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

Principles of Developing Biosimilars

Integration of Information to Biosimilarity209-05-2017

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)

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• Immunogenicity

• Safety & Toxicity

•PK/PD

• Efficacy

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Biosimilar Development: Average Timelines

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Stages of Development of a Biosimilar Drug

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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

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

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

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

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

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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 antiseraagainst 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 Innovator1109-05-2017

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

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 Innovator1309-05-2017

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

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 biosimilarsfor 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

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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.gnew 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

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

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

Principles of Developing Biosimilars: Totality of Evidence

Integration of Information to Biosimilarity1909-05-2017

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

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

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

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

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

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

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

Trial Duration

• Experience with the reference product

• Experience with other products in the classShould reflect clinicalreality 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

End Points

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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

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

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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

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

Requirements for Approval: Examples

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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

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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

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Patients with NAb can Develop PRCA

PRCA = Pure Red Cell Aplasia or Aplastic Anemia3709-05-2017

Post-approval Commitment [example]

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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’spotency, 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

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Other Resources on Biosimilars & Biotech Drugs

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Thank You Very Much

09-05-2017