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International Regulatory Workshop:
Biotherapeutic Medicines – regulatory challenges and current
practices. Approaches for harmonization
Session 2: Biosimilars. Regulatory framework and quality
considerations – dynamics of international practices
Non-clinical evaluation of biosimilars
according to current EMA guidelines
Hans-Karl Heim
Non-clinical Assessor,
Federal Institute for Drugs and Medical Devices, Germany
Moscow, May 15, 2013
Disclaimer
Opinions and conclusions
presented on the following slides reflect
the personal view of the presenter
Outline
● Legal basis for marketing authorisation of
biosimilars in the EU
● Non-clinical evaluation of biosimilars in the EU
- General considerations
- Product-specific considerations
Biosimilars
Proposed definition (GL on similar biological medicinal products)
A biosimilar is a biological medicinal product that
contains a version of the active substance of an already
authorised original biological medicinal product
(reference medicinal product, RMP).
Based on a comprehensive comparability exercise, a
biosimilar demonstrates similarity to the RMP in terms
of
-quality characteristics
-biological activity
-safety and
-
Differences: Biosimilars vs (Chemical) Generics
Example: Biotechnology-derived Biosimilars
• Production process
recombinant DNA technology ↔ chemical synthesis
• Size and Complexity
large, high complexity ↔ small, low complexity
• Immunogenicity
potential antigen ↔ potential hapten
Biotechnology-derived proteins - Size
Chemical
Substance:
Acetylsalicylic
acid
MG = 180 Da
B-D Protein:
Erythropoietin
MG ≈ 30.000 Da ASA (red) placed on top of EPO (cyan)
for comparison
Biotechnology-derived proteins - Glycosylation
Glycosylation can further increase the structural and
functional complexity of B-D Proteins
One gene → one protein → many glycoproteins
Erythropoietin (EPO)
- Isoforms differing in glycosylation
Eur. Pharmacopoiea:
EPO standard
contains a family
of closely related
glycoproteins
Glycosylation - Possible relevance for efficacy and
safety of Biosimilars
Glycosylation pattern can modulate:
• Protein charge, folding and stability
• Binding affinity to receptors and other biomolecules
• Immunogenicity
• Pharmacokinetics incl. tissue distribution
Biosimilars – Importance of manufacturing process
Biosimilars are usually produced on basis of a complex
manufacturing process.
Even minor changes in the manufacturing process of a
biological may significantly alter relevant product
parameters such as
- post-translational modification (e.g. glycosylation)
- impurity profile
- immunogenicity etc.
Question:
Can a generic approach be used for
marketing approval of Biosimilars?
Legal Definition of Generics in the EU
Directive 2001/83/EC, Art. 10.2(b)
‘Generic medicinal product’ shall mean a medicinal product
which
-has the same qualitative and quantitative composition in active
substances as the reference medicinal product (RMP)
-the same pharmaceutical form as the (RMP), and
-whose bioequivalence with the RMP has been demonstrated by
appropriate bioavailability studies.
(Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal
product meets the relevant criteria as defined in the appropriate detailed guidelines).
Question:
Can a generic approach be used for
marketing approval of Biosimilars?
Answer*:
Due to the complexity of biological/
biotechnology derived medicinal products
- the generic approach is (usually)
not appropriate for these products
- to establish safety and efficacy of a
Biosimilar (usually) the “biosimilar” approach,
based on a comprehensive comparability
exercise, will then have to be followed
Legal Basis for MA of Biosimilars in the EU
Directive 2001/83/EC, Art. 10.4
Where a biological medicinal product (BMP) which is similar to a
reference biological product (RBP)
does not meet the conditions in the definition of generic medicinal
products,
owing to, in particular, differences
-relating to raw materials or
-in manufacturing processes of the BMP and the RBP
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 Annex I and the related
detailed guidelines.
The results of other tests and trials from the RBP´s dossier shall not be
provided.
Legal Basis for MA of Biosimilars in the EU
Directive 2001/83/EC, Annex I, Part II, 4
´The general principles to be applied [for similar
biological medicinal products] are addressed in a
guideline taking into account the characteristics of the
concerned biological medicinal product published by the
Agency’
→ Guideline on Similar Biological Medicinal
Products (CHMP/437/04/Rev 1)
16
Regulatory framework for non-clinical evaluation of Biosimilars
in the EU
Directive 2001/83/EC as amended
↓
Guideline (GL) on SBMP GL on SBMP containing
• Biological products containing biotechnology-derived
biotechnology-derived → proteins as active substance
proteins as active substance - Non-clinical and clinical
• Immunologicals such as issues
vaccines and allergens ↓
• Blood or plasma- derived Product specific GLs:
products and their • rh Somatropin • rh G-CSF
recombinant alternatives • rh Erythropoietin • rh FSH
• Other Biological MP • rh Insulin • rh Interferon alfa
• rh Interferon beta
Product specific GL • Monclonal antibodies
• Low MW Heparins
↓
Regulatory Status of Individual Biosimilar GLs
First Generation GL Second Generation GL
Coming into effect Coming into effect
Overarching GLs
GL ON SIMILAR BIOLOGICAL 10/2005 Revision (public)
MEDICINAL PRODUCTS
GL ON SBMP CONTAINING 06/2006 Revision (internal)
BT-DERIVED PROTEINS :
NON-CLINICAL AND CLINICAL ISSUES
Product specific GLs
ERYTHROPOIETINS 07/2006 10/2010
G-CSF 06/2006
SOMATROPIN 06/2006
HUMAN INSULIN AND INSULIN ANALOGUES 06/2006 Revision (public)
INTERFERON ALFA (04/2009)*
MONOCLONAL ANTIBODIES 12/2012
FSH 09/2013
INTERFERON BETA 09/2013
LOW-MOLECULAR-WEIGHT-HEPARINS 10/2009 Revision (public)
* Reflection paper
Outline
● Legal basis for marketing authorisation of
biosimilars in the EU
● Non-clinical evaluation of biosimilars in the EU
- General considerations
- Product-specific considerations
Biosimilars – Development programme
To establish that a biosimilar demonstrates similarity to a
chosen reference medicinal product (RMP) in terms of
-quality characteristics
-biological activity
-safety and
-efficacy
a comprehensive comparison (the so-called
´comparability exercise`) is usually required.
Comparability exercise for Biosimilars
As to decide on a case by case basis, the comparability
exercise (Biosimilar versus RMP) may comprise the
following components:
• Quality studies (full analysis)
• Non-clinical studies (reduced programme*)
• in vitro studies
• in vivo studies
• Clinical studies (reduced programme*)
• Clinical pharmacokinetics/pharmacodynamics
• Efficacy
• Safety
Comparability exercise for Biosimilars
Taken from: CK Schneider et al., Nature Biotechnology 2012, 30:1179-1185
Biosimilars - Non-clinical evaluation
- Stepwise approach
● Non-clinical studies should be performed before
initiating clinical trials.
● A step-wise approach should be applied to evaluate
the similarity of biosimilar and reference product.
- Step 1: In vitro studies should be conducted first
- Step 2: A decision should then be made
(on basis of the available quality and in vitro non-clinical data)
whether (and to what extent) in vivo animal
studies are required
[- Step 3: In vivo animal studies (if needed)].
Biosimilars – Adapted non-clinical approach
First Generation GLs Second Generation GLs
Quality Quality
Characterization Characterization
Non-clinical S1:Non-clinical
In vitro studies In vitro studies S2:Evaluation
Non-clinical S3:Non-clinical Decision
In vivo studies In vivo studies
Clinical studies Clinical studies
Step 1: In vitro studies - Spectrum of studies (i)
In order to assess any difference in biological activity
between the biosimilar and the RMP,
data from a number of comparative in vitro studies (some
of which may already be available from quality-related assays) should
normally be provided.
Together these assays should broadly cover the
spectrum of pharmacological/toxicological aspects
known to be of relevance for the RMP and for the
product class.
Step 1: In vitro studies - Spectrum of studies (ii)
Studies could include relevant assays on:
- Binding to target(s)
e.g. receptors, antigens, enzymes
- Signal transduction
Functional activity
Viability
of cells
known to be of relevance for the
pharmaco-toxicological effects of the RMP
Step 1: In vitro studies - Study design
The studies should
● be comparative in nature and should not just assess
the response per se.
● evaluate parameters sensitive enough to detect
differences.
● assess the concentration-activity/binding
relationship between the biosimilar and the RMP,
covering a concentration range where differences are
most sensitively detected.
● be performed with an appropriate number of batches
of product representative of that intended for clinical
use.
Step 1: In vitro studies –
Relevance for in vivo situation
Since in vitro assays may often be more specific and
sensitive to detect differences between the biosimilar and
the RMP than studies in animals,
these assays can be considered as paramount for the
non-clinical comparability exercise.
However, the applicant should justify that the in vitro
assays used are predictive for the in vivo situation.
Step 1: In vitro studies –
Consequence of relevant differences
If the biosimilar comparability exercise indicates early on
that there are significant differences between the
intended biosimilar and the RMP
making it unlikely that biosimilarity will eventually be
established,
a stand-alone development, should be considered
instead.
Step 2: Determination of the need for in vivo
studies – General considerations
Biotechnology-derived proteins may mediate in vivo
effects that cannot be fully elucidated by in vitro
studies
Therefore, in specific cases non-clinical in vivo studies
may be necessary to provide complementary
information,
provided that a relevant in vivo model with regard to
species or design is available
Factors to be considered when the need for in vivo non-
clinical studies is evaluated, include, but are not
restricted to quality and pharmacokinetic factors
Step 2: Determination of the need for in vivo studies –
Quality related arguments
● Presence of relevant quality attributes that have not been
detected in the RMP (e.g. new post-translational modification
structures)
● Significant quantitative differences in quality attributes
between the intended biosimilar and the RMP
● Relevant differences in formulation (e.g. use of excipients not
widely used for biotechnology-derived proteins)
→ Although each of the factors mentioned above do not
necessarily warrant in vivo testing, these issues should be
considered together to assess the level of concern and
whether there is a need for in vivo testing
Step 2: Determination of the need for in vivo studies
– Pharmacokinetic-related arguments
If product-inherent factors that impact PK and/or
biodistribution,
like extensive glycosylation,
cannot sufficiently be characterized on a quality and in
vitro level, in vivo studies may be necessary
→ Applicants should then carefully consider if these
should be performed in animals or as part of the
clinical testing (e.g. in healthy volunteers)
Step 2: Determination of the need for in vivo studies
– Decision process (i)
Step 2: Determination of the need for in vivo studies
– Decision process (ii)
● If there is a need for additional in vivo information,
→ the availability of
- a relevant animal species or
- other relevant models (e.g. transgenic animals,
transplant models)
should be considered
● If a relevant in vivo animal model is not available
→ the applicant may choose to proceed to
human studies taking into account principles
to mitigate any potential risk
Step 3: In vivo studies - Spectrum of studies
● If an in vivo evaluation is deemed necessary, the focus
of the study/studies (PK and/or PD and/or safety)
depends on the need for additional information
● Studies regarding safety pharmacology,
reproduction toxicology, and carcinogenicity are not
required for non-clinical testing of biosimilars
Step 3: In vivo studies - Specific problems
Recombinant human proteins
• may show species-specific pharmacodynamic activity
• it may be difficult to identify a relevant species for
pharmacodyamic and toxicological studies
• will, as foreign proteins, usually elicit an antibody
response in long-term animal studies
• results of long-term (> 2 - 4 weeks) pharmacodyamic and
toxicological studies may be difficult to interpret due to
the formation of biosimilar/antibody complexes
Step 3: In vivo studies - 3R Principles
● Animal studies should be designed to maximise the
information obtained
● The principles of the 3Rs (replacement, refinement,
reduction) should be considered when designing any
in vivo animal study*
→ Depending on the endpoints needed, it may not be
necessary to sacrifice the animals at the end of the
study
* Directive 2010/63/EC on the protection of animals used for scientific purposes
Step 3: In vivo studies - PK/PD studies
● When the model allows, the PK and PD of the
biosimilar and the RMP should be quantitatively
compared
- including concentration-response assessment
covering the therapeutic dose range in humans.
● The duration of the study/studies (including
observation period) should be justified, taking into
consideration
- the PK behaviour of the biosimilar and
- its clinical use
Step 3: In vivo studies - Safety studies
For safety studies a flexible approach should be
considered, in particular if non-human primates are the
only relevant species
- the conduct of standard repeated dose toxicity studies in
non-human primates is usually not recommended
If appropriately justified,
● a repeated dose toxicity study with refined design
- e.g. using just one dose level of biosimilar and reference
product and/or just one gender and/or no recovery animals) or
● an in-life evaluation of safety parameters
- such as clinical signs, body weight and vital functions
may be considered.
Step 3: In vivo studies – Local tolerance
● Studies on local tolerance are usually not required.
● However, if excipients are introduced for which there
is no or little experience with the intended clinical
route, local tolerance may need to be evaluated.
→ If other in vivo studies are performed, evaluation
of local tolerance may be included in the design
of that studies
Step 3: In vivo studies - Non-relevant animal species
The conduct of toxicity studies in non-relevant species
- i.e. to assess unspecific toxicity only, based on impurities
is not recommended
● Due to the different production processes used by
the biosimilar and RMP manufacturers, qualitative
differences of process related impurities will occur
● The level of such impurities should be kept to a
minimum, which is the best strategy to minimise
any associated risk
Step 3: In vivo studies - Immunogenic potential
● Qualitative or quantitative difference(s) of product-
related variants (e.g. glycosylation patterns, charge variants)
may have an effect on immunogenic potential and the
potential to cause hypersensitivity
→ These effects are difficult to predict from animal<
studies and should be further assessed in
clinical studies
● However, although immunogenicity assessment in
animals is generally not predictive for immunogenicity
in humans, it may be needed for interpretation of in
vivo studies in animals
→ Therefore, blood samples should be taken and stored for
future evaluations if then needed.
Outline
● Legal basis for marketing authorisation of
biosimilars in the EU
● Non-clinical evaluation of biosimilars in the EU
- General considerations
- Product-specific considerations
- Monoclonal Antibodies
- Interferon beta
- FSH
EU Biosimilar GL - Monoclonal Antibodies
Non-clinical evaluation - Step 1: in vitro studies
Should include relevant assays on:
● Binding to target antigen(s)
● Binding to Fc receptors (Fc gamma receptor subtypes, FcRn)
● Binding to complement (C1q)
● Fab-associated functions (e.g. neutralization of soluble
ligands, receptor activation/blockade)
● Fc-associated functions e.g.
- antibody-dependent cell-mediated cytotoxicity, (ADCC);
- complement-dependent cytotoxicity (CDC); complement activation
→ an evaluation of ADCC and CDC is generally not needed for
mAbs directed against nonmembrane bound targets
EU Biosimilar GL - rh Interferon beta
Non-clinical evaluation - Step 1: in vitro studies
To assess any differences in biological activity between the
biosimilar and RMP, data from a number of bioassays/
pharmacological studies should be provided, e.g.
● receptor-binding studies
● assays for characterisation of
- antiviral effects
- anti-proliferative effects
- immunomodulatory effects
→ Analytical methods should be standardised and validated according to
relevant GLs (e.g. evaluation of antiviral effects in cell culture in
accordance with the provisions of the European Pharmacopoiea)
EU Biosimilar GL - rh FSH
Non-clinical evaluation - Step 1: in vitro studies
To assess any differences in biological activity between the
biosimilar and RMP, data from a number of bioassays/
pharmacological studies should be provided, e.g.
● receptor-binding studies
● receptor-activation studies e.g.
- plasminogen activator production (granulosa cell assay)
- increase in intracellular cAMP (granulosa cell assay, CHO
cell assay)
→ Two principal approaches exist: (i) primary granulosa or sertoli cells
can be used. (ii) Permanently cultured cells (e.g. CHO) stably transfected
with the human FSH receptor may be constructed.
EU Biosimilar GL - rh FSH
Non-clinical evaluation - Step 2: Determination of the
need for in vitro studies
FSH is a highly glycosylated protein and in vitro studies
may therefore not fully reflect the more complex situation in
vivo.
Hence, the need for additional comparative in vivo animal
studies should be considered.
EU Biosimilar GL - rh FSH
Non-clinical evaluation - Step 3: in vivo animal studies
● The potency/biological activity of r-hFSH-containing
products is usually established by the Steelman-Pohley
assay (FSH-induced increase in ovarian weight in female
rats) by calibration against an international or internal
standard.
● If a different (in vivo, ex vivo, in vitro) bioassay is
intended to be used, this should be justified by the
Applicant with appropriate data.
Thank You
For Your Attention

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11. Dr. Hans-Karl Heim - Federal Institute for Drugs and Medical Devices (Germany)

  • 1. International Regulatory Workshop: Biotherapeutic Medicines – regulatory challenges and current practices. Approaches for harmonization Session 2: Biosimilars. Regulatory framework and quality considerations – dynamics of international practices Non-clinical evaluation of biosimilars according to current EMA guidelines Hans-Karl Heim Non-clinical Assessor, Federal Institute for Drugs and Medical Devices, Germany Moscow, May 15, 2013
  • 2. Disclaimer Opinions and conclusions presented on the following slides reflect the personal view of the presenter
  • 3. Outline ● Legal basis for marketing authorisation of biosimilars in the EU ● Non-clinical evaluation of biosimilars in the EU - General considerations - Product-specific considerations
  • 4. Biosimilars Proposed definition (GL on similar biological medicinal products) A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product, RMP). Based on a comprehensive comparability exercise, a biosimilar demonstrates similarity to the RMP in terms of -quality characteristics -biological activity -safety and -
  • 5. Differences: Biosimilars vs (Chemical) Generics Example: Biotechnology-derived Biosimilars • Production process recombinant DNA technology ↔ chemical synthesis • Size and Complexity large, high complexity ↔ small, low complexity • Immunogenicity potential antigen ↔ potential hapten
  • 6. Biotechnology-derived proteins - Size Chemical Substance: Acetylsalicylic acid MG = 180 Da B-D Protein: Erythropoietin MG ≈ 30.000 Da ASA (red) placed on top of EPO (cyan) for comparison
  • 7. Biotechnology-derived proteins - Glycosylation Glycosylation can further increase the structural and functional complexity of B-D Proteins One gene → one protein → many glycoproteins
  • 8. Erythropoietin (EPO) - Isoforms differing in glycosylation Eur. Pharmacopoiea: EPO standard contains a family of closely related glycoproteins
  • 9. Glycosylation - Possible relevance for efficacy and safety of Biosimilars Glycosylation pattern can modulate: • Protein charge, folding and stability • Binding affinity to receptors and other biomolecules • Immunogenicity • Pharmacokinetics incl. tissue distribution
  • 10. Biosimilars – Importance of manufacturing process Biosimilars are usually produced on basis of a complex manufacturing process. Even minor changes in the manufacturing process of a biological may significantly alter relevant product parameters such as - post-translational modification (e.g. glycosylation) - impurity profile - immunogenicity etc.
  • 11. Question: Can a generic approach be used for marketing approval of Biosimilars?
  • 12. Legal Definition of Generics in the EU Directive 2001/83/EC, Art. 10.2(b) ‘Generic medicinal product’ shall mean a medicinal product which -has the same qualitative and quantitative composition in active substances as the reference medicinal product (RMP) -the same pharmaceutical form as the (RMP), and -whose bioequivalence with the RMP has been demonstrated by appropriate bioavailability studies. (Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinal product meets the relevant criteria as defined in the appropriate detailed guidelines).
  • 13. Question: Can a generic approach be used for marketing approval of Biosimilars? Answer*: Due to the complexity of biological/ biotechnology derived medicinal products - the generic approach is (usually) not appropriate for these products - to establish safety and efficacy of a Biosimilar (usually) the “biosimilar” approach, based on a comprehensive comparability exercise, will then have to be followed
  • 14. Legal Basis for MA of Biosimilars in the EU Directive 2001/83/EC, Art. 10.4 Where a biological medicinal product (BMP) which is similar to a reference biological product (RBP) does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences -relating to raw materials or -in manufacturing processes of the BMP and the RBP 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 Annex I and the related detailed guidelines. The results of other tests and trials from the RBP´s dossier shall not be provided.
  • 15. Legal Basis for MA of Biosimilars in the EU Directive 2001/83/EC, Annex I, Part II, 4 ´The general principles to be applied [for similar biological medicinal products] are addressed in a guideline taking into account the characteristics of the concerned biological medicinal product published by the Agency’ → Guideline on Similar Biological Medicinal Products (CHMP/437/04/Rev 1)
  • 16. 16 Regulatory framework for non-clinical evaluation of Biosimilars in the EU Directive 2001/83/EC as amended ↓ Guideline (GL) on SBMP GL on SBMP containing • Biological products containing biotechnology-derived biotechnology-derived → proteins as active substance proteins as active substance - Non-clinical and clinical • Immunologicals such as issues vaccines and allergens ↓ • Blood or plasma- derived Product specific GLs: products and their • rh Somatropin • rh G-CSF recombinant alternatives • rh Erythropoietin • rh FSH • Other Biological MP • rh Insulin • rh Interferon alfa • rh Interferon beta Product specific GL • Monclonal antibodies • Low MW Heparins ↓
  • 17. Regulatory Status of Individual Biosimilar GLs First Generation GL Second Generation GL Coming into effect Coming into effect Overarching GLs GL ON SIMILAR BIOLOGICAL 10/2005 Revision (public) MEDICINAL PRODUCTS GL ON SBMP CONTAINING 06/2006 Revision (internal) BT-DERIVED PROTEINS : NON-CLINICAL AND CLINICAL ISSUES Product specific GLs ERYTHROPOIETINS 07/2006 10/2010 G-CSF 06/2006 SOMATROPIN 06/2006 HUMAN INSULIN AND INSULIN ANALOGUES 06/2006 Revision (public) INTERFERON ALFA (04/2009)* MONOCLONAL ANTIBODIES 12/2012 FSH 09/2013 INTERFERON BETA 09/2013 LOW-MOLECULAR-WEIGHT-HEPARINS 10/2009 Revision (public) * Reflection paper
  • 18. Outline ● Legal basis for marketing authorisation of biosimilars in the EU ● Non-clinical evaluation of biosimilars in the EU - General considerations - Product-specific considerations
  • 19. Biosimilars – Development programme To establish that a biosimilar demonstrates similarity to a chosen reference medicinal product (RMP) in terms of -quality characteristics -biological activity -safety and -efficacy a comprehensive comparison (the so-called ´comparability exercise`) is usually required.
  • 20. Comparability exercise for Biosimilars As to decide on a case by case basis, the comparability exercise (Biosimilar versus RMP) may comprise the following components: • Quality studies (full analysis) • Non-clinical studies (reduced programme*) • in vitro studies • in vivo studies • Clinical studies (reduced programme*) • Clinical pharmacokinetics/pharmacodynamics • Efficacy • Safety
  • 21. Comparability exercise for Biosimilars Taken from: CK Schneider et al., Nature Biotechnology 2012, 30:1179-1185
  • 22. Biosimilars - Non-clinical evaluation - Stepwise approach ● Non-clinical studies should be performed before initiating clinical trials. ● A step-wise approach should be applied to evaluate the similarity of biosimilar and reference product. - Step 1: In vitro studies should be conducted first - Step 2: A decision should then be made (on basis of the available quality and in vitro non-clinical data) whether (and to what extent) in vivo animal studies are required [- Step 3: In vivo animal studies (if needed)].
  • 23. Biosimilars – Adapted non-clinical approach First Generation GLs Second Generation GLs Quality Quality Characterization Characterization Non-clinical S1:Non-clinical In vitro studies In vitro studies S2:Evaluation Non-clinical S3:Non-clinical Decision In vivo studies In vivo studies Clinical studies Clinical studies
  • 24. Step 1: In vitro studies - Spectrum of studies (i) In order to assess any difference in biological activity between the biosimilar and the RMP, data from a number of comparative in vitro studies (some of which may already be available from quality-related assays) should normally be provided. Together these assays should broadly cover the spectrum of pharmacological/toxicological aspects known to be of relevance for the RMP and for the product class.
  • 25. Step 1: In vitro studies - Spectrum of studies (ii) Studies could include relevant assays on: - Binding to target(s) e.g. receptors, antigens, enzymes - Signal transduction Functional activity Viability of cells known to be of relevance for the pharmaco-toxicological effects of the RMP
  • 26. Step 1: In vitro studies - Study design The studies should ● be comparative in nature and should not just assess the response per se. ● evaluate parameters sensitive enough to detect differences. ● assess the concentration-activity/binding relationship between the biosimilar and the RMP, covering a concentration range where differences are most sensitively detected. ● be performed with an appropriate number of batches of product representative of that intended for clinical use.
  • 27. Step 1: In vitro studies – Relevance for in vivo situation Since in vitro assays may often be more specific and sensitive to detect differences between the biosimilar and the RMP than studies in animals, these assays can be considered as paramount for the non-clinical comparability exercise. However, the applicant should justify that the in vitro assays used are predictive for the in vivo situation.
  • 28. Step 1: In vitro studies – Consequence of relevant differences If the biosimilar comparability exercise indicates early on that there are significant differences between the intended biosimilar and the RMP making it unlikely that biosimilarity will eventually be established, a stand-alone development, should be considered instead.
  • 29. Step 2: Determination of the need for in vivo studies – General considerations Biotechnology-derived proteins may mediate in vivo effects that cannot be fully elucidated by in vitro studies Therefore, in specific cases non-clinical in vivo studies may be necessary to provide complementary information, provided that a relevant in vivo model with regard to species or design is available Factors to be considered when the need for in vivo non- clinical studies is evaluated, include, but are not restricted to quality and pharmacokinetic factors
  • 30. Step 2: Determination of the need for in vivo studies – Quality related arguments ● Presence of relevant quality attributes that have not been detected in the RMP (e.g. new post-translational modification structures) ● Significant quantitative differences in quality attributes between the intended biosimilar and the RMP ● Relevant differences in formulation (e.g. use of excipients not widely used for biotechnology-derived proteins) → Although each of the factors mentioned above do not necessarily warrant in vivo testing, these issues should be considered together to assess the level of concern and whether there is a need for in vivo testing
  • 31. Step 2: Determination of the need for in vivo studies – Pharmacokinetic-related arguments If product-inherent factors that impact PK and/or biodistribution, like extensive glycosylation, cannot sufficiently be characterized on a quality and in vitro level, in vivo studies may be necessary → Applicants should then carefully consider if these should be performed in animals or as part of the clinical testing (e.g. in healthy volunteers)
  • 32. Step 2: Determination of the need for in vivo studies – Decision process (i)
  • 33. Step 2: Determination of the need for in vivo studies – Decision process (ii) ● If there is a need for additional in vivo information, → the availability of - a relevant animal species or - other relevant models (e.g. transgenic animals, transplant models) should be considered ● If a relevant in vivo animal model is not available → the applicant may choose to proceed to human studies taking into account principles to mitigate any potential risk
  • 34. Step 3: In vivo studies - Spectrum of studies ● If an in vivo evaluation is deemed necessary, the focus of the study/studies (PK and/or PD and/or safety) depends on the need for additional information ● Studies regarding safety pharmacology, reproduction toxicology, and carcinogenicity are not required for non-clinical testing of biosimilars
  • 35. Step 3: In vivo studies - Specific problems Recombinant human proteins • may show species-specific pharmacodynamic activity • it may be difficult to identify a relevant species for pharmacodyamic and toxicological studies • will, as foreign proteins, usually elicit an antibody response in long-term animal studies • results of long-term (> 2 - 4 weeks) pharmacodyamic and toxicological studies may be difficult to interpret due to the formation of biosimilar/antibody complexes
  • 36. Step 3: In vivo studies - 3R Principles ● Animal studies should be designed to maximise the information obtained ● The principles of the 3Rs (replacement, refinement, reduction) should be considered when designing any in vivo animal study* → Depending on the endpoints needed, it may not be necessary to sacrifice the animals at the end of the study * Directive 2010/63/EC on the protection of animals used for scientific purposes
  • 37. Step 3: In vivo studies - PK/PD studies ● When the model allows, the PK and PD of the biosimilar and the RMP should be quantitatively compared - including concentration-response assessment covering the therapeutic dose range in humans. ● The duration of the study/studies (including observation period) should be justified, taking into consideration - the PK behaviour of the biosimilar and - its clinical use
  • 38. Step 3: In vivo studies - Safety studies For safety studies a flexible approach should be considered, in particular if non-human primates are the only relevant species - the conduct of standard repeated dose toxicity studies in non-human primates is usually not recommended If appropriately justified, ● a repeated dose toxicity study with refined design - e.g. using just one dose level of biosimilar and reference product and/or just one gender and/or no recovery animals) or ● an in-life evaluation of safety parameters - such as clinical signs, body weight and vital functions may be considered.
  • 39. Step 3: In vivo studies – Local tolerance ● Studies on local tolerance are usually not required. ● However, if excipients are introduced for which there is no or little experience with the intended clinical route, local tolerance may need to be evaluated. → If other in vivo studies are performed, evaluation of local tolerance may be included in the design of that studies
  • 40. Step 3: In vivo studies - Non-relevant animal species The conduct of toxicity studies in non-relevant species - i.e. to assess unspecific toxicity only, based on impurities is not recommended ● Due to the different production processes used by the biosimilar and RMP manufacturers, qualitative differences of process related impurities will occur ● The level of such impurities should be kept to a minimum, which is the best strategy to minimise any associated risk
  • 41. Step 3: In vivo studies - Immunogenic potential ● Qualitative or quantitative difference(s) of product- related variants (e.g. glycosylation patterns, charge variants) may have an effect on immunogenic potential and the potential to cause hypersensitivity → These effects are difficult to predict from animal< studies and should be further assessed in clinical studies ● However, although immunogenicity assessment in animals is generally not predictive for immunogenicity in humans, it may be needed for interpretation of in vivo studies in animals → Therefore, blood samples should be taken and stored for future evaluations if then needed.
  • 42. Outline ● Legal basis for marketing authorisation of biosimilars in the EU ● Non-clinical evaluation of biosimilars in the EU - General considerations - Product-specific considerations - Monoclonal Antibodies - Interferon beta - FSH
  • 43. EU Biosimilar GL - Monoclonal Antibodies Non-clinical evaluation - Step 1: in vitro studies Should include relevant assays on: ● Binding to target antigen(s) ● Binding to Fc receptors (Fc gamma receptor subtypes, FcRn) ● Binding to complement (C1q) ● Fab-associated functions (e.g. neutralization of soluble ligands, receptor activation/blockade) ● Fc-associated functions e.g. - antibody-dependent cell-mediated cytotoxicity, (ADCC); - complement-dependent cytotoxicity (CDC); complement activation → an evaluation of ADCC and CDC is generally not needed for mAbs directed against nonmembrane bound targets
  • 44. EU Biosimilar GL - rh Interferon beta Non-clinical evaluation - Step 1: in vitro studies To assess any differences in biological activity between the biosimilar and RMP, data from a number of bioassays/ pharmacological studies should be provided, e.g. ● receptor-binding studies ● assays for characterisation of - antiviral effects - anti-proliferative effects - immunomodulatory effects → Analytical methods should be standardised and validated according to relevant GLs (e.g. evaluation of antiviral effects in cell culture in accordance with the provisions of the European Pharmacopoiea)
  • 45. EU Biosimilar GL - rh FSH Non-clinical evaluation - Step 1: in vitro studies To assess any differences in biological activity between the biosimilar and RMP, data from a number of bioassays/ pharmacological studies should be provided, e.g. ● receptor-binding studies ● receptor-activation studies e.g. - plasminogen activator production (granulosa cell assay) - increase in intracellular cAMP (granulosa cell assay, CHO cell assay) → Two principal approaches exist: (i) primary granulosa or sertoli cells can be used. (ii) Permanently cultured cells (e.g. CHO) stably transfected with the human FSH receptor may be constructed.
  • 46. EU Biosimilar GL - rh FSH Non-clinical evaluation - Step 2: Determination of the need for in vitro studies FSH is a highly glycosylated protein and in vitro studies may therefore not fully reflect the more complex situation in vivo. Hence, the need for additional comparative in vivo animal studies should be considered.
  • 47. EU Biosimilar GL - rh FSH Non-clinical evaluation - Step 3: in vivo animal studies ● The potency/biological activity of r-hFSH-containing products is usually established by the Steelman-Pohley assay (FSH-induced increase in ovarian weight in female rats) by calibration against an international or internal standard. ● If a different (in vivo, ex vivo, in vitro) bioassay is intended to be used, this should be justified by the Applicant with appropriate data.
  • 48. Thank You For Your Attention