1. Introduction to Biosimilars Biologicals Marketing Authorization Directorate Central Administration for Pharmaceutical Affairs www.eda.mohealth.gov.eg biologicals@eda.mohealth.gov.eg biologicals@eda.mohealth.gov.eg Presented by:Dr/Kholoud Mamdouh

2. Biosimilar concept (Q,S and E pov) 1 Biosimilars are not generics

3. EMA concept 2

4. 3

5. Similar Versions 4

6. Generic Vs Biosimilar 5

7. Chemical Vs Biological Aspirin Vs Monoclonal antibody Source: New England Journal of Medicines, “Developing the Nation’s Biosimilars Program,” August 4, 2011

8. Chemical Vs Biological 7

9. Product is the process 8 The Rule in Biologicals The product is the process

10. Guidelines for changing the process 9 Guidelines addressing the changes in the manufacturing process for biological product FDA (April 1996) Guidance for Industry Comparability Protocols Protein Drug Products and Biological Products - Chemistry, Manufacturing, and Controls Information ICH (June 2005) Comparability of biotechnological/biological products subject to changes in their manufacturing process

11. Comparability of biotechnological/biological products subject to changes in their manufacturing process 10

12. Comparability of biotechnological/biological products subject to changes in their manufacturing process 11

13. Guidance for Industry Comparability Protocols Protein Drug Products and Biological Products - Chemistry, Manufacturing, and Controls Information 12

14. Problems issued from changing process of Epotin alfa 13 Eprex formulations With Human serum albumin (HSA) With Polysorbate 80 (Tween ) Diagnosis EPO antibody mediated PRCA cases Unexplained loss of effect (LOE) Anaemia (Hb decreases by about 0.1 g/dl/day) Low reticulocyte count (< 10 000/μl) Platelets. White blood cells : normal Bone marrow (strongly recommended) – Normal cellularity – Erythroblasts very rare (< 5 %) Positive Epo antibody test

15. Change in formulation 14 Immune-response and adverse reactions: PRCA case example Nicole Casadevall - EMA

16. Change in formulation continue 15 The interaction of Tween and the uncoated rubber in pre-filled syringes appears to cause leachates. These leachates have been implicated in causing aggregation of epoetin molecules that then enhance their antigencity.

17. Biosimilars guidance world wide 16

18. Biosimilars guidance world wide 17 Health AuthorityDate of guidance release EMA 2005 WHO 2009 MHLW(Japan) 2009 HC 2010 KFDA 2010 FDA Draft 2012 SFDA 2012 CDSCO (India) 2012

19. EMA (Biosimilars) 18 First guide line 2005 Scope: In principle, the concept of similar biological medicinal product is applicable to any biological product. However, in practice, the success of such a development approach will depend on the ability to characterise the product and therefore to demonstrate the similar nature of the concerned product Reference Should be licensed in EMA

20. Approved EMA Biosimilar Products 19 Product NameActive Substance Authorisation Date Manufacturer/Company Name Abseamed epoetin alfa28 Aug 2007Medice Arzneimittel Pütter GmbH & Co KG Binocrit epoetin alfa28 Aug 2007Sandoz GmbH Biograstim Filgrastim15 Sep 2008CT Arzneimittel GmbH Epoetin alfa Hexal epoetin alfa28 Aug 2007Hexal AG Filgrastim Hexal Filgrastim6 Feb 2009Hexal AG Filgrastim ratiopharm Filgrastim15 Sep 2008 Withdrawn on 20 Apr 2011 Ratiopharm GmbH Nivestim Filgrastim8 Jun 2010Hospira UK Ltd Omnitrope Somatropin12 Apr 2006Sandoz GmbH Ratiograstim Filgrastim15 Sep 2008Ratiopharm GmbH Retacrit epoetin zeta18 Dec 2007Hospira UK Ltd Silapo epoetin zeta18 Dec 2007Stada R & D AG Tevagrastim Filgrastim15 Sep 2008Teva Generics GmbH Valtropin Somatropin24 Apr 2006BioPartners GmbH Zarzio filgrastim6 Feb 2009Sandoz GmbH

21. FDA (Biosimilars/Follow-on protein) 20 (ANDA) process in section 505(j) (ANDA) process in section 505(j) pathway described in section 505(b)(2) pathway described in section 505(b)(2) PHS Act FDC Act section 505 Section 351 Generic drugs Follow on proteins Ammendment BPCI Act Ammendment BPCI Act Biosimilars

22. Follow-On Protein Products: Regulatory and Scientific Issues Related to Developing 21

23. FDA (Follow on proteins) 22

24. FDA (Follow on proteins) 23 The Agency indicated its intention to issue guidance documents to specifically address human growth hormone and insulin. But, as our knowledge of this issue expanded, we reconsidered our focus and determined it would be more appropriate to initially promulgate guidance that is more broadly applicable to follow-on protein products in general. We are in the process of developing such guidance with respect to products approved under the FDC Act (updated 7/2009)

25. Approved follow-on proteins in FDA 24 FDA (Follow on protein) Hylenex (hyaluronidase recombinant human) Hydase (hyaluronidase) Fortical (calcitonin salmon recombinant) Nasal Spray Amphadase (hyaluronidase) GlucaGen (glucagon recombinant for injection) Omnitrope (somatropin [rDNA origin])

26. Case Study: Omnitrope 25 Omnitrope is the first recombinant human growth hormone product approved through the abbreviated pathway, Specifically, the approval was based on the following:

27. FDA (Biosimilars) 26 Scope: The guidance focuses on therapeutic protein products Protein means any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size. Reference: Should be licensed in US

28. WHO (Similar Biotherapeutic Products SBPs) Scope: Applies to well-established and well-characterized biotherapeutic products such as recombinant DNA-derived therapeutic proteins. Vaccines, plasma derived products, and their recombinant analogues are excluded from the scope Reference: 27

29. Health Canada (Subsequent Entry Biologic SEBs) Scope : The guidance applies to biologic drugs that contain, as their active substances, well characterized proteins derived through modern biotechnological methods such as use of recombinant DNA and/or cell culture Canadian Guidelines shares the similar concept of the WHO 28

30. Korean FDA (Biosimilars) Scope: Similar to EMA Concept Reference: should be a biological product authorized in Korea. Preclinical and Clinical aspects Similar to WHO 29 Scope:, well characterized proteins derived through modern biotechnological methods such as use of recombinant DNA technology Rerefence: Registrered in CDSCO (Indian) (Similar Biologic)

31. Thank You