“Clinical aspects of Interchangeability, substitution and therapeutic switch of Biological Medicinal Products. From the Medical Community Point of View” Provides an overview of the concerns around interchangeability and automatic substitution from the perspective of the physicians and the patients

1. 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

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

4. 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.

5. Biosimilars: Existing Approaches
• Biosimilar = generic
Simplified registration procedure
after minimal clinical trials

6. Filgrastims registered in RF, May 2013 (GRLS, MoH)
Trade name Manufacturer MA status Country
Granogen® 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 Mexico
Zarsio I.D.T. Biologika GmbH valid Germany
Immugrast® Dr. Reddi’s Laboratories Ltd. valid India
Leucostim® Biocad CJSC valid Russia
Leucyta BEG Health Care GmbH valid Germany
Myelastra Lance-Pharm LLC valid Russia
Neupogen® 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 Mexico
Filgrastim Masterclon CJSC valid Russia
Filgrastim Pharmapark LLC valid Russia
Filgrastim
Shandung Casing Bioproducts Co.
Ltd. valid China
Filergim® Intas biopharmaceuticals Ltd. valid India

7. An efficient originator medicinal product must
not be substituted with a biosimilar (?) with
unknown properties.

8. 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.

9. 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, 2013
On Making Amendments to Federal Law on Circulation of Medicines and to Article
333.32.1, Part 2, Tax Code of the Russian Federation

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

11. When interchangeability can be allowed?

12. Drugs that proved their
pharmacological and clinical
comparability (conventional identity)
are interchangeable
-
(with certain assumptions)

13. 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

14. 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, 2013
On Making Amendments to Federal Law on Circulation of Medicines and to Article
333.32.1, Part 2, Tax Code of the Russian Federation

15. 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)

17. 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)

18. Regulatory Agency Structure and cooperation

19. Regulatory Cooperation

20. Issue of Biosimilars