This document provides an overview of biosimilars and their regulatory framework. It begins with definitions of biologics and biosimilars. Biosimilars are highly similar versions of approved biologics whose patents have expired. The development of biosimilars is unique compared to small molecule generics due to the complex nature of biologics. The document then discusses issues with biosimilars including potential efficacy, safety and substitution concerns. Finally, it provides details on the regulatory frameworks and guidelines established by organizations like WHO, EU, US and India to help facilitate the development and approval of biosimilars.

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
Blood derivatives &
Human tissues
Vaccines
Proteins
Cellular & gene
therapies
Biological
products

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

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

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

10. Trend of biologics
Percentage of sales attributable to
each

11. 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

12. 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

14. 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%

15. 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

16. Terminologies used for biosimilars
1
US-FDA,
Japan,
Brazil:
Follow on
Biologics
2
WHO:
Similar Bio
therapeuti
c Product
3
India:
Similar
Biologics
4
Europe:
Biosimilar
5
Canada:
Subseq-
uent Entry
Biologics

17. 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

20. Biosimilars approved in INDIA

21. Development of
biosimilars

22. Golden Period 2012-2019

23. Biosimilar development is unique

24. Issues with the
use of biosimilars
 EFFICACY ISSUES
 SAFETY ISSUES
 SUBSTITUTION
 NAMING AND LABELLING

25. 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

26. 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

27. 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

28. 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

29. 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:
1. Prescribing & dispensing of biopharmaceuticals
2. Precise pharmacovigilance
3. Assist the physician & pharmacist in making informed decisions

30. 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 India have recently regulatory guidelines

31. 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

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

33. 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

34. 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

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

36. 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…)

37. 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…)

38. 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…)

39. 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.

40. 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

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

42. 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…)

43. 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..)

44. 2. Toxicological Studies
 At 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..)

45. 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..)

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

47. 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…)

48. 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

49. 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

50. 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…)

51. 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…)

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

53. 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…)

54. V. Extrapolation of Efficacy & Safety Data to other
Indications
 If following conditions are met:
1. Similarity with respect to quality has been proven to RB
2. Similarity with respect to preclinical assessment
3. Clinical safety & efficacy is proven in one indication
4. Mechanism of action is same for other clinical indications
5. 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…)

55. Market authorization application
Application for
market
authorisation
CDSCO

56. 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…)

57. 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…)

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

59. 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

60. 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

61. 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