Biosimilars and Development

Biosimilars, its development and it's regulatory guidelines.

1. Biosimilars Presenter – Dr. Likith HV Guide – Dr. Dinesh Dhodi

2. Outline of Presentation Introduction Definitions Biosimilar vs Generics Development of biosimilars Issues with biosimilars Regulations of biosimilars

3. Biologics Genetically engineered proteins derived from human systems

4. Biologics (contd..) More structurally/molecularly complex

5. Biologics (contd..) More structurally/molecularly complex Identity variance Affected by external conditions Immunogenic

6. Development of biologics

7. Current status of biologics Blood conditions : leuko /neutron/ pancytopenias Endocrine disorders Neoplasm : colon/ breast / NHL Immune system disorders Neurological Disorders Many are under clinical trial

8. Top selling biologics Biologics Global sales in US billlion Adalimumab 10.7 Bevacizumab 7.0 Etanercept 8.3 Insulin glargine 7.8 Rituximab 8.6 Pegfilgrastim 4.4 Trastuzumab 6.8 Infliximab 8.9

9. Trend of biologics Percentage of sales attributable to each

10. Biosimilars Highly similar to an already existing FDA approved biological product Highly similar in molecular structure and bioactivity Have no clinically meaningful differences New version of an existing biologics whose patent has been expired

11. Non-operative parts of the molecule may have some differences in composition and conformation Biologically active parts of the molecule have same composition and conformation

12. Biosimilar history First approved in Europe – Omnitrope , 2006 US – Filgrastim-sndz , 2015 India Strict approval process has been developed 400 million patient-days of clinical experience & it has been estimated to decrease the health care cost by 20-30%

13. Biosimilar (contd..) WHO - A bio therapeutic product that is similar in terms of quality, safety and efficacy to an already licensed reference bio therapeutic product US-FDA : A biological product that is highly similar and has no clinically meaningful differences from an existing FDA-approved reference product

14. Terminologies used for biosimilars

15. Biosimilar vs Generics Generics - Chemically and therapeutically equivalent to the branded original low molecular weight chemical drugs Identical to the chemical drugs Most countries have well established regulatory for the approval of generics

16. Biosimilars approved in INDIA

17. Development of biosimilars

18. Golden Period 2012-2019

19. Biosimilar development is unique

20. Issues with the use of biosimilars Efficacy ISSUES Safety issues Substitution Naming and labelling

21. Efficacy Issues Due to the difference between the bioactivity of the biosimilar and the innovator product Example 1: 11 epoetin alfa products from 4 different countries (Korea, Argentina, China, India) Significant diversions from specification for in vivo bioactivity: Ranged from 71-226% 5 products failed to fulfill their own specification

22. Efficacy Issues (contd..) Example 2: Study compared quality parameters (purity, content & efficacy) Carried out on 16 commercial brands covering 3 different biopharmaceuticals: pegylated G-CSF, G-CSF & erythropoietin Marked lack of comparability between biosimilars & innovator products Significant difference in the level of purity was observed

23. Safety issues Concerns regarding immunogenicity Example ↑ in no. of cases of Pure Red Cell Aplasia associated with specific formulation of epoetin α • Caused by the production of neutralizing antibodies against endogenous epoetin Cause → subtle changes in manufacturing process of Eprex , human albumin stabilizer was replaced by polysorbate 80 → ↑ immunogenicity → formation of epoetin -containing micelles

24. Substitution One that may be substituted for the prescribed product without the intervention of the doctor Same substitution rules should not be applied: Decrease the safety of therapy or cause therapeutic failure Uncontrolled substitution → confounds accurate pharmacovigilance

25. Naming and labelling Generic adaptation of chemical medicines is assigned the same name→ identical copies of the reference products Biosimilars require unique naming, as this would facilitate: Prescribing & dispensing of biopharmaceuticals Precise pharmacovigilance Assist the physician & pharmacist in making informed decisions

26. Regulatory framework Strong need for regulations governing biosimilars Implementation of an abbreviated license pathway for biological product presents challenges European union has regulations in place for quite some time US and I ndia have recently regulatory guidelines

27. WHO Guidelines Scientific basis for the evaluation & regulation of biosimilars was discussed & agreement for developing WHO guidelines was reached at the first ‘ WHO informal consultation on Regulatory evaluation of Therapeutic Biological Medicinal Products’held in Geneva , 2007 Published detailed guidelines on clinical development in October 2009

28. Regulatory framework in EU Guidelines on similar biological products were adopted by European Medical Agency(EMA) Issued product specific guidelines

29. Regulatory framework in US US-FDA issued draft guidelines on biosimilar product development under Biologics Price Competition & Innovation act (BPCI Act) Based on sponsors proving structural, composition & clinical similarities with an approved biologics

30. Regulatory framework in India Similar biologics are regulated as per The Drugs and Cosmetics Act, 1940 The Drugs Cosmetics Rules, 1945 Rules for the manufacture, use, import, export & storage of hazardous microorganisms/genetically engineered organisms or cells, 1989. Notified under the Environment Protection Act

31. Authorities involved in the approval CDSCO(DCGI ) Review Committee on Genetic Manipulation(RCGM): (DBT ) Regulates import, export, carrying out research, preclinical permission, No objection certificate for clinical trial (CT) Genetic Engineering Appraisal Committee (GEAC): Functions under the MoEF .Statutory body for review & approval of activities where final drug product contains genetically modified organisms Institutional Bio-safety Committee (IBSC) Regulatory framework in India ( contd …)

32. Selection of Reference Biologics Should be licensed/approved in india /ICH countries Same RB should be used throughout the study Active substance, dosage form, strength & route of administration of the SB→ same as that of RB Approved SB cannot be used as RB Regulatory framework in India ( contd …)

33. Manufacturing process Validated and demonstrated to be highly consistent and robust If host cell line used for production of RB is disclosed, use the same cell line Alternatively any cell line that is adequately characterized & appropriate for intended use Applicant should submit a full quality dossier Regulatory framework in India ( contd …)

34. Prerequisites before Conducting Preclinical Studies Data for submission should include: • Detailed description of the drug substance and drug product processes • Critical and key Quality Attributes of the product • Manufacturing process controls • Critical process parameters • Stability data • Comparability of product manufactured at clinical scale against Reference Biologic Regulatory framework in India ( contd …)

35. Regulatory framework in India ( contd …) Basic information about the Reference Biologic Information about the drug, route of administration, absorption and elimination rate, therapeutic index, dose, vehicle, mode of administration, dose response etc. Bioequivalence range, if available. Tissue‐specific localization, if available. Available toxicity data on Reference Biologic. Mode of action.

36. Regulatory framework in India ( contd …) Basic information about the Similar Biologic Known / proposed clinical use Target population (Age, sex, pregnancy, lactating, children etc.) Dosage (frequency and intervals) –units Route / alternate routes of administration Final formulation + adjuvants, additives etc. ‐ Toxicology data of adjuvants Diluents Presentation e.g. pre filled syringe, cartridge, vial

37. Regulatory framework in India ( contd …) Data Generated Approval of IAEC & IBSC RCGM Permission for pre-clinical studies

38. Pre-clinical studies Comparative in nature & designed to detect differences Study design depends on: Therapeutic index, type & number of indications applied Conducted with the final formulation Regulatory framework in India ( contd …)

39. 1. Pharmacodynamic studies In vitro studies: Comparability established by in vitro cell based bioassay (e.g. cell proliferation assays or receptor binding assays ) In vivo studies: When in-vitro assays do not reflect the pharmacodynamics  In vivo studies Preclinical studies (cont..)

40. 2. Toxicological Studies A t least one repeat dose toxicity study in a relevant species Animal model used – scientifically justifiable Route of administration→ include only intended route Duration - >28 days with 14 days recovery period Dose → Calculated based on the therapeutic dose RB Three levels of doses (low, medium and high) → Corresponding to 1X, 2X & 5X of human equivalent dose Schedule of administration→ therapeutic schedules Preclinical studies (cont..)

41. 3.Immune Responses in Animals Test serum samples tested for reaction to host cell proteins Immune complexes in targeted tissues by histopathology→ evaluating immune toxicity Preclinical studies (cont..)

42. Regulatory framework in India ( contd …) Preclinical study report RCGM DCGI After the successful completion of the preclinical studies

43. I. Pharmacokinetic studies Standards to demonstrate bioequivalence should meet the CDSCO Guideline for Bioavailability and Bioequivalence studies Comparative pharmacokinetic (PK) studies → Healthy volunteers or patients to demonstrate similarities in pharmacokinetic characteristics If patient population is used for PK studies, Phase III / PD study can be coupled in one study design Clinical studies ( contd …)

44. Clinical studies- 1. PK studies (contd..) A. Single Dose Comparative PK Studies Dosage within the therapeutic dose range of RB Appropriate rationale for sample size selection Parallel arm design→ Biologics with a long half life or proteins for which formation of antibodies is likely or study is done in patients Cross over design→ Drugs with short half life

45. Clinical studies- 1. PK studies (contd..) B. Multiple Dose Comparative PK Studies Biologic used in a multiple dose regimen Markedly higher or lower concentrations expected at steady state than that expected from single dose data Pk measurements Time-dependence & dose-dependence of PK parameters cannot be ruled out

46. II. Pharmacodynamic Studies If PD marker is available in healthy volunteers→ PD in healthy volunteers can be done At least one PD marker→ linked to efficacy of molecule Surrogate markers  clinically validated At least one PK-PD study combined → PK/PD relationship has to be characterized PD study can also be a part of Phase III clinical trial wherever applicable Clinical studies ( contd …)

47. III. Confirmatory safety and efficacy studies Based on the comparability established during preclinical & PK / PD studies Comparative, parallel arm or cross-over To demonstrate the similarity in safety & efficacy profiles, Nature, severity & frequency of Adverse events should be compared Clinical studies ( contd …)

48. Clinical studies ( contd …) Waiver of confirmatory & efficacy studies Structural & functional comparability characterized to a high degree by physicochemical & in vitro techniques The SB is comparable to RB in all preclinical evaluations PK / PD study has demonstrated comparability & done: in in-patient setting safety measurement (including immunogenicity) for adequate period & with efficacy measurements

49. IV. Safety and immunogenicity data Comparative safety data based on adequate patient exposure (numbers & time) with published data on RB Both pre-approval & post-approval assessment of safety is desired Pre-approval safety assessment → Intended to provide assurance of absence of any unexpected safety concerns Clinical studies ( contd …)

50. V . Extrapolation of Efficacy & Safety Data to other Indications If following conditions are met: Similarity with respect to quality has been proven to RB Similarity with respect to preclinical assessment Clinical safety & efficacy is proven in one indication Mechanism of action is same for other clinical indications Involved receptors are same for other clinical indications However, new indication not mentioned by innovator will be covered by a separate application Clinical studies ( contd …)

51. Market authorization application Application for market authorisation CDSCO

52. Pharmacovigilance plan Clinical studies done on SB prior to market authorization are limited in nature→ Rare adverse events are unlikely to be encountered Comprehensive Pharmacovigilance plan should be prepared by manufacturer Periodic safety update reports (PSURs) submitted every six months for the first two years after approval For subsequent two years the PSURs to be submitted annually to DCGI office Clinical studies ( contd …)

53. Post Marketing Studies (PMS) At least one non-comparative post-marketing clinical study with focus on safety & immunogenicity should be performed Neutralizing antibodies→ their impact on the PK/PD parameters, safety & efficacy assessed Clinical studies ( contd …)

54. Archiving of Data Applicant should archive all the data for a period of at least FIVE years after marketing approval

55. Timelines by regulatory committee Procure Time Period RCGM approval for pre-clinical animal studies 45 Days DCGI approval for Human Clinical Trials protocol 45 Days DCGI examination of clinical trial data and response 90 Days DCGI & GEAC decisions (simultaneous) 45 Days

56. Conclusion Biological medicines is becoming an important part of the future healthcare landscape With many patents expiring, the availability of biosimilars is expected to increase across the globe How similar is similar enough? Careful design and implementation of registries will generate quality evidence to support decision-making

57. References Misra , M. (2012). Biosimilars : Current perspectives and future implications . Indian Journal of Pharmacology, 44 (1), 12-14 . Misra M. Biosimilars : Current perspectives and future implications. Indian Journal of Pharmacology. 2012;44(1):12 . Guidelines on Similar Biologic: Regulatory Requirements for Marketing Authorization in India [Internet]. Cdsco.nic.in. 2016 [cited 23 February 2019 ]. Kumar R, Singh J. Biosimilar drugs: Current status. International Journal of Applied and Basic Medical Research. 2016;4(2):63 Timesofindia.indiatimes.com. (2019).  The Times of India: Archive | 22 Sep, 2019