1. Biosimilars & EU regulation
Alice DOMINIQUE - M2 AREIPS

2. Content
Definitions 1
Regulation in EU 2
Biosimilars in practice 3

3. Definitions

4. What is a biological medicine ?
Biological medicine = Biologic medical product
= Biological
= Biologic
Medicine made by or derived from a biological source (human, animal or microorganism), using biotechnology
Active substance larger and more complex than chemical medicine
 Degree of variability
Examples : d
Medicines that are made by or derived from a biological source (human, animal or microorganism)
The active substances of biological medicines are larger and more complex than those of non-biological medicines
Their exact characteristics are subject to inherent variability
Examples of biopharmaceuticals : 
Vaccines
blood and blood products
allergenic extracts
human cells and tissues used for transplantation
gene therapies
cellular therapies
Vaccines
Blood and blood products
Allergenic extracts
Gene therapies
Human cells and tissues used for
transplantation
Cellular therapies

5. What is a biosimilar ? Similar biological = biosimilar medicine
A biological medicine developed to be similar to an existing biological medicine that has already been authorized for use. (‘Reference medicine’)
Active substance: essentially the same
But minor differences due to their complex nature and production methods
 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
A similar biological or 'biosimilar' medicine is a biological medicine that is similar to another biological medicine that has already been authorised for use. Biological medicines are medicines that are made by or derived from a biological source, such as a bacterium or yeast. They can consist of relatively small molecules such as human insulin or erythropoietin, or complex molecules such as monoclonal antibodies.
Biosimilars can only be authorised for use once the period of data exclusivity on the original 'reference' biological medicine has expired. In general, this means that the biological reference medicine must have been authorised for at least 10 years before a similar biological medicine can be made available by another company.
A biosimilar medicinal product and its reference medicinal product are expected to have the same safety and efficacy profile
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.

6. Biosimilars ≠ Generics
PROPERTIES
GENERICS
BIOSIMILARS
SIZE
Small
Large
MOLECULAR WEIGHT
< Daltons
4000 to >140,000 Daltons
STRUCTURE
Simple and well-defined
Complex with potential structural variations
MANUFACTURING
Predictable chemical process to make identical copy
Specialized biological process to make similar copy
COMPLEXITY
Easy to fully characterize
Difficult to characterize due to heterogeneity
APPROVAL REQUIREMENTS
Quality information
+ Bioequivalence
Full quality dossier
+ Comparability exercise (quality, safety, efficacy)
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.

7. EU Regulation

8. Regulation in EU EU = first region to have set up a legal framework
Concept of biosimilar adopted in EU legislation in 2004
Directive 2001/83/EC, as amended by Directive 2003/63/EG and Directive 2004/27/EC
First biosimilar medicine : approved by the EC in 2006
Marketing authorisation application: Centralised Procedure
Only authorized once the period of data exclusivity has expired
EU = first region to have set up a legal framework
Concept of biosimilar adopted in EU legislation in 2004
Directive 2001/83/EC, as amended by Directive 2003/63/EG and Directive 2004/27/EC
First biosimilar medicine : approved by the EC in 2006
Marketing authorisation applications: reviewed centrally by the EMA
Can only be authorized for use once the period of data exclusivity on the original 'reference' biological medicine has expired
Guideline : This document outlines the general principles to be applied for similar biological medicinal products (also known as biosimilars). It describes and addresses the application of the biosimilar approach, the choice of the reference product and the principles for establishing biosimilarity.
With the legal framework for biosimilar medicines established, the EMA, together with the Committee for Medicinal Products for Human Use (CHMP), the Biotechnology Working Party (BWP) and the Working Party on Similar Biological Medicinal Products (BMWP), released specific guidelines to deal with all aspects of the development, production, testing and regulation of biosimilar medicines. This was done after consultation with all the relevant stakeholders, which include national regulatory bodies, scientific advisory groups, industry, clinicians, and patient groups.
The initial guidelines, published in 2005 and 2006, comprised an overarching guideline as well as other more general guidelines concerning the product quality, clinical
| EMA building in London
and non­clinical issues. These guidelines have been revised according to the latest views of the regulators which have evolved based on the scientific and technological developments as well as on experience gained in the past ten years since the first biosimilar products became available for EU patients.
In addition, product­ specific guidelines listing the non­clinical and clinical requirements are also available, and the EMA is in the process of developing additional guidelines as well as revising existing ones (for more information, please see appendix 1).

9. EMA guidelines relevant for biosimilars
OVERARCHING BIOSIMILAR MEDICINES GUIDELINES
General
Quality
Non­clinical and Clinical
PRODUCT-SPECIFIC BIOSIMILAR MEDICINES GUIDELINES
Recombinant human insulin and insulin analogues
Somatropin
G­CSF
Recombinant erythropoietins
Low-molecular-weight heparins
Interferon IFN­β
FSH
Monoclonal antibodies
Guideline : This document outlines the general principles to be applied for similar biological medicinal products (also known as biosimilars). It describes and addresses the application of the biosimilar approach, the choice of the reference product and the principles for establishing biosimilarity.
With the legal framework for biosimilar medicines established, the EMA, together with the Committee for Medicinal Products for Human Use (CHMP), the Biotechnology Working Party (BWP) and the Working Party on Similar Biological Medicinal Products (BMWP), released specific guidelines to deal with all aspects of the development, production, testing and regulation of biosimilar medicines. This was done after consultation with all the relevant stakeholders, which include national regulatory bodies, scientific advisory groups, industry, clinicians, and patient groups.
The initial guidelines, published in 2005 and 2006, comprised an overarching guideline as well as other more general guidelines concerning the product quality, clinical
| EMA building in London
and non­clinical issues. These guidelines have been revised according to the latest views of the regulators which have evolved based on the scientific and technological developments as well as on experience gained in the past ten years since the first biosimilar products became available for EU patients.
In addition, product­ specific guidelines listing the non­clinical and clinical requirements are also available, and the EMA is in the process of developing additional guidelines as well as revising existing ones (for more information, please see appendix 1).

10. Biosimilars authorised in EU
ACTIVE SUBSTANCE
BIOSIMILAR
MARKETING AUTHORISATION HOLDER
AUTHORISATION DATE
REFERENCE MEDICINAL PRODUCT
NATURE
SOMATROPIN
Omnitrope®
Sandoz
12/04/2006
Genotropin®
Human Growth Hormone
EPOETIN
Abseamed®
Medice
28/08/2007
Eprex®
Erythropoeitin
Binocrit®
Epoetin Alfa Hexal®
Hexal
Retacrit®
Hospira
18/12/2007
Silapo®
Stada
FILGRASTIM
Ratiograstim®
Ratiopharm
15/09/2008
Neupogen®
G-CSF
Tevagrastim®
Teva
Biograstim®
AbZ-Pharma
Filgrastim Hexal®
06/02/2009
Zarzio®
Nivestim®
08/06/2010
Grastofil®
Apotex
18/10/2013
Accofil®
Accord Healthcare
18/09/2014
INFLIXIMAB
Inflectra®
10/09/2013
Remicade®
Monoclonal antibody
Remsima®
Celltrion
Flixabi®
Samsung Bioepis
26/05/2016
FOLLITROPIN ALFA
Bemfola®
Finox Biotech
27/03/2014
Gonal-ff®
FSH
Ovaleap®
27/09/2013
INSULIN GLARGINE
Abasaglar®
Eli Lilly
09/09/2014
Lantus®
Insulin
ETANERCEPT
Benepali®
14/01/2016
Enbrel®
TNF inhibitor
ENOXAPARIN SODIUM
Inhixa®
Techdow Europe AB
15/09/2016
Clexane®
Low molecular weight heparin
Thorinane®
Pharmathen S.A. 23

11. How to demonstrate biosimilarity?
Similarity to the reference medicinal product in terms of:
 based on a comprehensive comparability
Similar active substance, in molecular and biological terms
For example: for a protein, same amino acid sequence
Same posology and route of administration
Deviations from the reference product as regards strength, pharmaceutical form, formulation, excipients or presentation require justifications
Any difference should not compromise safety
Intended changes to improve efficacy are not compatible with the biosimilarity approach.
quality characteristics
biological activity
safety
efficacy
Similarity to the reference medicinal product in terms of:
quality characteristics,
biological activity,
safety
efficacy
based on a comprehensive comparability
The Marketing Authorisation (MA) application dossier of a biosimilar medicinal product shall provide:
a full quality dossier (module 3)
together with data demonstrating comparability with the reference medicinal product by using appropriate physico-chemical and in vitro biological tests, non-clinical studies and clinical studies.
Similar active substance, in molecular and biological terms
For example, for an active substance that is a protein, the amino acid sequence is expected to be the same.
Same posology and route of administration
Deviations from the reference product as regards strength, pharmaceutical form, formulation, excipients or presentation require justification. If needed, additional data should be provided. Any difference should not compromise safety.
Intended changes to improve efficacy (e.g. glycooptimisation) are not compatible with the biosimilarity approach.

12. Marketing Autorisation application dossier
Full quality dossier (module 3)
A stepwise comparability exercise
First Step : Quality Comparability (physicochemical and biological comparability)
Second Step : Non-Clinical Comparability (Comparative non-clinical studies)
Multiple in vitro studies
In vivo studies in exceptional cases
Third Step : Clinical Comparability (Comparative clinical studies)
Comparative pharmacokinetic / pharmacodynamic, efficacy and safety studies
Pharmacovigilance
Risk Management Plan (RMP)
Biosimilar medicinal products are systematically developed to be highly similar to the reference medicinal product with regards to quality, safety, and efficacy. The biosimilar development is started with the definition of the molecular characteristics and quality attributes of the target product profile of the biosimilar medicinal product and its comparability with the reference medicinal product.
This is followed by a comparability exercise performed in several steps:
first step - quality comparability (physicochemical and biological comparability)
second step - non-clinical comparability (comparative non-clinical studies)
third step - clinical comparability (comparative clinical studies)
Quality comparability is established with regard to the molecular structure as well as with regard to the functionality and must be demonstrated with comprehensive analytical characterisation, relevant receptor binding studies and bioassays, all to be performed with the biosimilar and the reference medicinal product in a rigorous comparative manner.
The non-clinical and clinical comparability then provides the confidence that any differences observed at the quality level have no impact on the safety and efficacy of the biosimilar medicinal product when compared to the reference medicinal product.
The comparability exercise is consequently based on a robust head-to-head comparison between the biosimilar and the reference medicinal product at the levels of quality, safety and efficacy.
Every biosimilar medicinal product application is assessed on an individual basis.

13. Biosimilars in practice

14. Why do we use biosimilars?
In EU, in 2014 : 7/10 of the most sold medicines
Biological costs > Chemical medicines costs
Biosimilars:
More cost-effective alternative
Offer a major opportunity to provide greater access to affordable healthcare
Difficult production methods
Supply difficulties
Stock-outs
In 2014 in Europe 7 out of 10 of the most sold medicinese were biologicals
Cout bien superieur à celui des medicaments chimiques
Moindre couts
Biosimilar medicines offer a major opportunity to provide greater access to affordable healthcare
Production delicate des biologics  difficultés approvisionnement  marché moins sensible aux tensions, ruptures de stocks

15. Interchangeability EMA:
Medical practice of changing one medicine for another that is equivalent, in a given clinical setting on the initiative, or with the agreement of the prescriber
EMA:
Decisions on interchangeability :
Outside its remit
No recommendations
Rely on national competent authority
For questions related to switching from one biological medicine to another, patients should speak to their doctor or pharmacist
Medical practice of changing one medicine for another that is equivalent, in a given clinical setting on the initiative, or with the agreement of the precriber
The EMA evaliates biosimilar medicines for authorisation purposes. The Agency’s evaluations do not include recommendations on whether a biosimilar should be used interchangeably with its reference medicine. For questions related to switching from one biological medicine to another, patients should speak to their doctor or pharmacist
The decisions on interchangeability and/or substitution rely on national competent authorities and are outside the remit of EMA/CHMP. Member States have access to the scientific evaluation performed by the CHMP and all submitted data in order to substantiate their decisions.
Fimeas ( Finnish Medicines Agency: “Biosimilars are interchangeable with their referenc products underthe supervision of a health care person”
ANSM: Si le choix entre 2 medicaments biologiques reste libre en l’absence de traitement antérieur identifié, il n’est pas souhaitable, pour des raisons de sécurité et de traçabilité, de modifier la prescription initiale
Au vu de l’évolution des connaissances et de l’analyse continue des données d’efficacité et de sécurité des médicaments biosimialires au sein de l’UE, il ressort qu’une posiriton excluant formellement toute interchangeabilité en cours de traitement n’est plus justifiée

16. Interchangeability ANSM: FIMEA:
According to the evolution of the knowledge and the continuous analysis of efficiency and safety data of biosimilars in EU, it appears that a position excluding formally any interchangeability during the treatment is no longer justified
But, for security and traceability reasons it’s not recommended to modify the initial prescription
Medical practice of changing one medicine for another that is equivalent, in a given clinical setting on the initiative, or with the agreement of the precriber
The EMA evaliates biosimilar medicines for authorisation purposes. The Agency’s evaluations do not include recommendations on whether a biosimilar should be used interchangeably with its reference medicine. For questions related to switching from one biological medicine to another, patients should speak to their doctor or pharmacist
The decisions on interchangeability and/or substitution rely on national competent authorities and are outside the remit of EMA/CHMP. Member States have access to the scientific evaluation performed by the CHMP and all submitted data in order to substantiate their decisions.
Fimeas ( Finnish Medicines Agency: “Biosimilars are interchangeable with their referenc products underthe supervision of a health care person”
ANSM: Si le choix entre 2 medicaments biologiques reste libre en l’absence de traitement antérieur identifié, il n’est pas souhaitable, pour des raisons de sécurité et de traçabilité, de modifier la prescription initiale
Au vu de l’évolution des connaissances et de l’analyse continue des données d’efficacité et de sécurité des médicaments biosimialires au sein de l’UE, il ressort qu’une posiriton excluant formellement toute interchangeabilité en cours de traitement n’est plus justifiée
FIMEA:
“Biosimilars are interchangeable with their reference products under the supervision of a health care person”

17. Conclusion

18. Conclusion Important sub-category of biologics
One the fastest growing segments of pharmaceutical industry
2014: worldwide sales ≈ US$200 billion
Importance in healthcare budget
Complex structure
Small differences can result in a significant impact on quality, safety & efficacy
Importance of legislation and harmonisation

20. Bibliography
Guideline on similar biological medicinal products CHMP/437/04 Rev 1, 2014
Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, EMEA/CHMP/BMWP/42832/2005 Rev1, 2014
Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1), EMA/CHMP/BWP/247713/2012 , 2014
Biosimilar medicines handbook, 3rd edition , The Biosimilar Medicines Group
État des lieux sur les médicaments biosimilaires, Mai 2016, ANSM