Comparability Assessment of Biological Products A Clinical Pharmacology

Comparability Assessment of Biological Products – A Clinical Pharmacology Perspective Hong Zhao, Ph. D. Office of Clinical Pharmacology OTS/CDER/FDA www. diahome. org

Disclaimer The views and opinions expressed in the following Power. Point slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These Power. Point slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners. www. diahome. org

Outline Biological Product Comparability Program • Why are PK and PD studies necessary? • What is the role of PK & PD studies? • When should PK & PD studies be conducted? • How are PK & PD studies conducted? • How is the PK & PD comparability assessed? • What are the challenges? Summary and Comments www. diahome. org

Biological Product Comparability Manufacturing process changes to improve product quality, yield and manufacturing efficiency • during product development • post approval Comparability: highly similar quality attributes, no adverse impact on the efficacy and safety, including immunogenicity www. diahome. org

Comparability Program Mainly Occasionally Sometimes Identity Activity PK Efficacy Strength Toxicity PD Safety Quality e. g. , Purity NTR agents Toxic Impurities Adventitious agents Potency Immunogenicity www. diahome. org Rarely e. g. , Efalizumab

Why are PK and PD studies necessary? Major changes can impact Minor changes may affect Quality attributes not well understood Clinical performance Analytical Technology Prediction of Knowledge Clinical performance Experience PK and PD studies are considered complementary to CMC testing to reduce the need for clinical studies www. diahome. org

Why PD? • Limitations with PK studies (PK assays) • Potency assays reflecting multiple mechanisms of action (MOA) may not be available, eg. Relevant bioassays for TNF antagonists – Prevention of joint inflammation in animal models – Blocking TNF mediated inhibition of cell proliferation – Blocking tyrosine phosphorylation of downstream signaling components • PD may provide information on product activity • Support PK to further reduce uncertainty www. diahome. org

What is the role of PK & PD studies? Preclinical Clinical Development Phase 1 Phase 2 Phase 3 Post Approval Manufacturing changes occur to bridge animal pharmacology and toxicology data to humans and to determine the relevance of the data obtained in Phase 1 PK & PD characterization to Phase 2 dose ranging and proof-of-concept studies www. diahome. org

What is the role of PK & PD studies? Preclinical Clinical Development Phase 1 Phase 2 Phase 3 Post Approval Manufacturing changes occur to determine the need to change the dose(s) selected in Phase 2 for Phase 3 studies due to manufacturing changes to determine the need for repeating the PK and PD characterization studies in humans www. diahome. org

What is the role of PK & PD studies? Preclinical Clinical Development Phase 1 Phase 2 Phase 3 Post Approval Manufacturing changes occur to establish PK & PD comparability between the to-bemarketed (TBM) product and the product tested in Phase 3 trials This is a critical stage and the assessment of comparability is more rigorous Differences in PK & PD between the products may translate to differences in efficacy and safety www. diahome. org

When should PK & PD studies be conducted? Determined by Types and magnitude of changes Stage of product development Therapeutic window Ability to link the altered product characteristics with product activity www. diahome. org

When should PK & PD studies be conducted? Potentially for the following situations: Upstream process changes (such as change of cell lines or fermentation process, modifying glycosylation pattern and/or sialic acid content) Changes to the product formulation Appearance of new product- or process-related impurity (raising immunogenicity concern) Changes to a product characteristics Changes for novel products with unique structure, function or mechanism of action www. diahome. org

How are PK & PD studies conducted? Study Population Advantages Limitations Animals Easy access, shorter study time and lower cost, often used in early stage studies Lack of relevance to humans, immunogenicity, small sample size Healthy Volunteers Homogeneous, less variability, often used in late stage studies Not suitable for cytotoxic agents, CNS compounds, immunomodulators, products with diseasespecific or targetmediated disposition Patients Indicated population, most relevant, often used in late stage studies Heterogeneity in nature, larger variability, feasibility www. diahome. org

How are PK & PD studies conducted? Study Design Cross-over • Pros: requires smaller sample size • Cons: not suitable for products with long t 1/2, carryover effects including immunogenicity Parallel • Pros: suitable for products with long t 1/2 (m. Abs) • Cons: requires larger sample size Sequential • Pros: used in clinical setting, dosing interval > 5 t 1/2 Cons: carry-over effects including immunogenicity www. diahome. org

How are PK & PD studies conducted? Sample Size • Many PK&PD comparability studies are conducted with small sample size, especially in NHP and patients • Failed to show comparability due to inadequate power (primary reason) or study design and/or study conduct • Results from an underpowered study are inconclusive regarding product comparability • PK&PD studies should enroll adequate # of subjects to generate definitive conclusion on comparability, especially in the evaluation of post phase 3 or post-marketing manufacturing changes www. diahome. org

How are PK & PD comparability assessed? • Bioequivalence (BE) criteria – PK parameters (AUC 0 -t, AUC , Cmax) – 2 -sided 90% Confidence Intervals for the geometric mean ratios to be within [80%, 125%] • Other appropriate statistical analysis methods for evaluation of PD parameters • Acceptance of any deviations depends on the stage of product development, the role of the comparability study and the implication of the results • It is crucial to demonstrate PK & PD comparability between the to-be-marketed product and the clinical trial product www. diahome. org

Summary • Major components in comparability program, and their roles in the comparability assessment • PK & PD comparability studies - why, what, when & how • Acceptance of PK & PD comparability results depends on the stage of product development, the role of the study and the implication of the results • Additional clinical trials may become necessary when PK&PD studies failed to demonstrate the comparability between the TBM product and the clinical trial product www. diahome. org

What are the challenges? Identify critical product quality attributes Understand the relationships between these critical quality attributes and clinical performance Establish a risk assessment system PK & PD comparability evaluation: – Products with a long half-life – Products with a large variability – Influence of immunogenicity – Limited sample size (especially for NHPs, patients) www. diahome. org

Comments • Make major manufacturing changes at early stage • Include the to-be-marketed product in the clinical trials • Design critical PK & PD comparability studies with sufficient power • Need to consider both PK and PD and look at the data in totality • Consider relevance to clinical efficacy and safety www. diahome. org

www. diahome. org