A.N. Vasilyev

16 May 2013Moscow

FEDERAL STATE BUDGETARY INSTITUTION «SCIENTIFIC CENTRE FOR EXPERT EVALUATION OF MEDICINAL PRODUCTS»

MINISTRY OF HEALTH RUSSIAN FEDERATION

Medicinal product containing biological active substance.

Biological active substance is a substance that is produced by or extracted from a biological source and needs for its characterisation and determination of its quality a combination of physico-chemical-biological testing, together with production process and control.

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Item «b» section 3.2.1.1 Part I Annex I to Directive 2001/83/ЕС

Automatically◦ Immunological medicinal products◦ Human blood and plasma products◦ Medicinal products developed with the help of the

following biotechnological processes Recombinant DNA technique Controlled gene expression coding for biologically active

proteins in procaryotes or eukaryotes including transformed mammalian cells

Hybridoma and monoclonal antibody methods◦ Advanced therapy medicinal products

On the resolution of CMDh (subject to agreement with EMA)◦ Low molecular weight heparins and pancreatines (2006)◦ See further (2007)

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Directive 2001/83/EC, Provision (EC) № 726/2004, EMA

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The list is not full

CMDh: Overview of Biological Active

Substances of Non-Recombinant Origin

Biosimilar (bioanalogous) medicinal product – biological medicinal product◦ which is developed or manufactured with the help of gene

engineering and/or biotechnology methods,◦ which is similar to the reference product (original medicinal

product) in terms of quality, safety and efficacy, provided that the detected differences 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 now being considered in the Russian Federation.

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Guideline on evaluation of medicinal products, FSBI “SCEMP”

When evaluating innovative biological and biosimilar products the FSBI “SCEMP” of the Ministry of Health of Russia takes into account international regulatory practices (EMA, WHO)

Guidelines on conducting investigations and evaluating their results are harmonised to the extent possible with international approaches and cumulative regulatory experience of the Ministry of Health of Russia.

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According to article 14 – stepwise evaluation (Clinical trials stage) is not performed for those medicinal products that have been authorised for medical use on the territory of the Russian Federation for more than 20 years and for which it is impossible to carry out bioequivalence studies.

However biosimilars are not assumed as a perfect copy of the reference product, therefore this rule does not apply to them.

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Enoxaparin sodium has been authorised in Russia since 1992 (>20 years), in Europe – since 1991.

However taking into account the biological origin of the pharmaceutical substance and impossibility of assuring efficacy and safety based only on analytical tests and bioequivalence studies, the EMA recommends using biosimilarity concept.

This opinion is shared by leading Russian scientists including the All-Russian Scientific Society of Cardiologists*.

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* Scientific session of the ARSSC: “Medicinal products of biological origin and their similars”

Comparability to innovator

Orthogonality◦ Tests based on

different principles Sequence

◦ Quality◦ Non-clinical◦ Clinical

The more complex the formulation is, the more tests are needed

The scope of testing at each stage depends on the degree of biosimilarity, confirmed at previous stages

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1. Manufacturing according to the principles and guidelines of Good Manufacturing Practice

2. The focus should be on the control of manufacturing process – not on analytical tests of medicinal products

3. Assurance of pharmaceutical (pharmacopoeial) quality

4. Confirmation of comparable quality◦ Identification◦ Impurities (process-related and product-related) ◦ Biological (pharmacodynamic) activity◦ Stability of the mentioned indicators through the shelf

life

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The above-mentioned principles apply to all groups of biosimilars

Identification◦ Amino acid sequence and

modifications 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 methods

similar to identification studies

Biological activity◦ See non-clinical

pharmacodynamic activity in vitro

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Regulatory documents are, in fact, specifications for quality control, and not for the description of physico-chemical, pharmaceutical and biological properties. Quite often regulatory documents do not contain reasoning for the choice of methods, their types and number.

Quality dossier often contains no data or very few data (including statistical analysis 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 safety

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Scope of testing depends on the degree of biosimilarity, confirmed at the 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

biological molecule 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 potential differences.

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The above-mentioned principles apply to all groups of biosimilars

Target antigen binding◦ Cell binding capacity to trans-membrane domain of tissue necrosis

factor (TNF)- Fc-associated functions

◦ Complement-dependent cytotoxicity◦ Antibody-dependent cell cytotoxicity

Fab-associated functions◦ Counteracting TNF- activity◦ Binding capacity to TNF-◦ Apoptosis

Bindings to representative isoforms of three corresponding Fc-gamma receptors (FcRI, FcRII и FcRIII), FcRn and complement (C1q)◦ Binding capacity to FcRI◦ Binding capacity to FcRIIIa◦ Binding capacity to C1q

Cross reactivity with tissues◦ 40 various human tissues

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There is no rationale for non-clinical programme of development

Execution of reports often gives no possibility of determining their authenticity

There is no detailed description of examination methods

There are no detailed results, their statistical processing and analysis

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Scope of testing depends on the degree of biosimilarity, confirmed at the previous stage

Study of pharmacokinetic and pharmacodynamic properties (Phase I) is obligatory

During Phase III studies one should examine end-points that are more sensitive in terms of potential differences between the compared products. ◦ They may not be the same as efficacy end-points,

examined with regard to the reference product The safety data base, including immunogenicity,

should be cumulated for at least 12 months

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The above-mentioned principles apply to all groups of biosimilars

Pharmacokinetics: crossover study with single subcutaneous and intravenous 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 cytotoxic chemotherapy in a homogenous group of patients◦ Primary end-point – continuance of severe neutropaenia (ANC

<0,5109/l)◦ Secondary: frequency of febrile neutropaenia, infections and cumulative

dose of rG-CSF Safety: total time of observation should be no less than 6

months Immunogenicity: total time of collecting data should be no less

than 12 months

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There is no rationale for clinical development programme ◦ with due regard to the results of comparative

studies of quality and non-clinical studies There is no rationale for the examined

surrogate and clinical end-points The time of studying safety is not sufficient,

it is not given enough attention There is no description of

pharmacovigilance measures

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It is necessary to ensure uninterrupted monitoring of a biosimilar’s clinical safety, including regular assessment of expected benefit vs potential risk ratio at the postmarketing stage

It is necessary to take into account the requirements to safety monitoring, that were made with regard to the reference product or to the whole pharmacotherapeutic group

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The above-mentioned principles apply to all groups of biosimilars

It is recommended to provide a complete package of documents and data *

When changing the production technology of biological pharmaceutical substances and medicinal products, it is recommended to provide documents on non-clinical and clinical studies**

Preparation of documents is an important administrative component of the registration procedure, the documents should be drawn up in a proper way

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*For instance, in accordance with the Common Technical Document (CTD)**For instance, in accordance with ICH Q5E

Relying on its own and foreign experience the FSBI “SCEMP” of the Ministry of Health 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 of medicinal 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 of control 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

biotechnological methods◦ Chapter13. Quality control, non-clinical and clinical studies of biosimilars◦ Chapter 14. Assessment of immunogenicity of therapeutic proteins, produced by

biotechnology

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Introducing changes into the applicable legislation

Special attention paid to quality Non-clinical and clinical trials Training of all participants of pharmaceutical

distribution Scientific guidelines on separate groups of

biosimilars and types of studies Quality, safety and efficacy of biosimilars can

not be assured without the implementation of the GMP, GLP, GCP, GVP and GDP standards and principles

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