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Objectives Outline 4/6/2018 Biosimilars: What Prescribers Need To Know Diana Webber, DNP, APRN-CNP April 2018 Objectives • Compare and contrast the terms biosimilar and biologic reference product regarding structure, manufacturing, regulatory pathway, and clinical properties. • Discuss potential safety concerns with biosimilars • Describe current FDA policy related to prescribing biosimilar agents. • Evaluate if biosimilar agents are appropriate for select patients based on risks/benefits, disease/treatment-related factors, and patient preferences. Outline A. Definition “biologic” drug product i. Comparison biologic with small-molecule chemical drug ii. Nomenclature biologic products B. Definition “biosimilar” drug product i. Comparison biosimilar to generic small-molecule drug ii. Comparison biosimilar to biologic reference product iii. General principles of biosimilarity C. Biosimilar safety i. Immunogenicity ii. Interchageability & Extrapolation D. FDA Policy and Prescriber Concerns i. Approval process ii. Nomenclature iii. Prescriber Concerns E. Prescribing Scenario 1 4/6/2018 Quiz Time! 1. Small-molecule chemical drugs and biologics are used to treat a variety of diseases. Do you think that there is a significant difference between a small-molecule drug and a biologic agent? A. YES B. NO 2. In which ways do biosimilars and generic chemical drugs resemble each other? A. Both involve complex manufacturing processes, and it is impossible to ensure identical copies B. Both are stable products, not sensitive to external conditions C. Both products are non-immunogenic D. Biosimilars do not resemble generic chemical drugs Definition “Biologic” • Biological product • Biopharmaceutical examples: – Botox – Herceptin – Enbrel – Insulin analogs • Biologics 20-35% of new drugs in pipeline • Source materials • Recombinant DNA https://www.ecfr.gov/cgi-bin/text- idx?SID=a3931adb89f6a292d67a7c48340f5b1a&mc=true&node=se21.7.600_13&rgn=div8 Development of a Biologic product Identification and isolation of the gene of interest: https://www.youtube.com/watch?v=a Yhf-FXpoYs 2 4/6/2018 Chemical vs Biologic Drug Chemical versus Biologic Drug Chemical (e.g. aspirin) Biologic (e.g. monoclonal antibody) Low molecular weight High molecular weight Well-defined, homogeneous Complex, heterogeneous structure chemical structure Produced by chemical Produced in living cell culture; difficult synthesis; predictable to control process; impossible to chemical process; can make ensure identical copy identical copies Stable Unstable, sensitive to external conditions Mostly non-immunogenic Immunogenic Li, et al. (2015); CCO (2017), clinicaloptions.com Chemical vs Biologic Drug Kozloski, 2011 Biosimilars • Reverse-engineered copies of FDA- approved biologic agents no longer under patent protection • Biologic products designed to mimic existing, approved biologic agents • Similar but not identical to reference biologic agent • Not “generic” for reference drug 3 4/6/2018 Biosimilar Definition • A biologic product that is –“highly similar to the reference product notwithstanding minor differences in clinically inactive components ” – “there are no clinically meaningful differences between the reference product and the biologic product in terms of the safety, purity, and potency of the product.” Biologics Price Competition and Innovation (BCPI) Act of 2009 Biosimilar Not Generic Property Generic Chemical Drug Biosimilar Structural complexity Small, simple, Large, complex, biologic reproducible molecule molecule Comparison to •Identical active •Same amino acid sequence Reference Agent ingredients •May differ in some •Same dosage, route of parameters administration, •Higher potential bioequivalence, strength, immunogenicity purity Manufacturing •Chemical synthesis •Created in living systems Process •Predictable set •Unique cell lines & chemical reactions production steps from reference product FDA-approval •Abbreviated New Drug •Biosimilar Biologics License Process Application Application (abbreviated) •Demonstrate •Demonstrate similar safety, bioequivalence purity, potency, efficacy Li, et al. (2015); CCO (2017 ) Biosimilar Not Generic Property Generic Chemical Drug Biosimilar Immunogenic Less likely; allergic Possible; requires testing potential reactions can occur and monitoring Interchangeability Allowed by FDA if standards Only when a FDA “higher with reference of purity and bioequivalence standard of agent have been met interchangeability” has been met Automatic Generally allowed, FDA guidance pending substitution depending on state law and prescriber preference Nomenclature Name is generally the same FDA proposes unique as the International Non- nomenclature that shows proprietary Name (INN) relationship but distinction from reference product Cost Much less than branded Varies: 15-90% less than product reference product; greater cost savings outside of U.S. Rak Tkaczuk & Jacobs (2014); Kay, et al. (2018); Blackstone & Joseph (2013); ACR (2016) 4 4/6/2018 What Features Do Biosimilars Share With Their Reference Biologics? Reference Host cell line Host cell line Biosimilar Biologic Manufacturing Manufacturing processes processes Amino acid sequence Protein structure Protein structure Inactive ingredients Mechanism Inactive ingredients of action Proven efficacy, safety Proven similarity to reference biologic Li E, et al. J Manag Care Spec Pharm. 2015;21:532-539. Weise M, et al. Blood. 2012;120:5111-5117. Lucio SD, et al. Am J Health Syst Pharm. 2013;70:2004-2017. FDA. Information on biosimilars. 2016. Slide credit: clinicaloptions.com https://www.clinicaloptions.com/Immunology/Treatment%20Updates/Biosimilar%20Perspectives.aspx General Principles Biosimilarity • Biosimilar must demonstrate no clinically significant difference from reference product – Robust analytical, toxicologic, PK/PD, and immunogenicity studies compared to reference product – Smaller comparative effectiveness clinical trials, which must be conducted in patients with a disease for which the reference product is licensed – No need to demonstrate efficacy in all indications • No differences in safety/efficacy between approved biosimilar and reference product – Same mechanism of action – Same route of administration, dosage form, dosage strength Slide credit: clinicaloptions.com General Principles Biosimilarity 5 4/6/2018 Critical Attributes for Biosimilarity High-Quality Biosimilar Not a Biosimilar Primary Similar Primary structur Acceptable differences structur e Difference with critical e Higher Higher or unknown impact order Biological order Biological structure function structure function Product purity Product purity General Stability General Stability properties Particles properties Particles and and and and excipients aggregates excipients aggregates Process- Process- related related ° 95 attributes similar ° 87 attributes similar impurities impurities ° 2 acceptable ° 7 acceptable differences differences ° 0 critical differences ° 3 critical differences FDA. Overview of biosimilar products. 2016. Slide credit: clinicaloptions.com Lot-to-lot variability of critical quality attributes must be assessed and controlled to ensure consistent product quality Terms Related to Safety • Interchangeability: “designation that allows a biosimilar agent to be substituted for its reference product with prescriber input.” • Substitution: “interchange or replacement of a biosimilar agent with its reference product by someone other than the prescribing health professional.” • Switch: “therapeutic transition from a reference product to a biosimilar agent or vice versa, based on prescriber decision.” Dorner & Kay (2015) Biosimilar Safety • Biosimilar has same risk profile as its reference product • Potential adverse reactions due to variations in manufacturing of reference biologic and biosimilar • Potential risk associated with interchageability and automatic switching by pharmacy • Potential risk associated with extrapolation of data Khraishi, et al. (2016) 6 4/6/2018 “Switching” NOR-SWITCH study (2017) – 52-week randomized, double-blind Phase 4 trial in pts with RA, SpA, CD, Ps, PsA, or UC; stable on infliximab for ≥ 6 mos – Primary endpoint: disease worsening during 52-wk follow-up – Infliximab (n=202); infliximab-dyyb (n=206) – Result: switching from infliximab to infliximab-dyyb non-inferior to continued treatment with infliximab Jӧrgensen, et al. (2017) EGALITY trial (2017) Extrapolation Examples: – Adalimumab (Humira): approved for RA, Ps, PsA, AS, CD, UC – Adalimumab-atta (Amjevita): same indications – Rituximab (Rituxin): approved for non- Hodgkin lymphoma, CD-20 + CLL, moderate- severe RA – GP2013 (Rixathon- biosimilar rituximab): license application accepted by FDA 9/2017 Quiz Time! 1. According to FDA guidance, what types of studies serve as the beginning or “foundation” for the stepwise development of a biosimilar? A. Structure/function B. Toxicity C. Immunogenicity D. Clinical efficacy and safety 2. A biosimilar approved by the FDA may be substituted without the intervention of the provider who prescribed the reference product under what circumstances? A. Any biosimilar with FDA approval may be substituted for approved indications. B. If allowed by state substitution laws C. If approved as interchangeable by the FDA and allowed by state laws D. Substitution rules vary depending on therapeutic class 7 4/6/2018 FDA Approval Process • 351(k) abbreviated approval pathway • Standards for approval – FDA goal: to establish biosimilarity with the reference product, not to independently establish safety and effectiveness.
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