Оглавление
Группа авторов. Biologics, Biosimilars, and Biobetters
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
Biologics, Biosimilars, and Biobetters. An Introduction for Pharmacists, Physicians, and Other Health Practitioners
List of Contributors
Foreword
Preface
1 Innovator Biologics, Biosimilars, and Biobetters: Terminology, Nomenclature, and Definitions
KEY POINTS
Abbreviations
1.1 Place of Biologics in Modern Therapeutics
1.2 Background to Terminology, Nomenclature, and Definitions
1.3 Innovator Biologics, Biosimilars, and Biobetters. 1.3.1 What Is a Biologic Medicine?
1.3.2 What Is a Biosimilar?
1.3.3 What Is a Biobetter?
1.4 Differences Between Biosimilars and Generic Medicines
1.5 Interchangeability, Switchability, and Substitution. 1.5.1 Interchangeability
1.5.2 Switchability
1.5.3 Substitution
1.6 Other Clinical Considerations with Biosimilars. 1.6.1 Indication Extrapolation
1.6.2 Nocebo Effect
1.6.3 Immunogenicity Reactions
1.6.4 Definition of Frequency of Adverse Effects
1.6.5 Pharmacovigilance of Biologics
1.7 Manufacture, Delivery, and Naming Considerations. 1.7.1 Post‐Translational Modifications (PTMs)
1.7.2 Quality by Design Paradigm
1.7.3 Delivery Devices for Biologics
1.7.4 Naming and Labeling of Biosimilars
1.8 Listing of Approved Biologics. 1.8.1 Purple Book in the United States
1.8.2 European Generic Medicines Association (EGA) Biosimilars Handbook
1.9 Biosimilar Initiatives and Organizations
1.9.1 Generics and Biosimilars Initiative (GaBi/GaBI)
1.9.2 Biologics Price Competition and Innovation Act in the United States
1.9.3 Biosimilars Action Plan (USFDA)
1.9.4 NHS England Commissioning Framework for Biological Medicines
1.9.5 PrescQIPP
1.9.6 The Association of the British Pharmaceutical Industry
1.9.7 NHS Scotland
1.9.8 National Institute for Health and Care Excellence
1.9.9 Australian Biosimilar Awareness Initiative
1.9.10 NPS MedicineWise (Australia)
1.10 Common Terms Used in the Biologics Literature
1.10.1 Real‐World Evidence
1.10.2 Patent Dance
1.10.3 Evergreening
1.10.4 Limited Distribution Network
1.10.5 Drug Tendering
1.10.6 Pharmacy and Therapeutics Committees
1.10.7 Quality Use of Medicine
1.10.8 European Public Assessment Report
1.11 Abbreviations Associated with Biologic Medicines
1.12 Concluding Remarks
Acknowledgement
References
2 Approved Biologic Medicines and Biosimilars in Major Regulatory Jurisdictions
KEY POINTS
Abbreviations
2.1 Regulatory Frameworks
2.2 Major Regulatory Jurisdictions. 2.2.1 Food and Drug Administration
2.2.2 European Medicines Agency
2.2.3 Pharmaceuticals and Medical Devices Agency (Japan)
2.2.4 Therapeutic Goods Administration (Australia)
2.2.5 Centre of Drug Evaluation, CDE (China)
2.3 Maturation of the Biologic Market
2.4 Player Archetypes in a Maturing Market
2.4.1 Established Biologic Players
2.4.2 Niche Biologic Innovators
2.4.3 Players Looking to Enter the Biologic Space
2.4.4 Biosimilar Players
2.5 Outlook: Landscape of the Biologic Market
2.5.1 Biologics in Nontraditional Biologic Disease Areas
2.6 Technology and Science Innovation in the Long Term? 2.6.1 The Potential of Innovative Technologies
2.6.2 Drug Delivery: Calls for Change
2.6.3 Biologic Asset Deal Frenzy
2.7 The Arrival of Major Biosimilars. 2.7.1 Biosimilar Immediacy
2.7.2 Regulatory Hurdles for Biosimilar Launch
2.7.3 Interchangeability and Substitution
2.8 Biosimilars in Emerging Markets
2.9 Top 10 Biologic Drugs in the United States
2.9.1 Humira ®
2.9.2 Rituxan ®
2.9.3 Enbrel ®
2.9.4 Herceptin ®
2.9.5 Avastin ®
2.9.6 Remicade ®
2.9.7 Lantus ®
2.9.8 Neulasta ®
2.9.9 Avonex ®
2.9.10 Lucentis ®
2.10 Top 10 Biologic Drugs in the EU
2.11 Conclusions
References
3 Status of Biologic Drugs in Modern Therapeutics‐Targeted Therapies vs. Small Molecule Drugs
KEY POINTS
Abbreviations
3.1 Biologics in Contemporary Medicine. 3.1.1 A History of Drug Development and Commercialization
3.1.2 The Business Model for Chronic Disease
3.1.3 Complexity of Biologics
3.2 Clinical Characteristics of Biologic Drugs. 3.2.1 Biologics vs. Small Molecule Drugs
3.2.2 Vaccines
3.2.3 Antibodies
3.2.4 Enzymes
3.2.5 Cytokines
3.2.6 Cytokine‐Interferons
3.2.7 Cytokine‐Interleukins
3.2.8 Tumor Necrosis Factor
3.2.9 Hormones
3.2.10 Blood Factor Products
3.3 rDNA and Biologic Drug Manufacturing
3.4 What Does the Future Hold? 3.4.1 Gene Therapy
3.4.2 Personalized Medicine
3.5 Global Biologics Market
3.6 Summary
References
4 Major Classes of Biotherapeutics
KEY POINTS
Abbreviations
4.1 Major Classes of Biotherapeutics
4.2 Antibodies and Antibody‐Based Therapeutics
4.2.1 Monoclonal Antibodies
4.2.2 Structure of Therapeutic mAbs
4.2.3 Therapeutic Applications of mAbs
4.3 Alternative mAb‐Based Therapeutics. 4.3.1 Fc‐Fusion Proteins
4.3.2 Antibody–Drug Conjugates
4.3.3 Bispecific Antibodies
4.3.4 Immune Checkpoint Inhibitors
4.4 Therapeutic Signaling Molecules
4.4.1 Peptide and Protein Hormones. 4.4.1.1 Insulins and Glucagon‐like Peptide Analogs
4.4.1.2 Growth Hormone, Gonadotropins, and Other Hormones. 4.4.1.2.1 Human Growth Hormone
4.4.1.2.2 Gonadotropins
4.4.2 Hematopoietins and Related Molecules. 4.4.2.1 Colony‐Stimulating Factors
4.4.2.2 Erythropoietin
4.5 Blood‐Related Products
4.5.1 Recombinant Coagulation Factors
4.5.2 Anticoagulants and Thrombolytic Agents
4.6 Biosimilars
References
5 Drug Targets for Biologics
KEY POINTS
Abbreviations
5.1 Introduction
5.2 Immune Checkpoints
5.3 Human Epidermal Growth Factor Family
5.3.1 EGFR
5.3.2 HER2
5.4 Vascular Endothelial Growth Factor
5.5 Interleukins
5.5.1 IL‐1
5.5.2 IL‐6
5.5.3 IL‐17
5.5.4 IL‐12 and IL‐23
5.5.5 Interleukin‐Directed Therapies
5.6 Tumor Necrosis Factor
5.7 Receptor Activator of Nuclear Factor‐ΚB Ligand (RANKL)
5.8 Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
5.9 Concluding Remarks
References
6 Pivotal Biology, Chemistry, Biochemistry, and Biophysical Concepts of Biologics and Biosimilars
KEY POINTS
Abbreviations
6.1 Definitions: Biologics vs. Small Molecule Drugs
6.2 Biochemical and Biophysical Properties. 6.2.1 Protein Structure
6.2.2 Post‐Translational Modifications
6.2.2.1 Glycosylation
6.2.2.2 γ‐Carboxylation and β‐Hydroxylation
6.2.2.3 Amidation
6.2.2.4 Sulfation
6.2.2.5 Disulfide Linking
6.3 Chemical and Physical Stability
6.3.1 Aggregation
6.3.2 Unfolding/Denaturation
6.3.3 Fragmentation
6.3.4 Oxidation
6.3.5 Deamidation
6.3.6 Pyroglutamate Formation
6.4 Formulation Considerations and Devices
6.5 Analytical Methods/Tools
6.5.1 Spectroscopic Methods
6.5.1.1 UV‐Vis
6.5.1.2 Fluorescence Spectroscopy
6.5.1.3 Mass Spectrometry
6.5.1.4 CD and FTIR
6.5.2 Microscopy Methods
6.5.2.1 TEM
6.5.2.2 Light Obscuration and Dynamic Imaging Microscopy
6.5.3 Separation Methods
6.5.3.1 Chromatography
6.5.3.2 AUC
6.5.3.3 Electrophoresis Methods (SDS‐PAGE, CE‐SDS)
6.5.4 Calorimetric Methods
6.5.5 Accelerated Studies
6.6 Influenza Vaccines
References
Notes
7 Biosimilarity and Interchangeability of Biologic Drugs‐ General Principles, Biophysical Tests, and Clinical Requirements to Demonstrate Biosimilarity
KEY POINTS
Abbreviations
7.1 Introduction. 7.1.1 The Biosimilar Development Paradigm
7.1.2 Establishing Analytical and Functional Similarity
7.1.3 Demonstration of Clinical Similarity
7.2 Interchangeability
Scheme 7.1 Terminology Relating to Interchangeability
7.2.1 Global Approaches to Interchangeability. 7.2.1.1 The European Approach
7.2.1.2 The United States Approach
7.2.1.3 Approaches in Other Regions
7.2.2 Experience from Switching Biosimilars
7.2.2.1 Data from Registration Trials
7.2.2.2 Real‐World Evidence
Scheme 7.2 Nocebo Effects
7.2.2.3 Biosimilar to Biosimilar Switching
7.3 Conclusions
References
8 Pharmacokinetics of Biologics
KEY POINTS
Abbreviations
8.1 Introduction
8.1.1 Focus of This Chapter
8.2 Pharmacokinetics and Pharmacodynamics of Biological Medicines
8.2.1 Absorption
8.2.2 Distribution
8.2.3 Elimination
8.2.4 Renal Elimination
8.2.5 Nonlinear Pharmacokinetics of Monoclonal Antibodies
8.3 Understanding Pharmacokinetic Variability for Monoclonal Antibodies
8.3.1 Body Size
8.3.2 Albumin, FcRn, and Inflammation
8.3.3 Pharmacogenomics
8.3.4 Impact of ADAs on Pharmacokinetics and Pharmacodynamics
8.3.5 Drug Interactions Involving Biologics
8.4 Pharmacokinetics of Biosimilar and Biobetter Biologics
8.5 Modeling and Simulation of Monoclonal Antibody Pharmacokinetics and Pharmacodynamics
8.6 Individualizing Therapy and the Role of TDM
8.7 Conclusions
Acknowledgements
References
9 Pharmacogenomics of Biologics
KEY POINTS
Abbreviations
9.1 Introduction
9.2 Approaches to the Identification of Genetic Variants Influencing Response to Biologic Medicines
9.2.1 Candidate Gene Studies
9.2.2 Genome‐Wide Association Studies (GWAS)
9.2.3 Limitations of Pharmacogenomic Studies
9.3 Pharmacogenomics of Biologics in Rheumatoid Arthritis
9.3.1 Predictors of Clinical Response
9.3.2 Predictors of Anti‐drug Antibody Formation
9.4 Pharmacogenomics of Biologics in Inflammatory Bowel Disease (IBD)
9.4.1 Predictors of Clinical Response
9.4.2 Predictors of Pharmacokinetics
9.4.3 Predictors of Anti‐drug Antibody Formation
9.5 Pharmacogenomics of Biologics in Psoriasis
9.6 Pharmacogenomics of Biologics in Age‐Related Macular Degeneration (AMD)
9.7 Pharmacogenomics of Biologics in Asthma and Chronic Obstructive Pulmonary Disease
9.8 Conclusions
References
10 International Regulatory Processes and Policies for Innovator Biologics, Biosimilars, and Biobetters
KEY POINTS
Abbreviations
10.1 Introduction
10.2 Major International Regulatory Agencies
10.2.1 World Health Organization (WHO)
10.2.2 United States of America (USA) – Food & Drug Administration (FDA)
10.2.3 Europe (EU) – European Medicines Agency (EMA)
10.2.4 Australia – Therapeutic Goods Administration (TGA)
10.2.5 Canada – The Biologics and Genetic Therapies Directorate (BGTD)
10.2.6 China – National Medical Products Administration (NMPA)
10.2.7 India – Central Drugs Standard Control Organization (CDSCO)
10.2.8 Brazil – Agência Nacional de Vigilância Sanitária (ANVISA)
10.2.9 South Korea – Ministry of Food and Drug Safety (MFDS)
10.2.10 Japan – Pharmaceuticals and Medical Devices Agency (PMDA)
10.3 General Requirements for Biologics Approval. 10.3.1 Innovator/Reference Biologics
10.3.2 Biosimilars
10.4 Specific Requirements for Innovator/Reference Biologics and Biosimilars. 10.4.1 Innovator/Reference Biologics. 10.4.1.1 USA (FDA)
10.4.1.2 Europe (EMA)
10.4.1.3 Australia (TGA)
10.4.1.4 Canada (BGTD)
10.4.1.5 China (NMPA)
10.4.1.6 India (CDSCO)
10.4.1.7 Brazil (ANVISA)
10.4.1.8 South Korea (MFDS)
10.4.1.9 Japan (PMDA)
10.4.2 Biosimilars. 10.4.2.1 WHO
10.4.2.2 USA (FDA)
10.4.2.3 Europe (EMA)
10.4.2.4 Australia (TGA)
10.4.2.5 Canada (BGTD)
10.4.2.6 China (NMPA)
10.4.2.7 India (CDSCO)
10.4.2.8 Brazil (ANVISA)
10.4.2.9 South Korea (MFDS)
10.4.2.10 Japan (PMDA)
10.5 Approval of Biobetters
10.6 Conclusions
References
11 Pharmacovigilance of Innovator Biologics and Biosimilars
KEY POINTS
Abbreviations
11.1 Introduction
11.2 Premarketing Period
11.2.1 The EU Experience
Case Study: Epoetin alfa Biosimilar Approval in the EU
11.2.2 The US Experience
Case Study: Filgrastim Biosimilar Approval in the United States
11.2.3 Limitations
11.3 Post‐marketing Period. 11.3.1 Rationale and Challenges
11.3.2 Processes
11.3.3 Passive Surveillance
11.3.4 Active Surveillance
11.3.4.1 PCORnet
11.3.4.2 Sentinel System
11.3.4.3 BBCIC
11.3.4.4 CNODES
11.3.4.5 EU‐ADR
11.3.4.6 AsPEN
11.3.4.7 REMS
11.4 New Directions
11.5 Conclusions
References
12 Pharmacoeconomics of Biologic Medicines and Biosimilars
KEY POINTS
Abbreviations
12.1 Pharmacoeconomics of Innovator Biologics
12.2 Variation in Usage of Innovator Biologics
12.3 Payer Management of Innovator Biologic Costs
12.4 Value of Innovator Biologics
12.5 Innovator Biologic Development Costs
12.6 Coverage of Rare Disease Drugs
12.7 Pharmacoeconomics of Biosimilars
12.7.1 Biosimilars in Europe
12.7.2 Biosimilars in the United States
12.7.3 Cost of Biosimilar Development
12.7.4 Data Exclusivity and Patent Battles
12.7.5 Provider Knowledge of and Attitudes Toward Biosimilars
12.7.6 Biosimilar Savings
12.7.7 Interchangeability, Switching, and Indication Extrapolation
12.7.8 Incentives for Biosimilar Adoption
12.8 Conclusions
References
13 New Emerging Biotherapies: Cutting‐Edge Research to Experimental Therapies
KEY POINTS
Abbreviations
13.1 Introduction
13.2 Methods to Enhance Stability of Biologics
13.3 Bispecific Antibodies (bsAbs) 13.3.1 Current Perceptions, Clinical Trials, and Observed Issues
13.3.2 Approved Bispecifics. 13.3.2.1 Catumaxomab (Removab®)
13.3.2.2 Blinatumomab (Blincyto®)
13.3.2.3 Emicizumab (Hemlibra®)
13.4 Antibody–Drug Conjugates
13.4.1 Antigen Targeting, ADC Uptake, and the Linker
13.4.2 Conjugation of the Payload to the Antibody
13.4.3 Payloads
13.4.4 Antibody Format
13.5 CAR T‐cell Therapy
13.5.1 Treatment Steps
13.5.2 Structure of CARs
13.5.3 CAR T‐Cell Clinical Uses and Trials in Blood Malignancies
13.5.4 An Alternative Approach to CAR T‐Cell Therapy
13.5.5 Nonviral Engineering of CAR T‐Cells
13.5.6 Is It Possible to Mass‐Produce and Automate CAR T‐Cells?
13.5.7 Alternatives to T‐Cells
13.6 Immune Checkpoint Antagonism
13.6.1 CTLA‐4 Inhibitors
13.6.2 PD‐1/PD‐L1 Inhibitors
13.6.3 Adverse Effects of Immune Checkpoint Inhibitors
13.7 Conclusions and Future Outlook
References
14 Optimizing Use of Biologic Medicines Using a Quality Use of Medicines Approach
KEY POINTS
Abbreviations
14.1 Introduction
14.2 Quality Use of Medicines Approach
14.2.1 Judicious Use
14.2.2 Appropriate Selection
14.2.3 Safe and Effective Use
14.3 Influences on Prescribing and Use of Biologic Medicines
14.3.1 Health Professional Knowledge, Attitudes, and Beliefs
14.3.2 Patient Knowledge, Attitudes, and Beliefs
14.3.3 Patient Characteristics, Industry, and Environmental Influences
14.4 Policy to Support Appropriate Uptake of Biologic Medicines
14.5 Formulary Management
14.5.1 Evaluation of Biologic Medicines by PTCs
14.5.2 Recommendations for Interchangeability at the Local Level
14.6 Sources of Information and Education. 14.6.1 Objective Information
14.6.2 Education and Training
14.6.3 Interventions to Influence Prescribing
14.7 Adherence and Persistence
14.8 Cost‐effectiveness Considerations
14.9 Monitoring and Real‐World Experience
14.9.1 Therapeutic Drug Monitoring
14.10 Conclusions
References
Note
15 Knowledge Areas and Competency Standards on Biologic Medicines for Pharmacists and Pharmacy Students
KEY POINTS
Abbreviations
15.1 Chapter Background
15.2 Current Knowledge of Pharmacists and Pharmacy Students About Biologics
15.3 Prescriber Knowledge of Biologic Medicines
15.4 Pharmacist’s Role in Biologic Medicine Education
15.5 General Background on Biologic Medicines
15.6 History of Pharmacy Education
15.7 Accreditation of Pharmacy Degrees
15.8 Content of Pharmacy Degree Curricula
15.8.1 High School Basic Science Prerequisites
15.8.2 University‐Level Basic Sciences
15.8.3 Enabling Biomedical Sciences
15.8.4 Enabling Pharmaceutical Sciences
15.8.5 Enabling Pharmacy and Public Health Practice
15.9 Recommended Knowledge Areas on Biologics in the Published Literature
15.10 Modes of Learning and Teaching Delivery and Assessments
15.11 Urgent Need for Curriculum Reform
15.12 Concluding Remarks
References
16 A Checklist for Pharmacists on Biologics and Biosimilars : Tips to Enhance Patient‐Centered Discussions
KEY POINTS
Abbreviations
16.1 Context of This Checklist for Pharmacists and Health Professionals
16.2 Summary of Biologics, Biosimilars, and Biobetters
16.3 Storage and Handling of Biologics
16.4 Regulatory Requirements
16.5 Naming and Labeling of Biologic Therapies
16.6 Funding of Biosimilars: Australian Approach
16.7 Pharmacovigilance
16.8 Medicines Use Evaluation
16.9 Reducing Clinical Risks from Innovator Biologics, Biosimilars, and Biobetters
16.10 Checklist on Biologics
16.11 Practice Points: Anticipated Questions from Health Professionals. 16.11.1 How Safe Are Biosimilars?
16.11.2 What Are the Potential Advantages to Using Biosimilars?
16.11.3 Can Patients Be Switched from Reference Biologics to Biosimilars?
16.11.4 In a Case of Nonresponse to a Biosimilar, Can the Patient Be Switched Back to the Reference Biologic?
16.12 Practice Points: Anticipated Questions from Patients. 16.12.1 What Is a Biologic?
16.12.2 What Is a Biosimilar?
16.12.3 Why Are Biosimilars Valuable in Therapy?
16.12.4 Who Chooses Whether the Biosimilar or Reference Biologic Is Used?
16.12.5 Will the Treatment Outcomes Be the Same Using a Biosimilar?
16.12.6 Are the Side Effects the Same for a Biosimilar and a Reference Biologic?
References
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