Optimizing the Development of Biosimilars Using PK/PD: Recent Scientific and Regulatory Advances

Transcription

1 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

2 Disclaimer The information presented is in the public domain and contains no proprietary information or trade secrets 2

3 Highlights Quick overview for biosimilar approvals in Canada Purpose of conducting PK/PD Issues and Concerns with Comparative PK/PD Studies for Biosimilars 3

4 Guidance Development 2005 Working group for SEB/biosimilar created 2006* Fact sheet published History of Biosimilar Regulation in Canada Submission 2005* Received first G-CSF developed with the SEB/biosimilar concept 2009* First biosimilar growth hormone authorized 2008 Draft Guidance document released 2009 Revised Guidance document released 2010* Finalized Guidance released 2015 Updating the Guidance document based on lessons learned Since 2011 >20 pre-market and pipeline meetings 2014* First biosimilar mab authorized 2015 Several biosimilar submissions under review New indications added for biosimilar hgh 2015 Biosimilar clinical trial applications keep coming in Canada 4

5 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 Physicochemical characterization Biological activity Nonclinical Clinical PK/PD Clinical trials Case-by-case risk based approach tailored to individual product

6 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) 6

7 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.) 7

8 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 8

9 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 9

10 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 % 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

11 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 % inclusively the relative mean minimum concentration (Cmin) at steady-state of the test to the reference should not be less than 80% 11

12 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 ) 12

13 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

14 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

15 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 15

16 Recent Canadian Authorization: Infliximab Indications for Canadian Reference Product Indications for Biosimilar based on Clinical Data Indications for Biosimilar based on Extrapolation rheumatoid arthritis (RA) ankylosing spondylitis (AS) psoriatic arthritis (PsA) plaque psoriasis (Ps) Crohn s disease (CD) ulcerative colitis (UC) pediatric CD and UC rheumatoid arthritis (RA) ankylosing spondylitis (AS) psoriatic arthritis (PsA) plaque psoriasis (Ps) 16

17 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 17

18 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 18

19 Biosimilar: PK/PD Profiles Biosimilars Patients Therapeutic Effects Immunogenicity Receptor binding Effector effect Cross-react with native protein and induce adverse reactions Neutralise biological effects and compromise further therapy Alter PK/PD Affect efficacy/safety

20 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 20

21 Thank you Merci