EVOLUTION OF BIOSIMILAR MEDICINES ASSESSMENT IN RUSSIA.

CURRENT PRACTICES AND MAIN CHALLENGES

FEDERAL STATE BUDGETARY INSTITUTION “SCIENTIFIC CENTRE FOR EXPERT EVALUATION OF MEDICINAL PRODUCTS” THE MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION

15 15 MayMay 2013 2013 MoscowMoscow

A.N. Mironov

«Evolution of any system is the result of more or less longstanding variations of its

previous state”

Philosophical encyclopaedia in 5 volumes. – Moscow, Soviet encyclopaedia, under the editorship of F.V. Konstantinov. 1960-1970.

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REGULATION OF APPROCAHES TO BIOSIMILARS ASSESSMENT. BACKGROUND

The main task of the healthcare system is fighting against chronic diseases.

 

Biotechnology and biosimilars pros and cons.

 

Market globalization harmonization of regulatory systems.

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REGULATION OF APPROCAHES TO BIOSIMILARS ASSESSMENT.

BALANCE OF INTERESTS

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MANUFACTURER PATIENT

HEALTHCARE

TIGHTENING OF REQUIREMENTS THERAPEUTIC EQUIVALENCE

FACILITATION OF ACCESS TO THE MARKETGUARANTEED MARKET

ECONOMIC EFFECTIVENESSTHERAPEUTIC EFFICACY

BIOSIMILARS

THE PHENOMENON OF «REGULATORY INERTIA»

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BIOLOGICAL MEDICINAL PRODUCTS

• Immunobiological medicinal products

• Products derived from donor blood and plasma

• Biotechnology-derived medicinal products

• Gene therapy products, somatic cell therapy products and tissue therapy products.

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EVOLUTION OF RUSSIAN REGULATORY SYSTEM

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1994State committee for sanitary and epidemiological control (SCSEC)

1996Ministry of health and medical industry, SCSEC

1998Federal service on surveillance in healthcare (Roszdravnadzor)

1999Roszdravnadzor Federal service on surveillance of human rights protection and well-being MH RF

2010MH RF

2013MH RF

System of domestic medicines

registration and certification

Uniform procedure for evaluation of

foreign and domestic medicines

Federal Act-86 «On

medicines»

Federal Act-61 «On circulation of medicines»

Improvement of evaluation and testing systems

Draft Federal Act

EVOLUTION OF RUSSIAN REGULATORY SYSTEM. TERMINOLOGY

Year Regulatory act Definition

1992 Resolution of State Committee for Sanitary and Epidemiological control “On registration of foreign medicinal immunobiological preparations”

medicinal immunobiological products – preparations intended for specific prophylaxis, diagnostics and treatment of infectious, parasitic diseases and allergic states: vaccines, immunoglobulins, interferons, cytokines, sera, bacteriophages, eubiotics, allergenes, diagnostic preparations, growth media, immunomodulators of bacterial origin

1998 Federal ActN 157-FA «On immunoprophylaxis of infectious diseases»

medicinal immunobiological products – vaccines, toxoids, immunoglobulins and other medicinal products intended for creating specific immunity to infectious diseases

1998 Federal Act N 86-FA «On medicines»

immunobiological medicinal products – medicinal products intended for immunoprophylaxis and immunological therapy

2010 Federal Act N 61-FA «On circulation of medicines»

Immunobiological medicinal products – medicinal products of biological origin, intended for immunological diagnostics, prophylaxis and treatment of diseases

BIOSIMILAR (BIOANALAGOUS) MEDICINAL PRODUCT

Biological medicinal product which is developed or manufactured with the help of gene engineering and/or biotechnology methods, and 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, and which does not fall within the definition of a generic medicinal product.

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Biosimilar medicinal product

Bioanalagous medicinal product

Current state of medicinal products evaluation in the Russian Federation

• 61-FA «On circulation of medicines», set out for the first time the principles of evaluation, as well as requirements to evaluation and to experts.

• The creation of a single expert institution made it possible to work out uniform approaches to requirements concerning the evaluation procedure.

• A team of experts with various specializations takes part in evaluation, the evaluation process has stringent time specifications, the expert conclusions are properly formalized.

• Increasing the transparency of the system, increasing quality and improving the organization of work, greater involvement of expert community into the work.

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Current expert practice• The existing Russian legislation does not have separate regulatory

acts covering biosimilars registration (access to the market), therefore one might think that biosimilars evaluation is based on approaches governing evaluation of generic medicinal products.

• Before 2010 two expert organizations (Roszdravnadzor and State

Scientific-Research Institute for Standardization and Control of MIBP under Federal Service on Surveillance of Human Rights Protection and Well-being) placed contradictory demands on assessment of biologicals: original and generic.

• The approach to assessment of biosimilar medicinal products can not be viewed in the frames of generic products assessment.

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Pharmaceutical preparations, authorized in the Russian Federation

Pharmaceutical preparation

Pharmaceutical substance

INSULINS 26 8SOMATOTROPIN 8 1ERYTHROPOIETIN 12 4G-CSF 16 5INTERFERONS alfa 32 5LMWH 8 3MONOCLONAL ANTIBODIES

23 -

INTERFERONS beta 8 1FSH 12 1

Current practice

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API domestic manufacturing

Finished dosage forms manufacture

Сontinuous manufacturing cycle

API foreign manufacturing

1 2

Drug marketing authorization

Variations to a drugAPI composition Manufacturing site

Quality expert

evaluation

Stepwise similarity

confirmation

API inclusion (marketing authorization)

STEPWISE SIMILARITY CONFIRMATION

• Drug quality assurance• Relative quality confirmation

– Identification– Impurities– Biological (specific) activity– Stability of the mentioned indicators through the expiration date

• Stepwise preclinical safety and efficacy confirmation, including comparative studies

• Stepwise clinical safety and efficacy confirmation, including comparative studies

KEY CONCEPTS AND ISSUES

• Legislation

• Quality

• Preclinical and clinical trials

• Scientific quidelines

BIOSIMILARS EXPERT EVALUATION PROCEDURE

Stage 1. Quality comparative studies for the purpose of similarity confirmation for a biosimilar and an original drug/

Stage 2. Defining the extent of preclinical trials depending on the results of the Stage 1, as well as on the molecule properties and it’s pharmacotherapeutic group.

The lowest amount of required documents include the following:•Inhouse comparative pharmacodynamic studies  in vitro and (or) in vivo results.•Inhouse comparative pharmacokinetic studies results (if applicable).•Inhouse comparative toxicology studies results (subchronic toxicity studies with the assessment of local irritative effect and the influence on immunological status).

Stage 3. Defining the extant and specificity of the intended clinical trials depending on the results of the Stage 2. Clinical Trials within I-III Phases or I and III Phases or clinical research stages with obligatory Phase III or Stage in the Russian Federation.

16Federal State Budgetary Institution «Scientific Centre for Expert Evaluation of Medicinal Products» of the Ministry of Health of the Russian Federation

GUIDELINES AND REFERENCES ELABORATION PROCEDURE

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Current expert practice

Russian legislation

International regulatory practice

CONCEPT

Scientific research

plan

WORKING PARTIES DRAFT

Science

Experts

Laboratories

BiosimilarsReference standards

Cell cultures

GUIDELINES AND REFERENCES ELABORATION PROCEDURE

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DRAFTQUIDELINES,

MONOGRAPHS, ARTICLES

State Pharmacopoeia,

ACTS

STATUS – REGULATORY LEGAL ACT LEVEL

STATUS – NONBINDING LEVEL

SCIENTIFIC QUIDELINES

• Published (2013) as a part of Guideline on expert evaluation, Volume I:– Quality control, preclinical and clinical

research of biosimilar preparations (Chapter 13)

– Immunogenicity assessment of biotechnology-derived. therapeutic proteins (Chapter 14)

SCIENTIFIC QUIDELINES

• Under development:– Guidelines on 9 groups of biosimilars– Guidelines on biological preparations (6

guidelines)– Guidelines on drug quality and preclinical

trials (9 guidelines)– Additional Guidelines (6 guidelines)

CHALLENGES

• The legal status of intellectual property• Complicated molecular structure and high-

technology manufacture• Differences in regulatory requirements,

regulatory inertia• Time scale from the development to the market

access

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SOLUTIONS

Short-term

Long-term

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Elaboration and publishing guidelines and references

Creating a sustainable system model of permanent, continuous improvement of drug marketing authorization and expert evaluation system

THANK YOU FOR YOUR ATTENTION!

FEDERAL STATE BUDGETARY INSTITUTION “SCIENTIFIC CENTRE FOR EXPERT EVALUATION OF MEDICINAL PRODUCTS” THE MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION