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

Master's Thesis 2013 254 Pages

Medicine - Pharmacology

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 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

Bibliography or References

List of Appendices
Appendix: 1
Appendix: 2
Appendix: 3
Appendix: 4
Appendix: 5

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

Acknowledgements

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

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 thesis.

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 thesis was carried out with no other means and input beside the ones cited in this thesis. M. Osmane is the genuine author of this thesis 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

illustration not visible in this excerpt

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 thesis, 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 Thesis 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 thesis 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 thesis. 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 thesis bears the potential to bring a new perspective to the European biosimilar regulations, overall an excellent strategic opportunity for the elaboration of a master thesis.

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).

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].[3]

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 issuesEMEA/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 thesis 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 thesis. (The below figure was incorporated in this thesis and called Figure: 1.)

illustration not visible in this excerpt

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).

illustration not visible in this excerpt

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 thesis 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 thesis 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 ofEMA/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 thesis is looking to answer. For this thesis, 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 ofEMA/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 Thesis “Within Scope” and “Out of Scope”

This thesis 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: 1Questions and comments submitted to the EMA and Appendix: 2Questions 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 thesis 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 thesis 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.

illustration not visible in this excerpt

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 thesis.

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)

Chapter 2: Literature review

The literature research in this chapter is subdivided into the following sections:

2.1. Re-presenting the current biosimilar legislation and regulatory requirements

(This includes a reference to section: 4.2.2. Questions and comments submitted to the EMA, where comments were forwarded to the EMA in relation to the mAbs guide in 2011.)

The literature published online was used exclusively for this thesis, as there was no access possible to D.I.T. or other libraries from aboard. For the elaboration of this thesis, literature available exclusively online was employed and a multilayer literature review was conducted where dedicated keywords were employed and were carefully selected to obtain specific information on the research questions. Whenever possible, the reference papers and articles were downloaded, also refer to the

Bibliography or References. The main sources consulted were the following:

1) EMA website, including EMA guidance documents on biosimilars (30)

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c

This site contained all the relevant guidance documents related to the stages of approval.

2) Pubmed (31)

http://www.ncbi.nlm.nih.gov/pubmed/

The Pubmed online library contains regularly published articles specifically related to the research questions. However, the authors of those articles may have diverse links to industry thorough their research field of biosimilars so caution and critical thinking are strongly recommended.

3) Gabionline (32)

http://www.gabionline.net/

Gabi-online is associated mainly with the generics and biosimilar industry, from where it presumably receives its funding (Pro Pharma Communications International among others).

4) Google (33)

www.google.com/

For very general purposes, the main search engine used was Google; it was not used to tackle the research questions.

2.2 Life cycle in relation to heterogeneity and variation

2.3 Screening the above presented literature related to current biosimilar regulation with regard to the research questions

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?

2.4. Reference to other biosimilar regulations

- US
- Japan
- Canada
- WHO

2.1. Re-presenting the current biosimilar legislation and regulatory requirements

2.1.1 The European biosimilar approval pathway and its regulatory framework

The regulatory framework:

All medicinal products manufactured using biotechnological processes, including biosimilars, are required to be approved via the “Centralized Procedure”. For biosimilars, the European Commission amended article 10 of directive 2001/83/EC in 2004 and opened thereby a new path to biosimilar approval. The amendment was carried out through directive 2004/27/EC. Directive 2004/27/EC displaced the term essential similarity with two new terms: generic medicinal products and similar biological medicinal product (3).

Directive Article 10(4) 2001/83/EC and Section 4, Part II, Annex I of the Directive 2001/83/EC lay down the requirements for the Marketing Authorisation on a legal basis. The first guidance specific for biosimilars was issued from 2004 onwards; whereas, already in 2003, biosimilars were included in guidance documents for comparability exercises. It is outlined that the CHMP[30] will issue specific guidance with regard to data requirements, substantiate and proof of similarity. Similarity of the biosimilar to the reference product is the basis for the M.A. application for a biosimilar medicinal product.

Article 10(4) of the Directive 2001/83/EC states:

“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. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in the Annex and the related detailed guidelines. The results of other tests and trials from the reference medicinal product's dossier shall not be provided.”

The biosimilar submission and approval process:

The CHMP is responsible for preparing the Agency's opinions on all questions concerning medicines for human use within the European Union, in accordance with Regulation EC 726/2004. Its responsibilities include conducting the initial assessment of medicines for authorisation, the post-authorisation and maintenance activities as well as modifications and extensions to an existing marketing authorisation. The EMAs scientific committee (usually CHMP for human medicinal products) designates a rapporteur and a co-rapporteur who receive the full copies of the marketing authorisation application file.

The rapporteur plays the key role in this process even after the authorisation is granted. Their main tasks are: assessing and submitting the applicant replies for discussion, as well as preparing a final assessment report. This process ensures that the respective medicines have a positive risk-benefit balance in favour of patient benefits.

The CHMP provides a positive or negative opinion on the product, as well as the granting of the authorisation by submitting a draft summary of the product characteristics, the package leaflets and the texts proposed for the various packaging materials. This process takes at most 210 days after which EMA will have to forward its opinion to the Commission.

In a second phase, the Commission ensures that the marketing authorisation is compliant with the EU directive 2001/83/EC from 2004 (latest version). The EMA sends to the Commission its opinion and assessment report together with annexes containing the summary of the product characteristics (Annex 1), the details for batch release, the details and the manufacturer of the biological active substance as well as the condition of the market authorisation (Annex 2), the labelling and the packaging leaflet (Annex 3).

There is a delay of fifteen days during which the Commission has to prepare a draft decision. In the end, the medicinal product will obtain a Community registration number that will be placed on the packaging in the case where the marketing authorisation is granted.

In cases where a favourable opinion is obtained, then there will take place the empowerment procedure by the Commission’s Secretariat-General who notifies the Commission decision to the marketing authorisation holder and furthermore publishes it in the Community register. The marketing authorisations are valid for 5 years and the applications for renewal are requested to be made to the EMEA at least 6 month before the 5-year period expires.

The CHMP publishes a European Public Assessment Report (EPAR) for every centrally authorised medicine that is granted a marketing authorisation, setting out the scientific grounds for the Committee’s opinion in favour of granting the authorisation, plus a ‘summary of product characteristics’ (SPC), labelling and package leaflets (most specifically, the patient/user information leaflet) for the medicine, and details of the procedural steps taken during the assessment process. EPARs are published on the Agency’s website, and are generally available in all official languages of the EU.

In 2006 Omnitrop[31] received its M.A. and was the first biosimilar approved within the EU, it is manufactured by SANDOZ (34, 35).

2.1.2 Regulatory guidance literature

General literature on biosimilars can be found on the EMA website (36). Summary of the main items has been included in Figure: 3.

The literature research was limited to:

1. Guidance documents about the principles of biosimilarity.
2. General guidance documents for quality and clinical issues.
3. Product specific guidance documents for mAbs, as the most recent product specific guidance available from the EMA.

The reasons:

1. Larger molecules with a certain complexity represent the most challenging regulatory topic.
2. For some of those guidance documents comments could be forwarded to EMA.
3. Assessing all available guidance documents would represent a too big challenge for the scope of this thesis, especially taking into account time restrictions.

illustration not visible in this excerpt

Figure : 3

Overview of the regulatory guidance literature used as the basis of this thesis, including the overarching guides and the general guides.

Product specific guides are not further evaluated, with exception of the mAb guide, as part of Appendix: 1.

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

For the following proposed or old documents, questions, comments and suggestions for improvement were submitted to the EMA. The submission process is open to the public and the draft guidance itself contains the information about how to proceed in the case where it is desired to submit questions and comments with regard to the draft, to the EMA.

1. A word format template is proposed for the submission.
2. A postal address is provided.
3. Equally final submission deadlines were indicated.

There was the opportunity to submit comments to the EMA until the end of 2011 for the draft guide on the guideline on similar biological medicinal products containing monoclonal antibodies:

1. The proposed draft guidance:

“EMA/CHMP/BMWP/403543/2010 Guideline on similar biological medicinal products containing monoclonal antibodies Draft”

2. The following comments were made by M. Osmane in relation to the research questions treated in this thesis:

EMA/205886/2012Overview of comments received on 'Guideline on similar biological medicinalproducts containing monoclonal antibodies' (EMA/CHMP/BMWP/403543/2010), also referred to

Appendix: 2

Questions and comments submitted to the EMA

3. The outcome:

The outcome is further analyzed as part of chapter 4, section: 4.2.3 Survey research questions of this thesis and the responses from the EMA are available under:

“EMA/CHMP/BMWP/403543/2010 Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues”.

There was a further opportunity to submit comments to the EMA till the end of 2012 for a revised guide on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues.

1. The proposed draft guidance:

EMA/CHMP/BWP/247713/2012

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

2. The following comments were made by M. Osmane in relation to the research questions treated in this thesis:

Mentioned in Appendix: 2.

3. The outcome:

The outcome will be further analyzed as part of chapter 4, section: 4.2.3 Survey research questions of this thesis.

At the time of submission for this thesis, the EMA had not answered the submitted comments.

2.2 Life cycle in relation to heterogeneity and variation

Biologics based on recombinant[32] biotechnology are usually proteins; therefore, their size can range from roughly 19kDa (for interferon-alpha) to roughly 150 kDA (for IgG molecules); they have a complex three dimensional structure, which allows them to exert their biological functions.

When proteins interact in the body, the mode as well as the chemical interaction (bonding to a target molecule, docking to a receptor, etc. is based on various types of chemical interaction, such as hydrogen bonds, hydrophobic interactions[33], Van der Waals[34] and ionic bonds[35] that can trigger a multitude of biological effects).

Nevertheless the complexity of proteins is not limited to the above basic considerations. In the same way that nature does not like empty spaces, or strict mathematical shapes, proteins, as one of nature’s products, are imperfect in a mathematical (or chemical) sense. They exhibit a natural variability.

In this thesis the term ‘heterogeneity’ is employed for describing this aspect. It means that there are always differences between such large and complex molecules. Surely, those difference often have no effect or are minor; however, they do exist, are present and will be always be present, assuming of course that the detection method is detailed enough to detect them. Heterogeneity is therefore the result of the bioprocesses that lead to the construction, modification and destruction of protein. The biopharmaceutical can be produced as different isomers and can form aggregates. The structure and activity of some proteins are complicated by glycosylation and other posttranslational modifications that lead to heterogeneity. (37)

In contrast to this situation, there is variation that is meant as a summary of variability introduced by man-made technology. This starts with upstream processes such as cell banking, the conditions of the bioreactor[36] in which the cells are manufactured, the protein of interest is multiplied to the downstream processes of harvesting the target protein and separation of it via a series of purification steps usually accompanied by various filtration and virus inactivation steps.

All of those steps may potentially impact on the variability of the biologic due to technical influences of the production process. For example, the purification process will highly impact which isoform(s) of the manufactured target protein will be finally present in the active substance. Therefore, the quality profile of the biologic is highly dependent of the production process, in line with Annex II of EudraLex Vol. 4[37] ‘the process is the product’. (38)

2.2.1 Heterogeneity of biologics (proteins only)

If biologics are considered to be proteins only, then the following sources of heterogeneity can occur. This takes into consideration the previous definition of heterogeneity, as a biological variation caused by nature. However for simplification purposes, we define heterogeneity within the limitations of a single cell.

Errors can occur at the DNA level. For example, external factors such as UV light and radiation can cause DNA damage to coding regions. Also the DNA replication enzyme (DNA-polymerase) has a certain error rate and inserts the wrong nucleotide or too many or too few nucleotides into a sequence. Various repair processes fix most errors, but some errors become permanent mutations in the coding region. If those issues occur, they are passed on to subsequent cellular generations. (39)

Then the DNA gets transcribed into mRNA in the nucleus. Point mutations of the template DNA (i.e. the coding region) or errors during transcription (the process of transcribing double stranded DNA into single stranded RNA, called messenger RNA or simply mRNA) can activate a cryptic splice site in which part of the transcript is usually not spliced. This is important to note, as a gene has introns and exons. Introns are that parts that do not contain coding sequences, which are usually cut out unless an event triggering splice variants occurs. Exons contain the coding sequence of a gene. The result of the transcription process is the single stranded mRNA, which does not contain the introns[38]. Via the process of translation[39], the mRNA which migrated into the cytosol[40] will give rise to an enchained amino acid sequence.

Usually, N-terminal signalling sequences are responsible for the insertion of the elongating protein chain (based on amino acids) in the endoplasmatic reticulum[41]. The signal peptide[42] sequences are subsequently removed from the endoplasmic reticulum. This sequence is successively prolonged until the full protein sequence is formed; simultaneously the folding process of the protein occurs, which may be assisted by chaperones. Simplifying, the hydrogen bonding between different groups of amino acids of the protein sequence causes folding; in addition, there is the other basic driving factor of protein folding, hydrophobic interactions between hydrophobic amino acid groups of the protein sequence.

The folding process gives the protein its three dimensional structure. Complex proteins like antibodies, for example, are composed form a hetero-dimer of a light and a heavy chain. Thus four subparts are joined via disulfide[43] bonds to form a complex molecule.

The formation of disulfide bonds is a posttranslational modification and leads to structural changes in one protein chain or the joining and inter-connecting of two or more distinguished protein chains. External factors such as temperature, electric or magnetic fields and special limitations have an impact on protein folding and can cause mis-folding of the protein.

The assembly of proteins, either in the ER or the Golgi apparatus[44], creates a series of refinements, called posttranslational modification, which can include folding, cutting, joining and modifying of proteins to form the required variant (also called isoform) of the final protein.

Posttranslational modification of proteins can give the protein a manifold means to exercise its biological functions. Usually, biologically active groups are added to the protein such as acetate, phosphate[45], various lipids[46]and glycans.

Glycosylation is a post translational modification resulting from the addition of a carbohydrate (glycosyl) group to exposed amino acids, such as asparagine, cysteine, hydroxylysine, serine, threonine, tyrosine or ortryptophan.

For mAbs, the glycosylation is of major importance for its biological actions. The amount and complexity of glycosylation differs, which results in different isoforms for the same basic protein skeleton. This causes considerable weight differences and possible disparity in biological activity patterns. For example, the weight of mAbs (ca. 145 kDA, IgG) can vary by 1000 Dalton due to heterogeneity (40).

The effects of this glycosylation on Abs are manifold. The circulation rate of an Abs in the vascular system is largely influenced by its glycosylation; an increase of the degree of glycosylation (sial-groups) determines the decrease in the clearance rate. This results in better bioavailability[47]. The glycosylation also affects the effector function aspects of Abs. For example, antibody-dependent cellular cytotoxicity (ADCC) was shown to vary inversely with respect to the Ab’s glycosylation level.

“Rituximab was produced from Chinese hamster ovary (CHO) cells with a relatively high level of glycosylation and was found to be several-fold less cytotoxic[48] in vitro than another anti-CD20 mAb (KM3065), which was synthesized with fewer glycan residues from a rat cell line”. (41)

2.2.2 Variation in the biotechnology processes

Modern biotechnological processes have generated a wide range of novel products, including antibiotics, recombinant proteins, vaccines and monoclonal antibodies. Pharmaceutical biotechnology typically consists of cell banking, upstream (production) and downstream (separation/purification) operations.

2.2.2.1 Cell banking issues

Once the target gene is isolated and inserted into a suitable host cell for expression, a master cell bank is established. This cell bank will serve as the genetic source for all subsequent manufactured target proteins. However, technical issues are associated with creating stable cell lines that secrete the desired (i.e. previously inserted by recombinant DNA technology) target protein. (42)

Variation occurs between the different cells of the master cell bank due to genetic heterogeneity in the original cell line from which the master cell bank was derived, prior to insertion of the target gene.

“In addition to genetic heterogeneity, a significant fraction of total variation may arise from phenotypic differences between cells in each pure clone making up a pool. This, in turn, appears to result from random expression fluctuations in individual cells over time, as elegantly demonstrated in the landmark study of Sigal et al”. (43)

A biosimilar developer will not be able to reproduce the reference biologic 100%, including all is heterogeneity, as different cell lines will likely be used to manufacture the target protein.

“Particularly, transfection of the host cell represents a unique event which cannot be identically replicated – if done twice, the result would be a manufacturing cell line with different properties. The conditions used for cell fermentation will depend on the properties of the master cell bank and therefore cannot be identical for a second manufacturing process. In addition, the details of upstream and downstream manufacturing and the methods and criteria chosen for in-process analytics are not in the public domain and are therefore not known to a second, independent manufacturer”. (44)

2.2.2.2 Upstream issues

Upstream, the cells are thawed and multiplied in a series of volume increasing pre-cultures, after that they are transferred into the large scale production bioreactor. The final protein product is influenced by physico-chemical factors, such temperature, pH, osmolarity[49], CO2, O2 saturation and oscillation rate of the propeller, operation related factors, such as the type and mode of operation of the bioreactor (including the time in which the biopharmaceutical process is conducted in the bioreactor) and chemical factors derived from the cell culture media such as growth factors, carbohydrates, essential metals and vitamins, all affect the finial protein product.

At this stage, those external factors influence the cells during their division and protein expression phases. As mentioned in section: 2.2.1 Heterogeneity of biologics (proteins only), this influences the protein formation and its subsequent post translational modifications. The importance of this was already discussed in the example of mAbs.

“Cell stress can lead to aberrant glycosylation, protease activity, protein truncation, disulfide shuffling, and the release of undesirable by-products and cellular wastes”. (45)

2.2.2.3 Downstream issues

The aim of downstream processing is to bring the target protein through progressive refinement steps to the required purity and concentration level. The harvesting process is initiated, depending on the type of bioreactor and the mode of operation, when certain key parameters are reached. The cells and supernatant (i.e. the remaining media) are separated and either the media or cell part is discarded, depending on whether the target protein is extracellularly or intracellularly expressed.

The target protein is further purified by adsorption, ultra-filtration and precipitation in order to reduce the volume and to increase the concentration of the target protein. Further purification of the bio-product can be achieved through a series of separation techniques that rely on the unique physico-chemical properties of the target protein, for example, affinity-, size exclusion- or HPLC-chromatography. These chromatography steps may be altered by ultra-filtration steps to exchange buffer and/or to increase the concentration of the target protein. These separation techniques aim to separate process related proteins from the host cell (different form the target protein), host cell DNA and other impurities will be present.

However, the uniqueness of the separation cascade will most likely result in the creation of a unique product, from the point of view of the isoform composition. Any change in the purification process can alter the purity of the product. (46)

Additional variation occurs in the target protein during downstream processes such as oxidation and de-amination. Of equal concern is the formation of protein aggregates, which have a major impact on the bioavailability and immunogenicity of the medicinal product and degradation of the target protein. (41, 45)

For the production of the active substance into the medical product, there are usually excipient and additives added to the formulation. At that stage issues may occur, as the additives can impact the safety profile.

“Initial analyses of a biosimilar’s active ingredient may indicate acceptable similarity to the reference molecule, but the final product formulation may reveal potential risk factors. Absorption spectra of different formulations of similar products can reveal differences between them and identify chemicals and impurities that may have leached into the formulation”. (40)

2.2.2.4 Storage and stability issues

Final processing ends with conserving and packaging the target protein in a stable form that is easily transportable and convenient. Crystallization through lyophilisation is commonly used. However, some bio-products may be frozen in their buffer, or are aseptically processed and sterilely filtered. Once reconstituted and made ready for use (i.e. finial medicinal product), the stability is an issue, and the medicinal product is affected by environmental factors, and must be stored and transported under optimal conditions.

“A biopharmaceutical from the same manufacturer may also degrade at different speed and at different conditions due to inadequate control of the production process. Decreased stability in comparison with the reference product may either be due to an unstable formulation or an active ingredient”. (40)

2.2.3 The biologics life cycle

Broadly outlined, the biologics life cycle follows the life cycle of any other medical product. In the past, the one main difference was that there were practically no follow on versions (biosimilars) available, as there are in the case of innovator chemical medical products produced by generic companies. The generic industry could not simply copy a biologic like it did for small drug using only pharmacopeia specification. The complexity of biologic does not allow such an approach.

The life cycle of a biologic starts with a R&D phase, were the entity is discovered, and the proof of principles and concepts is performed.

In the next stage, the product and the process are developed. Usually, the process is successively scaled up, which often involves the usage of different processes and equipment. During that phase of the process, understanding, a prerequisite for a successful process validation, is generated.

In parallel, the pre-clinical testing kicks off, this compromises of animal studies to toxicity studies, as well as studies of pharmacological effects through in vitro and in vivo laboratory animal testing. Genotoxicity testing is carried out as well as investigations on the absorption and metabolism rates.

Then, when the process is running at a pilot plant level with controls on parameters relevant for patient safety, such as virus inactivation steps, filtration steps and quality control tests, for example, for endotoxines; the phase I studies are initiated with healthy volunteers. The main aim is to prove the basic safety of the product. Potential immunogenic complications are assessed, and some metabolical testing is carried out.

During p hase II, the clinical trials consist of controlled clinical studies intended to answer particular questions on the effectiveness of the biologic.

In phase III, the process should be at a commercial scale, which is ready to be validated. Usually, concurrent to phase III, the validation process is carried out. Phase III trials are intended to gather additional information about the effectiveness and safety, and to contribute data to evaluate the benefit-risk of the biologic.

The time frame to obtain a MA can cover many years, refer also to section: 1.2.1.1 Outline of a biologics life cycle.

For example, the discovery and development process for Avastin (bevacizumab) from Roche (a mAb for cancer indication) took many years, as follows:

- After isolation of the vascular endothelial growth factor (VEGF) an anti-VEGF antibody was published in 1993.
- In 1996 the mAb was humanized (modified to be less immonugenetic).
- In 1997 an investigational new drug application for this antibody was submitted to the FDA, and a phase I trial for bevacizumab began in 1997.
- Phase II started in 1998.
- Phase III started in 2000.
- In February 2004, the FDA approved bevacizumab as the first anti-angiogenic drug for treating cancer, 15 years after the first isolation of VEGF. (47)

Upon successful approval by a regulatory authority, the commercial phase of a medicinal product begins. This is an area that is more relevant to the topic of this research. During its lifecycle, the biologic may change its quality profile. In fact one may distinguish between:

1) Normal lot to lot variability, due to the heterogeneity of the biologic itself and minor process variation (fluctuation). This normal variability is covered through the MA authorisation.
2) Factor dependent variation that leads to a more significant change of a biotechnological process. This can be due to inspection outcome, changes in equipment, shortages of a certain raw material, closedown of a facility and process transfer to another facility or process improvements, etc., the process might change.

It is well known that these changes need to undergo regulatory approval and require a comparability exercise in the case of biologics. The extent of the comparability exercise depends on the scope of the change and the complexity of the biologic itself. It has been argued that, “these changesmay lead to differences just as they occur in independently manufactured biosimilar products”. (44)

For example (21), it was reported that innovator companies may also fail comparability exercises required by the FDA in the case of a product transfer.

“The FDA ruled that the Genzyme’s Myozyme (alglucosidase alfa) treatment for Pompe disease produced at its facility in Allston, MA, was actually a different product than its Myozyme product already registered and produced at its facility in Framingham, MA. The agency determined that because of “differences in the biological signature of the active molecule” and concerns about how the protein is glycosylated, the same drug produced in two facilities within the same company were in fact not “similar””. (21)

2.2.4 Discussion

As outlined above, heterogeneity will result from complex biological processes, but is also interlinked to the environment, which stands for certain process conditions, for example. Heterogeneity can result from the manufacturing process and/or storage of the product.

“The pattern and variability of protein microheterogeneity will depend on the way how the protein is manufactured. Not all of these variations will have an impact on the clinical safety and efficacy profile, but since only a limited number of attributes can be assessed analytically, one cannot assume a priori that proteins which are produced using different processes have identical properties”. (44)

Thus, it is required to characterize all isoforms of a biologic, and degradation products should be well characterized. If the process is altered or degradation products change, the quality profile should be compared to the original pre-change product. The example, the glycosylation level of mAbs has a major influence on the receptor binding (Fc-Receptor binding), protein protein interaction (Ab-Antigen interaction) and pharmacokinetics of the protein substances (circulation time defining its half-life and therefore its bioavailability). By that, mAbs immune effector functions, such as antibody-dependent cellular cytotoxicity (ADDC), which is a major mechanism of action, are influenced, refer also to section: 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 and section: 4.4 Discussion when discussing the impact of those minor differences, which occur during the life-cycle.

Variation, as described above, is mainly related to the process, and possibly even more so, to the downstream process during which the purification occurs. For example, the employed cascade to purify the protein of interest may be unique and difficult to replicate, especially when taking the raw materials, which are required for that purification cascade, into account.

However, prior to discussing the impact of heterogeneity and variation one needs to become clear on how this relates to the research questions, and this requires a discussion of how this heterogeneity and variation can be viewed, and the resulting issues, when interpreting regulatory guidance documents. The summary of analyzable heterogeneity and variation forms what is called a quality profile.

However, there are undoubtedly two aspects to consider:

1. The quality profile of a batch: the quality profile of a batch is fixed and analyzable.
2. The quality profile of a biologic: the quality profile of a biologic is dynamic in time as the summary of the quality profiles of all batches, and is therefore not fully analyzable.

Refer to section: 4.3.2 Results from the questions and comments submitted to EMA, when discussing those aspects.

“It should be emphasized that batch-to-batch variations are unavoidable even with well-controlled, consistent protein manufacturing procedures and are acceptable within the limits defined by the specifications, but usually they are much smaller than differences between products made by totally different manufacturing processes”. (44)

This implies that there is not only within one batch level presence of variation and heterogeneity (isoforms and impurities for example); an even more complex situation raises where the degree and possible nature of heterogeneity and variation between batches varies (different ratio and identity of isoforms and different ratio and identity of impurities).

This results in variable quality profiles, when considered on a life cycle bases, with possibly different ratios and glyco-forms of the protein of interest (isoforms). As outlined above, the impact of even small structural differences can be clinically relevant. For example, differences in the glycosylation can affect the efficacy of a biologic, by influencing the mode/intensity of the action between molecules and their circulation time, as outlined above.

It is important for the conceptual understanding of the research question to understand this notion.

One result of heterogeneity and variation is the influence on the safety profile. Biologics as bio-molecules have the inherent risk of causing immune responses, either against the protein based active substance (including all its isoforms) or against an impurity or added excipient.

2.3 Screening the above presented literature related to current biosimilar regulation with regard to the research questions

The regulatory literature was selected based on Figure: 3 in section: 2.1.2 Regulatory guidance literature. All overarching and general guidance literature was reviewed with regard to text passages relevant for the research questions of this thesis:

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 ofEMA/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 in order to show comparability?
2.2 Under what circumstances 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?

This also included concept papers and draft guidance. Further, one product specific guide was reviewed, EMA/CHMP/BMWP/403543/2010 Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues (48). The reason for this is that the product specific guide was for the latest adopted biosimilar guide from EMA. Questions and comments were submitted to the EMA for this guide as part of this thesis and the contents of the guide itself are very relevant for the research questions.

Other product specific biosimilar guides were not included in this literature review, since the burden to review them was judged to be too extensive.

Directly after the selected text passage, comments and conclusions from the author were made. The headlines of the selected sections were then grouped and ordered in a table. Subsequently the findings were briefly summarised and discussed as part of Chapter 4.0: Main research question for research question 1, Chapter 5.0: What should be the scope of trials? for research question 2 and

Chapter 6.0: Why is extrapolation of indications for biosimilar controversial? for research question 3.

2.3.1 Guideline on similar biological medicinal products CHMP/437/04 (49)

General comment:

In the context of the surrounding biosimilar documentation, this guidance document can be considered as lacking clarity. Most aspects deal with the quality profile and are of utmost importance for a successful biosimilar development program.

Emphasis is also put on characterisation whereas in other documents it is fully acknowledged that biologics can rarely be fully characterised, given the complexity and structural differences between large biologics such as proteins or even vaccines, which are not mentioned as part of recent EMA legislation.

Same reference material:

There is a section requiring that during the whole comparability exercise, the “same reference product” should be used for all three parts of the dossier, i.e. quality, safety and efficacy.

This is not possible as a development program can take years to be performed and the quality profile of the reference biologic can change at any stage without any influence from the biosimilar developer.

Conclusion/Comment:

It shows that the reference will change in the foreseeable future, but maybe those changes are considered to lead to a similar clinical outcome. If so, then, depending on the complexity of the biologic in question, that approach is likely to fail.

There is no guarantee that this approach is feasible for the future, and likely clinical comparability for more complex biologics will fail or is going to require multiple and repeat trials as data might not be fully conclusive.

Heterogeneity and variation:

As biologics are variable and the EMA acknowledges this variability, EMA argues that the success of a biosimilar program is based on the ability to characterise and reference the biosimilar; and therefore, show the similar nature of the products concerned. This was partially outlined in the sentence below:

In principle, the concept of a “similar biological medicinal product” is applicable to any biological

medicinal product. However, in practice, the success of such a development approach will depend on the ability to characterise the product and therefore to demonstrate the similar nature of the concerned products”.

This is also confirmed in the recent draft for the quality guide: 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), for example. However, the EMA acknowledges in the same guide the difficulties encountered to characterise a biologic in 2004 by mentioning:

“Biological medicinal products are usually more difficult to characterise than chemically derived

medicinal products. In addition, there is a spectrum of molecular complexity among the various

products (recombinant DNA, blood or plasma-derived, immunologicals, gene and cell-therapy, etc.)”.

Conclusion/Comment:

This represents a good example of regulatory requirements as they are laid down in a formal way and subsequently when faced with reality/nature, adaptation and sensible flexibility is required by the regulator. The extent of similarity is, and will remain, difficult to be described.

Changes (issue of dynamic of the quality profile) during the life cycle:

With regard to the life cycle EMA also acknowledges early that, “changes can impact on the three-dimensional structure, the amount of acido-basic variants or post-translational modifications such as the glycosylation profile”.

Conclusion/Comment:

The term “changes” reflects the words ‘heterogeneity’ and ‘variation’ employed in this thesis, based on my understanding when reading the context. Interestingly, EMA employed the term ‘change’, which, in the regulatory context, comes from a situation where a M.A. is already issued for a medicinal product and something potentially impacting quality, safety or efficacy changes (usually a process change). This may reflect the EMA’s limited experience with biosimilars at the time, and the similarity to the guidance related to the comparability exercise, refer to section: 2.1.2 Regulatory guidance literature.

“Those changes which may initially be considered to be ‘minor’ in the manufacturing process. Thus, the safety/efficacy profile of these products is highly dependent on the robustness and the monitoring of quality aspects”.

Highly purified products:

The EMA outlines further that:

“Due to the complexity of biological/biotechnology-derived products the generic approach is scientifically not appropriate for these products. The “similar biological medicinal products” approach, based on a comparability exercise, will then have to be followed.

– Comparability exercises to demonstrate similarity are more likely to be applied to highly purified products, which can be thoroughly characterised (such as some biotechnology derived medicinal products)”.

Conclusion/Comment:

The term ‘highly purified’ needs to be set in the context of the research question as being very arguable and misleading. In later guidance, the EMA requires a thorough evaluation and discussion. In situations where the biosimilar is more or less pure refer to Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Quality issues (revision 1) Draft

EMA/CHMP/BWP/247713/2012. Surprisingly, EMA’s guide was only updated in 2013.

EMA even though puts emphasis on the analytical characterisation and mentions it as a prerequisite for highly purified protein, it is also recognised that the fact that each biologic has its particularities is due to normal heterogeneity and variation. Therefore, it is written in the EMA guide that:

Highly purified products:

“It should be recognised that, by definition, similar biological medicinal products are not generic medicinal products, since it could be expected that there may be subtle differences between similar biological medicinal products from different manufacturers or compared with reference products, which may not be fully apparent until greater experience in their use has been established”.

Conclusion/Comment:

In the situation when dealing with references biologics, which themselves are not highly pure, the notion of ‘high purity’ and biologics is in this context is that only one isoform or sub type of molecule is being dealt with, is contradicted by other the EMA documents Guideline on comparability of medicinal products containing biotechnology derived proteins as active substance: Quality issues EMEA/CPMP/BWP/3207/00 and Concept paper on the revision of the guideline on similar biological medicinal product EMA/CHMP/BMWP/572643/2011.

Comparability exercise:

The EMA outlines in this overarching guide again the import factors for the success of the biosimilar approval.

1. Analytical procedures
2. The manufacturing processes
3. Clinical and regulatory experiences

Conclusion/Comment:

None

Clinical aspects:

The clinical aspect is then further outlined:

“The requirements to demonstrate safety and efficacy of similar biological medicinal products have to comply with the data requirements laid down in Annex I to Directive 2001/83/EC”.

Conclusion/Comment:

These aspects should be understood in conjunction with other documents, refer to Guideline on comparability of medicinal products containing biotechnology derived proteins as active substance: Quality issues EMEA/CPMP/BWP/3207/00 and Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues EMEA/CHMP/BMWP/42832/2005. In other words, EMA expects the safety and efficacy to be comparable within margins of tolerance, but does not expect proof of safety or efficacy per se, as this was already proven by the reference biologic itself.

Other aspects:

It was also announced in this guide that EMA would issue product-class specific guidance.

illustration not visible in this excerpt

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

The guide on comparability, “Guideline on comparability of medicinal products containing biotechnology derived proteins as active substance”, came into effect in 2003.

Highly purified proteins:

The reference is to highly pure molecules (as in section: 2.3.1 Guideline on similar biological medicinal products CHMP/437/04) and the consistency that forms between batches.

Conclusion/Comment:

Both are achievable only when giving them biologically meaningful margins. However they remain ideals, barely achieved.

The guide also mentions that the main tasks will be to establish to what extend the analytical methods used are able to detect any slight modification possibly introduced by the change.

This is an issue for biosimilars too. Mainly because after the initial approval of the reference biologic, many years will elapse and the analytical methods will be more evolved, thus always detecting differences within the quality profile of biologics. In cases where no differences are detected, the method’s sensitivity should be questioned.

On the other hand, those differences in the quality profile have an impact on the clinical outcome. This answer remains open and is further analysed using the questionnaire, refer also to section: 4.3.3 Results from the survey research method. (50)

Comparability in relation to isoform ration/process changes for an already approved biologic:

The “Guideline on comparability of medicinal products containing biotechnology derived proteins as active substance” mentions there is a case to consider conducting comparability studies when seeking a marketing authorization for a biotechnology derived product claimed to be similar to one already authorised.

Conclusion/Comment:

This aspect needs to be considered in context, if, for example, the production process of the innovator biologic changes, for example, the production site changes. In principle, biosimilar production could be regarded as a similar case. However, the change it represents to the production process is still reasonably considered as being of a lower impact compared to the change the biosimilar itself represents, compared to the reference biologic.

However, from a life-cycle perspective this guide outlines the requirements for changes in the production process of an approved biologic. The comparability exercise principles apply to both the biosimilar and the reference biologic.

Five stages were mentioned for conducting the comparability exercise:

1) Characterisation studies
2) Validation manufacturing process
3) Release data
4) Stability data
5) Clinical and preclinical studies

The definition of a comparability exercise is outlined in the guide as the follows: “Comparability is the exercise that will demonstrate that two products have similar profile in terms of quality, safety and efficacy”. It has already been outlined that, possibly next to quality data, clinical data might be required.

Conclusion/Comment:

As outlined in section: 2.1.2 Regulatory guidance literature, the complexity of the molecular entity should be considered as a major criterion when discussing the comparability.

The guide mentions one particular train of thought worth mentioning as directly relevant to the thesis:

“In many cases due to inherent variability of the biotechnological process, the end-product consists of a complex mixture of molecules (product-related substances). This heterogeneity, which is taken into account when assessing the in-vivo behaviour of the product should be characterised to assure batch to batch consistency”.

Conclusion/Comment:

This can be interpreted as the ratio of the isoform that should be consistent over batches, refer to section: 4.1 Introduction. During the life-cycle of a biologic, heterogeneity and variation always occur; however, the overarching biosimilar guide (49) does as well as this guide does in not satisfactorily acknowledging the fact and does not reflect the biological realities. (50)

Clinical trials and comparability exercise depend on:

The 3rd chapter of the guide mentions that the process is different and comparing to public standards is not sufficient. Thus, an extensive comparability exercise is required. The extent of pre-clinical and/or clinical testing need to be considered with regard to the complexity of the biopharmaceutical itself, as well being based on possible differences in the reference biologic itself; from the point of view of this thesis, those differences require a thorough investigation.

The following factors should be taken into account for a comparability exercise:

1) The complexity of the molecules
2) The type of changes in the process
3) Their impact on quality, safety and efficacy

Conclusion/Comment:

It is acknowledges that each individual situation requires a step-by-step approach. However, the way in which the guidelines were formulated does not apply to all the potential issues. This statement could be judged as a backdoor for discussion with EMA in cases where the limitations of the comparability exercise were reached, which cannot be excluded. (50)

Table: 4

Summary of Guideline on comparability of medicinal products containing biotechnology derived proteins as active substance: Quality issues EMEA/CPMP/BWP/3207/00 (50) with regard to the research question of this thesis.

illustration not visible in this excerpt

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)

Immunogenecity:

There is also a guide for the comparability exercise with regard to clinical and non-clinical issues available. Biosimilars were mentioned as well. The main concern was on safety and immunogenicity with regard to biosimilars.

However, there were no requirements outlined for efficacy. Input or discussion on clinical trial requirements impacting clinical trial size were not detected. Thus, this guide remains of a more abstract nature with regard to the research questions of this thesis.

Conclusion/Comment:

None

Table: 5

Summary of Guideline on comparability of medicinal products containing biotechnology-derived proteins as active substance: Non-clinical and clinical issues EMEA/CPMP/3097/02/Final (51) with regard to the research question of this thesis.

illustration not visible in this excerpt

[...]


[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/

[30] CHMP:

The Committee for Medicinal Products for Human Use (CHMP) is the committee at the European Medicines Agency that is responsible for preparing opinions on questions concerning medicines for human use. http://www.emea.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000094.jsp&mid=WC0b01ac0580028c79

[31] Omnitrope:

Generic Name – somatropin

Omnitrope is a form of human growth hormone. http://www.drugs.com/omnitrope.html

[32] Recombinant:

Relating to or denoting an organism, cell, or genetic material formed by recombination: the DNA of these recombinant viruses revealed no signs of instability, according to Oxford Online Dictionary.

[33] Hydrophobic interactions:

Another type of attraction is that between nonpolar side chains of valine, leucine, isoleucine and phenylalanine; the attraction results in the displacement of water molecules and is called hydrophobic interaction. Britannica Academic Edition.

[34] Van der Waals forces:

Weak, short-range electrostatic attractive forces between uncharged molecules, arising from the interaction of permanent or transient electric dipole moments, according to Oxford Online Dictionary.

[35] Ionic bond:

Also called electrovalent bond, type of linkage from the electrostatic attraction between oppositely charged ions in a chemical compound. Britannica Academic Edition.

[36] Bioreactor:

An apparatus in which a biological reaction or process is carried out, especially on an industrial scale, according to Oxford Online Dictionary.

[37] http://www.it-asso.com/gxp/eudralex_v21/contents/vol-4/pdfs-en/anx02en200408.pdf

[38] Intron:

A segment of a DNA or RNA molecule which does not code for proteins and interrupts the sequence of genes. Oxford Online Dictionary.

[39] 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.

[40] Cytosol:

The aqueous component of the cytoplasm of a cell, within which various organelles and particles are suspended, according to Oxford Online Dictionary.

[41] Endoplasmic reticulum (ER):

A continuous membrane system that forms a series of flattened sacs within the cytoplasm of a eukaryotic cell and is important in the biosynthesis, processing and transport of proteins and lipids. Britannica Academic Edition.

[42] Peptide:

A compound consisting of two or more amino acids linked in a chain, the carboxyl group of each acid being joined to the amino group of the next by a bond of the type –OC-NH-. Oxford Online Dictionary.

[43] Disulphide; A sulphide containing two atoms of sulphur in its molecule or empirical formula. Oxford Online Dictionary.

[44] Golgi apparatus:

Membrane-bound organelle of eukaryotic cells that is made up of a series of flattened , stacked pouches called cisterne. Britannica Academic Edition.

[45] Phosphate: A salt or ester of phosphoric acid, containing PO43− or a related anion or a group such as OPO(OH)2. Oxford Online Dictionary.

[46] Lipid: Any of a class of organic compounds that are fatty acids or their derivatives and are insoluble in water but soluble in organic solvents. They include many natural oils, waxes, and steroids. Oxford Online Dictionary.

[47] Bioavailability: The proportion of a drug or other substance which enters the circulation when introduced into the body and so is able to have an active effect., according toOxford Online Dictionary.

[48] Cytotoxic: Toxic to living cells, according to Oxford Online Dictionary.

[49] Osmolarity:

The concentration of a solution expressed as the total number of solute particles per liter, according to Oxford Online Dictionary.

Details

Pages
254
Year
2013
ISBN (eBook)
9783656517382
ISBN (Book)
9783656517399
File size
3.9 MB
Language
English
Catalog Number
v262089
Institution / College
Dublin Institute of Technology – Chemistry
Grade
1 st CLASS HONS
Tags
Biosimilar quality profile life cycle CMC EMA clinical trials

Author

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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