29. Prof. Sergey Tulyandin - Russian Scientific Oncology N.N. Blokhin Center

Clinical aspects of Intercheangibility, substitution and therapeutic switch of Biological Medicinal Products.

From the Medical Community Point of View.

S.A. Tjulandin

Russian Academy of Medical Science, N.N. Blokhin Russian Cancer Research Center

Moscow

Russian Society of Clinical Oncology (RUSSCO)www.rosoncoweb.ru

Biosimilar medicinal product means a biological medicinal product with quality, efficacy and safety parameters similar to the originator biological medicinal product in the same dosage form

MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION Site search:

News Ministry Pool of Documents Public Reception Room Events Contact Us

Home Pool of Documents Draft Regulations Draft Federal Law dated May 6, 2013

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Draft Federal Law dated May 6, 2013On Making Amendments to Federal Law on Circulation of Medicines and to Article 333.32.1, Part 2, Tax Code of the Russian Federation

What are we (patients and physicians) afraid of?

• The existing chemical structure differences between the biosimilar and the originator medicinal product may: – Lead to clinically significant changes in the drug

efficacy;

– Increase toxicity and, in particular, frequency of complications caused by the drug immunogenicity.

Biosimilars: Existing Approaches

• Biosimilar = generic

Simplified registration procedure after minimal clinical trials

Filgrastims registered in RF, May 2013 (GRLS, MoH)

Trade name Manufacturer MA status CountryGranogen® Pharmapark LLC Valid Russia

Granulocyte colony stimulating human recombinant factor (rhG-CSF)

Vector VB GNTs FGUN of the Federal Service for Human Rights and Consumer Welfare valid Russia

Grasalva Lemeri S.A. De S.V. valid MexicoZarsio I.D.T. Biologika GmbH valid GermanyImmugrast® Dr. Reddi’s Laboratories Ltd. valid IndiaLeucostim® Biocad CJSC valid RussiaLeucyta BEG Health Care GmbH valid GermanyMyelastra Lance-Pharm LLC valid RussiaNeupogen® F.Hoffmann La Roche Ltd. valid Switzerland

Neupomax Pharmstandard – Ufa Vitamin Plant OJSC valid Russia

Neutrostim®

Vector – Main Scientific Center for Virusology and Biotechnology valid Russia

Tevagrastim Lemeri S.A. De S.V. valid MexicoFilgrastim Masterclon CJSC valid RussiaFilgrastim Pharmapark LLC valid Russia

FilgrastimShandung Casing Bioproducts Co. Ltd. valid China

Filergim® Intas biopharmaceuticals Ltd. valid India

An efficient originator medicinal product must not be substituted with a biosimilar (?) with

unknown properties.

Interchangeability-substitution is not acceptable due to the following reasons:

• Insufficient pharmacovigilance system & supervision;

• Absence of GMP at most pharmaceutical production facilities in Russia;

• Inadequate quality control by the state.

An interchangeable medicinal product is a medicinal product, other than a biological medicinal product, with proven therapeutic equivalence to the originator medicinal product

MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION Site search:

News Ministry Pool of Documents Public Reception Room Events Contact Us

Home Pool of Documents Draft Regulations Draft Federal Law dated May 6, 2013

Forward MS Word Version Printable Version

Draft Federal Law dated May 6, 2013On Making Amendments to Federal Law on Circulation of Medicines and to Article 333.32.1, Part 2, Tax Code of the Russian Federation

But if interchangeability is prohibited, there are no incentives to create and manufacture

biosimilars.

When interchangeability can be allowed?

Drugs that proved their pharmacological and clinical comparability (conventional identity) are interchangeable

-(with certain assumptions)

Streamlining biosimilar study and registration

• Pre-clinical trials (intensive study of action mechanisms; in vitro/in vivo efficacy and toxicity as compared with the originator medicinal product).

• Clinical trials – Pharmacological comparability (pharmaco-kinetic trial in comparison

with the originator medicinal product, in healthy volunteers or patients);

– Therapeutic comparability (Phase III comparable study to assess efficacy and toxicity of the originator medicinal product and the biosimilar in terms of some particular indication in a homogenous patient group).

• Pharmacovigilance

ЕMA, 2012

The changes planned do not describe any requirements to registration of biosimilars

MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION Site search:

News Ministry Pool of Documents Public Reception Room Events Contact Us

Home Pool of Documents Draft Regulations Draft Federal Law dated May 6, 2013

Forward MS Word Version Printable Version

Draft Federal Law dated May 6, 2013On Making Amendments to Federal Law on Circulation of Medicines and to Article 333.32.1, Part 2, Tax Code of the Russian Federation

Outstanding issues in biosimilars’ registration and clinical application

• Extrapolation to other clinical indications;• Immunogenicity;• Switch from the original medicinal product to the

biosimilar and back (multiple) and developmental toxicity assessment.

Thus, there can be no automatic interchangeability=substitution (it does not exist

anywhere in Europe)

Outstanding issues in biosimilars’ registration and clinical application

• Extrapolation to other clinical indications;• Immunogenicity;• Transfer from the original medicinal product to the

biosimilar and back (multiple) and developmental toxicity assessment.

Thus, there can be no automatic interchangeability=substitution (it does not exist

anywhere in Europe)

Regulatory Agency Structure and cooperation

Regulatory Cooperation

Issue of Biosimilars