Optimizing the Development of Biosimilars

Using PK/PD: Recent Scientific and

Regulatory Advances

Jian Wang, MD, PhD

Chief, Clinical Evaluation Division

Biologics and Genetic Therapies Directorate

Health Canada

AAPS 2015, San Francisco, USA, June 2015

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Disclaimer

The information presented is in the public domain

and contains no proprietary information or trade

secrets

Highlights

• Quick overview for biosimilar approvals in Canada

• Purpose of conducting PK/PD

• Issues and Concerns with Comparative PK/PD Studies for Biosimilars

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Guidance Development Submission

2005

Working group for SEB/biosimilar created

2005*

Received first G-CSF developed with the

SEB/biosimilar concept

2006*

Fact sheet published

2009*

First biosimilar growth hormone authorized

2008

Draft Guidance document released

Since 2011

>20 pre-market and pipeline meetings

2009

Revised Guidance document released

2014*

First biosimilar mAb authorized

2010*

Finalized Guidance released

2015

Several biosimilar submissions under

review

New indications added for biosimilar hGH

2015

Updating the Guidance document based on

lessons learned

2015

Biosimilar clinical trial applications keep

coming in Canada

History of Biosimilar Regulation in Canada

Biosimilars Development: Basic Steps

The foundation of a biosimilar development program is based on the

extensive side-by-side structural and functional characterization of

the biosimilar and the reference to demonstrate similarity

Step-by-step sequential development program, evaluating residual

uncertainty at each step

Case-by-case risk based approach tailored to individual product

Physicochemical characterization

Biological activity

Non-clinical

Clinical PK/PD

Clinical trials

Comparative PK/PD Studies

The goal of the human PK/PD is to rule out unacceptable PK/PD

differences that could indicate the presence of structural and

functional differences

• A biosimilar mAb that has a lower affinity for FcRn receptors than its

reference could have a shorter half-life

PK/PD studies can also be used to

• Bridge gaps for using multiple non-domestic references

• Justify reducing subsequent clinical studies (e.g., insulin)

• Monitor immunogenicity during comparative clinical trials (e.g., altered

PK)

• Establish bioequivalence between different strengths and formulations of

biosimilars

• Demonstrate bioavailability for the different routes of administration

• Establish evidence for extrapolation of indications (e.g., cancer vs RA;

adult vs paediatric)

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Design of Clinical PK Studies for Biosimilars

Comparative clinical PK data are generally required

• The comparative PK studies should be conducted in a setting

that is reflective of the clinical situation and is sensitive to

detect differences

• Route of administration is an important factor to consider in the

design and conduct of comparative PK studies

• Use of a route that requires an absorption step is recommended (if

applicable)

• The design of PK studies depends on various factors, including

clinical context, safety, PK characteristics of the reference

product (target-mediated disposition, linear or non-linear PK,

time-dependency, half-life, etc.)

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Design of Clinical PK Studies for Biosimilars

• The most sensitive PK study design to detect potential

differences between the biosimilar and the reference is the

single dose cross-over design (short half-life) and could be

conducted in healthy volunteers

• Healthy volunteers may not always adequately reflect the PK

parameters in the patient population, since host factors such as

receptor expression, receptor internalization rate, and

patient status can affect the disposition and clearance of

biologics (target-mediated disposition for mAbs)

• Biologics with serious toxicity — studies in patient population

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Design of Clinical PK Studies for Biosimilars

• The cross-over, single dose design can be limited by the properties of the biologics,

• long half-life

• formation of antidrug antibody (ADA)

• Alternatively, parallel and/or multiple-dose design could be considered

• The number of studies required would depend on the degree of similarity of the biosimilar to the reference drug from the C&M data, and indications for which the biosimilar sponsor applies

• Principles of study design, statistical methods and criteria of acceptance for small molecules are used as a general guidance

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Comparative Pharmacokinetic Studies

Need to know

• Comparative bioavailability criteria between FDA, EMEA and HC

are different

• According to the HC guidance document for PK studies, the 90%

CI of AUCt, as well as of the relative mean Cmax of the

biosimilar to the reference product should be within 80 –125%

• At the same time, the FDA recommends applicants to provide

the geometric means, arithmetic means, geometric mean ratios

and 90% CI for AUCt, AUCi, and Cmax

• Strong justification is required for any widening of these criteria

Comparative Pharmacokinetic Studies

Other parameters for clinical PK studies

• When the IV route of administration is involved, additional

parameters (T1/2, CL, Vd or Vss) might also be investigated

• For steady state studies (as part of clinical trial)

• the 90% CI of the relative mean area under the concentration

versus time curve at steady-state over the dosing interval

(AUCtau)

• the ratio of the test to the reference (Cmax) at steady state should

be within 80–125% inclusively

• the relative mean minimum concentration (Cmin) at steady-state

of the test to the reference should not be less than 80%

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Comparative Pharmacokinetic Studies

Other analysis for biosimilars

Example: infliximab

• As an alternative approach for assessing similarity, a multivariate

discriminant analysis (MDA) was conducted

• The outcome of this analysis demonstrated that the Inflectra/Remsima

drug could not be distinguished from the reference product, based on

the seven PK parameters (AUCtau, Cmax, Cmin, Half-life, CL, Vss,

and Fluctuation )

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Comparative Pharmacodynamic Studies

Comparative pharmarcodynamic (PD) data are desirable and can

help to reduce residual uncertainty

Following factors should be considered:

• Availability of PD marker/surrogate marker

• Sensitivity of PD marker to detect changes

• Availability of reliable assay(s) for the PD marker

• Correlation between the PK and PD values

• Relevance of the PD marker to the mechanism of action

• Quantitative relationship between the surrogate and clinical endpoint

Special Considerations for Comparative PD

PDPK/PDStudies • Comparative in nature (95% confidence intervals to be used)

• Equivalence margins should be pre-defined and justified

• PD surrogates validated and correlated to clinical outcomes or

other parameters considered to be clinically relevant

• For many biologics, especially mAbs, there is no relevant PD

surrogate

• Ceiling effect in healthy volunteers masking differences at

therapeutic dose levels

• Dose in the steep part of the dose-response curve (assay

sensitivity)

• Disposition and clearance of biologics (target-mediated disposition

for mAbs) affected by patient status

Special Considerations for Comparative PD Studies

PD parameters used in comparative studies should be clinically

validated, and are considered as surrogate markers, e.g.,

absolute neutrophil count for a biosimilar G-CSF

PD parameters are generallyi nvestigated in the context of

combined PK/PD studies or part of clinical trials

Comparative PK/PD studies may provide useful information on

the relationship between dose, systemic exposure, as well as

safety and efficacy

For most mAbs, there are no sensitive PD markers to confirm

comparability between the biosimilar and the reference, and to

be used to reduce the clinical studies

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Recent Canadian Authorization: Infliximab

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Indications for Canadian

Reference Product

rheumatoid arthritis (RA) ankylosing spondylitis (AS)

psoriatic arthritis (PsA) plaque psoriasis (Ps) Crohn’s disease (CD) ulcerative colitis (UC) pediatric CD and UC

Indications for Biosimilar based on

Clinical Data

rheumatoid arthritis (RA)

ankylosing spondylitis (AS)

Indications for Biosimilar based on

Extrapolation

psoriatic arthritis (PsA)

plaque psoriasis (Ps)

Extrapolation of Indications: Not Considered

Extrapolation to indications and uses pertaining to IBD could not be

recommended because the comparability between the reference

and the biosimilar infliximab indicated insufficient similarity between

the two products

This arose from the observed differences in the level of

afucosylation, FcγRIIIa receptor binding, and in vitro Antibody-

Dependent Cell-Mediated Cytotoxicity (ADCC) activity in NK cells

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PK/PD Study to Address Uncertainty

• Differences were observed in quality assessment - a lower ADCC

activity

• Clinical significance of a lower ADCC activity is still unclear

• ADCC mediated effects in IBD cannot be ruled out

• Clinical studies were conducted only in populations where ADCC is

unlikely to be involved

Can this issue be addressed by a PK/(PD) study in IBD population?

The answer is “No”

• There is no valid PD marker that is correlate with clinical response

• PK data only are not useful in this case, as it is not an exposure issue

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Biosimilar: PK/PD Profiles

Biosimilars Patients

Alter PK/PD

Neutralise biological effects and compromise

further therapy

Cross-react with native protein and induce adverse

reactions

Affect efficacy/Safety

Immunogenicity Receptor binding Effector effect

Therapeutic Effects

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Conclusions

• The foundation of a biosimilar development program is based on

extensive side-by-side structural and functional characterization of

a biosimilar and a chosen reference to demonstrate similarity

• The goal of the human PK/PD is to rule out unacceptable PK/PD

differences that could indicate the presence of structural and

functional differences, and to support a demonstration of

biosimilarity in

• PK

• PD

• PK/PD relationship

Thank you

Merci

jian.wang@hc-sc.gc.ca

613-957-0833