International Regulatory Workshop:Biotherapeutic Medicines – regulatory challenges and currentpractices. Approaches for ha...
DisclaimerOpinions and conclusionspresented on the following slides reflectthe personal view of the presenter
Outline● Legal basis for marketing authorisation ofbiosimilars in the EU● Non-clinical evaluation of biosimilars in the EU...
BiosimilarsProposed definition (GL on similar biological medicinal products)A biosimilar is a biological medicinal product...
Differences: Biosimilars vs (Chemical) GenericsExample: Biotechnology-derived Biosimilars• Production processrecombinant D...
Biotechnology-derived proteins - SizeChemicalSubstance:AcetylsalicylicacidMG = 180 DaB-D Protein:ErythropoietinMG ≈ 30.000...
Biotechnology-derived proteins - GlycosylationGlycosylation can further increase the structural andfunctional complexity o...
Erythropoietin (EPO)- Isoforms differing in glycosylationEur. Pharmacopoiea:EPO standardcontains a familyof closely relate...
Glycosylation - Possible relevance for efficacy andsafety of BiosimilarsGlycosylation pattern can modulate:• Protein charg...
Biosimilars – Importance of manufacturing processBiosimilars are usually produced on basis of a complexmanufacturing proce...
Question:Can a generic approach be used formarketing approval of Biosimilars?
Legal Definition of Generics in the EUDirective 2001/83/EC, Art. 10.2(b)‘Generic medicinal product’ shall mean a medicinal...
Question:Can a generic approach be used formarketing approval of Biosimilars?Answer*:Due to the complexity of biological/b...
Legal Basis for MA of Biosimilars in the EUDirective 2001/83/EC, Art. 10.4Where a biological medicinal product (BMP) which...
Legal Basis for MA of Biosimilars in the EUDirective 2001/83/EC, Annex I, Part II, 4´The general principles to be applied ...
16Regulatory framework for non-clinical evaluation of Biosimilarsin the EUDirective 2001/83/EC as amended↓Guideline (GL) o...
Regulatory Status of Individual Biosimilar GLsFirst Generation GL Second Generation GLComing into effect Coming into effec...
Outline● Legal basis for marketing authorisation ofbiosimilars in the EU● Non-clinical evaluation of biosimilars in the EU...
Biosimilars – Development programmeTo establish that a biosimilar demonstrates similarity to achosen reference medicinal p...
Comparability exercise for BiosimilarsAs to decide on a case by case basis, the comparabilityexercise (Biosimilar versus R...
Comparability exercise for BiosimilarsTaken from: CK Schneider et al., Nature Biotechnology 2012, 30:1179-1185
Biosimilars - Non-clinical evaluation- Stepwise approach● Non-clinical studies should be performed beforeinitiating clinic...
Biosimilars – Adapted non-clinical approachFirst Generation GLs Second Generation GLsQuality QualityCharacterization Chara...
Step 1: In vitro studies - Spectrum of studies (i)In order to assess any difference in biological activitybetween the bios...
Step 1: In vitro studies - Spectrum of studies (ii)Studies could include relevant assays on:- Binding to target(s)e.g. rec...
Step 1: In vitro studies - Study designThe studies should● be comparative in nature and should not just assessthe response...
Step 1: In vitro studies –Relevance for in vivo situationSince in vitro assays may often be more specific andsensitive to ...
Step 1: In vitro studies –Consequence of relevant differencesIf the biosimilar comparability exercise indicates early onth...
Step 2: Determination of the need for in vivostudies – General considerationsBiotechnology-derived proteins may mediate in...
Step 2: Determination of the need for in vivo studies –Quality related arguments● Presence of relevant quality attributes ...
Step 2: Determination of the need for in vivo studies– Pharmacokinetic-related argumentsIf product-inherent factors that i...
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 in...
Step 3: In vivo studies - Spectrum of studies● If an in vivo evaluation is deemed necessary, the focusof the study/studies...
Step 3: In vivo studies - Specific problemsRecombinant human proteins• may show species-specific pharmacodynamic activity•...
Step 3: In vivo studies - 3R Principles● Animal studies should be designed to maximise theinformation obtained● The princi...
Step 3: In vivo studies - PK/PD studies● When the model allows, the PK and PD of thebiosimilar and the RMP should be quant...
Step 3: In vivo studies - Safety studiesFor safety studies a flexible approach should beconsidered, in particular if non-h...
Step 3: In vivo studies – Local tolerance● Studies on local tolerance are usually not required.● However, if excipients ar...
Step 3: In vivo studies - Non-relevant animal speciesThe conduct of toxicity studies in non-relevant species- i.e. to asse...
Step 3: In vivo studies - Immunogenic potential● Qualitative or quantitative difference(s) of product-related variants (e....
Outline● Legal basis for marketing authorisation ofbiosimilars in the EU● Non-clinical evaluation of biosimilars in the EU...
EU Biosimilar GL - Monoclonal AntibodiesNon-clinical evaluation - Step 1: in vitro studiesShould include relevant assays o...
EU Biosimilar GL - rh Interferon betaNon-clinical evaluation - Step 1: in vitro studiesTo assess any differences in biolog...
EU Biosimilar GL - rh FSHNon-clinical evaluation - Step 1: in vitro studiesTo assess any differences in biological activit...
EU Biosimilar GL - rh FSHNon-clinical evaluation - Step 2: Determination of theneed for in vitro studiesFSH is a highly gl...
EU Biosimilar GL - rh FSHNon-clinical evaluation - Step 3: in vivo animal studies● The potency/biological activity of r-hF...
Thank YouFor Your Attention
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11. Dr. Hans-Karl Heim - Federal Institute for Drugs and Medical Devices (Germany)

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“Evolution of biosimilar medicines assessment in Russia. Current practices and main challenges”

Illustrates the current Russian legislative scenario and ongoing developments on the regulation of biotherapeutics and biosimilars

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

  1. 1. International Regulatory Workshop:Biotherapeutic Medicines – regulatory challenges and currentpractices. Approaches for harmonizationSession 2: Biosimilars. Regulatory framework and qualityconsiderations – dynamics of international practicesNon-clinical evaluation of biosimilarsaccording to current EMA guidelinesHans-Karl HeimNon-clinical Assessor,Federal Institute for Drugs and Medical Devices, GermanyMoscow, May 15, 2013
  2. 2. DisclaimerOpinions and conclusionspresented on the following slides reflectthe personal view of the presenter
  3. 3. Outline● Legal basis for marketing authorisation ofbiosimilars in the EU● Non-clinical evaluation of biosimilars in the EU- General considerations- Product-specific considerations
  4. 4. BiosimilarsProposed definition (GL on similar biological medicinal products)A biosimilar is a biological medicinal product thatcontains a version of the active substance of an alreadyauthorised original biological medicinal product(reference medicinal product, RMP).Based on a comprehensive comparability exercise, abiosimilar demonstrates similarity to the RMP in termsof-quality characteristics-biological activity-safety and-
  5. 5. Differences: Biosimilars vs (Chemical) GenericsExample: Biotechnology-derived Biosimilars• Production processrecombinant DNA technology ↔ chemical synthesis• Size and Complexitylarge, high complexity ↔ small, low complexity• Immunogenicitypotential antigen ↔ potential hapten
  6. 6. Biotechnology-derived proteins - SizeChemicalSubstance:AcetylsalicylicacidMG = 180 DaB-D Protein:ErythropoietinMG ≈ 30.000 Da ASA (red) placed on top of EPO (cyan)for comparison
  7. 7. Biotechnology-derived proteins - GlycosylationGlycosylation can further increase the structural andfunctional complexity of B-D ProteinsOne gene → one protein → many glycoproteins
  8. 8. Erythropoietin (EPO)- Isoforms differing in glycosylationEur. Pharmacopoiea:EPO standardcontains a familyof closely relatedglycoproteins
  9. 9. Glycosylation - Possible relevance for efficacy andsafety of BiosimilarsGlycosylation pattern can modulate:• Protein charge, folding and stability• Binding affinity to receptors and other biomolecules• Immunogenicity• Pharmacokinetics incl. tissue distribution
  10. 10. Biosimilars – Importance of manufacturing processBiosimilars are usually produced on basis of a complexmanufacturing process.Even minor changes in the manufacturing process of abiological may significantly alter relevant productparameters such as- post-translational modification (e.g. glycosylation)- impurity profile- immunogenicity etc.
  11. 11. Question:Can a generic approach be used formarketing approval of Biosimilars?
  12. 12. Legal Definition of Generics in the EUDirective 2001/83/EC, Art. 10.2(b)‘Generic medicinal product’ shall mean a medicinal productwhich-has the same qualitative and quantitative composition in activesubstances as the reference medicinal product (RMP)-the same pharmaceutical form as the (RMP), and-whose bioequivalence with the RMP has been demonstrated byappropriate bioavailability studies.(Bioavailability studies need not be required of the applicant if he can demonstrate that the generic medicinalproduct meets the relevant criteria as defined in the appropriate detailed guidelines).
  13. 13. Question:Can a generic approach be used formarketing 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 aBiosimilar (usually) the “biosimilar” approach,based on a comprehensive comparabilityexercise, will then have to be followed
  14. 14. Legal Basis for MA of Biosimilars in the EUDirective 2001/83/EC, Art. 10.4Where a biological medicinal product (BMP) which is similar to areference biological product (RBP)does not meet the conditions in the definition of generic medicinalproducts,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 mustcomply with the relevant criteria stated in Annex I and the relateddetailed guidelines.The results of other tests and trials from the RBP´s dossier shall not beprovided.
  15. 15. Legal Basis for MA of Biosimilars in the EUDirective 2001/83/EC, Annex I, Part II, 4´The general principles to be applied [for similarbiological medicinal products] are addressed in aguideline taking into account the characteristics of theconcerned biological medicinal product published by theAgency’→ Guideline on Similar Biological MedicinalProducts (CHMP/437/04/Rev 1)
  16. 16. 16Regulatory framework for non-clinical evaluation of Biosimilarsin the EUDirective 2001/83/EC as amended↓Guideline (GL) on SBMP GL on SBMP containing• Biological products containing biotechnology-derivedbiotechnology-derived → proteins as active substanceproteins as active substance - Non-clinical and clinical• Immunologicals such as issuesvaccines and allergens ↓• Blood or plasma- derived Product specific GLs:products and their • rh Somatropin • rh G-CSFrecombinant alternatives • rh Erythropoietin • rh FSH• Other Biological MP • rh Insulin • rh Interferon alfa• rh Interferon betaProduct specific GL • Monclonal antibodies• Low MW Heparins↓
  17. 17. Regulatory Status of Individual Biosimilar GLsFirst Generation GL Second Generation GLComing into effect Coming into effectOverarching GLsGL ON SIMILAR BIOLOGICAL 10/2005 Revision (public)MEDICINAL PRODUCTSGL ON SBMP CONTAINING 06/2006 Revision (internal)BT-DERIVED PROTEINS :NON-CLINICAL AND CLINICAL ISSUESProduct specific GLsERYTHROPOIETINS 07/2006 10/2010G-CSF 06/2006SOMATROPIN 06/2006HUMAN INSULIN AND INSULIN ANALOGUES 06/2006 Revision (public)INTERFERON ALFA (04/2009)*MONOCLONAL ANTIBODIES 12/2012FSH 09/2013INTERFERON BETA 09/2013LOW-MOLECULAR-WEIGHT-HEPARINS 10/2009 Revision (public)* Reflection paper
  18. 18. Outline● Legal basis for marketing authorisation ofbiosimilars in the EU● Non-clinical evaluation of biosimilars in the EU- General considerations- Product-specific considerations
  19. 19. Biosimilars – Development programmeTo establish that a biosimilar demonstrates similarity to achosen reference medicinal product (RMP) in terms of-quality characteristics-biological activity-safety and-efficacya comprehensive comparison (the so-called´comparability exercise`) is usually required.
  20. 20. Comparability exercise for BiosimilarsAs to decide on a case by case basis, the comparabilityexercise (Biosimilar versus RMP) may comprise thefollowing 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. 21. Comparability exercise for BiosimilarsTaken from: CK Schneider et al., Nature Biotechnology 2012, 30:1179-1185
  22. 22. Biosimilars - Non-clinical evaluation- Stepwise approach● Non-clinical studies should be performed beforeinitiating clinical trials.● A step-wise approach should be applied to evaluatethe 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 animalstudies are required[- Step 3: In vivo animal studies (if needed)].
  23. 23. Biosimilars – Adapted non-clinical approachFirst Generation GLs Second Generation GLsQuality QualityCharacterization CharacterizationNon-clinical S1:Non-clinicalIn vitro studies In vitro studies S2:EvaluationNon-clinical S3:Non-clinical DecisionIn vivo studies In vivo studiesClinical studies Clinical studies
  24. 24. Step 1: In vitro studies - Spectrum of studies (i)In order to assess any difference in biological activitybetween the biosimilar and the RMP,data from a number of comparative in vitro studies (someof which may already be available from quality-related assays) shouldnormally be provided.Together these assays should broadly cover thespectrum of pharmacological/toxicological aspectsknown to be of relevance for the RMP and for theproduct class.
  25. 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 transductionFunctional activityViabilityof cellsknown to be of relevance for thepharmaco-toxicological effects of the RMP
  26. 26. Step 1: In vitro studies - Study designThe studies should● be comparative in nature and should not just assessthe response per se.● evaluate parameters sensitive enough to detectdifferences.● assess the concentration-activity/bindingrelationship between the biosimilar and the RMP,covering a concentration range where differences aremost sensitively detected.● be performed with an appropriate number of batchesof product representative of that intended for clinicaluse.
  27. 27. Step 1: In vitro studies –Relevance for in vivo situationSince in vitro assays may often be more specific andsensitive to detect differences between the biosimilar andthe RMP than studies in animals,these assays can be considered as paramount for thenon-clinical comparability exercise.However, the applicant should justify that the in vitroassays used are predictive for the in vivo situation.
  28. 28. Step 1: In vitro studies –Consequence of relevant differencesIf the biosimilar comparability exercise indicates early onthat there are significant differences between theintended biosimilar and the RMPmaking it unlikely that biosimilarity will eventually beestablished,a stand-alone development, should be consideredinstead.
  29. 29. Step 2: Determination of the need for in vivostudies – General considerationsBiotechnology-derived proteins may mediate in vivoeffects that cannot be fully elucidated by in vitrostudiesTherefore, in specific cases non-clinical in vivo studiesmay be necessary to provide complementaryinformation,provided that a relevant in vivo model with regard tospecies or design is availableFactors to be considered when the need for in vivo non-clinical studies is evaluated, include, but are notrestricted to quality and pharmacokinetic factors
  30. 30. Step 2: Determination of the need for in vivo studies –Quality related arguments● Presence of relevant quality attributes that have not beendetected in the RMP (e.g. new post-translational modificationstructures)● Significant quantitative differences in quality attributesbetween the intended biosimilar and the RMP● Relevant differences in formulation (e.g. use of excipients notwidely used for biotechnology-derived proteins)→ Although each of the factors mentioned above do notnecessarily warrant in vivo testing, these issues should beconsidered together to assess the level of concern andwhether there is a need for in vivo testing
  31. 31. Step 2: Determination of the need for in vivo studies– Pharmacokinetic-related argumentsIf product-inherent factors that impact PK and/orbiodistribution,like extensive glycosylation,cannot sufficiently be characterized on a quality and invitro level, in vivo studies may be necessary→ Applicants should then carefully consider if theseshould be performed in animals or as part of theclinical testing (e.g. in healthy volunteers)
  32. 32. Step 2: Determination of the need for in vivo studies– Decision process (i)
  33. 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 tohuman studies taking into account principlesto mitigate any potential risk
  34. 34. Step 3: In vivo studies - Spectrum of studies● If an in vivo evaluation is deemed necessary, the focusof 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 notrequired for non-clinical testing of biosimilars
  35. 35. Step 3: In vivo studies - Specific problemsRecombinant human proteins• may show species-specific pharmacodynamic activity• it may be difficult to identify a relevant species forpharmacodyamic and toxicological studies• will, as foreign proteins, usually elicit an antibodyresponse in long-term animal studies• results of long-term (> 2 - 4 weeks) pharmacodyamic andtoxicological studies may be difficult to interpret due tothe formation of biosimilar/antibody complexes
  36. 36. Step 3: In vivo studies - 3R Principles● Animal studies should be designed to maximise theinformation obtained● The principles of the 3Rs (replacement, refinement,reduction) should be considered when designing anyin vivo animal study*→ Depending on the endpoints needed, it may not benecessary to sacrifice the animals at the end of thestudy* Directive 2010/63/EC on the protection of animals used for scientific purposes
  37. 37. Step 3: In vivo studies - PK/PD studies● When the model allows, the PK and PD of thebiosimilar and the RMP should be quantitativelycompared- including concentration-response assessmentcovering the therapeutic dose range in humans.● The duration of the study/studies (includingobservation period) should be justified, taking intoconsideration- the PK behaviour of the biosimilar and- its clinical use
  38. 38. Step 3: In vivo studies - Safety studiesFor safety studies a flexible approach should beconsidered, in particular if non-human primates are theonly relevant species- the conduct of standard repeated dose toxicity studies innon-human primates is usually not recommendedIf appropriately justified,● a repeated dose toxicity study with refined design- e.g. using just one dose level of biosimilar and referenceproduct 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 functionsmay be considered.
  39. 39. Step 3: In vivo studies – Local tolerance● Studies on local tolerance are usually not required.● However, if excipients are introduced for which thereis no or little experience with the intended clinicalroute, local tolerance may need to be evaluated.→ If other in vivo studies are performed, evaluationof local tolerance may be included in the designof that studies
  40. 40. Step 3: In vivo studies - Non-relevant animal speciesThe conduct of toxicity studies in non-relevant species- i.e. to assess unspecific toxicity only, based on impuritiesis not recommended● Due to the different production processes used bythe biosimilar and RMP manufacturers, qualitativedifferences of process related impurities will occur● The level of such impurities should be kept to aminimum, which is the best strategy to minimiseany associated risk
  41. 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 thepotential to cause hypersensitivity→ These effects are difficult to predict from animal<studies and should be further assessed inclinical studies● However, although immunogenicity assessment inanimals is generally not predictive for immunogenicityin humans, it may be needed for interpretation of invivo studies in animals→ Therefore, blood samples should be taken and stored forfuture evaluations if then needed.
  42. 42. Outline● Legal basis for marketing authorisation ofbiosimilars in the EU● Non-clinical evaluation of biosimilars in the EU- General considerations- Product-specific considerations- Monoclonal Antibodies- Interferon beta- FSH
  43. 43. EU Biosimilar GL - Monoclonal AntibodiesNon-clinical evaluation - Step 1: in vitro studiesShould 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 solubleligands, 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 formAbs directed against nonmembrane bound targets
  44. 44. EU Biosimilar GL - rh Interferon betaNon-clinical evaluation - Step 1: in vitro studiesTo assess any differences in biological activity between thebiosimilar 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 torelevant GLs (e.g. evaluation of antiviral effects in cell culture inaccordance with the provisions of the European Pharmacopoiea)
  45. 45. EU Biosimilar GL - rh FSHNon-clinical evaluation - Step 1: in vitro studiesTo assess any differences in biological activity between thebiosimilar 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, CHOcell assay)→ Two principal approaches exist: (i) primary granulosa or sertoli cellscan be used. (ii) Permanently cultured cells (e.g. CHO) stably transfectedwith the human FSH receptor may be constructed.
  46. 46. EU Biosimilar GL - rh FSHNon-clinical evaluation - Step 2: Determination of theneed for in vitro studiesFSH is a highly glycosylated protein and in vitro studiesmay therefore not fully reflect the more complex situation invivo.Hence, the need for additional comparative in vivo animalstudies should be considered.
  47. 47. EU Biosimilar GL - rh FSHNon-clinical evaluation - Step 3: in vivo animal studies● The potency/biological activity of r-hFSH-containingproducts is usually established by the Steelman-Pohleyassay (FSH-induced increase in ovarian weight in femalerats) by calibration against an international or internalstandard.● If a different (in vivo, ex vivo, in vitro) bioassay isintended to be used, this should be justified by theApplicant with appropriate data.
  48. 48. Thank YouFor Your Attention

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