18. Dr. Andrey Vasiliev - Ministry of Health (Russian Federation)


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“Approaches to evaluation of various groups of biological products in Russia”

Provides an overview of the current assessment approaches applicable to biotherapeutics in the Russian Federation

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  • Координационная группа по процедуре взаимного признания и децентрализованной процедуре по лекарственным препаратам для медицинского применения ( Co-ordination group for Mutual recognition and Decentralised procedures – Human, CMDh)
  • С целью оптимизации обращения биологических лекарственных средств и их аналогов участники научной сессии ВНОК считают целесообразным : 1. Рекомендовать к рассмотрению включение понятия ≪ биологическое лекарственное средство ≫ и ≪ биологический аналог ≫ или ≪ биоаналог ≫ в ≪ Закон об обращении лекарственных средств ≫ . 2. Предложить изменения процедуры регистрации биоаналогов низкомолекулярных гепаринов на территории РФ с обязательным представлением данных специально спланированных проспективных клинических исследований по сопоставлению эффективности и безопасности оригинального и воспроизведенного лекарственных средства ( исследова - ний на клиническую эквивалентность ). При внесении изменений руководствоваться современными документами , разработанными Европейским медицинским агентством (EMA) и Международным обществом по тромбозу и гемостазу (ISTH). 3. До внесения изменений в процедуру регистрации биологических аналогов низкомолекулярных гепаринов при принятии решения об использовании лекарственных средств такого рода у конкретного больного или на организационном уровне рекомендовать учитывать полноту доказательств не только их фармакологической , но и клинической эквивалентности оригинальному препарату по каждому из предложенных показаний .
  • Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry Матрично-активированная лазерная десорбция/ионизация с время-пролётным масс-анализом High Performance Anion Exchange Chromatography with Pulsed Amperometric Detection Высокоэффективная анионообменная хроматография с импульсным амперометрическим детектированием
  • 18. Dr. Andrey Vasiliev - Ministry of Health (Russian Federation)

    2. 2.  Medicinal product containing biological activesubstance. Biological active substance is a substance that isproduced by or extracted from a biological sourceand needs for its characterisation anddetermination of its quality a combination ofphysico-chemical-biological testing, together withproduction process and control.2Item «b» section Part I Annex I to Directive2001/83/ЕС
    3. 3.  Automatically◦ Immunological medicinal products◦ Human blood and plasma products◦ Medicinal products developed with the help of the followingbiotechnological processes Recombinant DNA technique Controlled gene expression coding for biologically active proteins inprocaryotes or eukaryotes including transformed mammalian cells Hybridoma and monoclonal antibody methods◦ Advanced therapy medicinal products On the resolution of CMDh (subject to agreement withEMA)◦ Low molecular weight heparins and pancreatines (2006)◦ See further (2007)3Directive 2001/83/EC, Provision(EC) № 726/2004, EMA
    4. 4. 4The list is not fullCMDh: Overview of Biological ActiveSubstances of Non-Recombinant Origin
    5. 5.  Biosimilar (bioanalogous) medicinal product –biological medicinal product◦ which is developed or manufactured with the help of gene engineeringand/or biotechnology methods,◦ which is similar to the reference product (original medicinal product) interms of quality, safety and efficacy, provided that the detecteddifferences are not clinically relevant,◦ which does not fall within the definition of a generic medicinal product. The issue of securing the definition of biosimilar(bioanalogous) medicinal product in legislation is nowbeing considered in the Russian Federation.5Guideline on evaluation ofmedicinal products,FSBI “SCEMP”
    6. 6.  When evaluating innovative biological andbiosimilar products the FSBI “SCEMP” of theMinistry of Health of Russia takes into accountinternational regulatory practices (EMA, WHO) Guidelines on conducting investigations andevaluating their results are harmonised to theextent possible with international approaches andcumulative regulatory experience of the Ministry ofHealth of Russia.6
    7. 7.  According to article 14 – stepwise evaluation (Clinicaltrials stage) is not performed for those medicinalproducts that have been authorised for medical use onthe territory of the Russian Federation for more than20 years and for which it is impossible to carry outbioequivalence studies. However biosimilars are not assumed as a perfect copyof the reference product, therefore this rule does notapply to them.7
    8. 8.  Enoxaparin sodium has been authorised in Russiasince 1992 (>20 years), in Europe – since 1991. However taking into account the biological origin of thepharmaceutical substance and impossibility ofassuring efficacy and safety based only on analyticaltests and bioequivalence studies, the EMArecommends using biosimilarity concept. This opinion is shared by leading Russian scientistsincluding the All-Russian Scientific Society ofCardiologists*.8* Scientific session of the ARSSC: “Medicinalproducts of biological origin and their similars”
    9. 9.  Comparability to innovator Orthogonality◦ Tests based on differentprinciples Sequence◦ Quality◦ Non-clinical◦ Clinical The more complex theformulation is, the moretests are needed The scope of testing at eachstage depends on the degreeof biosimilarity, confirmed atprevious stages9
    10. 10. 10
    11. 11. 1. Manufacturing according to the principles andguidelines of Good Manufacturing Practice2. The focus should be on the control of manufacturingprocess – not on analytical tests of medicinal products3. Assurance of pharmaceutical (pharmacopoeial) quality4. Confirmation of comparable quality◦ Identification◦ Impurities (process-related and product-related)◦ Biological (pharmacodynamic) activity◦ Stability of the mentioned indicators through the shelf life11The above-mentioned principles apply toall groups of biosimilars
    12. 12.  Identification◦ Amino acid sequence andmodifications Amino acid analysis Amino acid terminal sequence analysis Peptide mapping◦ Interaction of subunits Ion-exchange chromatography◦ Folding Circular dichroism Capillary isoelectric focusing◦ Immunochemical properties◦ Glycosylation Capillary zone electrophoresis MALDI-TOF HPAEC-PAD◦ Heterogenicity in size, aggregates,charge, hydrophobic nature Polyacrylamide gel electrophoresis Impurities◦ Orthogonal methodssimilar to identificationstudies Biological activity◦ See non-clinicalpharmacodynamicactivity in vitro12
    13. 13.  Regulatory documents are, in fact, specifications for quality control, and not forthe description of physico-chemical, pharmaceutical and biological properties.Quite often regulatory documents do not contain reasoning for the choice ofmethods, their types and number. Quality dossier often contains no data or very few data (including statisticalanalysis of results) on◦ production of a pharmaceutical substance and medicinal product, including: process description control of materials and processes validation of production processes development of production process◦ quality control of a pharmaceutical substance and medicinal product, including: analytical methods validation of analytical methods batch analysis justification of specifications◦ pharmaceutical development of a medicinal product◦ excipients quality control◦ viral safety13
    14. 14.  Scope of testing depends on the degree of biosimilarity, confirmed atthe previous stage Assurance of relative pharmacodynamic activity in vitro◦ Main obligatory type of studies Assurance of relative pharmacodynamic activity in vivo◦ Different animal models depending on the properties of a separate biologicalmolecule Comparative toxicity studies◦ 4-week toxicity studying with multiple-dose introduction, accompanied by studying local tolerance toxicokinetics immunogenicity In certain cases - provided there is scientific rationale -pharmacodynamic (in vivo) and toxicity studies are not needed,because they are not always sensitive enough to detect potentialdifferences.14The above-mentioned principles apply toall groups of biosimilars
    15. 15.  Target antigen binding◦ Cell binding capacity to trans-membrane domain of tissue necrosis factor (TNF)-α Fc-associated functions◦ Complement-dependent cytotoxicity◦ Antibody-dependent cell cytotoxicity Fab-associated functions◦ Counteracting TNF-α activity◦ Binding capacity to TNF-β◦ Apoptosis Bindings to representative isoforms of three corresponding Fc-gammareceptors (FcγRI, FcγRII и FcγRIII), FcRn and complement (C1q)◦ Binding capacity to FcγRI◦ Binding capacity to FcγRIIIa◦ Binding capacity to C1q Cross reactivity with tissues◦ 40 various human tissues15
    16. 16.  There is no rationale for non-clinical programme ofdevelopment Execution of reports often gives no possibility ofdetermining their authenticity There is no detailed description of examinationmethods There are no detailed results, their statisticalprocessing and analysis16
    17. 17.  Scope of testing depends on the degree ofbiosimilarity, confirmed at the previous stage Study of pharmacokinetic and pharmacodynamicproperties (Phase I) is obligatory During Phase III studies one should examine end-points that are more sensitive in terms of potentialdifferences between the compared products.◦ They may not be the same as efficacy end-points, examinedwith regard to the reference product The safety data base, including immunogenicity,should be cumulated for at least 12 months17The above-mentioned principlesapply to all groups of biosimilars
    18. 18.  Pharmacokinetics: crossover study with single subcutaneous andintravenous administration◦ Primary end-point – AUC◦ Secondary: Cmax and T1/2 Pharmacodynamics: healthy volunteers, different doses◦ Primary end-point – absolute white blood cells count◦ Secondary – number of CD34+-cells Efficacy: prophylaxis of severe neutropaenia after cytotoxicchemotherapy in a homogenous group of patients◦ Primary end-point – continuance of severe neutropaenia (ANC <0,5×109/l)◦ Secondary: frequency of febrile neutropaenia, infections and cumulative dose ofrG-CSF Safety: total time of observation should be no less than 6 months Immunogenicity: total time of collecting data should be no less than 12months18
    19. 19.  There is no rationale for clinical developmentprogramme◦ with due regard to the results of comparative studies ofquality and non-clinical studies There is no rationale for the examined surrogateand clinical end-points The time of studying safety is not sufficient, it isnot given enough attention There is no description of pharmacovigilancemeasures19
    20. 20.  It is necessary to ensure uninterrupted monitoring of abiosimilar’s clinical safety, including regular assessmentof expected benefit vs potential risk ratio at thepostmarketing stage It is necessary to take into account the requirements tosafety monitoring, that were made with regard to thereference product or to the whole pharmacotherapeuticgroup20The above-mentioned principlesapply to all groups of biosimilars
    21. 21.  It is recommended to provide a complete packageof documents and data * When changing the production technology ofbiological pharmaceutical substances andmedicinal products, it is recommended to providedocuments on non-clinical and clinical studies** Preparation of documents is an importantadministrative component of the registrationprocedure, the documents should be drawn up ina proper way21*For instance, in accordance with theCommon Technical Document (CTD)**For instance, in accordance with ICH Q5E
    22. 22.  Relying on its own and foreign experience the FSBI “SCEMP” of the Ministry ofHealth of Russia worked out the Guideline on evaluation of medicinal products,including biosimilars, harmonized with requirements of the WHO, ICH and EMA:◦ Chapter 1. Non-clinical studies of safety with the purpose of conducting clinical trials ofmedicinal products and their official authorisation◦ Chapter 2. Studying of pharmacological safety of medicinal products◦ Chapter 3. General principles of conducting clinical trials◦ Chapter 4. Drawing up a protocol for a controlled clinical trial of a medicinal product (choice ofcontrol group)◦ Chapter 5. Statistical principles of conducting clinical trials◦ Chapter 6. Structure and content of clinical trial reports◦ Chapter 7. Bioequivalence studies of generic drugs◦ Chapter 12. Non-clinical assessment of safety in products, produced by biotechnologicalmethods◦ Chapter13. Quality control, non-clinical and clinical studies of biosimilars◦ Chapter 14. Assessment of immunogenicity of therapeutic proteins, produced bybiotechnology22
    23. 23.  Introducing changes into the applicable legislation Special attention paid to quality Non-clinical and clinical trials Training of all participants of pharmaceuticaldistribution Scientific guidelines on separate groups of biosimilarsand types of studies Quality, safety and efficacy of biosimilars can not beassured without the implementation of the GMP, GLP,GCP, GVP and GDP standards and principles23