This document discusses the regulatory requirements for clinical development of biosimilars in India. It provides an overview of the applicable regulations, guidelines, and authorities overseeing clinical trials. The key principles for developing biosimilars are to demonstrate comparability to the reference biologic through a stepwise characterization and clinical development program involving pharmacokinetic, pharmacodynamic, and confirmatory safety and efficacy studies. Post-marketing requirements include pharmacovigilance plans and potential post-marketing studies to further evaluate safety and immunogenicity.

1. CLINICAL
DEVELOPMENT OF
BIOSIMILARS IN
INDIA
Dr. Bhaswat S. Chakraborty
Sr. VP & Chair, R&D Core Committee
Cadila Pharmaceuticals Ltd.
Presented at the “Regulatory Requirements for
Biopharmaceuticals – From Science to
Commercialization’’, C-CAMP, Bengaluru, Oct. 15, 2015
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2. CONTENTS
 Understanding the latest clinical trials regulatory
guidelines as per DCGI and ICMR (IND Committee)
 Clinical requirements to demonstrate Safety, Efficacy
and immunogenicity parameters of Biosimilars
 Clinical trial documentation standards for Biosimilars
 The Pharmacovigilance (PV) requirements
2

3. REGULATORY MECHANISM IN
INDIA
 Legal:
 Drugs and Cosmetics Act 1940 and Rules 1945
 Patent Act of India 2005 Amendment
 Regulatory: Schedule Y of the Drugs and Cosmetics Act
 Indian regulation for Clinical Studies by DCGI (CDSCO)
 Guidelines:
 CDSCO Guidelines
 Indian GCP Guidelines
 ICMR Guidelines
 DBT Guidelines
3

4. CURRENT D&C ACT: AMENDED
UP TO 2005
 Chapter I: Introductory – scope, definitions etc.
 Chapter II: The Drugs Technical Advisory Board, The Central
Drugs Laboratory & The Drugs Consultative Committee
 Chapter III: Import of Drugs & Cosmetics
 Chapter IV: Manufacture, Sale and Distribution of Drugs and
Cosmetics
 Chapter IVA: Provisions Relating to Ayurvedic, Siddha & Unani
Drugs
 Chapter V: Miscellaneous
 Schedules including Schedule M (2001) and Schedule Y (2005)
4

5. MAJOR AMENDMENTS IN 2013
BILL
 Insertion of 3 subchapters
 Chapter 1A – Constitution of Central Drugs Authority
(expanded multi-level authority)
 Chapter 1B – Clinical Trials (permission & penalties)
 Chapter IIA – Import, Manufacture, Sale, Distribution and
Export of Medical Devices
 The proposed changes in this bill and a few other
changes are still being publicly debated as D&C
Amendment 2015; likely to be passed this year
 Industry has already started following the directives
5

6. OVERSEEING AUTHORITIES OF
CTS IN INDIA
 Apex Committee (Chaired by Secretary, Ministry of Health and
Family Welfare) for supervising and monitoring the CTs in India
 Assisted by the Technical Committee for evaluation and input related
to clinical trials to the Apex Committee
 For clinical trials allowed by the DCG(I)
 The NDACs evaluate non-clinical (including pharmacological
toxicological data & clinical trial data (Phase I, II, III, and IV) etc.
for approval of NCEs or NBEs to be introduced in the country for
the first time including vaccines and r-DNA products
 Assessment of Risk vs. Benefit to the patient
 Innovation vis-à-vis existing therapeutic option
 Unmet medical need in India
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7. 12

8. APPLICABLE REGULATIONS &
GUIDELINES FOR BIOSIMILARS
 Recombinant DNA Safety Guidelines, 1990
 Guidelines for generating preclinical and clinical data for rDNA
vaccines, diagnostics and other biologicals, 1999
 CDSCO guidance for industry, 2008:
 Submission of Clinical Trial Application for Evaluating Safety and Efficacy
 Requirements for permission of New Drugs Approval
 Post approval changes in biological products: Quality, Safety and Efficacy
Documents
 Preparation of the Quality Information for Drug Submission for New Drug
Approval: Biotechnological/Biological Products
 Guidelines and Handbook for Institutional Biosafety Committees
(IBSCs), 2011
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9. PRINCIPLES OF DEVELOPING
BIOSIMILARS
 Biosimilars are developed through sequential characterization studies
revealing the molecular and quality attributes comparable with
reference biologic
 Although the extent of testing of the biosimilar is less than that for the
reference, but be sufficient to ensure acceptable levels of safety, efficacy
and quality
 A reduction in data requirements is possible for preclinical & clinical
development program
 Demonstration of comparability with reference & onsistency in production
process
 Any significant differences in safety, efficacy and quality studies would
require a more extensive preclinical & clinical evaluation
 The product will not qualify as a similar biologic
 If the reference has more than one indication, the efficacy and safety of
the biosimilar has to be justified and may be demonstrated separately
for each indications
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10. PRINCIPLES OF DEVELOPING
BIOSIMILARS
Integration of Information to Biosimilarity
15

11. THE REFERENCE BIOLOGIC
 The reference biologic should be licensed in India
 The innovator product
 If not marketed in India, it should be licensed and widely
marketed for 4 years post approval in innovator & regulated
jurisdiction
 The same reference should be used throughout
 For safety, efficacy and quality studies of biosimilar
 Same route of administration of biosimilar & reference
 The active ingredient of the reference & biosimilar
must be shown to be similar
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12. DATA REQUIREMENTS FOR
CLINICAL DEVELOPMENT
 Pharmacokinetic studies
 Pharmacodynamic studies
 Confirmatory safety and efficacy study
 Safety and immunogenicity data
 Extrapolation of efficacy and safety data to other
indications
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13. PHARMACOKINETIC (PK)
STUDIES
 PK studies performed in healthy volunteers or patients to
demonstrate the similarities in PK characteristics between
biosimilar & reference
 Design:
 Single dose, comparative, PK studies
 Parallel arm or
 Cross over
 Multiple dose, comparative parallel arm steady state PK studies
 Other design of comparative PK takes the following factors into
consideration:
 T1/2 ; Linearity/non-linearity of PK; • Endogenous levels and
diurnal variations of the biosimilar (if applicable); Conditions
and diseases to be treated; • Route(s) of administration; &
Indications
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14. SINGLE DOSE COMPARATIVE PK
STUDIES
 Comparative PK Study (Studies)
 Dosage studied should be within the therapeutic dose range of reference
 Appropriate rationale for dose selection
 RoA: to detect differences with the largest sensitivity
 Sample size: statistically justified
 Comparability limits defined and justified a priori
 Analytical method:
 Validated wrt specificity, sensitivity and dynamic with adequate accuracy and
precision
 Detects and follows the time course of the parent &/or degradation products) in
a complex biological matrix that contains many other proteins
 Similarity in terms of absorption / bioavailability of B & R
 But also differences in elimination kinetics (e.g., CL & T1/2)
 A parallel arm design is more appropriate for:
 Biologics with a long T1/2 ; proteins for which formation of antibodies is likely; or
patient PK studies
 For short T1/2 biosimilars, justified cross over design may be OK
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15. MULTIPLE DOSE COMPARATIVE
PK STUDIES
 Multiple-dose, comparative, parallel arm steady state
PK studies are required
 For a biosimilar used in a multiple dose regimen
 Where a markedly different (higher or lower) concentrations are
expected at SS than that expected from SD PK measurements
 Where dose- & time-dependence PK may exist
 Multi-dose comparative PK studies may not be required
with adequate justification
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16. COMPARATIVE
PHARMACODYNAMIC (PD) STUDIES
 Comparative, parallel arm or cross-over, PD study in patients or healthy
volunteers:
 For detecting differences between biosimilar & reference
 If a PD marker is available, study in healthy volunteers can be done
 Comparative PD studies are recommended when the PD properties of reference
are well characterized with at least one PD marker being linked to the efficacy of
the molecule
 Dose-Response & marker relationships of the reference should be well
established to justify the design
 Acceptance ranges for similarity in PD parameters should be predefined &
justified.
 PD study can also be a part of Phase III clinical trials wherever applicable
 PD parameters
 Clinically relevant
 Surrogate markers be clinically validated
 If PK/PD relationship exists & characterized, Combined PK-PD studies
can be done 21

17. CONFIRMATORY CLINICAL S&E
STUDY
 One or more comparative S&E trial in relevant patient population is
mandatory for all biosimilars
 Biosimilar will be treated as a “stand-alone product” if not comparable with
reference in preclinical & PK/PD studies (>1 CT may be needed)
 Exception of requiring both S&E; e.g. recombinant human soluble insulin
products: only clinical safety
 Efficacy and primary efficacy endpoints:
 Design & clinical comparability margins of the primary efficacy endpoints
should be carefully chosen
 Be justified on clinical grounds
 Equivalence trials with lower and upper comparability margins are
preferred
 Non-inferiority trials when required must be clearly justified & consulted
with CDSCO a priori to study initiation
 Sample sizes should have statistical rationale and power; comparability
limits defined and justified
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18. CONFIRMATORY CLINICAL S&E
STUDY..
 Safety:
 A separate Ph1 safety study is not required
 Nature, severity & frequency of AEs should be compared
between B & R
 Based on safety data from a sufficient number of patients
treated for an acceptable period of time
 Sufficient number of patients should be treated for acceptable
period of time to allow detection of significant differences in
safety between B & R
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19. WAIVER OF CONFIRMATORY
CLINICAL S&E STUDY
 If structural and functional comparability of B & R can be
characterized by well validated physicochemical and in vitro
techniques
 The biosimilar is comparable to reference in all preclinical
evaluations
 PK / PD study has demonstrated comparability and
 Preferentially done in in-patient setting
 With safety measurement (including immunogenicity) for adequate
period justified (from efficacy studies)
 With a comprehensive post-marketing risk management plan
 That will gather additional safety data with an emphasis
immunogenicity data
 The confirmatory clinical S&E study study cannot be waived if
there is no reliable and validated PD marker 24

20. SAFETY AND IMMUNOGENICITY
DATA
 Both pre-approval and post-approval safety assessment for
biosimilars
 Pre-approval safety assessment:
 Comparative pre-approval safety & immunogenicity data is required
for biosimilars for which confirmatory CT waiver given
 Pre-approval safety data: absence of any unexpected safety concerns.
 Proposed non-comparative post-marketing study
 And comparative pre-approval data (adequate patients and time) and
published data on the reference provide a comprehensive evaluation of
safety of the biosimilar
 For immunogenicity & reactogenicity
 Assay using the same platform technology, the same reagents under the
same assay conditions is best
25

21. AND SAFETY DATA TO OTHER
INDICATIONS
 Extrapolation of S&E data of an indication for which clinical
studies done of a biosimilar to other clinical indications may be
possible if:
 Similarity wrt quality has been proven to reference
 Similarity wrt preclinical assessment has been proven to reference
 Clinical safety and efficacy is proven in one indication
 Mechanism of action is same for other clinical indications
 Involved receptor(s) are same for other clinical indications
 New indication not mentioned by innovator will be covered by a
separate application.
26

22. REQUIREMENTS FOR APPROVAL:
EXAMPLES
29

23. POST-MARKET DATA FOR
BIOSIMILARS
 Risk Management Plan
 To monitor and detect both known inherent safety concerns & unknown potential
safety signals
 Pharmacovigilance Plan
 PSURs every 6 months for the first 2 years after approval and annually for
subsequent 2 years
 ADR Reporting
 All cases involving serious unexpected ADRs must be reported to the licensing
authority within 15 days of initial receipt of information
 Post Marketing Studies (PMS)
 At least one non-comparative post-marketing clinical study with focus on
safety & immunogenicity
 Designed to confirm that the biosimilar does not have therapeutic
consequences of unwanted immunogenicity
 If immunogenicity is evaluated in clinical studies, no additional
non-comparative Post-market immunogenicity studies
30

24. PATIENTS WITH NAB CAN DEVELOP
PRCA
PRCA = Pure Red Cell Aplasia or Aplastic Anemia
31

25. POST-APPROVAL COMMITMENT
[EXAMPLE]
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26. ARCHIVING OF DATA
 Applicant should archive all the data up to clinical evaluation for
a period of at least five years after marketing approval in India
 Archiving site should be indicated in the study protocols and
reports
 Archived material should also be mentioned
 They include test substance, vehicle, plasma / serum, tissues, paraffin
blocks, microscope slides, documents, electronic material etc and the
individual durations (e.g.test material until date of expiry)
 Archivist and their associates should be approachable for
inspection or retrieval when required & indicated in the study
report
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27. CONCLUDING REMARKS
 Recent changes in D&C Regulations & SC directives are
progressive and have made many things transparent
 CDSCO and DBT guidelines are clear and more or less
harmonized with international standards
 Differences between Biosimilar & Reference would affect
the Biosimilar’s potency, Clinical & PK characteristics
and safety profile
 A particular Biosimilar might never be interchangeable
with the Reference
 Demonstrate clinical biosimilarity through
immunogenicity, PK & PD and clinical outcomes
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29. Thank You