Biosimilars

Biosimilars / Follow on Biologics/ Subsequent Entry Biologics

1. BIOSIMILARS DR. SAHIL KUMAR

2. BACKGROUND Technology + Biology Biopharmaceutical drugs / Biologic(al ) medical product/ Biological/ Biologic. Biopharmacology

3. Preventive Therapeutic Diagnostic

4. BIOSIMILARS: INTRODUCTION A biotherapeutic product similar in quality , safety and efficacy to an already licensed reference biotherapeutic product . ( WHO , G uideline for Similar B iotherapeutic P roducts, 2013) A Similar Biologic product is that which is similar in terms of quality, safety and efficacy to an approved reference biological product. ( CDSCO , Guidelines on Similar Biologics, 2016) Biological medicine developed to be highly similar and clinically equivalent to existing biological medicine . ( EMA , 2012) A biological product highly similar to an FDA-approved biological product and has no clinically meaningful differences in safety and effectiveness . ( FDA , 2017)

5. The Synonyms… Follow-on Biologics ( FoBs ) Follow-on Protein Follow-on Biologic Similar Biomedicines Subsequent entry biologicals SBMP (Similar Biological Medicinal Product ) Biosimilars are not ( Bio)generics.

6. How are they manufactured? Develop host cell Establish a cell bank. No two master cell banks are exactly alike . 3. Protein production 4. Purification 5. Analysis 6. Formulation 7. Storage and handling

7. FACTS AND FIGURES >500 million patients helped. (Karpusas M et al. Cell Mol Life Sci1998;54:1203–1216). Biopharmaceuticals - fastest growing segments of pharmaceutical industry (≈50% of the market). Global biosimilars market - $1.3 billion (2013) → $35 billion (2020) (Pharmaceutical Technology . 2015). Patent for original products is going to expire. 418 new biopharmaceuticals being developed . ↑ healthcare services, hopefully “ price war ” will ↓ expenditures.

8. [ Calo-Fernández B, Martínez -Hurtado J (December 2012). "Biosimilars: Company Strategies to Capture Value from the Biologics Market". Pharmaceuticals. 5 (12): 1393–1408]

9. 32% 51% 17% Recombinant non-glycosylated proteins Recombinant glycosylated proteins Recombinant peptides

10. Examples

11. REGULATORY FRAMEWORK

12. THE EUROPEAN SCENARIO First recommendation in 2005; Revision in 2015. Europe forerunner in biosimilar legal framework and regulations. EMA guideline 2015 recommends a stepwise conduct of non-clinical and clinical studies. Non-clinical: binding capability, signal transduction & potentially relevant differences compared .

13. Before approval, EMA requires studies which should include: Pharmacokinetic and Pharmacodynamic studies , Clinical trials of appropriate patient populations, Choice of clinical endpoints in efficacy trials, Evaluation of the immunogenicity of the biosimilar, Pharmacovigilance studies aimed at extrapolating safety and efficacy of the new biosimilar with respect to the already authorized branded medicinal product.

14. THE US SCENARIO

15. INDIAN SCENARIO Regulatory bodies- Deptt . of Biotech. (DBT), & the CDSCO – under the MoHFW . 15 th Aug 2016: “Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India ” Salient features – If reference biologic not marketed in India, can be licensed in other specific countries. Post-marketing : >200 patients; completed within 2 years.

16. If immunogenicity evaluated in clinical studies, not mandatory to carry out in post-marketing studies. If pre-approval studies >100 pts; no. of pts for safety data can be reduced.

17. ISSUES WITH BIOSIMILARS 1) Efficacy: Difference b/w bioactivity of biosimilars and reference products.

18. 2) Safety: Concerns regarding immunogenicity . Consequences : ↓ or ↑ of efficacy, neutralization of a native protein & general immune effects (allergy , anaphylaxis, serum sickness ). Eg. Pure Red Cell Aplasia (PCRA) by Epoetin α . Prone for batch to batch variation. Need for continuous robust pharmacovigilance monitoring to ensure the traceability of the products.

19. 3 ) Substitution: ↓ safety of therapy, causes therapeutic failure. Can confound pharmacovigilance. Should be made with physician’s consent. 4 ) Labeling : Labels should be different . A summary of product characteristics should be transparent and clear. Reference products should be defined . Substitution advice should be provided.

20. CHALLENGES Higher development cost. Same company may market 2 nd Generation agents. Less stable. Traceability. Nomenclature.

21. CONCLUDING REMARK

22. THANK YOU “The process is the product.”