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Draft Guidance document released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
613-957-0833
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