Current Trends and Future of Biosimilars

Transcription

1 Current Trends and Future of Biosimilars Jian Wang, MD, PhD Chief, Clinical Evaluation Division Biologics and Genetic Therapies Directorate Health Canada Global Bio Conference 2017 June 28-30, 2017 Seoul, Korea

2 Brief History of Biosimilars Europe First approved biosimilar somatropin approved biosimilars USA First approved biosimilar filgrast im approved biosimilars Canada First approved biosimilar somatropin approved biosimilars and 7 under review

3 Unlike small-molecule generic drugs, these large, complex protein molecules cannot be absolutely identical to the original Biosimilars are similar to the reference...but not identical to the reference Different cell lines Different manufacturing processes Biosimilarity is a regulatory concept that defines the acceptable degree of similarity to the reference product 3

4 Basic Regulatory Requirements Must be the same The amino acid sequence Dosage and the route of administration Must be similar The active substance in terms of molecular and biological characteristics Need to be justified Differences in strength, pharmaceutical form, formulation, excipients Not allowed Intended changes to improve efficacy ( biobetters ) 4

5 Biosimilar Development Program 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 biological drug (RBD) 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 based approach tailored to individual product. 5

6 Quality Comparison 6

7 Critical Quality Attributes: Extensive Quality Comparison Quality Attribute Amino acid sequence and modifications Folding Subunit interactions Methodology Mass spectrometry (MS), peptide mapping, chromatographic separation S-S bonding, calorimetry, HDX and ion mobility MS, NMR, dyes, circular dichroism, Fourier transform spectroscopy, fluorescence chromatography, ion mobility MS Heterogeneity of size, charge, hydrophobicity Glycosylation Bioactivity Aggregation Impurities Adventitious Agents Chromatography resins; gel & capillary electrophoresis, light scatter, IM-MS Anion exchange, enzymatic digestion, peptide mapping, CE, MS cellular and animal bioassays; ligand & receptor binding (ELISA, surface plasmon resonance), signal transduction Analytical ultracentrifugation, size-exclusion chromatography, field flow fractionation, light scatter, microscopy proteomics, immunoassays, metal & solvents analysis sterility, qpcr, bioassays, clearance

8 Non-clinical Comparison 8

9 Comparative Non-Clinical Studies Comparative non-clinical studies following principles recommended by ICH S6 (R1) to detect significant differences between the biosimilar and the reference In vitro studies Extensive receptor binding studies and cell-based assays (considered to be more sensitive) In vivo studies Animal PK/PD studies when feasible At least one repeat-dose toxicity study, including characterization of toxicokinetic parameters, conducted in a relevant species Other relevant safety observations (e.g., local tolerance), which can be made during the same toxicity study Future: Regulatory expectations for comparative toxicology studies have changed over time. Flexible approaches have been considered, Non-comparative animal studies in vitro studies only, if justifiable 9

10 PK/PD Comparison 10

11 Comparative Clinical Development Paradigm Comparative Pivotal PK Comparative Pivotal PD Comparative Pivotal Clinical o Measure of API in blood AUCt (CI %) AUCi Cmax o PD response Surrogate marker Biomarker o Efficacy/safety/ immunogenicity Within predefined equivalence margin Similarity Assessment Most sensitive Least sensitive 11

12 Comparative PK Studies Design of Clinical PK Studies for Biosimilars Comparative clinical PK data are required. The comparative PK studies should be conducted in a setting that is reflective of the clinical situation and/or is sensitive to detect differences between the biosimilar and the reference. The most sensitive PK study design to detect potential differences is the single dose cross-over design (short half-life). The cross-over, single dose design can be limited by the properties of the biologics. Alternatively, parallel and/or multipledose design could be considered. 12

13 Design of Clinical PK Studies for Biosimilars (Cont.) In general, the PK study can be conducted in healthy volunteers. However, healthy volunteers may not always adequately reflect the PK parameters of the patient population, since host factors such as receptor expression, receptor sub-types, pathophysiological process of disease and patient status can affect the disposition and clearance of the biosimilar. Principles of study design, statistical methods and criteria of acceptance for small molecules are used as a general guidance. AUCt (90% CI %) AUCi (90% CI %) Cmax (90% CI or ratio %) 13

14 Comparative Pivotal PD studies Sensitivity of Comparative PD studies Comparative PD data are desirable (if available) and can help to reduce residual uncertainty. Clinical sensitivity Assay sensitivity Dosing sensitivity PD endpoints used should be clinically relevant e.g., absolute neutrophil count for a biosimilar G-CSF and be clinically validated Dose in the steep part of the dose-response curve should be considered A therapeutic dose for patients may induce a ceiling effect in healthy volunteers, thus masking potential differences A lower dose may be required 14

15 Clinical Comparison 15

16 Comparative Clinical Studies The innovator has established efficacy and safety for each indication. A biosimilar does not have to re-establish the de novo benefit/risk (provided it can be considered highly similar from a quality perspective). The purpose of the clinical program is to show that residual uncertainty from quality assessment does not cause clinically meaningful differences in efficacy, safety and/or immunogenicity in a sensitive population. 16

17 Sensitive Clinical Study Population The comparative clinical study should be conducted in a sufficiently sensitive population that is representative of the authorized indications to detect differences between the biosimilar and the reference. A homogeneous population would give a better chance to detect potential differences between a biosimilar and its reference Observed clinical effects are the direct action by the biosimilar or the reference without interference of other drugs A large body of historical data is available for validation of study outcomes Mechanism of action is well-understood and representative Large effect size 17

18 Comparative Pivotal Clinical Studies Clinical Trials: Equivalence Design Equivalence over non-inferiority Justified margins (clinical and statistical considerations) Control Superior -) Equivalence +) Region Test Superior ICH E9: A trial with the primary objective of showing that the response to two or more treatments differs by an amount which is clinically unimportant. This is usually demonstrated by showing that the true treatment difference is likely to lie between a lower and an upper equivalence margin of clinically acceptable differences. 18

19 Sensitive Clinical Study Endpoint A sensitive study endpoint should be considered to improve the detection of potential differences between the biosimilar and the reference within the sensitive population. A study endpoint different from the innovator's original study endpoint(s) may be used, e.g., ORR or PFS as primary endpoint instead of OS in oncology trials for biosimilars. A new surrogate or a more sensitive clinical endpoint identified in clinical practice may be acceptable, e.g., assess clinical response before the plateau phase for better sensitivity (time-dependent sensitivity). 19

20 Sensitivity of Clinical Assessment Time Points

21 Other factors Structural properties Immunogenicity Most biologics induce some level of anti-drug antibodies (ADAs) and these ADAs may have undesirable clinical effect on pharmacokinetics, efficacy and/or safety, including immunogenicity. Factors that influence immunogenicity: Schellekens H. Nat Rev Drug Discov 2002:

22 Immunogenicity Assessment Strategy Anti-drug antibody (ADA) is a key concern Immunogenicity should be compared between the biosimilar and the reference in at least one clinical study that enrolled a sufficient number of patients for a sufficient period of time. Immunogenicity assessment strategy: Screening Assays Quickly assess all binding antibodies with a sensitive assay Confirmatory Assays Eliminate false positives due to non-specific binding Neutralizing Assays Discriminate neutralizing/non -neutralizing ADAs PK/Clinical Impact Assessment A biosimilar should not be more immunogenic than its reference in terms of ADA incidence or ADA concentration 22

23 Therapeutic Indications for Biosimilars A single biologic may be indicated for use in a variety of diseases Infliximab Indicated diseases Rituximab NHLs Chronic Lymphocytic Leukemia Rheumatoid Arthritis Wegener s Granulomatosis 23

24 Authorization of Indications Since a biosimilar is very similar in structure and function to a reference biologic drug with well-established safety and efficacy, clinical studies do not need to be repeated for each indication. Totality of Evidence The decision to authorize the requested indications is dependent on the demonstration of similarity between the biosimilar and reference biologic drug based on data from comparative structural, functional, non-clinical and clinical studies and a detailed scientific rationale. 24

25 Authorization of Indications for Biosimilars A biosimilar sponsor is eligible to apply for the indication(s) and condition(s) of use that are held by the reference biologic drug authorized in the region. However, The biosimilar manufacturer may choose not to seek all indications held by the reference. Some indications may be under patent/data protection and therefore cannot be authorized. Regulatory agencies may decide not to authorize a biosimilar for a certain indication based on scientific and regulatory considerations. 25

26 Totality of Evidence for Granting Therapeutic Indications Physicochemical characterization Biological activity/mechanism of action Non-clinical studies PK/PD Profile Clinical Trial, Route gdhjh of Admin & Dosage Range Monotherapy & Combination Therapy Biosimilars can receive all indications of the reference based on the totality of evidence obtained from all comparative analyses 26

27 Interchangeability Health Canada Europe EMA US FDA Health Canada's Authorization by the Interchangeability authorization of a biosimilar is not a declaration of equivalence to the reference biologic drug EMA does not include a recommendation on interchangeability designation and standards are mandated by law The authority to declare two products interchangeable rests with each province and territory Substitution policies vary between member states Draft guidance published by FDA in Jan Comment period extended and closed in May. No interchangeable biosimilar products licenced to date 27

28 Compare Multiple Switches With Continued Treatment GP2015 N=150 N=100 First transition N=96 Enbrel N=151 GP2015 Enbrel Pooled switched Pooled continued Wk 0 Randomization Wk 12 Wk 18 Wk 24 Wk 30 Wk 52 Screening Treatment Period 1 Primary endpoint Re-randomization if response PASI 50 Treatment Period 2 Extension Period undergoing repeated switches (GP2015 and Enbrel) adopted from the Sandos presentation to Arthritis Advisory Committee Meeting on July 13, 2016

29 Future of Biosimilars 29

30 Biosimilar Pipeline

31 Regulatory Challenges An increasing number and percentage of biologics entering the market are biosimilars. A modern regulator s future success will depend on our ability to adapt to our changing environment. Specifically, this means: Identifying the horizon issues that are likely to challenge regulators Creating agile and flexible regulatory frameworks that can adapt to rapid scientific and technological advances Leveraging collaborative opportunities with international partners that emphasize regulatory harmonization in a globalized market

32 Potential Differences: Clinical and Statistical Agency 1 Agency 2 Stats for CMC Yes No Equivalence Margin ±17 ±15 Equivalence Margin asymmetric symmetric Confidence Interval (CI) 90% 95% Statistical Power 90% 80% Sensitive Population (e.g. oncology) monotherapy combination therapy Statistical Analysis on endpoint (e.g. oncology) Risk Ratio Risk Difference Sensitive Endpoint (e.g. RA) DAS28 Different Naming Yes No ACR20

33 Biosimilar Cluster Meeting Current membership includes FDA, EMA, PMDA, and Health Canada Meet 3 4 times/year by TC Under Inter-Agency Confidentiality Agreements Purpose Promote global development of biosimilars Discuss general scientific review issues and specific programs Discuss and share policy Share lessons learned Identify emerging issues Focus on scientific alignment

34 International Collaboration Activities International Pharmaceutical Regulators Forum (IPRF) Biosimilars Working Group Broad membership; quarterly teleconferences and one annual face to face meeting Key activities/deliverables: Public assessment of summary information for biosimilars (PASIB) (completed) Reflection Paper on Extrapolation of Indications in Authorization of Biosimilar Products (seeking management committee endorsement May 2017) Development of training manual for regulatory reviewers: Analytical comparability of biosimilar monoclonal antibodies (seeking management committee endorsement May 2017) 34

35 International Collaboration Activities APEC The APEC Harmonisation Center has identified two biotherapeutics Centres of Excellence: Seoul National University (Korea) and Northeastern University (US). Training sessions, including analytical testing in the lab, case studies in the class and expert presentation/discussion, on biosimilars have been conducted, and are being planed this year for regulatory agencies in the developing countries. 35

36 Conclusions When regulatory agencies authorize the use of a biosimilar, it means that, The biosimilar has to meet all quality, safety, and clinical standards The biosimilar is structurally and functionally (highly) similar to the reference product Residual uncertainty from quality assessment does not cause clinically meaningful differences in efficacy, safety and/or immunogenicity Rapidly Evolving Field Ongoing challenge of policy/regulatory approaches keeping pace with science Regular review of biosimilars guidance document International collaborations extremely useful 36

37 Thank you Merci