This presentation mainly deals with clinical development of biosimilar products. It also gives enough on non-clinical development so that the audience is well oriented.

1. Clinical Development of
Biosimilars
Dr. Bhaswat S. Chakraborty
Sr. VP, Research & Development
Cadila Pharmaceuticals Ltd.
Presented at the National Conference on “Impact of Pharmaceutical
Biotechnology on the Future of Medicine” organized by
Geetanjali University, 24-25 March 2017
109-05-2017

2. Principles of Developing Biosimilars
Integration of Information to Biosimilarity
209-05-2017

3. Purpose of Biosimilarity Determination
• The primary purpose of the
assessment of a biosimilar
product is not the
characterisation of the
benefit/risk profile of the
product as such
• But the qualitative and
quantitative evaluation of the
comparability (similarity) of the
biosimilar product (B) to the
reference product (R)
3
•Immunogenicity
•Safety &
Toxicity
•PK/PD
•Efficacy
Comparable
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4. Biosimilar Development: Average Timelines
409-05-2017

5. Stages of Development of a Biosimilar Drug
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6. 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
609-05-2017

7. Reasons of Biosimilars’ Heterogeneity
• Reasons of Biosimilars’ heterogeneity (potential differences
between the biosimilar and the innovator drug):
• biologics are a complex mixture consisting of the parent drug, multimers,
truncated fragments
• components may or may not exhibit biological activity, post-translational
modifications of the parent and/or truncated fragments, host cell proteins
as well as process related impurities
• Any one of these can cause differences in the way these drugs
behave in the immunoassay, bioassay and electrophoresis
709-05-2017

8. Structural Analysis
• Appropriate analytical methodology with adequate sensitivity and
specificity for structural characterization & comparisons of the
drug substances of B & R
 Primary structures, such as amino acid sequence
 Higher order structures, including secondary, tertiary, and quaternary
structure (including aggregation)
 Enzymatic post-translational modifications, such as glycosylation and
phosphorylation
 Other potential variants, such as protein deamidation and oxidation
 Intentional chemical modifications, such as PEGylation sites and
characteristics
809-05-2017

9. Protein Characterization Assays
• Use validated bioassays or receptor-binding assays; quantitative
PCR would be excellent
• Show equivalency of potency and batch consistency
• Usual acceptance criteria: 80-125% but could be wider for
bioassays
• When wider, this assay may not be used for PK/TK comparability
• Isotyping – significant issue in characterizing assays
• It is important to evaluate if assay is indeed due to
immunoglobulin and, if so, what type of antibody
• If not IgG but IgE class, it could have potentially serious safety
outcomes.
909-05-2017

10. Immunogenicity Assays
• The immunogenicity of therapeutic proteins must be assessed for safety
and efficacy concerns
• small process changes during the production can change immunogenicity rate &
extent
• Immunogenicity rate is difficult to measure, particularly at low incidence
• e.g., from autoimmune reactions to self proteins
• large sample size would be required if the rate of immunogenicity incidence is low
• It is critical to assess the immunogenicity of the B relative to R
• An assay using the same platform technology, the same reagents under
the same assay conditions to evaluate antidrug antibodies (ADAs) would
be desirable to assess reactogenicity
1009-05-2017

11. Immunogenicity Assays..
• Initiate very early during development of B, immunization of
animals to develop a positive control (against both B & R)
• Evaluate the two ADA positive controls (ADA B & R)
• Differences in the starting titers of the positive control antisera
against either the B or are possible due to the individual immune
response of each animal
• Assay platform could be ELISA, bridging assays, electrochemi-
luminescence (ECL) or RIA addressing:
• Can the assay reagents detect both B & R comparably?
• Can the assay tolerate both biosimilar and B & R conc. comparably?
B = Biosimilar; R = Reference Innovator 1109-05-2017

12. Non-comparable (Non-similar) Assays
• If comparability is not demonstrated, separate assays should
be validated for B & R Immunogenicity Assays
• If separate assays are to be used for future preclinical or
clinical comparability studies, interpretation is difficult
• samples from different arms of the study will be tested using
different assays
B = Biosimilar; R = Reference Innovator 1209-05-2017

13. Neutralizing-antibody (NAb) Assays
• For clinical studies, once a test sample is confirmed to be ADA positive,
evaluate it for NAb assay
• to see if it is neutralizing the biologic activity of the drug (B or R)
• Regulatory agencies usually prefer to have a cell-based NAb assay
• but other assay formats (e.g., immuno-based assays) are OK when appropriate cell-
lines are not available during development
• If a cell-based assay exists for R, use the same platform for NAb of B
• Validating cell-based NAb assays is technically difficult
• due to higher variability and a longer turnaround time for these assays
B = Biosimilar; R = Reference Innovator 1309-05-2017

14. Non-clinical studies
• Comparability in terms of physiochemical properties and of biological
and immunological parameters (where appropriate); comparative
purity/impurities
• In vitro studies should normally be undertaken
• In vivo studies should be performed in a relevant species
• Detailed guidance is often available
• At least one repeat dose toxicity study in a relevant species required
• Genotoxicity, carcinogenicity &/or reproductive tox may be required
in some cases
1409-05-2017

15. 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.
• Non-comparative post-marketing study
• a single arm study of N≥200 evaluable patients and compared to historical data of R
• the study should be completed preferably within 2 years of the marketing approval
• For immunogenicity & reactogenicity
• Assay using the same platform technology, the same reagents under the same assay
conditions is best
1509-05-2017

16. In-vitro studies
•Assess binding to
target(s)
•Assess signal
transduction and
functional
activity/viability
Determine if in-
vivo studies are
needed
•Necessary only if
factors of concern
are indentified, e.g
new translational
modification
structures
In-vivo studies
•Focus of study
depends on the
need for additional
information
EMA guidance on biosimilar mAbs : a stepwise approach
Preclinical
1609-05-2017

17. EMA guidance on biosimilar mAbs : a stepwise approach
Phase I
PK/PD Studies
•Single dose cross-over or parallel group
designs preferred
•PD markets selected on the basis of
their clinical relevance
•Affinity is a key determinant of the PK
and PD profile of MABS and soluble
receptor constructs
•Close reproduction of conformational
structure for biosimilar MABS and
soluble receptor constructs is needed to
ensure comparable biological effect
Safety and Efficacy
•No clinically significant
difference in efficacy to
reference product
•Compare severity and
frequency of adverse
events, in particular for
immunogenicity
Phase III
1709-05-2017

18. Building Totality of Evidence
• A risk-based, totality-of-the-evidence approach is used to evaluate
all data and information provided by a sponsor to support a
demonstration of biosimilarity
• overall no clinically meaningful differences between B & R in safety, purity,
and potency
• includes structural and functional characterization, nonclinical evaluation,
human PK and PD data, clinical immunogenicity data, and comparative
clinical study(ies) data
• Sufficient data and information demonstrating that the differences
are not clinically meaningful and the proposed product
• differences in excipients; slight differences in rates of AE occurrence 1809-05-2017

19. Principles of Developing Biosimilars: Totality of
Evidence
Integration of Information to Biosimilarity
1909-05-2017

20. Human PK & PD (Phase I)
• If PK/PD relationship exists & characterized, Combined PK-PD studies can be done
• Comparative PK Study (Studies) parallel arm or cross-over
• using validated analytical method
• Similarity in terms of absorption / bioavailability of B & R
• Multiple-dose, comparative, parallel arm steady state PK studies are required
• for a biosimilar used in a multiple dose regimen
• Comparative, parallel arm or cross-over, PD study in patients or healthy volunteers:
• 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
• Acceptance ranges for similarity in PK &/or PD parameters should be predefined & justified
• PK &/or PD study can also be a part of Phase III clinical trials wherever applicable
2009-05-2017

21. Extrapolation of Indications
• In general, all authorities recommend extrapolation of clinical data across indications
• However, scientific justification must be provided for extrapolating clinical data for each
condition
• A sensitive sample of population needs to be studied in Phase III CTs which can detect
clinically meaningful differences in S & E and quality. General rules for extrapolation:
• 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.
2109-05-2017

22. 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
2209-05-2017

23. 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
2409-05-2017

24. Study Design
• Obviously superiority trials
are not appropriate for
biosimilar development
• Equivalence or non-inferiority
designs are useful for
biosimilarity demonstration
• Equivalence or non-inferiority
margins should be well
accepted by Authorities
2509-05-2017

25. Notes on Non-inferiority Trials
• Demonstration of non-inferiority does not mean the two products are
equivalent
• One-sided non-inferiority design may be advantageous reducing sample size
• Also when the reference product is used at or near the maximal level of clinical
effect
• A non-inferiority design may be adequate for immunogenicity or other safety
outcomes, when lower immunogenic or other safety events would not have
efficacy implications
• Not appropriate for complex biologics (eg, those for inflammatory diseases)
2609-05-2017

26. Sample Size
• Sample size and duration of the Phase III Clinical safety &
efficacy trials should allow
• Sufficient exposure to the biosimilar & reference products
• Detection of relevant safety signals (including immunogenicity)
except for rare events or those require prolonged exposure and
• Detection of clinically meaningful differences in effectiveness &
safety between the two
2709-05-2017

27. Trial Duration
• Experience with the reference product
• Experience with other products in the class
Should reflect clinical
reality of the disease
• Often biologics are used for chronic diseases
• With periods of exacerbations &remissions
Long enough for the
biosimilar to exert both
beneficial & deleterious
effects
• Results from interference of patient/physician
behaviors, co-medications & dropouts
• Less likely in biosimilar trials than new NCE trials
Care should be taken
for longitudinal bias
2809-05-2017

28. End Points
29
09-05-2017

29. Adaptive Design and Interim Analysis
• Adaptive design: prospectively
planned modification
• Allows modifications to the trial,
hypotheses or statistical procedures
• by observing outcomes or AEs
• maintaing its validity and integrity
• based on interim data analysis on a
prescribed schedule
• may use adaptive randomization
• treatment assignment changes
• The purpose is to make clinical trials
more flexible, efficient and fast
3009-05-2017

30. ITT & PP Analyses
• Intention to treat (ITT)
• maintains the integrity of the randomization
• includes all the subjects who were randomized whether or not they received the
assigned treatment
• also those who withdrew from the study for any reason including protocol violations
• Per protocol (PP)
• includes only those subjects who received the assigned treatment and followed the
protocol
• in a superiority trial, the PP analysis provides an optimized comparison of treatment
groups
• in contrast, ITT analysis tends to increase the likelihood of a positive result in equivalence
or noninferiority trials in which PP analysis would be the more conservative and preferred
3109-05-2017

31. Evaluation of Phase III Biosimilar CTs
• Comparability
• 90% or 95% CI equivalence or non-infereiority
• Relevant subjects
• patient population should be sensitive – clinically meaningful differences in
S&E between B & R are most likely to be detected
• Sufficient statistical power & sample size
• to detect potential differences between B & R
• Dose
• Dose & RoA are consistent with R
32Alten and Cronstein (2015). Seminars in Arthritis and Rheumatism, 44: S2–S809-05-2017

32. Evaluation of Phase III Biosimilar CTs..
• End points
• relevant to disease & sensitive enough to detect clinically relevant differences in S&E
• Study duration
• appropriate to detect clinical/untoward effects
• Statistical analysis
• per-protocol (PP) analysis includes only patients who followed the protocol
• good for equivalence & non-inferiority trials
• intention-to-treat (ITT) analysis includes all randomized patients
• Efficacy
• efficacy measures within specified acceptable margin of equivalence?
• Safety
• AEs comparable between B & R
33Alten and Cronstein (2015). Seminars in Arthritis and Rheumatism, 44: S2–S809-05-2017

33. Requirements for Approval: Examples
3409-05-2017

34. Waiver of Confirmatory Clinical S&E Trial
• 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 cannot be waived if there is no reliable
and validated PD marker
3509-05-2017

35. 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
3609-05-2017

36. Patients with NAb can Develop PRCA
PRCA = Pure Red Cell Aplasia or Aplastic Anemia3709-05-2017

37. Post-approval Commitment [example]
3809-05-2017

38. 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
• Equivalence or non-inferiority RCTs in relevant subjects with appropriate
endpoints are required
• Immunogenicity concerns should be addresses comprehensively
3909-05-2017

39. Other Resources on Biosimilars & Biotech Drugs
4009-05-2017

40. 41
ThankYouVeryMuch
09-05-2017