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 HeimNon-clinical Assessor, Federal Institute for Drugs and Medical Devices, Germany

Moscow, May 15, 2013

Disclaimer

Opinions and conclusionspresented 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-efficacy

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

ChemicalSubstance:

Acetylsalicylicacid

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 standardcontains a familyof closely relatedglycoproteins

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

* GL on similar biological medicinal products

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 areference 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 RBPthe results of appropriate pre-clinical tests or clinical trialsrelating 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)

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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 GLsGL 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 GLsERYTHROPOIETINS 07/2006 10/2010G-CSF 06/2006SOMATROPIN 06/2006 HUMAN INSULIN AND INSULIN ANALOGUES 06/2006 Revision (public)INTERFERON ALFA (04/2009)*MONOCLONAL ANTIBODIES 12/2012FSH 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

* Compared with stand alone application

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 QualityCharacterization Characterization

Non-clinical S1:Non-clinicalIn vitro studies In vitro studies S2:Evaluation

Non-clinical S3:Non-clinical DecisionIn 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 thepharmaco-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.

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