Basics of Biologics| Biosimilars| USFDA| In View of Regulatory Point.pptx

A detailed introduction of Biologics and Biosimilars regulatory framework with respect to USFDA framework

1. Brief About Biologics Presented By Jaya Prakash Veluchuri

2. Table of Contents. 01 | Biologics 02 | Biosimilars 04 | Biologic License Application 05 | P urple Book 03 | Interchangeable Biosimilars 06 | BPCI Act

3. Biologics are medicines derived from living cells or through biological processes . They are relatively complex molecules usually consisting of proteins , carbohydrates, nucleic acids, cells or tissues. Biologics 01

4. Biological products are a subset of drugs defined by PHS Act as a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings. The use of living organisms to produce therapeutic extracts is not new. What is new is manipulation of these organisms genetics to produce specific therapeutics. Biologics include hormones, vaccines, blood products, allergenics, monoclonal antibodies, recombinant therapeutic proteins, gene and cellular therapies, growth factors, cytokines, insulin, among others. (excluding peptides)

5. Why do we need Biologics? Biologics are very target-specific and their side-effects are mostly related to exaggerated pharmacological effects, whereas small molecules are more prone to induce harmful non-target effects . Perhaps the most significant benefit of biologics is their promise in treating diseases that were once considered either untreatable or difficult to treat. 

6. Biologics are designed to interact with the immune system in specific ways; they bind with high specificity to their targets on intracellular components or cell surfaces. Biologic drugs are less likely to interact with other drugs and reduces the most common adverse effects caused by drug-drug interactions .

7. Biologics Vs. Small Molecule Drugs Technically, biologics differ from small molecules based on size and manufacturing process . While biologics are typically greater than 1 kDa in size , small molecules are relatively smaller, usually between 0.1 and 1 kDa .

8. A biological product that is approved based on a showing that it is highly similar to an already approved biological product, and has no clinically meaningful differences in terms of safety, purity and potency from the reference product. Biosimilars 02

9. Biosimilars: ‘Similar But Not the Same’ Biosimilars manufactured by different manufacturers will differ from the innovative product and from each other They are not generic biologics They use a different ‘host cell’ to develop the biosimilar product The active ingredient of a biosimilar can at best only resemble that of the original biologic How an innovator makes its biologic can never be copied down to the last detail; a biosimilar is made using different cells and different processes

10. Two Different Processes Create Two Non-Identical Biologic Products START Different vectors to insert the gene B ot h may u s e t h e s a m e g e n e s e qu e n c e Different host cells to grow the protein E N D Different biophysical characteristics in final product Different downstream processing Different fermentation/ culture conditions

11. Which Changes Matter? Which Don’t? A single additional H-bond increases thermodynamic stability and could change the aggregation. Molecular Weight: 148,683.5 [g/mol] Molecular Formula: C6,440 H9,928 N1,704 O2,011 S56 V al T h r A s p We don’t know unless identified and clinically tested! Does this impact safety/efficacy?

12. Innovator Manufacturing Change vs. Biosimilar Product Development Comparability Testing Manufacturing Lab A pp r o v e d Inn o v a t o r Product Manufacturing Lab Product Optimization Phase I P r e c l i n ic a l Testing Phase III Clinical Testing Phase II Animal Testing O p t i m i z e d Innovator Product Approved? Patent Publication M a nu f act u r i n g Lab – Product Design Bi os i mil a r Product S imil a r i ty Testing A pp r o v e d Inno v a t o r Product Approved? Innovator Manufacturing Change Biosimilar Product Development W o r ks to r eve r s e eng i nee r i nno v a t o r p r odu ct using publically available information Works to optimize already approved product for which a lot of information is already known to manufacturer

13. Interchangeable Biosimilar 3

14. Interchangeable or Interchangeability means : The biological product is biosimilar to the reference product; It can be expected to produce the same clinical result as the reference product in any given patient. The product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch. Note: The interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.

15. A Biologics License Application (BLA) is submitted to the Food and Drug Administration (FDA) to obtain permission for distribution of a biologic product. It is regulated under 21 CFR 600-680 which explains the regulations and permissions associated with “a request for permission to introduce, or deliver for introduction, a biologic product.” Biologics License Applications 4

16. Public Health Service Act describes two approval pathways: Section 351 (a) : The Full BLA Section 351 (k) : The Biosimilar BLA To submit a BLA, applicants are required to submit a Form FDA 365h CBER. A Form FDA 356h is an application submitted to place a new drug, biologics or antibiotics in the market.

17. 351( a) 351(a) is the traditional pathway for approval of biologics and innovator biologics under the Public Health Service (PHS) act. The submitted application must contain all the information regarding the safety and effectiveness of a biological product. It is also known as a “ stand alone ” application.

18. 351(k) Demonstration of the product-in-review to be biosimilar to a reference product Usage of same mechanism(s) of action for the intended condition(s) of use, limiting to the mechanisms of the reference product Previously approved condition(s) of use for labeling Route of administration , dosage form and strength as per the reference product Details regarding the manufacturing of the product to ensure the safety and efficiency of the manufacturing plant and process.

19. The Purple Book database contains information on all FDA-licensed (approved) biological products https://purplebooksearch.fda.gov/ Purple Book 5

20. Licensed Biological Products List for Blood and Plasma Products: https://www.fda.gov/vaccines-blood-biologics/licensed-biological-products-supporting-documents Biologics Approvals By Year: https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/biological-approvals-year

21. BPCI Act 2009 6

22. The Biologics Price Competition and Innovation Act of 2009 (BPCI Act)  amends the Public Health Service Act (PHS Act) to create an abbreviated approval pathway for biological products shown to be  biosimilar  to, or interchangeable with, an FDA-licensed reference biological product. The BPCI Act is closely related to the Drug Price Competition and Patent Term Restoration Act of 1984 (or referred to as the " Hatch-Waxman Act "), which established abbreviated pathways for the approval of drug products under the Federal Food, Drug, and Cosmetic Act (FD&C Act).

23. Thank you! Do you have any questions?