Implications for Preclinical and Clinical Programs. Novartis Pharmaceuticals Oncology Business Unit June 2, 2011

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1 EU Biosimilarityi il it Guidance Implications for Preclinical and Clinical Programs Shefali Kakar Novartis Pharmaceuticals Oncology Business Unit June 2, 2011

2 Biologics are more complex than small molecules Aspirin small chemical molecule Calcitonin simple biologic Monoclonal Antibody (IgG) complex biologic Molecular l weight Molecular l weight Molecular l weight = 180 Daltons = 3,455 Daltons = 150,000 Daltons 0 amino acids ~ 32 amino acids ~ 1300 amino acids 2 EU Biosimilarity Guidance Shefali Kakar June 2, w/o host cell modifications o -w/host cell modifications o - produced in yeast, bacteria (glycosylations, etc) - produced in mammalian cells

3 What is a biosimilar? Overview Regulatory Definition Description Successor to a biologic medicine that has lost exclusivity Not a simple generic due to complexity: size, structure and manufacturing A biologic approved via a stringent regulatory defined pathway demonstrating comparability mau Robust analytical characterization GCSF Peptide Mapping Min Zarzio Neupogen Determination of Receptor Binding: Surface plasmon resonance spectroscopy 80 Comparability Approach Highly analogous structure (via robust analytical characterization) Comparable quality, safety and efficacy (via clinical trials) rel. response e (RU) Batch 1 Batch 2 Batch 3 Batch 4 Batch 5 Batch 6 Batch time (s) Association rate Dissociation rate 3 EU Biosimilarity Guidance Shefali Kakar June 2, 2011

4 Biosimilars are recognized around the world as safe and effective medicines EU draft general guidelines adopted Sandoz Somatropin first biosimilar approved and launched in EU Sandoz first EPO approved and launched in Filgrastim* Draft mab EU approved in EU guidelines Sandoz Somatropin first biosimilar type medicine approved in Australia Sandoz Somatropin first biosimilartype medicine approved and launched in US Japan regulatory guidelines Sandoz Somatropin first biosimilar approved and launched in Japan & Canada US regulatory pathway 4 EU Biosimilarity Guidance Shefali Kakar June 2, 2011

5 How do we assess Biosimilarity? Key scientific issues include In vitro, Pre-clinical and Clinical In Vitro Quality assessment Bioassays Effector functions Understanding Impurities Glycosylation Patterns PK Efficacy Preclinical Safety Immunogenicity Clinical PK population, TMDD, disease status Efficacy - Appropriate Indication. Safety Translating data from one indication to another 5

6 Clinical evidence required from a biosimilar depends upon degree of similarity established Clinical Trials PK/PD Highly Similar Molecular Structure Preclinical Biological characterization Analytics Physicochemical characterization Process development Once a proposed biosimilar is shown to be highly similar at the analytical level, this demonstration should streamline pre-clinical and clinical studies If the product quality attributes of a proposed biosimilar deviate from the reference, this should increase preclinical and clinical study requirements

7 Biosimilars Pathway Around the World USA Patient Protection o and Affordable Care Act (2010); abbreviated application under 351(k) pathway FDA Public Hearing (2010) Two step review process announced (2011) Draft Guidance is expected by Nov 2011 Asia Japan issued guidelines for subsequent entry protein products March 2009 Malaysia, Singapore adopted EU guidelines Taiwan and Korea FDA published their guidance in 2009 India OPPI issued a position paper on biosimilars EU Biosimilarity Guidance Shefali Kakar June 2, 2011 Europe Biosimilar framework since 2004 Specific Monoclonal antibody biosimilar draft Guidance (2010) 14 biosimilars approved EMA received scientific advice requests on 6 monoclonal antibodies in 2009, on 11 mabs in 2010 WHO Guidelines on Evaluation of Similar Biotherapeutics Published Oct 2009 Canada Final guidance published in Refers to EU guidance for product specific guidelines. Australia In 2005, Australia adopted EU guidelines

8 EU mab biosimilar Guidance (draft) Summary Risk Based, Step Wise approach to evaluate mab NonClinical Target, Fcγ, FcRn binding, ADCC etc. If minor differences, preclinical comparability may not be necessary Large scale powered comparative tox studies not required Ph I PK PD Equivalence in PK required prior to large scale efficacy study A sensitive population desired (adequately demonstrates differences. Not confounded by variability) Conventional equivalence margins of 80%-125% If an appropriate PD available, demonstrating dose response with this PD marker may already provide pivotal biosimilarity information Efficacy PhIII Study Appropriately sensitive population (unlicenced indication OK) Non EU populations acceptable Powered, randomized, parallel group, double blinded, normal equivalence trial expected Oncology Focus is biosimilarity, not patient benefit! PFS /DFS or Overall survival (OS) not suitable ORR, or ORR at x months may be acceptable Novel endpoints acceptable if well justified 8 EU Biosimilarity Guidance Shefali Kakar June 2, 2011

9 Clinical development: Four Step Process Avg Time Characteristics 1 Pre-clinical 6 12 months Animal models toxicology and efficacy/ safety in relevant disease models 2 Phase I (PK/PD) 9 12 months Showing PK/PD bioequivalence to originator (often in patients) 3 Phase III (confirmatory) 2 4 yrs Clinical trial to show comparable efficacy (~500pts) in one or more indications 4 Post approval trials Variable Additional data to meet regulatory / commercial needs 9 EU Biosimilarity Guidance Shefali Kakar June 2, 2011

10 Key Unanswered Questions: The Road Ahead The guidance for development of Follow on Biologics in the US Harmonization of global guidance Global development: Source of reference and comparator Product drifts in different markets Need for a common reference products (needs to be authorized in a highly regulated country or ICH-region) that enables data to be leveraged across the world Interchangeability Naming Conventions 10 EU Biosimilarity Guidance Shefali Kakar June 2, 2011

11 Backups 11 Presentation Title Presenter Name Date Subject Business Use Only

12 Need for Clinical Data Beyond PK Equivalence 12 EU Biosimilarity Guidance Shefali Kakar June 2, 2011

13 Ph III 89 children 7 year efficacy trial in growth hormone deficiency (GHD) children with growth retardation Compare safety and efficacy of Omnitrope with Genotropin Designed to compare efficacy and safety of Omnitrope with Genotropin and assess the long-term safety and efficacy of Omnitrope Also looked at switching from Genotropin to Omnitrope no increase in immunogenicity 13 EU Biosimilarity Guidance Shefali Kakar June 2, 2011 Romer T. Horm Res 2009;72:

14 EU mab biosimilar Guidance (draft) Nonclinical Risk Based, Step Wise approach to evaluate mab Step 1: In vitro PD assessment Step 2: Identification of key factors for in vivo nonclinical strategy Step 3: In vivo studies Target, Fcγ, FcRn binding Neutralization, receptor activation, ADCC etc. Differences in formulation, impurities Availability of appropriate in vivo models If comparability in Step 1 adequate AND no key issues identified in Step 3, In vivo studies in animals is not considered necessary 14

15 EU mab biosimilar Guidance (draft) Clinical Assessment of Clinical Pharmacokinetic Equivalence Population Sensitive Population PK equivalence may be in a different population than the efficacy For mabs licensed in several indications PK study in each indication not justified, Except when indications in distinct therapeutic area Special Considerations PK equivalence should precede efficacy trials (some exceptions) Parallel group design: long half-life and possible immunogenicity CHMP guidance Guideline on the clinical investigation of PK of therapeutic proteins referenced Endpoints Conventional equivalence margins of 80%-125% Sampling following first dose and steady state desired. Primary parameters: AUC, C max, C trough. g

16 EU mab biosimilar Guidance (draft) Clinical Assessment of Clinical Pharmacodynamic Equivalence Population Can be combined with a PK study. Special Considerations There is often a lack of specific clinical PD. Therefore the emphasis will be on nonclinical PD Endpoint Dose-concentration-response relationships encouraged PD data from lower dose(s) may, in principle, provide already pivotal information for the biosimilarity exercise Risk of immunogenicity when exposed to low doses Challenging to define an appropriate equivalence margin 16

17 EU mab biosimilar Guidance (draft) Clinical Assessment of Similar Clinical Efficacy Population Appropriately sensitive population Can be in a licenced or unlicenced indication Non EU populations acceptable Pediatric and Elderly populations not required Endpoints If no PD comparability Similarity in clinical efficacy required Powered, randomized, d parallel l group, double blinded, d normal equivalence trial ICH E10 guidance (Guideline on the choice of non-inferiority margin) is referenced. Focus is biosimilarity, not patient benefit! Classical endpoints: PFS /DFS or Overall survival (OS) may not be feasible or sensitive therefore not suitable Oncology ORR, or ORR at x months may be acceptable Novel endpoints on an exploratory basis acceptable if well justified 17

18 EU mab biosimilar Guidance (draft) Clinical Assessment of Clinical Safety Can be obtained within the efficacy study Population Recommended to exclude where possible, patients previously treated with the reference mab Immunogenicity Endpoints Comparable pharmacologically mediated adverse reactions should be considered as a measure of biosimilarity Post Marketing Applicants asked to propose pharmacovigilance and risk management activities for post-marketing at the time of registration 18