Regulatory Issues for CROs Evaluation of Biotechnology-Derived Pharmaceuticals

1. Regulatory Issues for CROs Evaluation ofBiotechnology-Derived Pharmaceuticals K.K. Tripathi, PhD Adviser and Member Secretary, RCGM Department of Biotechnology Ministry of S&T, GOI kkt@dbt.nic.in The views expressed in this presentation are those of the author and they have nothing to do with the regulatory authoriries in place and GOI

2. Structure of the Presentation • Basics • Defining Biotech Medicines, Biopharmaceuticals, Biogenerics & Biosimilars !!! • EU and USA scenario and perspectives • Indian Viewpoint • Regulation • EU and USA • India

3. What are Biopharmaceuticals? Compared to drug • Biopharma industry-25 yrs old with >350 marketed products. • Term widely used but hardly defined by users • Over 4 million entries on Google search • Involves use of biotechnology and pharmaceutical compared to drug • Antsense oligos, RNAi, synthetic peptides and other products mimic biopharma as well drug

4. Worldwide off Patent Biotech Medicines often referred as Generic Biophamaceuticals, (USA) Biogenerics, (USA) Follow-on Biologics, (USA) Biosimilars, (EU) (rDNA & hybridoma derived) Off Patent Biologicals, (All) and so on ,,,,,,,,,,,,,,, Definition is Market and Commerce based

5. What Are Biotech Medicines? Biotech medicines often replace or supplement a natural protein produced by the body, satisfying medical needs previously unmet by chemical medicines •More than 325 million patients worldwide have been helped by biotech medicines •More than 50% of medicines in development are biotech medicines

6. EU View: Biosimilars are not generic pharmaceuticals –Generics are clinically identical to their reference products –Biosimilars can never be identical to their reference products 􀂃Due to the complexity & variability of a biological, the quality profile is determined by the manufacturing process –'the product is the process' 􀂃Differences in process are inevitable between different manufacturers –minor process differences can lead to marked differences in clinical profile

7. Biosimilars are similar, not identical, to original biotech products Biosimilars are similar……. ….Not Identical Different cell lines Different mfg process Small differences in substrate and mfg process may affect patient safety and clinical efficacy of the product

8. Impact of small differences among biotech products on efficacy and safety is unpredictable • Safety and efficacy can differ significantly with small changes in –protein biophysical characteristics or –formulation of the drug produc • Long term safety profile of biosimilars has yet to be established • Prescribers and patients should be aware of this to ensure appropriate introduction into clinical practice • Need to recognize safety and efficacy issue in both approval process and introduction into clinical practice of biosimilars

9. INDIAN Scenario • No Biosimilar, only Biogeneric as in USA • No Guidelines • Schedule Y of Drugs and Cosmetics Act • EMEA/ICH Guidelines • More than 20 products approved so far • Guidelines to be put in place soon

10. Biogeneric products approved so far in India Refer DBT Website: www.igmoris.nic.in

11. The Primary Goals of Preclinical Safety Evaluation are • Identify an initial safe dose and subsequent dose escalation schemes in humans • Identify potential target organs for toxicity and for reversibility • Identify safety parameters for clinical monitoring

12. The Test Materials Monoclonal antibodies, Cytokines, Growth factors, Vaccines, Fusion proteins, Hormones, Chemically synthesized peptides, Enzymes, Plasma derived products, Receptors, Oligonucleotides, proteins extracted from human tissue, biotransformed drugs with small molecular weight as generic products of Pharma, and Guess what more !!!!!!

13. The Test Substances • Investigational new drug or new entities • Biologically similar to an already tested and used drug or molecule as a biologic • What to term it Biogeneric? Biosimilar? Or !!!!!

14. Comparability • Evaluated on the basis of biochemical and biological characterization (i.e., identity, purity, stability, and potency). • In some cases, additional studies may be needed (i.e., pharmacokinetics, pharmaco-dynamics and / or safety).

15. Preclinical Safety Testing Requirements • Selection of the relevant animal species; • Age; • Physiological state; • Dose, route of administration, and treatment regimen; and • Stability of the test material under the conditions of use.

16. Approaches • Conventional approaches to toxicity testing of pharmaceuticals may not be appropriate due to the unique and diverse structural and biological properties. • This includes species specificity, immunogenicity, and unpredicted activities. • Biological activity may be evaluated using in vitro assays.

17. Receptor / Epitope Distribution • Knowledge of receptor/ epitope distribution can provide greater understanding of potential in vivo toxicity . • Relevant animal species for testing of monoclonal antibodies are those that express the desired epitope and demonstrate a similar tissue cross-reactivity profile as for human tissues. • An animal species that does not express the desired epitope may still be of some relevance for assessing toxicity if comparable unintentional tissue cross reactivity to humans is demonstrated.

18. Species to be Studied • Safety evaluation programs should normally include two relevant species. • one relevant species may suffice (e.g., when only one relevant species can be identified or where the biological activity of the biopharmaceutical is well understood). • In addition, even where two species may be necessary to characterize toxicity in short term studies, it may be possible to justify the use of only one species for subsequent long-term toxicity studies(e.g., if the toxicity profile in the two species is comparable in the short term).

19. When No RelevantSpecies Exists • The use of relevant transgenic animals expressing the human receptor or the use of homologous proteins should be considered. • Pharmacological mechanism(s) may differ between the homologous form and the product intended for clinical use. • Where it is not possible to use transgenic animal models or homologous proteins evaluation in a single species, e.g., a repeated dose toxicity study of < 14 days duration that includes an evaluation of important functional endpoints (e.g., cardiovascular and respiratory).

20. Administration / Dose Selection • The route and frequency of administration as close as possible to proposed clinical use. • Pharmacokinetics and bioavailability of the product in the species being used. • Effects of volume, concentration, formulation, and site of administration. • The use of routes of administration other than those used clinically may be acceptable if the route must be modified due to limited bioavailability, limitations due to the route of administration, or to size/physiology of the animal species. • Two routes otherwise is not required.

21. Dosage levels • Dosage levels should be selected to provide information on a dose-response relationship, • Include a toxic dose and a no observed adverse effect level (NOAEL). • Products with little to no toxicity, it may not be possible to define a specific maximum dose. • In these cases, a scientific justification of the rationale for the dose selection and projected multiples of human exposure should be provided. • Where a product has a lower affinity to or potency in the cells of the selected species than in human cells, testing of higher doses may be important.

22. Immunogenicity • Antibody Formation In Humans • Safety Pharmacology • Pharmacokinetic studies • Single Dose Toxicity Studies • Repeated Dose Toxicity Studies • Immunotoxicity Studies • Reproductive Performance and Developmental Toxicity Studies • Genotoxicity Studies • Carcinogenicity Studies

23. Carcinogenicity Studies 2 • With some biopharmaceuticals, there is a potential concern about accumulation of spontaneously mutated cells (e.g., via facilitating a selective advantage of proliferation) leading to carcinogenicity. • The standard battery of genotoxicity tests is not designed to detect these conditions. • Alternative in vitro or in vivo models to address such concerns may have to be developed and evaluated.

24. Thank you