult to analyze. Their production process has a high impact on the final product.

5) Related to their protein structure, biologics are usually administered by injection, whereas chemical medicines can be administered in other forms such as pills, creams, ointments and sprays, etc.

6) Due to their differences in terms of administration and the foreign nature of these particular biologically active molecules to the body, potential adverse effects (the “immunogenic response”[13] ) with biologics are always a concern.

The EMA recently described biologics as:

“A biological medicine is a medicine that contains one or more active substances made by or derived from a biological source. Some of them may be already present in the human body and examples include proteins such as insulin, growth hormone and erythropoietins[14]. The active substances of biological medicines are larger and more complex than those of non-biological medicines. Only living organisms are able to reproduce such complexity. Their complexity as well as the way they are produced may result in a degree of variability in molecules of the same active substance, particularly in different batches of the medicine”. (2)

1.1.2 Definition of Biosimilar

In the pharmaceutical industry, the practice that innovator pharmaceutical companies[15] protect their inventions with patents, for obvious business reasons, is very common. After the patent expiry of the originator chemical medicine, generic versions of the originator chemical medicine are launched by competing pharmaceutical companies. The generic version of the pharmaceutical (chemical) product has the same active substance. That is possible because the active ingredients are identical to each other.

Directive 2001/83/EC describes a generic as:

“‘Generic medicinal product’ shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies ….” (3)

Already, prior to its introduction, the term biosimilar was heavily disputed between regulators and the different pharmaceutical industry branches, namely the generics and innovator industries. The term biosimilar, itself, already outlines the major difference between chemical medicine generics and biosimilars as biological medicines, which are similar to an innovator biological medicine. It contains the suffix “similar”, a term that means according to the Oxford Dictionary (4) “having a resemblance in appearance, character or quantity, without being identical”.

The innovator medicinal product is also called biological reference medicine, as it serves as a reference and standard for the biosimilar. Finally, the decision bodies within the EU agreed upon the fact that unlike standard generics, which are identical to innovator chemical medicinal products, biologics can only be similar to, but not identical to, innovator biologics.

From the regulatory perspective, the word biosimilar can be described as a “similar biological medicinal product”, where “similar” is to be understood in relation to a biological reference to the medicinal product.

“Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided”. (3)

Omnitrop® (Somatropin) was the first biosimilar product to be approved within the EU. In its EUROPEAN PUBLIC ASSESSMENT REPORT (EPAR)[16] the word biosimilar is described as:

“Omnitrop is a ‘biosimilar’ medicine. This means that Omnitrop is similar to a biological medicine that is already authorized in the European Union (EU) and contains the same active substance (also known as the ‘reference medicine’)”. (5)

High ranking members of the EMA gave the following definition of a biosimilar in a highly regarded scientific journal (Nature Biotechnology):

“A biosimilar is a copy version of an already authorized biological medicinal product with demonstrated similarity in physicochemical[17] characteristics, efficacy and safety, based on a comprehensive comparability exercise. As a biosimilar is highly unlikely to be identical to its reference product, the standard 'generic' approach (that is, demonstration of bioequivalence[18] in comparative bioavailability studies, established for small chemically derived and easily characterized molecules) is not sufficient for the development, regulatory assessment and licensing of such a product. For this reason, we argue that the term biogeneric is scientifically incorrect and should not be used for a biosimilar”. (6)

The EMA most recently described biosimilars as:

“A biosimilar medicine is a biological medicine that is developed to be similar to an existing biological medicine (the ‘reference medicine’). Biosimilars are not the same as generics, which have simpler chemical structures and are considered to be identical to their reference medicines. The active substance of a biosimilar and its reference medicine is essentially the same biological substance, though there may be minor differences due to their complex nature and production methods. Like the reference medicine, the biosimilar has a degree of natural variability. When approved, its variability and any differences between it and its reference medicine will have been shown not to affect safety or effectiveness”. (2)

1.2 Statement of the main problem, subsequent research questions and test-functions

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.

1.2.1.1 Outline of a biologics life cycle

Generally speaking, the life-cycle of a biologic can be split into two parts, which are separated by the granting of an M.A. The development phase of a biologics innovator medicinal product includes:

- Discovery-phase, where a new compound NCE is discovered.
- Development-phases, where the format of the new medicinal product and a manufacturing process is developed and non clinical testing is carried out.
- Clinical trial phases 1, 2a, 2b and 3, where the adjustment and refinements of the development phase are tested and evaluated with regard to safety and efficacy.
- Filing/review phase through the regulator.

It can take usually between 8 to 16 years, depending on many factors. During that time frame the product is made ready for M.A. approval.

The commercial phase, after the he M.A. is obtained and the medical product is on sale for use by the patients, depends on market exclusivity and patents of the innovator medicinal products. This will be addressed in detail in section: 2.2.3 The biologics life cycle. This does not mean that after that period of time the innovator product ceases production. However, due to competition with generics and nowadays biosimilars the market share will shrink.

The exclusivity period once a patent is filed may last between 10-15 years. In other words, a biologic will be available on the market for probably dozens of years. For instance, according to Sandoz, follow-on drugs take seven to eight years to develop compared with eight to 10 years for a new drug application. (7) During that period of time, biologics may undergo many changes. Companies will be bought and sold, moves that may affect the production site will occur. Due to the demands of the market, the production might be scaled up or if facing competition might go down, and the process requires permanent adaptation.

As the supplier changes their production processes, the quality of the raw materials might change as well. The purchase of new equipment might be needed to replace whole or part of the production and this might need to be redesigned in order to answer the requests of the market. Last but not least, the production might be optimized and new technologies introduced.

From an industrial production perspective, even once the M.A. is obtained the process and therefore the product (this will be further address in section: 1.1.2 Definition of Biosimilar) remain subject to several changes. Variation is a natural fact, which from a classical point may be considered detrimental to quality. However, variation is part of the natural process and therefore unavoidable.

1.2.1.2 Requirement for a comparability exercise

Thinking about the previous definitions of biosimilars (addressed in further detail in section: 1.1.2 Definition of Biosimilar), according to the E.U. regulations EMA considers a biosimilar medicinal product as a copy of an already authorized biological medicinal product (the reference medicinal product). However, as already discussed the generic approach used for chemical medicinal products cannot be adapted for use with biologics.

Thus, any biosimilar submitted to the E.M.A. for M.A., is required to demonstrate its similarity to the reference biologic medicinal product, including a comparison of the quality attributes of the reference biologic. Those attributes are quality characteristics, efficacy and safety. Therefore, comparative nonclinical studies and usually clinical studies are required, in order to ensure close resemblance in safety and efficacy.

The summary of studies required to show the similarity between biosimilar and reference biologic is called the “comparability exercise”.

- Refer also to section: 2.3.2 Guideline on comparability of medicinal products containing biotechnology derived proteins as active substance: Quality issues EMEA/CPMP/BWP/3207/00 (50) and section:

- 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) for more technical detail on the comparability exercise.

- Refer also to section: 2.2.3 The biologics life cycle in this study for commercial implication of the comparability exercise.

The rational for the requirement of a comparability exercise for biosimilars is mainly based on the following aspects:

1) Biologic medicinal products are composed as active substance form (larger) biological molecules such as proteins. The complexity of this molecular structure is difficult to characterize fully. In addition, from a scientific and practical point of view, the degree of heterogeneity[19] and variability of the biological system used for the manufacturing process will always impact the biological product and show variability. If variability is not detected this could mean that the assay sensitivity is not good enough (refer to section: 2.2.1 Heterogeneity of biologics (proteins only) for a discussion on heterogeneity). Simply, as already mentioned, the living cells produce proteins. This biologic process of protein manufacture requires a diverse cellular machinery of DNA, and different RNA forms, such as nucleic acids and mainly effector proteins such as enzymes (here the keywords transcription[20] and translation[21] should be mentioned, which can be read about in many sources). Furthermore, there is also a location component, as the protein production process requires the involvement of different locations and organelles[22] within the cell. Considered together, natural heterogeneity of the protein occurs as the cellular components involved in the protein manufacturing process vary because of a wide range of factors. For example, as a response to changing environmental condition components the glycosylation[23] on the protein may change. As a result, the glycol-protein molecules, which are manufactured by the cell, are not identical (refer also to section: 2.2 Life cycle in relation to heterogeneity and variation for details).

2) Biologic medicinal products are defined through their manufacturing process. Those manufacturing processes are individual and unique for each medicinal product.

It is unrealistic to assume that a complete biotechnological process, which is usually composed of a series of steps with high complexity, can be rebuilt and reproduced. Thus, the product, i.e. the biologic, is individual and unique. The notion that the product is the process and the process is the product is completely acknowledged by EMA: refer to Annex 2 Manufacture of Biological active substances and Medicinal Products for Human Use. EudraLex Volume 4 where it states:

“Unlike conventional medicinal products, which are manufactured using chemical and physical techniques capable of a high degree of consistency, the manufacture of biological active substances and medicinal products involves biological processes and materials, such as cultivation of cells or extraction from living organisms. These biological processes may display inherent variability, so that the range and nature of by-products may be variable. The methods employed in the manufacture of biological active substances and biological medicinal products for human use ('biological active substances and medicinal products') are a critical factor in shaping the appropriate regulatory control. Biological active substances and medicinal products can be defined therefore largely by reference to their method of manufacture. This annex provides guidance on the full range of active substances and medicinal products defined as biological”. (8)

Due to unavoidable differences in the manufacturing process between the biologic and the biosimilar, which may include the use of different expression systems, fermentation and purification processes, as well as different excipient, the quality attributes of the biosimilar and the reference medicinal products will not be strictly identical.

1.2.1.3 Heterogeneity and variability of biologics

Biosimilars cannot be identical to the reference biologic. There are differences to a certain extent. As both the reference biologic and the biosimilar are manufactured by dynamic and evolving processes due to raw material changes, for example, as a minor example or production site changes, variability is inherently associated with those products.

The above mentioned dogma according to which “the product is the process and the process is the product” is disputed by some experts. Evolution is viewed towards complex biologics from the theory that the source material defines the product (i.e. the process is the product) to the current thinking that the process affects the quality of the product, but does not uniquely define it (9).

Heterogeneity and variation are unavoidable facts; however, if dealt with adequately this may not be a matter of concern. This fact has been acknowledged by scientists, biologics pharmaceutical industry and also the regulatory agencies, since the introduction of biologic medicinal products.

1.2.2 Problem statement

For the biosimilar context as a whole it is important to understand well the connection with the previous and following sections as follows:

- There is the requirement to show comparability between the biosimilar candidate and the reference biologic.
- There is a life cycle of biologics, which is applicable to the innovator biologic and biosimilar.
- There is the natural variation associated with the process and inherent heterogeneity of bio-molecules, which is associated with cellular process that cannot be fully controlled.

Taking into account these three points, a biosimilar developer faces the following challenge:

To obtain its own MA for its biosimilar, they need to synchronise the biosimilar process dynamic with the unforeseeable process dynamic of the reference biologic while still meeting regulatory expectations with regard to quality, safety and efficacy during the comparability exercise.

The above thought is set into context well by McCamish et al in 2011 (10). They published a significant paper with regard to the topic.

Figure: 1 from McCamish et al in 2011 (10):

“Biosimilarity goal posts. The ‚goal posts‘ of biosimilarity are established by the biosimilar sponsor by their analysis of the distribution of product attributes present in the reference product pre- and post- manufacturing change. Then they use these to select the design space for their biosimilar candidate. While the complete quality range may be quite broad for the life time of the reference product, the biosimilar sponsor will select a tighter range of control for their biosimilar product”.

McCamish et al describes the quality profile of the reference biologic as well as the quality profile of the biosimilar. It shows clearly that both might change and evolve over time. This is one aspect and key train of thought of this study. (The below figure was incorporated in this study and called Figure: 1.)

Abbildung in dieser Leseprobe nicht enthalten

Figure: 1

The “Initial originator quality range” is the quality range of the reference biologic in dark blue.

The quality range of the quality profile of the biosimilar developer is in light blue.

Clearly, the quality profile of the biosimilar fits within the limits of the quality profile of the reference biologic.

Then in pink, the quality profile of the reference biologic has changed, whereas the quality profile of the biosimilar did not. With dissimilar quality profiles the comparability exercise is carried out.

However the conclusion that is drawn in the paper is that Figure: 1 is lacking clarity; thus, the schema should be as in Figure: 2. (11).

Abbildung in dieser Leseprobe nicht enthalten

Figure: 2

The “Initial originator quality range” is the quality range of the reference biologic in dark blue.

The quality range of the quality profile of the biosimilar developer is in light blue.

Clearly, the quality profile of the biosimilar fits within the limits of the quality profile of the reference biologic.

Then in pink, the quality profile of the reference biologic has changed. The new quality profile is adopted by the biosimilar and the comparability exercise is carried out with highly similar quality profiles.

The allowable quality range (quality profile) is dictated by the quality profile of the biosimilar.

Refer also to the discussion in section: 4.4 Discussion .

Based on McCamish et al’s train of thought, the research questions for this study were developed. They established correctly that the quality profiles of the reference and by consequence of the biosimilar as both are biologics are not stable. These quality profiles are dynamic when comparing them on a lot to lot basis for the same process (product) and when comparing the output of different processes (different products), as is the case for the reference biologic and the biosimilar. The heterogeneity and variation for the same process tend to be reduced compared to heterogeneity and variation for different processes.

The challenge for the biosimilar developer is to match the dynamic quality profile of the biosimilar to the dynamic quality profile of the reference biologic. Similar to the situation where in a car race one driver tries to match his speed to another car, however he is only in the position to control his own speed. Thus the matching of the speed of the two cars can be difficult, if the second driver changes his speed. That is the basic underlying concept of this study and is reflected in the research question series 1.0 to 3.0, in which the situation of the dynamic of quality profiles is evaluated and the resulting consequences of this dynamic of quality profiles are evaluated. The EMA issued a series of guidance documents on the topic that will be further address in detail in section: 2.3 Screening the above presented literature related to current biosimilar regulation with regard to the research questions. Despite the rich regulatory corpus, a great deal of questions (still) remain, as biosimilar approval is a process that is still relatively new within the EU. After a couple of years of experience, the EMA revisited many guides and clarifications were made, which also lead to the research questions below:

1.0 What are the implications of heterogeneity and variation through the life cycle of the biosimilar and the reference biologic, from a European perspective?

1.1 Taking into account the new amendment of EMA/CHMP/BWP/617111/2010, with emphasis on the life-cycle of the Biosimilar, does the Biosimilar need to achieve a quality profile which falls within the quality profile of the reference biologic?

Under which circumstances could this approach be deviated from?

1.2 What is proposed if the reference biologic changes its quality profile during the biosimilar development program?

2.0 What should be the scope of trials for biosimilars?

2.1 How extensive do biosimilar trials need to be?

2.2 Does one need to test multiple lots of the biosimilar vs. the reference medicinal product in trials?

2.3 Meta Analysis, maybe a sign for extensive trials, as such reflecting potential issues that show comparability at a first glance.

3.0 Why is extrapolation of indications for biosimilar controversial?

1.2.2.1. The dynamic of the quality profile during the life cycle of a biologic

The fundamental question within the biosimilar context is and will remain for a long time: “how similar does a biosimilar need to be to its reference biologic?” However, this is not what this study is looking to answer. For this study, the question is about exploring the issue of similarity, but only in conjunction with the whole lifecycle of the biologic. Thus, the correct question is:

1.0 What are the implications of heterogeneity and variation through the life cycle of the biosimilar and the reference biologic, from a European perspective?

The degree of heterogeneity and variation needs to be within boundaries. However, the life-cycle of any pharmaceutical product is likely to go through a certain dynamic that will be referred to further in section: 2.2.3 The biologics life cycle. Thus, what is the impact when taking those two aspects into account? A question that will be further referred to in Chapter 5.0: What should be the scope of trials?

As a direct result of research question 1.0, two concrete sub-aspects were further investigated.

One question is about the quality profile of the biosimilar. The quality profile is the summary analytical results and characterisation. The other question is related to the life-cycle and the dynamic of both the reference biologic and the biosimilar.

1.1 Taking into account the new amendment of EMA/CHMP/BWP/617111/2010, with emphasis on the life-cycle of the Biosimilar, does the Biosimilar need to achieve a quality profile which falls within the quality profile of the reference biologic? Under which circumstances could this approach be deviated from?

This issue is of relevance to this study, as this is fundamental in setting specifications for biosimilars and relates to the question of how similar a biosimilar needs to be. We will address this question in more detail in Chapter 5.0: What should be the scope of trials?

1.2 The question: “ What is proposed if the reference biologic changes its quality profile during the biosimilar development program? ” will be addressed in a dedicated section.

The question will be analysed with regard to the life cycle about the dynamic of the quality profile. The quality profile changes permanently. As a matter of fact, every lot is slightly different to other lots bearing a ratio of the protein isoform that is slightly different to previous lots and therefore unique. That is true for all biologics, as mentioned before.

However, the biosimilar developer usually monitors and analyses multiple reference biologic lots over extended periods, a procedure that allows for the creation of the so-called quality profile. This is a range in which the variation and heterogeneity occurs, but which is not exceeded under usual circumstances. On the other hand, as the period of time and the number of lots analysed only allows limited analysis, and the dynamic of the reference biologic is unforeseeable for the biosimilar developer, one may also encounter the situation that the quality profile of the reference biologic, as it was established initially by the biosimilar developer, changes as well. Thus making the biosimilars own quality profile different compared to the reference biologic profile.

Such an occurrence may happen at any stage of the development process of the biosimilar, a situation that poses unsolved challenges for the biosimilar developer and the regulatory authorities on how to proceed. The regulatory process is still in its infancy, as the only guidance from the regulatory side at the moment is that once the product was authorised, there are no requirements any more for similarity (refer to current mAbs and Quality guide draft: 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)).

1.2.2.2. The costs for a biosimilar

Other very relevant and problematic questions refer to the scope of trials. The costs of bringing a medicinal product to the market are of utmost interest in the industry. Therefore, regulatory aspects that impact significantly on costs, or reduces them, are of high interest. The scope and burden to show biosimilarity in clinical trials is disputed, due to their high costs. The questions on how large clinical trials for biosimilar should be are not clear. Thus a series of questions was forward to resolve this issue.

2.0 What should be the scope of trials for biosimilars?

2.1 How extensive do biosimilar trials need to be in order to show comparability?

What are the expectations and requirements based on the guidelines and the current state of discussion on clinical trials and how should a clinical trial design look like for a biosimilar clinical trial? This will reveal the requirements and current practices and will indicate the clinical trials scope including the number of subjects that participated.

2.2 Under what circumstances does one need to test multiple lots of the biosimilar vs. the reference medicinal product in trials?

Based on the dynamic of the quality profiles, does one need to take heterogeneity and variation aspects into account when conducting clinical trials, which leads to incorporation of multiple lots into the trial design? The extent on trials will evidently impact on the costs; therefore, this question has a potentially high impact on cost if answered positively.

2.3 Meta Analysis, maybe a sign for extensive trials, as such reflecting potential issues that show comparability at a first glance.

Meta Analysis can be interpreted as a sign that clinical comparability data was not conclusive enough or it has been controversial that questions the comparability. Thus, this will indicate the suitability of the clinical trial design employed, including its scope.

3.0 Why is extrapolation of indications for biosimilar controversial?

The EMA proposed to extrapolate indications without the requirement of additional clinical trials under the condition that for one indication biosimilarity was established and the mechanism of action is identical.

1.3 Study “Within Scope” and “Out of Scope”

This study deals with European biosimilars and more particularly analyses the framework set by the following guidance documents as questions and comments were send to the EMA with regard to those guidance documents, refer to

Appendix: 1 Questions and comments submitted to the EMA and

Appendix: 2 Questions and comments submitted to the EMA.

- GUIDELINE ON SIMILAR BIOLOGICAL MEDICINAL PRODUCTS CONTAINING BIOTECHNOLOGY-DERIVED PROTEINS AS ACTIVE SUBSTANCE: NON-CLINICAL AND CLINICAL ISSUES

EMEA/CHMP/BMWP/42832/2005

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003920.pdf

- Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1) Draft

EMA/CHMP/BWP/247713/2012

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/05/WC500127960.pdf

- Guideline on similar biological medicinal products containing monoclonal antibodies Draft

EMA/CHMP/BMWP/403543/2010

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdf

- Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues

EMA/CHMP/BMWP/403543/2010

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf

The main focus is on the implications of heterogeneity and variation through the life cycle of the biosimilar and the reference biologic, as stated in the main research questions.

The follow up theme of this main research question is the cost to conduct a comparability exercise based on regulatory exceptions.

This study does not envisage evaluating any situation external to the EFTA/EU regulatory situation, although a brief description of the biosimilar situation and links in the US, Canada and Japan will be mentioned for informational purposes in section:

2.4. Reference to other biosimilar regulations.

1.4 Description of the European Regulatory Environment with Regard to Biosimilars

The European Medicines Agency EMA (previously on called EMEA) was founded in 1995 in accordance with the European Community Regulation (ECC) No 2309/93. The EMA is responsible for the approval, assessment, supervision and monitoring of the medical domain and to promote public health in the EU/EEA, respectively the EFTA countries.

The EMA relies on the scientific resources of the national drug agencies (competent authorities in the respective 30 member states of the European Union and EEA countries). Also, its personal often play a decision making role within the national authority, but also within the EMA.

Through 2001/83/EC, via the so-called centralized procedure, formed a committee, the CHMP (for human medicines), to give scientific advice. CHMP can seek advice from the biologics working party (BWP). The BWP provides recommendations to the EMA scientific committees, such as the CHMP, on all matters relating directly or indirectly to quality and safety aspects relating to biological and biotechnological medicinal products. This includes biosimilars.

When it comes to granting a Marketing Authorisation (MA), the European Commission usually follows the recommendation of the CHMP.

The legal basis under which the EMA exercises its duties is the community regulation (EC) No 726/2004. The most important of the main regulations (directives and regulations) for medicinal products is undisputedly Directive 2001/83/EC that will be referred to later in section: 2.3 Screening the above presented literature related to current biosimilar regulation with regard to the research questions. Amendments of this Directive 2001/83/EC by European Directives in 2003/63/EC and 2004/27/EC, gave a new legal framework for biosimilars in Europe.

Article 10 of 2001/83/EC was changed in order to require the highest standards of safety and efficacy for biologics clinical data. This laid down the foundation for all subsequent guidance documents on how to interpret and conduct the comparative exercises (12).

1.5. Why are biosimilars interesting for the generic industry?

The main reason for industrial interest in biosimilars is financial. The biosimilar has lower development costs, will be approved following a faster timeline and there is an established market where the product is accepted.

“Worldwide sales of biologic drugs exceeded US$92 billion in 2009. With many biopharmaceutical patents expiring over the next decade, a wave of second-generation or ‘follow-on’ biologics will be vying for market share and regulatory approval. Patents cover not only the drugs, but also the molecular modalities that facilitate their high-level expression”. (13)

Innovator biologics are highly evaluated within the categories of biologics. For 2013, the volume of biologics sales is estimated to reach the level of 100 million EUR worldwide. As patents on many of those biologics are expiring this raises significant opportunities for biosimilar developers.

“Patents on several biopharmaceuticals have recently expired, or are due to expire”. (14)

Whereas the classical division between the generics industry and innovator industry does not exist, all stakeholders try to gain market share from competing companies. The hurdles to enter the biosimilar market are significantly higher compared to classical generics; however, there are also potentially high profit margins. This also attracts pharmaceutical companies as well as the generics giants.

The classical generic companies have difficulties in entering the biosimilars market. Therefore, the potential companies that may have the resources and experience to access this more complicated biosimilar market may be different.

For example, the mAbs are the largest and fastest growing category of biologics. Over 30% of new medicinal products, with an increasing tendency, are based on biologics. A very big portion of that is mAbs. Patents on these mAbs are expiring and many biosimilar versions are currently in different phases of development or are about to be submitted for approval via the centralized procedure to the CHMP. The cost for developing a suitably complex biosimilar, for example a mAb, could be estimated to be between 80 million EUR and 250 million EUR. The cost for a new biological medicinal product could be in the order of 1 billion EUR or more.

“ The pharmaceutical industry notes that the steep cost of developing an innovator biologic ($1.2 billion) and the lengthy time it takes a manufacturer to jump through the research, clinical testing and approval process (roughly ten years) warrants strong patent and patient protections. The American Association of Retired People (AARP) and other advocacy groups challenge those R&D figures. But there is no question that developing these treatments is costly, with many failures leading to a relative handful of well-rewarded successes. For better or worse, time and expense are the reality of the drug development model in a tightly regulated environment”. (15)

On Sandoz’s website, the company states that a biosimilar can cost between $75 million and $250 million to develop, with only 500 patients in clinical trials. (7) Some experts even estimate that costs could be lower. (16)

Novartis through its generics specialist Sandoz, Teva in combination with Lonza and Hospira are likely to be the leading players in forming and creating biosimilar versions of the blockbuster antibodies. However, the market entry cost is relatively high with at least 80million EUR needed.

“The research group Collins Stewart has estimated that developers will need to budget $100 million for the kinds of clinical trials that will be required to gain an approval. And once they hit the market, the follow-on are expected to offer discounts of 10 to 15 percent”. (17)

“In the European Union, Sandoz Inc. has successfully marketed three biosimilar drugs along with its biologics pipeline. In December of 2011, Baxter International Inc., based in Deerfield, Ill., announced collaboration with Momenta Pharmaceuticals Inc. to develop six biosimilars, or follow-on biologic products. Amgen Inc. and Watson Pharmaceuticals Inc. announced Dec. 19, 2011 that the two companies will draw upon their respective strengths to develop and market biosimilars in the specialty and generic markets. Watson Pharmaceuticals is expected to pay up to $400 million in costs over the development and marketing of several biosimilar products. In addition, Celerion and Ricerca Biosciences announced the formation of “The Biosimilars Alliance” in February of 2012. Celerion stated predicted the biosimilar market will grow in the U.S. from $2.4 billion in 2012 to $44 billion by 2020”. (18)

Pfizer's new pact with Biocon on biosimilar insulin products will help drive development of far more complex biologics, including the first round of biosimilar antibodies around 2014 and 2015.

1.5.1 What is the market size? What are the growth estimates for biologics and biosimilars?

Biosimilars are the future; this view is not only shared by the representatives of the biosimilar industry, but also by the classical innovator industry, where some players have entered the field of biosimilars as well.

The EMA has introduced regulatory frameworks for the approval of biosimilar mAbs medicinal products. However this path relies on a comparability exercise as outlined in Chapter 5.0: What should be the scope of trials? Thus, contrary to the classical generics pathway for M.A. approval, for biosimilars clinical trials are required, which are a significant cost factor, refer to section 5.3.1.2 Clinical trials conducted in the EU or USA. Total clinical trial requirements are difficult to foresee and are data driven, thus it will be a case by case decision that will be addressed in detail in Chapter 5.0: What should be the scope of trials?. mAb are one of the important categories of biologics, and for this study the focus will mainly be on mAbs.

Worldwide biologics sales in 2009 were at ca. 93 billion dollars and are expected to continue to grow at least twice as fast as those of small molecules. In 2010 sales of biologics amounted to 30 billion dollars in the United States, and EUR 60 billion in Europe (19). For example, many new and future biopharmaceuticals (biologics) are biotechnology derived mAbs. Ca. 300 (mAbs) are being developed (2011) for over 200 indications for oncology, inflammatory diseases, autoimmune diseases, metabolic and central nervous system disorders, infectious and cardiovascular diseases. (20)

Many blockbuster biopharmaceutical patents are expected to expire over the next decade. Thus, there is a good opportunity for the biosimilar industry to gain access and market share of this emerging biologics market with ever growing revenues. (21)

Biopharmaceuticals usually cost much more per patient than conventional pharmaceuticals, and their use is growing at a much higher rate than that of the overall pharmaceutical market. Annual treatment cost can span between 37,000 to 200,000 USD per year. (21)

It is estimated that in 2010, some 50% of all newly approved medicinal products will be biologics.

“There are now roughly 500 new biopharmaceutical products in various stages of development worldwide, 300 of them in Europe. In 2003 for example 7 of the 50 best selling medicines in Germany were biopharmaceuticals”. (22)

There are 150 marketed biologic products worldwide, with over 370 additional products under development (16). Worldwide biologic sales exceeded 100 billion USD in 2011, and 32% of those sales were related to mAbs (23).

“Further it is anticipated that in 2016, biologics half of the topselling biologics; of these, seven (Humira®, Avastin®, Rituxan®, Herceptin®, Remicade®, Prolia® and Lucentis®) are mAbs and one (Enbrel®) is a fusion protein containing antibody components.” (10)

In the top 10 best-selling drugs there will be as many as 8 biological drugs by 2014 (Table 1) compared to six in 2010 (Table 2), five in 2008 and only a single entry in 2000. In 2014 biologic drugs will account for 75% of sales, a two-fold increase in the relative contribution to the pharmaceutical sector, it has been estimated. They will mainly be used to treat cancer and rheumatoid arthritis.

The situation is predicted to change dramatically by 2014, see Table 2. At least six, and as many as eight, of the top 10 best-selling drugs are expected to be biological drugs. Moreover, biological drugs are predicted to account for 75% of sales, an almost two-fold increase in the relative contributions of biological drugs to the pharmaceutical sector.

Table 1:

Abbildung in dieser Leseprobe nicht enthalten

Table 2:

Abbildung in dieser Leseprobe nicht enthalten

Many small molecule drugs will be off patent in 2014, such as Lipitor (atorvastatin), Plavix (clopidogrel), Advair (fluticasone/salmeterol) and Diovan (valsartan), all current best sellers, and there will be major competition in the generics market due to this. In addition, from 2011 to 2015 biosimilars with a combined worth of US$17 billion will lose patent protection. (24)

It was estimated that biosimilar sales worldwide in 2011 were ca. $16.4 billion (25). The global biosimilars market is expected to grow to $17.9 billion by 2017, according to a press release issued by Global Industry Analysts Inc. However, there are also risks involved in the biosimilar market, which only the bigger players are willing to take or are capable of managing through their bigger financial means and expertise.

Clearly it is with worth citing and outlining those risks, as they highlight potential rift lines within the regulations and disputed areas.

Proteins, as the basis of most biologics, are not simple to manufacture, as outlined further in section: 2.2.3 The biologics life cycle, leading to higher costs related to manufacturing. They also require product safety that is higher than for small molecule[24] generics due to their potential increased immunogenicity[25]. Therefore, an extra burden of evidence is required for their approval, which means more time and more money to demonstrate product safety, as well as facing greater competition.

On the other hand, the degree of success of biosimilars is influenced by many factors. One of the most important is represented by the regulatory environment, the topic analysed in this study.

Taking again the example of mAbs, biosimilar mAbs constitutes a unique class of biosimilars. mAbs are heterodimeric[26] proteins, which are glycosylated. The (stringent) regulatory guidance for biosimilar monoclonal antibodies results from the complexity of their structure. Currently, there are still no mAbs approved within the EU, but several are awaiting approval.

It is expected that in the near future, biosimilar mAbs will be approved; however, some hurdles could infringe their economic success:

i) In view of their complexity the development costs can be expected to be significantly higher compared to that of “regular” biosimilars. Consequently, price reductions compared to the reference may be very small.
ii) Biosimilar MAs are also expected to experience significant competition from the next-generation MAs that will exhibit improved properties, e.g., through glycoengineering.
iii) Antibody-based therapeutics, such as Fc-linked fusion proteins[27] exhibiting improved therapeutic potential and improved pharmacodynamics[28], may also compete with biosimilar MAs.
v) Other antibody formats currently under development such as nanobodies[29], produced in bacteria and thus expected to be much cheaper may well form an alternative for reducing costs in healthcare (26).

Another issue is represented by potential market saturation, where many companies manufacture biosimilars for the same reference biologic and if that occurs, “it is going to be more difficult to recoup your investment dollars” (18) .

1.5.2 Patent protection and market exclusivity

Patent protection and market exclusivity is a key hurdle for biosimilar approval. However, those barriers are beginning to disappear, as they are time limited. For example, Sandoz estimates that innovator biologics worth $63 billion in sales will lose patent protection by 2015, which represents 40% of the total biologic market. (18)

This evaluation is largely in line with other estimates from consultancy experts in the field of biosimilars, which estimate that between 2009 and 2019, 21 blockbuster biologics with sales of over 50 billion dollars will lose patent protection. These are biologics mainly in the areas of oncology, inflammatory and cardiovascular diseases that will most likely lose their patent protection, which are often based on mAbs. (16)

Therefore, biosimilars remain an attractive investment project compared to the lengthy pathway from discovery to approval of a biologic medicine, which is long and uncertain, and can consume enormous resources and time. As for one successful innovator biologic between 10 and 15 years and costs on average of $1 .2 billion can be envisaged.

Innovator biologics are usually protected by an exclusivity phase (from the regulator, which is 12 years from the date of granting the M.A., for example) and also by a patent phase which is usually 20 years. The innovator industry usually tries to protect the source of their revenue by patents if feasible. The available exclusivity time frame on the market is usually limited by the patent protection time frame as it is the longer lasting one.

The patent is normally filed when the clinical trial phase begins, which can take up to 3 or 6 years. Given that some time is required to file for an M.A. with the regulator, the remaining market exclusivity timeframe is usually 13 to 16 years, given that some time will elapse for the regulatory approval process.

During the protected timeframe of the innovator pharmaceutical product, the innovator companies try to maximize their revenues to compensate for the expenses during the development phase.

The different types of protection of the innovator biologic medicinal product have to be taken into account by biosimilar developers, these are:

- Patents (20 years protection)
- Patent term extensions (plus 5 years protection)
- Market exclusivity (usually 12 years)

“Patents in the US and Europe last 20 years”. Because the patent generally lasts longer than the exclusivity period granted for a New Chemical Entity (NCE) by the regulatory agencies the patent is often the barrier to generic entry rather than the exclusivity period.

However, since the drug development and regulatory process can often be lengthy, both the US and Europe provide exclusivity extensions for patented drugs in order to compensate somewhat for some of this delay. The relationship between the date of patent filing and the initiation of clinical trials and the relationship between the date of patent filing and the market authorization date on the expected duration of marketing exclusivity are discussed in the following series of two articles”. (27)

Market exclusivity is the time period during which the new medicinal products are protected from direct competition from generic versions, which includes biosimilars.

“Every day of market exclusivity is a potential profit for an originator company because generic drug companies capture 80% market share within six months of entering the US market”. (27)

“The FDA grants for a limited period of time market exclusivity for each newly approved drug or formulation:

5 years for a new chemical entity (NCE)

3 years for a new formulation of an existing drug

7 years for an orphan drug” (28)

“After 2005 the EMA grants for a limited period of time market exclusivity in the following way:

8 years of data exclusivity dating from the EMA authorisation decision (before that, no generic applications may be filed)

Plus 2 years extra, for marketing protection: no generic applications may be approved.

Plus 1 year extra, for new indication(s) if it constitutes a significant clinical benefit”. (27)

However, those periods can be extended:

- “The US Patent Term Extension (21 CFR 60 and 35 USC 156) allows for up to 14 years of market exclusivity

- The European Supplemental Protection Certificate (SPC; described in EEC Council Regulation No. 1768/92) provides extensions for up to a maximum of 15 years of market exclusivity”. (28)

Patents may also create effective protection. However, there are often disputes surrounding them. Infringement on a claimed invention of a granted patent usually results in legal disputes. Patents usually last longer than the period of market exclusivity granted by the regulator.

“For patent applications that were filed after June 1995, statutory patent expiry in the United States and Europe occurs 20 years after the date of filing the non-provisional patent application (for example, a PCT (Patent Cooperation Treaty) application).

A provisional patent application is often filed 1 year earlier; in this case, patent expiry would occur 21 years after the provisional application was filed. However, because the patent holder does not receive commercial benefit until the product has been approved by regulatory agencies, authorities in the United States and Europe both provide exclusivity extensions for patented drugs, which are intended to compensate for patent life that is lost during the lengthy drug development and regulatory process. Such extensions can prolong the effective patent expiry date beyond 21 years after the filing of the provisional application”. (28)

However, extensions of the patents are possible. Within the EU a supplementary protection certificate (SPC) can be granted after the patent expires. This SPC grants another 5 years to the standard of 20 years granted per patent No 469/2009/EC. In the case where data from paediatric clinical trials is added to the dossier, another 0.5 years are grated for that, as set out in Article 36 of Regulation 1901/2006/EC. The total additional protection period based on the SPC can exceed 5.5 years for human medicinal products. The combined period of market exclusivity based on a patent and SPC should not exceed 15.5 years.

The FDA, for example, allows for a patent extension of up to 5 years according to the regulations governing the Patent Term Restoration program, which are located in the Code of Federal Regulations, 21 CFR Part 60. However, the maximum of 5 years can only be granted if a maximum of 14 years from the biologics approval date (M.A.) would not be exceeded. (29)

[...]


[1] Immunology:

The branch of medicine and biology concerned with immunity. Oxford Online Dictionary.

[2] Biologic: A) Relating to biology; biological: there is growing interest in the biologic activities of plant extracts in the treatment of disease; or

B) Another term for biological (noun): these natural biologics can be as potent as manufactured drugs. Oxford Online Dictionary.

[3] Biological medicine:

A medicine that contains one or more active substances made by or derived from a biological source. Questions and answers on biosimilar medicines, EMA.

[4] Biotechnology:

The exploitation of biological processes for industrial and other purposes, especially the genetic manipulation of microorganisms for the production of antibiotics, hormones, etc.. Oxford Online Dictionary.

[5] Recombinant DNA technology:

Joining together of DNA molecules from two different species that are inserted into a host organism to produce new genetic combinations that are of value to science, medicine, agriculture and industry. Britannica Academic Edition.

[6] Medicinal product: (a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or

(b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.Article 1, DIRECTIVE 2001/83/EC

[7] Gene: A distinct sequence of nucleotides forming part of a chromosome, the order of which determines the order of monomers in a polypeptide or nucleic acid molecule which a cell (or virus) may synthesize. Oxford Online Dictionary.

[8] Prokaryote: A microscopic single-celled organism which has neither a distinct nucleus with a membrane nor other specialized organelles, including the bacteria and cyanobacteria. Oxford Online Dictionary.

[9] Eukaryote: An organism consisting of a cell or cells in which the genetic material is DNA in the form of chromosomes contained within a distinct nucleus. Eukaryotes include all living organisms other than the eubacteria and archaea. Oxford Online Dictionary.

[10] Hybridoma: The fusion of a myeloma cell from a line that has lost the ability to secret immunoglobulin with a B cell known to secrete a particular antibody results in a remarkable hybrid cell that produces the antibody made by its B-cell component but retains the capacity of its myeloma component to multiply indefinitely. Britannica Academic Edition.

[11] Monoclonal antibodies: Antibodies with a defined specificity derived from cloned cells or organisms. PRODUCTION AND QUALITY CONTROL OF MONOCLONAL ANTIBODIES, EMA.

[12] Heterogeneous: Adjective diverse in character or content: a large and heterogeneous collection. Oxford Online Dictionary.

[13] Immune response: The reaction of the cells and fluids of the body to the presence of a substance which is not recognized as a constituent of the body itself. Oxford Online Dictionary.

[14] Erythropoietin:

Hormone produced largely in the kidneys that influences the rate of production of red blood cells. Britannica Academic Edition.

[15] Innovator pharmaceutical companies:

Interchangeable with the term originator pharmaceutical companies. Pharmaceutical companies which brought something new to the initial the medicinal product i.e. pharmaceutical organizations which conduct research.

[16] EPAR: The European Medicines Agency publishes an EPAR for every medicine granted a central marketing authorization by the European Commission. EPARs are full scientific assessment reports of medicines authorized at a European Union level, source EMA.

[17] Physicochemical: Relating to physics and chemistry or to physical chemistry. Oxford Online Dictionary.

[18] Bioequivalent:

Two medicinal products containing the same active substance are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailability (rate and extent) after administration in the same molar dose lie within acceptable predefined limits, source GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE, EMEA.

[19] Heterogeneous: Diverse in character or content: a large and heterogeneous collection. Oxford Online Dictionary.

[20] Transcription: The process of transcribing RNA, with existing DNA serving as a template, or vice versa. Oxford Online Dictionary.

[21] Translation: The process by which a sequence of nucleotide triplets in a messenger RNA molecule gives rise to a specific sequence of amino acids during synthesis of a polypeptide or protein. Oxford Online Dictionary.

[22] Organelle Any of a number of organized or specialized structures within a living cell. Oxford Online Dictionary.

[23] Glycosylation: the process by which sugars are chemically attached to proteins to form glycoproteins. The Free Dictionary, section Medical Dictionary.

[24] Molecule: A group of atoms bonded together, representing the smallest fundamental unit of a chemical compound that can take part in a chemical reaction. Oxford Online Dictionary.

[25] Immunogenic:

Relating to or denoting substances able to produce an immune response: immunogenic vaccines. Oxford Online Dictionary.

[26] Hetreodimer: Hetero – Prefix, the same.

Dimer - A molecule or molecular complex consisting of two identical molecules linked together. Oxford Online Dictionary.

[27] Fc-linked fusion proteins: Fc-based fusion proteins are composed of an immunoglobin Fc domain that is directly linked to another peptide. (102)

[28] Pharmacodynamics:

The branch of pharmacology concerned with the effects of drugs and the mechanism of their action. Oxford Online Dictionary.

[29] Nanobodies:

Are antibody-derived therapeutic proteins that contain the unique structural and functional properties of naturally-occurring heavy-chain antibodies. http://www.ablynx.com/en/research-development/nanobody-technology/understanding-nanobodies/

Details

Pages
282
Type of Edition
Erstausgabe
Year
2014
ISBN (eBook)
9783954896875
ISBN (Book)
9783954891870
File size
7.3 MB
Language
English
Catalog Number
v287475
Grade
Tags
Biosimilar Biosimilars EMA quality profile life cycle

Author

The author works in the life-science industry for over 7 years now. His educational and scientific background is in immunology, as he graduated at the Max Planck Institute for Immunology in Freiburg. Further he completed a MSc. in pharmaceutical quality assurance and regulatory affairs at the Dublin Institute of Technology.
Previous

Title: Rift-lines within european regulatory framework for biosimilars when taking heterogeneity and variation during lifecycle of the reference biologic and the biosimilar into account