Biosimilars: Nonclinical and Clinical Development Challenges and Considerations

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Agenda

Regulatory Environment

Early Development Challenges• Regulatory landscape• Characterization• CMC and in vitro• Animal studies• Assays

Clinical Development Challenges• Phase I• Phase III

Conclusions

Regulatory Environment

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Global Regulatory LandscapeEMA (The European Medicines Agency)

• Established EMA approval pathway: • 14 biosimilars approved* within the product classes of:

• Human growth hormone• Granulocyte colony-stimulating factor (G-CSF) • Erythropoietin

US FDA • Biologics Price and Innovation Act passed in 2010

• Empowers FDA to develop standards to evaluate and approve biosimilars• FDA February 2012 draft guidance documents

• Risk-based “totality-of-the-evidence” approach

Health Canada• Guidance came out in 2010

Japan• Guideline came out in 2009

WHO• Guideline document came out in 2009

ROW• Argentina, Australia (amending), Brazil, Jordan, Korea, Malaysia, Saudi Arabia, Singapore,

Taiwan, Turkey, Venezuela – Guidelines available• Colombia, Cuba, India, Mexico, South Africa, and Thailand – Draft Guidelines available

Biosimilar Regulatory Guidance documents and discussions are on-going and expanding globally.

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Regulatory Environment - EU

Established EMA approval pathway• 14 biosimilars approved within the product classes of:

• Human growth hormone• Granulocyte colony-stimulating factor (G-CSF) • Erythropoietin

Key EMA guidance documents• “Overarching” guideline on similar biological medicinal products

• From 2005, currently being updated

• Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances: quality issues

• From 2005

• Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substances: nonclinical and clinical issues

• From 2005, currently being updated to incorporate risk-related approaches

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Regulatory Environment – US

FDA approval pathway established

Biologics Price and Innovation Act passed in 2010 empowers FDA to develop standards to evaluate and approve biosimilars

FDA February 2012 draft guidance documents

• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product:

- Risk-based “totality-of-the-evidence” approach

• Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product:- Overview of analytical factors to consider, includes analytical, physico-

chemical and biological characterization

• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009:

- Provides answers to common questions that may arise in the early stagesof product development.

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Regulatory Environment - ICH Regions

How do the requirements compare?

• US, EU and Japan all require comparability with reference product

• Reference product must be registered under the Regulatory jurisdiction• In EU this is law• FDA will consider non-US registered reference product with studies to bridge

to US reference• Japan requires Japanese registered product

• Early engagement with Regulatory Authority is vital

• Extrapolation of indications will be considered

• At least one Phase III comparable efficacy study (usually with equivalence design) is required for licence

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Poll Question 1

Can extensive in vitro testing of reference from various regions support single-region reference in clinical studies?

A. Yes

B. No, clinical studies needed with all reference product

C. Not sure

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Regulatory Comparability PackageExtensive Analytical & In Vitro

• Extensive analytical characterization versus reference product(s)• If mAb

• Specificity & affinity to epitope• Potency using CDC, ADCC &/or functional in vitro cell-based assays

Limited in vivo Nonclinical• PK/PD studies, Toxicology (SD/MD), and Immunogenicity studies

(requirement for nonhuman primates?)

Limited Clinical• Phase I

• Comparability of PK/PD & Immunogenicity in volunteers or patients at reference dose and regimen for targeted indications

• Phase III• Comparability for safety and efficacy (single pivotal) based on PK/PD, surrogate

endpoints and clinical outcomes

Extensive Post-Approval • REMS and pharmacovigilance planning including patient registry(ies) for

assessment of incidence of specific safety issues

Early Development Challenges

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Development Challenges

Regulatory, manufacturing and marketing complexities

Biosimilar must be highly similar to innovator biologic, which can be difficult to demonstrate as all data for innovator will be lacking

A comparability exercise has to be followed with the innovator product at all levels of product development

• Physico-chemical characterization

• Biological activity

• Preclinical in vivo comparability

• Phase I PK and safety

It’s all about comparability

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Regulatory Landscape

Harmonization of regulatory expectations

• Most regulatory regions are in general agreement

• Main issue is reference material sourcing

Discuss plans early

• Early engagement with the regulators is key (especially in the USA)

• Characterization differences need to be fully understood and explained

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Characterization

Comprehensive Characterization• Physicochemical as well as biological

• Multiple batches of innovator spanning a number of years

• Understand innovator variability

• Specification changes over life of product

• No label change

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CMC and In Vitro

Detailed characterization of biosimilar and reference product needed before clinical trial work with consideration for:

• Physical properties

• Amino acid sequence

• High-order structure and post-translation form

• Product-related impurities (aggregates, oxidized forms, deaminated forms)

• Process-related impurities and contaminants (host cell protein, residual genomic DNA, reagents, downstream impurities)

• Receptor-binding or cell-based assays

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CMC and In Vitro

Recommendations• High resolution analysis

• Multiple methods

• Multiple batches

• Characterize reference over a number of batches (years) to understand specification range

• Confirm reference product labelled concentration or potency for each batch

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CMC and In Vitro

Detailed characterization of biosimilar and reference product needed before clinical trial work with consideration for:

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CMC and In Vitro

Cell-based assays

• Critical to assess the biological activity of the biosimilar

• Related to the actual function• Target binding

• Pharmacological effect e.g. proliferation inhibition

• mAb effector function (ADCC, CDC or FC-binding)

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CMC and In Vitro

Cell-based assays• Can be based on batch release assay

• Takes time to setup and validate

• May be possible to use as a basis for NAb assay (consider matrix effects)

• Will be required to support Phase III and pharmacovigilance

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Animal Studies

When to perform these?

• Regulators suggest a step-wise approach• Characterization differences need to be identified

and fully explained • If differences are seen and not adequately

characterized then in vivo studies may be required • Use of novel excipient in formulation may

necessitate in vivo studies• Use of NHPs not recommended• PK/PD endpoints rather than toxicity?

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Animal Studies

Examples

• rHu-EPO• 28d comparative multiple dose study in rat• Multiple dose levels to assess dose response• Primary endpoint was PK/PD but organs also assessed• No toxicity seen

• mAb• Primate toxicology study• Single dose level of innovator and biosimilar• 28d repeat dose toxicology study• No toxicity seen

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Animal Studies

Recommendations• In vivo efficacy studies

• Very useful if models exist• Models may be proprietary and thus difficult to obtain

• Where good PD marker exists• Useful to have comparative PK/PD and dose response• May take organs for assessment but not necessarily in the first

instance• ADA samples taken but not routinely tested unless effect on PK/PD

• Where no PD marker exists• Consider relevance of animal testing, especially if NHP is only

relevant species• If performed then minimal groups and maximum of 28d dosing

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Poll Question 2

Do comparative toxicology studies add to the body of evidence in determining comparability?

A. Definitely

B. Minimally

C. Not at all

D. Not sure

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Immunogenicity

Relative Immunogenicity

• Difficult to show statistical significance in animal studies

• Applicability to human?

• Useful in considering differences in TK/PK or PD

Immunogenicity recommendations

• ADA assay developed for animal studies but not necessarily validated in first instance

• Samples taken but not analyzed unless TK/PK or PD effect seen

• Used to interpret difference in TK/PK or PD but not for prediction of human immunogenicity

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Immunochemistry Assays

Option 1: Separate Assays for innovator/reference:

- Innovator Calibration standards & QCs- Reference Calibration standards & QCs

Option 2: Single Assay forinnovator/reference:

- Single Innovator Calibration curve with reference and innovator QCs

General principles for demonstration of bioequivalence are applicable:• Ratio analysis of mean result should be between 0.80 and 1.25 to

demonstrate bioequivalence

• This criteria should be demonstrated for validated assays using either option 1 or 2

Advantages of Option 2: • Less resource intensive • Blinding can be maintained

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Poll Question 3

Do you always aim for a single assay for PK/TK assessment?

A. Yes

B. No, always aim for separate assays

C. First test feasibility of single assay

D. Not sure

Clinical Development Challenges

ClinicalDesign trials with right endpoints and right population

Difficulty in identifying sites and patients in Phase I and III

Can take a long time and a lot of patients

Phase IPhase I studies supporting dose(s) for targeted indicationsPhase I Study:

• Healthy volunteers vs patients• Ethics committee considerations• Part 1 - Initial safety and comparative PK

arms (at labeled dose)• Part 2 - Comparative PK/PD, Immunogenicity

and Safety/Efficacy run in parallel to Phase III study submissions

• N=40 for Phase III start & Interim Analysis for PK/PD powering

Difficulties• Cross-over designs • Sentinel dosing group for Phase I

Phase III• Single Pivotal (therapeutic category)• Extrapolatability within category• Leverage established PD and Surrogate

endpoint(s)• PK/PD assessments with shorter cycles of

therapy• Immunogenicity determined with full

regimen of therapy• “Interchangeability” not yet addressed by

FDA

Conclusions

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Conclusions

Characterization is absolutely critical

Animal toxicology studies add little value but may be required by certain regulators. Animal studies should focus on efficacy models and PK/PD where possible

Relative immunogenicity is assessed most appropriately in clinical studies and post-marketing

Planning and multidisciplinary approach is key

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Drug Development Solutions from Discovery Through Commercialization

Reimbursement

Post-Marketing Commitments

Health Economics Assessment

Clinical Development: Special Populations

Outcomes/PE Studies

Clinical Development: Target Population

Central Labs Data: Safety and Genotyping

Phase I to Phase III Clinical Trials

Serum ProductionClinical Feasibility

DEVELOPMENT COMMERCIALIZATIONDISCOVERY

PHASE IVRESEARCH PRECLINICAL PHASE I PHASE III

Molecular Development (Program Management & Clinical)

Efficacy Model Development/Biomarker Development

Regulatory Strategy, EMA/FDA Documentation Prep & Meeting Attendance, CTA/IND/BLA Support and Submission

Viral Clearance

Immunogenicity, PK, TK

Process Development Support, Biomanufacturing Support, Biosafety Testing

Pharmacokinetics/Toxicity Tissue Cross Reactivity

In vivo/In vitro Biopotency

Immunotoxicity: CDC & ADCC

Physicochem & Biological Characterization

Stability and Release

Covance is uniquely positioned to be a valued partner at every stage in the biosimilar drug development process