10. Dr. Alex Kudrin - Medicines and Healthcare Products Regulatory Agency (UK)

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“EU regulatory and clinical development framework for biosimilars”

Explains the current EU experience and practices relating to the submission and approval of biosimilars

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  • [Key dialogue] Business opportunities in the global vaccine market has been growing. As suggested in the previous TGAB meeting in the last summer, Takeda has opportunities to be captured through global expansion of vaccine business leveraging our assets, including sIPV We have initiated 4 initiatives to assess potential opportunities to "Go global" 1. Reinforcement of Japan strategy to establish unique position in our core market 2. Assessment of opportunities for strategic partnering to enter emerging markets 3. Screening and evaluation of potential in-licensing targets for "innovation" to build competitive advantage 4. Formulation of roadmap to build required capability for sustained growth After introducing our initiatives, we would like to receive inputs from you about current direction of our global vaccine strategy Our key questions are; Whether our strategic concept and approach make sense Which actions are key for achieving successful expansion into emerging markets What other types of pipeline and technology would be in our focus Based on today's discussion, we will refine our strategy towards the MOC presentation in March
  • 10. Dr. Alex Kudrin - Medicines and Healthcare Products Regulatory Agency (UK)

    1. 1. IFPMA/AIPM Biotherapeutics Workshop, MoscowEU regulatory and clinical developmentframework for biosimilars15-16thMay 2013Dr Alex Kudrin, Medical Assessor in Biologicals, MHRA, London, UK
    2. 2. Disclaimer• This presentation is given in personal capacity andrepresents only the author’s personal views and does notrepresent policies or recommendations of MHRA, EMA,FDA, any other companies and regulatory bodiesmentioned in this presentation.• No confidential data is disclosed.• All relevant references and links are from public domain.
    3. 3. Biosimilars’ adoption will expand, but willremain modest to 2016• Market of biologics willcontinue to expand dueto new, superior productsand earlier access;• Spending on biosimilarswill increase but willconstitute only 2% of totalbiologic spending;• Biosimilar adoption isexpected to be modestdue to remaining patent,market exclusivity andlack of substitution
    4. 4. Lessons learned from first wave of biosimilars in EU• Current EU biosimilar market:- EPOs – 60%- GSFs – 20%- GHs – 20%• Uptake of EPOs, filgrastims and GHs was highly variablebetween EU countries (EPOs - 90% in Norway; <7% in Italy)• Discounting of both reference and biosimilar products isconsiderable: e.g. Eprex – 82% discount• The dynamics is affected by pricing and extent of decisionmaking by physicians (e.g. GHs)
    5. 5. Biosimilar products evaluated in the EUOmnitrope somatropin Sandoz Genotropin Approval Apr-06Valtropin somatropin BioPartners Humatrope Approval Apr-06Alpheon interferon alfa-2a BioPartners Roferon-A Refusal Jun-06Abseamed SandozEpoietin alfa Hexal HexalBinocrit MediceSilapo HospiraRetacrit StadaInsulin Rapid Marvel soluble insulinInsulin Long Marvel isophane insulinInsulin 30/70 Mix Marvel biphasic insulinTevagrastim TevaRatiograstim/Filgrastim Ratiopharm RatiopharmBiograstim CT ArzneimittelFilgrastim Hexal HexalZarzio SandozNivestim filgrastim Hospira Neupogen Approval Jun-10ApprovalAug-07Dec-07Jan-08Sep-08Feb-09ApprovalApprovalWithdrawalApprovalfilgrastimfilgrastimEprexEprexepoietin alfaepoietin zetaMarvel HumulinNeupogenNeupogenSince 2006: 14 biosimilars (2 somatrotropins, 5 EPOs and 7 GM-CSFs wereapproved in EU>40 EMA SA by Q4 2012
    6. 6. Next biosimilar targets• Pegfilgrastim (Neulasta)• Interferon beta (Avonex, Rebif)• Insulin glargine (Lantus)• Etanercept (Enbrel)Monoclonal antibodies:• Infliximab (Remicade) application under assessment• Trastuzumab (Herceptin)• Bevasizumab (Avastin)• Rituximab (MabThera)• Cetuximab (Erbitux)• Adalimumab (Humira)• Palivizumab (Synagis)
    7. 7. Definitions Biological substance: produced by or extracted from abiological source and for which a combination of physico-chemical-biological testing and the production process andits control is needed for its characterisation and thedetermination of its quality Similar biological medicinal product (SBMP or “biosimilar”):a new biological medicinal product claimed to be similar toa reference medicinal product authorised in the EUDoes not meet the definition of a generic product “owing to,in particular, differences relating to raw materials ordifferences in manufacturing processes” (Directive2004/27/EC)
    8. 8. Biosimilar: Definition• Reference is approved in EU or at least in one of EU countries• Biosimilarity development pathway involving relevant orthogonal analyticalcomparability methods, non-clinical and clinical models utilised from theoutset rather than in opportunistic fashion• Quality TTP should be achieved (atypical glycosylation profile and presenceof impurities should be justified)• An authorised biosimilar is generally administered via the same route ofadministration• The same dose (posology) as the reference products in indications approvedfor a reference medicinal products• Primary structure identical to the reference biological product• Like the reference medicine, the biosimilar has a degree of natural variability• Biosimilar and reference products have independent life cycle fate• Quality, non-clinical, and clinical attributes are sufficiently similar yet mightnot be identical between the biosimilar and the reference product• More data is required as ‘essential similarity’ cannot be met
    9. 9. Biosimilars and “biobetters”Attributes Biosimilars “Biobetters”Experience Number of precedents No cases described sofarQuality Similar TPP Different or atypical TPPPK / PD Similar to reference Exaggerated or atypicalEfficacy Similar to reference Enhanced efficacySafety Similar to reference Similar / improvedImmunogenicity Similar to reference Similar / improvedRoute of administration The same as forreferenceThe same or differentAdditional indications Potentially newindicationsDifferent or newindicationsRegulatory path Biosimilar New Active Substance
    10. 10. The biosimilar concept Stepwise development approachsufficient evidence of comparability at each stage quality non-clinical PK/PD efficacy/safety
    11. 11. Comparability toolsHighLow Probable clinical relevanceof differences foundSensitivity to productdifferencesReference BiosimilarReference BiosimilarReferenceReferenceBiosimilarBiosimilarAB
    12. 12. The biosimilar concept Holistic review processbiosimilarityconclusion based onall parts of the dossiertaken together
    13. 13. EMA Guidelines for Biosimilar ProductsOverarching Guidance (CHMP/437/04)Under revision: EMA/CHMP/BMWP/572643/2011Concept and basic principles for biosimilar developmentProduct Specific Annexes to Non-/Clinical GuidelinesQuality Guideline (Draft)EMA/CHMP/BWP/247713/2012Non-/ClinicalGuidelines(Under revision)EMA/CHMP/BMWP/572828/2011InsulinsEMEA/CHMP/BMWP/32775/2005(Under revision)(2011)IFN-betaBeta (draft)CHMP/BMWP/652000/2010IFN-alphaEMEA/CHMP/BMWP/102046/2006LMWHEMA/CHMP/BMWP/86572/2010SomatotropinsEMEA/CHMP/BMWP/94528/2005GM-CSFEMEA/CHMP/BMWP/31329/2005FSHCHMP/BMWP/671292/2010mABEMA/CHMP/BMWP/403543/2010(Draft)EpoietinEMEA/CHMP/BMWP/301636/08
    14. 14. EMA and FDA differences in evaluation of thebiosimilarityEMA FDASimilar TTP Highly similar TTPRisk driven non-clinical package NHP data still needed for biosimilar MABsPK/PD study PK/PD study (address any differencesbetween US and EU commercializedbatches of the reference product)Therapeutic equivalence study Might be waived in some casesRMP in all cases REMS in exceptional circumstancesNot appropriate Switching data
    15. 15. Stepwise process• Step 1: Orthogonal in vitro functional assays• Step 2: Determination of the need for animal studies• Step 3: Conduct of the relevant animal studies
    16. 16. Step 1: Orthogonal bioassays addressing multiplefunctions
    17. 17. Step 2: Determination of the need for in vivostudiesRelevant in vivo model:• Species (NHP, transgenic or transplant model)• Design: sensitivity and variabilityFactors to consider if relevant in vivo models available:• Presence of quality attributes not detected in reference (e.g.PTMs);• Presence of quality attributes in higher amounts than those inthe reference (e.g. impurities)• Relevant differences in formulation (excipients etc.)
    18. 18. Scenarios in step-wise decision making in non-clinical development of biosimilarsStep 1 is OKStep 2 is OKStep 1 is OKStep 2 some concerns(e.g. new formulation,relevant sensitivemodels exist)Step 1: differences foundStep 2: risks and concernsClinicaldevelopmentStep 3: in vivomodels andadditional dataDifferences betweenrequirements from FDA, EMA,PMDA and Indian Agency
    19. 19. Clinical requirementsThe clinical comparability exercise:a stepwise approach1. PK/PD studies: in all cases2. Clinical efficacy/safety trial(s)o PK/PD may be sufficient to establish clinical comparabilityregarding efficacy if PD marker is an accepted surrogate markerfor efficacy (e.g. insulin)o efficacy in an appropriate model (assay sensitivity)o safety & immunogenicity always necessary
    20. 20. Clinical requirementsPharmacokinetics not a standard bioequivalence study! comparison of absorption and elimination (Cl, T1/2) choice of the design and equivalence margins to be justifiedPharmacodynamics to be justified! relevance of the PD marker choice of the population (re assay sensitivity) choice of the study design, duration, dose (in the steep part ofthe dose response curve, preferably several doses)
    21. 21. Example of PK or PD failurePK solubleinsulintestPD isophaneinsulintestEPAR, EMAwebsite
    22. 22. Example of PK & PD successEPAR, EMAwebsite
    23. 23. PK studies in healthy normal volunteers• Ethical challenges• Provide with lesser variability and greater sensitivity• Immunocompetent host• Preferred in single dose settings• Optimal to gain initial clinical insight into PK/PD similarity• Should be avoided in situations when subjects are likely todevelop immunogenicity but may require product in the future• Avoid when high risk of immunogenicity or serious AEs (e.g.PML).
    24. 24. PK study design• Preferred: single dose in HV with full characterisation of PKprofile including late elimination phase (e.g. 5 half-lives)• Non-mediated clearance• Parallel / crossover (e.g. etanercept)- If not possible:• Single dose in patients• Multiple dose in patients
    25. 25. Sampling times• In SD studies: should cover whole PK profile,including late elimination phase• Sufficient sampling time-points around predicted Cmax• In MD studies:- Ideally, first dose (most sensitive comparability) andlast dose (for elimination)- Otherwise, first dose and steady state (e.g. during 4-8cycle NHL treatment with rituximab – after 6 cycle orin CLL: cycles 2-6 after 4 cycle).
    26. 26. PK parameters• In SD studies:- Primary: AUC(0-∞)- Secondary: Cmax, Tmax, Vd, T1/2- For subcutaneous route: Cmax should be co-primary; partial AUCsas secondary• In MD studies:- Primary: truncated AUC(0-t) after first dose and AUC(0-T) overa dosage interval at steady state;- Secondary: Cmax and Ctrough at steady state
    27. 27. Statistical tests• Primary- Equivalence margins of 80-125%- Justification of any widening (including the impact on safetyand efficacy) – if slightly outside without any impact on efficacymight be accepted.• Secondary- Descriptive statistics with ratio / difference and 90%CIs –discussion of results
    28. 28. Clinical efficacyAdequately powered randomised (double-blind) parallelgroup equivalence trial in the most sensitive andpreferably well-known model choice of the equivalence margin to be justified!Example : Adalimumab or infliximab biosimilarPrimary endpoint: equivalence of ACR20 or DAS28Both include some indices which are subjective, e.g. number of tender joints(DAS28, ACR20), patient assessment of pain, and physician and patientglobal assessments of disease activity (ACR20)ACR20 represents the change in activity over time (20% improvement)New 1 efficacy/safety study with one route 1 bridging multiple-dose PK/PD study with the other route
    29. 29. Patient population and dose selection• Homogenous and most sensitive to reduce variabilityattributed to disease, target expression, concomitanttherapies• No requirement to test all approved dose regimens• Most sensitive dose should be chosen• Low dose is more sensitive to study target-mediatedclearance (because the mechanism is less likely to besaturated)• High dose more appropriate in general to study nonspecific clearance and address safety differences
    30. 30. Justification for the margin sizePlacebo Reference product18% 42%∆24%Margin for equivalence 12%Prior knowledge: EPAR, literature and symposia
    31. 31. General principles in immunogenicity• The assay should be in place from Phase I study• Sensitive and specific assay: for both reference and biosimilar• Validated screening, confirmation and neutralisation assays• Justification of periodicity and timing of sampling• Sensitive patient population and subgroup analyses (exposurerelated, immunosuppression status related, across indications,AE-related, loss of efficacy, PK/PD modelling)• Monitoring of immunogenicity without switching up 12 month• Switch-associated immunogenicity data (not required in EU)• EU: descriptive evaluation of immunogenicity• US: one-sided margin for immunogenicity (larger study)
    32. 32. Extrapolation of indications• It is possible to extrapolate therapeutic similarity• Justification will depend on MOA, own clinical experience, andavailable literature data• Depends on the strength of knowledge around MOA (e.g. poorunderstanding of Fc-receptor binding pattern and functionality)• MABs with both immunomodulatory and anti-tumour MOA:quality, non-clinical database, potency assay(s) and in-vitroassays that cover the functionality of the molecule• In some cases extrapolation is more challenging: e.g. rituximab
    33. 33. Extrapolation: Outcomes• Reliant on the totality of biosimilarity exercise andsatisfactory results of clinical studies and functionalcellular assays• The preferred option is to grant all indications ratherthan just few core indications with shared MoA• Scenario with rituximab is the most complex
    34. 34. Pharmacovigilance of biosimilars: principles• Reference and biosimilar have independent from each other life cycles• No need to reiterate reference safety profile but safety burdenassociated with reference products is still attached• Pre-approval PV database will be limited and rarely exceed 500-700patients• RMPs for all new products including biosimilars are mandatory• RMP / Postmarketing PV activities will be expected in all cases• Risk management is closely linked with education of patients andprescribers• Biosimilar companies will have to deal with poor education around useof reference products• Closer monitoring of patients following the switch: 0-6 months and upto 1 year for the adequacy of response, AEs / complications, andimmunogenicity• Postmarketing observational studies / registries will be expected insome cases
    35. 35. Pharmacovigilance Plan Important identified and potential risks based on the referenceproduct – especially rare ADRs Planned activities outside routine PV• Traceability of batches• Monitoring of safety and risks in sub-populations (pregnancy, paediatric etc.)• Enhanced safety monitoring in indications based on extrapolation• Immunogenicity and switcheability• Risk for off-label usePost-authorisation safety/efficacy studiesinterventional• long-term or repeated treatment (e.g. continuation of pivotaltrial)• systematic antibody testing• other (extrapolated) indication, route of administrationnon interventional (registries)drug utilisation surveysClinical requirements: Risk Management Plan
    36. 36. Product labelling Same as the reference product, including same ADRs same PK/clinical efficacy study results However, a few additional wording possible, e.g. description ofstudy results“During clinical studies 541 cancer patients and 188 healthy volunteers wereexposed to Filgrastim ratiopharm. The safety profile of Filgrastim ratiopharmobserved in these clinical studies was consistent with that reported with thereference product used in these studies”. Specific statement in section 5.1 (Pharmacodynamic properties)<(Invented) Name> is a biosimilar medicinal product. Detailed information isavailable on the European Medicines Agency website; www.emea.europa.eu
    37. 37. “Changing one medicine for another that isequivalent” (WHO) Interchangeability: medical practice in a clinicalsetting, on the initiative or with the agreement ofthe prescriber Substitutability: dispensing at the pharmacy levelwithout requiring consultation with the prescriber Automatic substitution: obligation of substitutiondue to national or local requirements
    38. 38. Switching / interchangeability data• FDA: no precise study design, might be waived if highlevel of biosimilarity is declared• EMA: no pre-approval requirements but post-marketing PV monitoring of switch-associatedphenomena
    39. 39. Substitutability The rules for substitution are within theremit of the EU national authorities Most EU member states have already taken action. In the UK, MHRA recommendation (Feb-2008)“When prescribing biological products, it is good practice touse the brand name. This will ensure that automaticsubstitution of a biosimilar product does not occur when themedicine is dispensed by the pharmacist.”
    40. 40. Substitutability At EU level, same labelling for all erythropoietins(2010): SmPC (Special warnings): “In order to improvethe traceability of ESAs, the trade name of theadministered ESA should be clearly recorded (orstated) in the patient file” . Patient leaflet: “<Brand name> is one of a groupof products that stimulate the production of redblood cells like the human protein erythropoietindoes. Your healthcare professional will alwaysrecord the exact product you are using.”
    41. 41. SubstitutabilityNew EU pharmacovogilance directive (2010/84/EU) Some medicinal products are authorised subject to additionalmonitoring. This includes all medicinal products with a newactive substance and biological medicinal products, includingbiosimilars, which are priorities for pharmacovigilance. Member states shall ensure, through the methods forcollecting information and where necessary through the follow-up of suspected adverse reaction reports, that all appropriatemeasures are taken to identify clearly any biological medicinalproduct prescribed, dispensed, or sold in their territory which isthe subject of a suspected adverse reaction report, with dueregard to the name of the medicinal product, and the batchnumber.
    42. 42. Questions and thanks for your participation

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