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


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“Regulatory experience with monoclonal antibody submissions in the EU”

Provides an overview of the current EU assessment of biotherapeutics, focusing specifically on monoclonal antibodies

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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
  • Scientific justification for reduced or non-conventional package Some agencies still adopt tick-box approach
  • Causes for concern – linker molecules in conjugated proteins -PEGylated proteins- growth factors, immunosuppressive agents EMEA – tumorogenic potential Reprotox – intended patient population
  • 8. Dr. Alex Kudrin - Medicines and Healthcare Products Regulatory Agency (UK)

    1. 1. IFPMA/AIPM Biotherapeutics Workshop, MoscowRegulatory experience with monoclonalantibody submissions in the EU15-16thMay 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. Production of biologics• A total of about 270 antibodies are currently in phase II-IIIstudies (120 are forecasted to be approved based on ~50%attrition rate)• Products in development for numerous therapeutic indicationsand not only for conventional oncology and autoimmunedisorders• Total production: 18 tonnes in 2009 – expected to reach 80tonnes by 2020 (with at least 10% share of biosimilars: 10tonnes)• Yield of cell cultures will be improved 5-10-fold timesRef: Olav Zulian, 2012
    4. 4. EU assessment of biologics
    5. 5. Mandatory scope for centralised procedure• Recombinant produced biotechnology products, except forsome old biologics• Biosimilars• Advanced cell therapy products• Genetherapy• Orphan products• Generics versions of centralised authorised products• Products for diseases of public importance: oncology andinfectious diseases
    6. 6. Background on therapeutic MABs
    7. 7. MAB nomenclatureSourcestemSuffixo mAbxi mAbzu mAbu mAbImmunogenicity
    8. 8. Therapeutic indications for EU approved MABs• Autoimmune diseases (e.g. Humira, Remicade orMabthera)• Oncology (Avastin, Erbitux, Herceptin, Perjeta,Adcetris)• Passive immunotherapy for some infectious diseases,e.g. Synagis for RSV• Bone disorders: anti-RANKL for PMO (Prolia) andSRE in cancer (Xgeva)• In development: MABs for cardiovascular diseases,Alzheimer’s disease, neurology indications, musclewasting etc.
    9. 9. Very potentchemotherapeutic drug• Tubulin polymerization inhibitors• Maytansines (DM1, DM4)• Auristatins (MMAE, MMAF)• DNA damaging agents• Calicheamicins• Duocarmycins• Anthracyclines (doxorubicin)• Humanized monoclonalAb (IgG1)• mAb with Fcmodifications (modulateADCC, CDC activity)• Other mAb fragmentsLinker stable incirculationAntibody-Drug Conjugate (ADC)Schutten, 2012>100 of ADC is indevelopment
    10. 10. Quality issues
    11. 11. Q5B Genetic StabilityNumerous Quality Guidelines CoveringBiotech ProductsCell Banks Process Drug Substance Drug ProductQ5D Cell SubstratesQ5A Viral SafetyQ6B SpecificationsQ5C StabilityQ5E ComparabilityEMEA/CHMP/BWP/157653/2007: Guideline on development,production, characterisation and specifications for monoclonalantibodies and related products
    12. 12. Characterisation is complex• General characteristics– Appearance, pH, particulates,protein concentration• Identity– Peptide map, IEF,glycosylation, charge profile• Purity– SDS PAGE, RP-HPLC,CE-HPLC, SE-HPLC• Potency– Bio-assay• C-terminal sequencing• Amino acid composition• Monosaccharide ratios• Capillary electrophoresis• Denaturing IEF with Western blot• Circular dichroism• Mass spectroscopy• etc etcMultiple methodologies used to characterisequality attributes from different angles
    13. 13. Non-clinical issues
    14. 14. Safety• Conventional approaches may not be appropriatefor biopharmaceuticals (ICH S6)• Initial concerns = contamination with host cells and host cellDNA– Realization that safety concerns focused around exaggeratedpharmacology• Two key issues– Species selection– Immunogenicity
    15. 15. Typical Toxicology Studies• Single dose• Repeat dose–Generally 1-3 months for biotech products–Short term use / acute life threatening – 2 wks–Chronic use – 6 months• Genotoxicity / Carcinogenicity–Not required unless cause for concern• Reproductive toxicity–Case-by-case basis
    16. 16. Moving into FTIM Low relevance of NOAEL indetermination first dose inhumans; MABEL estimation usingdesirable receptoroccupancy rates of <1-10%using all available animaland in vitro assay data(human primary cell andtissue cultures); Specific consideration toinformed consentprocedures and clarificationof high-level of risksTGN1412 victimSource: Muller and Brennan (2009) Safety Assessment and Dose Selection forFirst-in-Human Clinical Trials With Immunomodulatory Monoclonal Antibodies:Clinical pharmacology & Therapeutics 85: 247-258
    17. 17. Clinical issues: efficacy, safety,immunogenicity and RMP
    18. 18. EMA clinical regulatory framework for MAB• Non-clinical requirements follow ICH guidelines on biotechnology products• Clinical guidance: no MAB specific guidelines• Development is guided by guidelines on development of new drugs forrheumatoid arthritis, cancer, multiple sclerosis etc.• Early pre-phase II-III CHMP SA is encouraged• General principles for establishing efficacy same as for NCEs• Case by case, based on therapeutic indication and patient population• Route of administration is typically parenteral.• Phases of development often blurred due to patient populations targeted e.goncology• Use of biomarkers is encouraged with co-development and validation ofdiagnostic companion test– Potential for highly targeted therapies e.g. HER2 (Herceptin); KRAS(Vectibix and Erbitux)
    19. 19. Evaluation of the efficacy data• The magnitude of the clinical effect (e.g. OS increase)• The longevity of the effect• Type of clinical benefits: disease modifying vs symptomaticeffects (e.g. radiographic data with anti-RA MABs)• Effect on quality of life• Effect on outcomes, e.g. effect on survival or CV-compositeendpoints• Effect in different sub-populations and age groups• Effect in subgroups stratified by biomarker
    20. 20. General principles in immunogenicity evaluation• The assay should be in place from Phase I study• Risk-driven evaluation of immunogenicity data• Assay validated for sensitivity and specificity• 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 up to 12 month• Commonly descriptive evaluation of immunogenicity
    21. 21. Examples of MAB-associated immunogenicityMAB Indication Type Patients withimmune response%Infliximab RA, CD Chimeric 10-60%Adalimumab RA, CD Human 12-25%Natalizumab CD, MS Humanized Up to 30%Trastuzumab Breast, gastriccancerHumanized 4%Rituximab RA, lymphoma Chimeric 1.1-12.7%
    22. 22. Immunogenicity: assessment–Deficiencies: assays are crude and notsufficiently sensitive with false-negative results–Lack of interpretation of the data, e.g. failure tocorrelate Ab presence with any detrimentalclinical effect in individual patients (trough levelsof MAB, and ACR20)–Clinical implementation of immunogenicity testingduring postmarketing period (has been done withRemicade)
    23. 23. Safety• Some serious and poorly understood risks:• Infusion reactions with rituximab• Opportunistic and serious infections• PML with rituximab, natalizumab, efalizumab, etc.• Tumorigenicity (lymphoma with adalimumab andinfliximab);• Osteonecrosis of the jaw and atypical fractures withdenosumabRisk management plan ismandatory for any newbiotechnology products
    24. 24. Safety of biologics• Singh et al. (2011) included 160 RCTs with 48,676 participants and 46extension studies with 11,954 participants. The median duration of RCTswas six months and 13 months for OLEs.• Biologics as a group were associated with a statistically significant higherrate of total AEs (OR) 1.28, 95% CI 1.09 to 1.50;• Number needed to treat to harm (NNTH) = 22, 95% CI 14-60,• Serious infections (OR, 1.37, 95% CI 1.04 to 1.82, NNTH = 108 95% CI, 50to 989)• TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143to 14706).• Infliximab was associated with a statistically significantly higher risk of totalAEs OR 1.55, 95% CI 1.01 to 2.35; NNTH = 13, 95% CI 8 to 505) andwithdrawals due to AEs compared with control (OR 2.34, 95% CI 1.40 to4.14; NNTH = 10, 95% CI 5 to 30) – put in context of NNT (1.5).Singh et al., 2011 Adverse effects of biologics: a network meta-analysis andCochrane overview (Review)
    25. 25. RMP examples: Infliximab and adalimumab• Routine PV activities will be sufficient for a majority ofsignals• Education of prescribers and patients (including alert cards)• If necessary, registries can be set-up if required on the basisof existing registries with Remicade, Humira and Cimzia inEU and US• Pregnancy registries or PASS study
    26. 26. Case example: Natalizumab• Natalizumab is approved for adult patients with relapsing forms of MS (EU)• Currently around 150 PML cases reported with nearly 80,000 patientsreceiving Tysabri worldwide, and >40,000 in the US• PML is seriously disabling and potentially fatal ADR (>20%)• Restricted prescribing and enhanced monitoring allows to reduce risk ofPML (based on TOUCH and Tygris data)• JC serology assay recently introduced into US and EU labels allowsguidance on risk stratification (the highest in JC-positive patients who weretreated with Tysabri for >24 months and who also receive otherimmunosuppressant therapy)
    27. 27. REMS / RMP: Natalizumab• US: A restrictive prototype of TOUCH-MS or TOUCH-CD REMS program are instituted• EU Enhanced research monitoring TYGRIS registry(5000 patients in EU and US)• JC serology assay companion diagnostic assay asper Tysabri SmPC• Pregnancy register• Industry led PML consortium (Roche, Pfizer, Biogen)
    28. 28. New EU pharmacovigilance directive 2010/84/EU) Some medicinal products are authorised subject toadditional monitoring. This includes all medicinal productswith a new active substance and biological medicinalproducts, including biosimilars, which are priorities forpharmacovigilance. Member states shall ensure, through the methods forcollecting information and where necessary through thefollow-up of suspected adverse reaction reports, that allappropriate measures are taken to identify clearly anybiological medicinal product prescribed, dispensed, or soldin their territory which is the subject of a suspected adversereaction report, with due regard to the name of the medicinalproduct, and the batch number.
    29. 29. Typical clinical issues arising during EMA evaluation ofMABs• The efficacy is insufficiently demonstrated (e.g. minor increasein overall survival with oncology MABs or lack of consistencybetween PFS/OS or lack of OS data)• Narrow net benefit• Risk confined to the drug and the type of ADRs: e.g. seriousinfections, malignancies and MACE AEs with briakinumab(anti-IL12) and not compatible with the proposed clinical use(outpatient treatment of psoriasis)• Important identified risks that are difficult to predict, control orminimise (e.g. Raptiva withdrawal from EU in 2009 due to PMLissue (4 cases reported with incidence of 1:500 in psoriasis vs1:800-1000 with Tysabri in MS)
    30. 30. CONCLUSIONS• EU regulations on novel MABs is focused around Qualityissues• Non-clinical guidance is drawn from ICH• Clinical guidance is product group specific and shared withNCE• Safety requirements vary but safety databases are usuallyextensive• RMP and enhanced postmarketing surveillance are mandatorywith MABs
    31. 31. Questions and thanks for your participation