Overview of Biologics (Including Biosimilars)

Transcription

1 Overview of Biologics (Including Biosimilars) 2015 Sandoz Inc. All Rights Reserved. The material contained in this slide deck may not be altered or reproduced without express written consent from Sandoz Inc. Unauthorized use is prohibited. Outline Introduction to Biologics Introduction to Biosimilars US Regulatory Approval Pathways FDA Approach to Biosimilarity Summary Part One: Introduction to Biologics 1

2 What is a biologic? Medical products made from a variety of natural sources (human, animal, or microorganism) Examples include vaccines gene therapies cellular therapies Biologics are complex and made in cellular systems Synthetic Bacteria, Yeast Mammalian Protein Without Sugars protein With Sugars 1x 32x Acetylsalicylic Recombinant acid Insulin kda ~5.8 kda 833x Monoclonal antibody 2 Kozlowski S, et al. N Engl J Med 2011;365(5):385 8; Revers L & Furczon E. Canadian Pharmacists Journal 2010;143(3):134 9 ~150 kda Accessed July 10, 2015 Revers L & Furczon E. Canadian Pharmacists Journal 2010;143(4): All images are stock photos, royalty free and purchased from 1 Can Stock Photo or 2 Shutterstock Biologic variability Biologics have inherent variability (multiple isoforms are present) Biologics vary over their manufacturing lifetime due to: Different batches of product Manufacturing changes Analytical and biological characterization technologies can be used to show that the functional integrity and structure of a biosimilar is as close as possible to its reference product McCamish M & Woollett G. Clin Pharmacol Ther. 2013; 93(4):

3 Biologics vary from batch to batch Monitoring batches of an approved monoclonal antibody reveals shifts in quality attributes Natural shifts in glycosylation (structure) pattern (not shown) result in different potency in cellbased assays (function) Shifts seen among batches did not lead to clinically meaningful differences (safety and efficacy) Such shifts observed in several original products/batches (EU and US) Marketed Biologic (rituximab) lifecycle variability 140 US rituximab EU rituximab 120 ADCC Potency 100 [% of internal reference] Sample Expiry Dates Schiestl, M. et al., Nature Biotechnology 29, , 2011 Manufacturing changes are controlled Changes in the manufacturing process after approval (ex-us) Stringently controlled by regulators Changes must NOT lead to clinically meaningful differences in risk/benefit Manufacturing changes were reviewed and approved by the EMA Rituximab Infliximab Etanercept Adalimumab Abatacept Tocilizumab Golimumab Certolizumab Rilonacept Canakinumab Belimumab Products in order of date of approval in Europe (from rituximab authorized on 2 June 1998 for the initial authorization in oncology, to belimumab licensed on 13 July 2011) C Schneider, Ann Rheum Dis 2013; 72(3): Part Two: Introduction to Biosimilars 3

4 Development of absolute neutrophil count (ANC) ANC (10E3/µL) Specific lysis (%) Hemoglobin (g/dl) What is a biosimilar? FDA defines it as: A type of biological product that is licensed (approved) by the FDA because it is highly similar to an already FDA-approved biologic known as the reference product and shown to have no clinically meaningful differences from the reference product in terms of safety, purity, and potency. Minor differences in clinically inactive components are allowed. The biosimilar must be highly similar to the reference product in all critical aspects STRUCTURE Originator Batch Biosimilar DP Clinical Batch Time (min) FUNCTION Originator Biosimilar Log[Abs](ng/ml) PK & PD 100 Originator 80 Biosimilar Time after administration (h) ADCC = antibody-dependent cell-mediated cytotoxicity McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther. 2012;91(3): Visser J, et al. BioDrugs. 2013;27(5): Gascon P, et al. Ann Oncol. 2010;21(7): Weigang-Köhler K, et al. Onkologie. 2009;32(4): EFFICACY & SAFETY Originator (n=34) 2 Biosimilar (n=60) Study week Part Three: US Regulatory Approval Pathways 4

5 The approval of pharmaceuticals in the United States Biologics U.S. PUBLIC HEALTH SERVICE ACT (PHSA) Small molecules U.S. FOOD, DRUG & COSMETIC ACT (FDCA) Biosimilars Generics Biologics license application (BLA) 351(a) Biosimilar biologics license application (BPCI Act) 351(k) New drug application (NDA) Abbreviated new drug application (ANDA), Hatch- Waxman Safety and efficacy must be demonstrated No clinically meaningful differences from the reference product in terms of safety, purity and potency Safety and efficacy must be demonstrated Bioequivalence must be established ANDA, Abbreviated New Drug Application; BLA, Biologics License Applications; NDA, New Drug Application Biologics Price Competition & Innovation Act Science-based pathway based on comparability with FDA discretion as to data required Limits biosimilar application to single reference biologic licensed under 351(a) Requires reliance on FDA s previous determination that reference product is safe, pure and potent, and publically available information Two potential approvals Biosimilarity Interchangeability Interchangeability Definition Safety/Efficacy Substitution Interchangeable products may be substituted for the originator product without the intervention of the prescribing healthcare provider If they demonstrate biosimilarity If they can be expected to produce the same clinical result in any given patient expectation meaning a population approach to be used high level of analytical similarity is a more sensitive consideration as to whether the molecule will behave the same in any patient If administered more than once, the risk in terms of safety or diminished efficacy when switching between the biosimilar and the originator product is not greater than the risk of using the originator without switching McCamish M, Woollett G. Worldwide experience with biosimilar development. MAbs. 2011;3(2):

6 Part Four: Achieving Biosimilarity 1 Define reference target variability Biosimilars are systematically developed to be highly similar to the reference product Iterative targeted development Process development Analytics 2 Biological variability Recombinant cell line development Bioprocess development Purification process development Drug product development 3 Confirm biosimilarity: Pre-clinical/clinical Target range Reference product variability McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther. 2012;91(3): Developmental Approach to Biosimilarity T O T A L I T Y O F E V I D E N C E, S T E P W I S E, A N D R I S K B A S E D A P P R O A C H PHYSICAL-CHEMICAL/ BIOLOGICAL CHARACTERIZATION PRECLINICAL 6-12 MONTHS PK/PD 6-12 MONTHS Phase III 2-4 YEARS Iterative analytical and process development to establish highly similar mechanism of action, structural activity relationship, primary/secondary/tertiary protein structure, glycosylation, etc. Flexibility regarding need for animal studies Animal toxicity studies may not be warranted Useful if safety uncertainties remain before first-in-man studies Followed by PK and PD studies (where there is a relevant PD measure) Scope and magnitude depends on extent of residual uncertainty from below steps No need to independently establish safety or efficacy Immunogenicity data is minimally expected Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Website Accessed June 16, 2015 McCamish M, et al. Clin Pharmacol Ther.2013;93(4):

7 Development Process and Cost C O M P A R I S O N W I T H T H E R E F E R E N C E P R O D U C T Reference product development Clinical PK/PD Non-clinical Analytical Biosimilar development Clinical PK/PD Non-clinical Analytical BLA pathway Time: ~11-13 years Cost: Often >$1 billion Pivotal Licensure Data: 2 adequate & well-controlled studies vs. placebo/standard of care Biosimilar pathway Time: ~6-8 years Cost: ~$ million Pivotal Licensure Data: Analytical & PK/PD comparisons to reference, clinical confirmation Regulatory pathway for biosimilar development ensures same level of confidence with regard to safety and efficacy as compared to the reference product Paul SA (2010) Nature Reviews Drug Discovery 9: ; Harding Starts with a comprehensive understanding of the reference product s structure High resolution, orthogonality and redundancy in analytical characterization provide full understanding Primary structure fully accessible to analytical verification Set of orthogonal analytical methods available to characterize the identity and amount of related variants with high sensitivity Glycosylation profile can be comprehensively determined with regard to identity and content of individual glycans with high sensitivity The combination of ~40 methods yields the complete quality profile with ~100 attributes Berkowitz SA, et al. Nat Rev Drug Discov ;11(7): Scientific justification is needed for extrapolation of indications Important to consider: Mechanism of action PK and bio-distribution in different patient populations Safety differences in each indication and patient population Based on totality of evidence, not applying one indication to support another, a biosimilar can be approved for the reference products other indications 7

8 Part Five: Summary In the end, the biosimilar must be highly similar to the reference product at all levels 1. Made in cellular systems 2. Highly similar to reference product with essentially the same safety, purity, and potency 3. Regulated by FDA through a stringent approval process 8