Mesenchymal Stromal Cells

Translational Pathways to Clinical Adoption
 
 
Academic Press
  • 1. Auflage
  • |
  • erschienen am 11. August 2016
  • |
  • 362 Seiten
 
E-Book | ePUB mit Adobe DRM | Systemvoraussetzungen
E-Book | PDF mit Adobe DRM | Systemvoraussetzungen
978-0-12-802840-7 (ISBN)
 

Mesenchymal Stromal Cells: Translational Pathways to Clinical Adoption provides the latest information on the necessary steps for successful production of stem cells for a clinical trial. Written by professionals with hands-on experience in bringing MSC therapies to the clinic, and building on the biology and mechanisms of action, this unique book covers the development and production of clinical-grade products that are suitable for use in humans. From design of a cell production facility, to obtaining regulatory approval and reimbursement issues, it is a useful guide for researchers and administrators across biomedical research.


  • Provides methodologies for clinical MSC production, from designing a facility, to post-market approval
  • Includes real-life examples of MSC production in academic centers and MSC production for biopharmaceutical clinical trials
  • Offers a unique perspective on the clinical aspects of MSC studies
  • Presents the principles of clinical trials that can be applied to the production of various cell therapies
  • Englisch
  • San Diego
  • |
  • USA
Elsevier Science
  • 11,92 MB
978-0-12-802840-7 (9780128028407)
0128028408 (0128028408)
weitere Ausgaben werden ermittelt
  • Cover
  • Title page
  • Copyright page
  • Dedication
  • Contents
  • Contributors
  • Foreword
  • Chapter 1 - MSCs Translational Process
  • 1.1 - MSCs and global clinical investigations
  • 1.1.1 - Translation Challenges for MSCs
  • 1.1.2 - Regulatory Classification of MSCs
  • 1.1.3 - Regulatory Process for Clinical Investigations
  • 1.2 - Preclinical studies
  • 1.2.1 - Regulatory Requirements for Preclinical Studies
  • 1.2.2 - Proof-of-Concept Studies/Animal Models
  • 1.2.3 - Safety Studies/GLP Requirements
  • 1.3 - Chemistry, manufacturing, and control
  • 1.3.1 - Regulatory Requirements
  • 1.3.2 - MSC Source Material
  • 1.3.3 - Ancillary Materials
  • 1.3.3.1 - Medium and supplements
  • 1.3.3.2 - Fetal bovine serum versus xenogeneic-free alternatives
  • 1.3.3.3 - Adhesion proteins and microcarriers
  • 1.3.3.4 - Antibiotics
  • 1.3.4 - Excipients Used in Final MSC Product Formulation
  • 1.3.5 - MSC Manufacturing Process
  • 1.3.5.1 - MSC in-process and final product release testing
  • 1.4 - Clinical protocol
  • 1.4.1 - Regulatory Requirements
  • 1.4.2 - Clinical Protocol Consideration
  • 1.5 - Implementation of MSC clinical investigation
  • 1.5.1 - Implementation of Regulatory Process
  • 1.5.2 - Implementation-Contracts
  • 1.5.3 - Clinical Implementation
  • 1.6 - Standardization efforts around MSCs
  • 1.7 - Summary
  • Abbreviations
  • References
  • Chapter 2 - Preclinical Animal Testing Requirements and Considerations
  • 2.1 - Introduction
  • 2.2 - Preclinical study conduct
  • 2.2.1 - Documentation
  • 2.2.2 - Staff Qualifications
  • 2.2.3 - Facilities
  • 2.2.4 - Equipment, Supplies, and Reagents
  • 2.2.5 - Preclinical Study Cellular Product
  • 2.2.6 - Preclinical Study Protocol
  • 2.3 - Proof-of-concept studies
  • 2.3.1 - Preliminary Efficacy Studies
  • 2.3.2 - Animal Model of Disease
  • 2.3.3 - Selection of an Appropriate Animal Model
  • 2.3.4 - Preliminary Evaluation of Safety
  • 2.3.5 - In Vitro Assessments
  • 2.3.6 - Cell-Based Assays
  • 2.4 - Preclinical safety studies
  • 2.4.1 - Preclinical Safety Assays
  • 2.4.2 - Preclinical Assessments in Animals
  • 2.4.3 - Preliminary Safety in Animals
  • 2.4.4 - Use of Hybrid Pharmacology/Toxicity Study Design
  • 2.5 - Preclinical safety protocol design
  • 2.5.1 - Protocol Design
  • 2.5.2 - Cellular Therapy Product Dose Selection
  • 2.5.3 - Study Endpoints
  • 2.5.4 - Materials
  • 2.6 - Conclusions
  • References
  • Chapter 3 - Delivery and Tracking Considerations for Cell-Based Therapies
  • 3.1 - Introduction
  • 3.2 - Cell delivery
  • 3.2.1 - Intravascular Infusion
  • 3.2.1.1 - Intravenous infusion
  • 3.2.1.2 - Intraarterial infusion
  • 3.2.2 - Direct Tissue Injection
  • 3.2.2.1 - Intramuscular injection
  • 3.2.2.2 - Intraparenchymal injection
  • 3.2.3 - Scaffold-Based Delivery
  • 3.2.4 - Trans-Mucosal Delivery
  • 3.3 - Cell tracking
  • 3.3.1 - Photon-Emitting Contrast Agents
  • 3.3.1.1 - Positron emission tomography
  • 3.3.2 - Single-Photon Emission Computed Tomography
  • 3.3.3 - Bioluminescence
  • 3.3.4 - Fluorescence Imaging
  • 3.3.5 - Tissue Contrast Agents
  • 3.3.5.1 - Magnetic resonance imaging
  • 3.4 - Conclusions
  • References
  • Chapter 4 - Allogeneic Versus Autologous Mesenchymal Stromal Cells and Donor-to-Donor Variability
  • 4.1 - Introduction
  • 4.2 - Immunogenicity of MSCs
  • 4.3 - Clinical considerations for the use of MSCs in transplantation
  • 4.3.1 - MSC Cotransplantation in Allogeneic Hematopoietic Stem Cell Transplantation
  • 4.3.1.1 - Clinical trials of MSCs to promote engraftment
  • 4.3.1.2 - Considerations for MSC donor source in Hematopoietic Stem Cell Transplantation
  • 4.3.2 - Considerations for MSC Donor Source in Solid Organ Transplantation
  • 4.4 - MSC donor-to-donor variability
  • 4.4.1 - Donor Age and Sex
  • 4.4.2 - Underlying Disease
  • 4.4.3 - Inherent Donor Differences
  • 4.5 - Conclusion
  • Abbreviations
  • References
  • Chapter 5 - Mesenchymal Stromal Cell Production in Academic Centers: Challenges and Opportunities
  • 5.1 - Introduction
  • 5.2 - Approach to manufacturing
  • 5.2.1 - General Considerations
  • 5.2.1.1 - Evaluation of research and preclinical studies
  • 5.2.1.2 - Scale-up and optimization
  • 5.2.1.3 - Methods validation
  • 5.2.2 - MSC-Specific Considerations
  • 5.2.2.1 - Source material and selection of donor
  • 5.2.2.2 - Culture container/device
  • 5.2.2.3 - Culture medium and supplements
  • 5.2.2.4 - Culture schema
  • 5.2.2.5 - Cryopreservation
  • 5.2.2.6 - Quality control and lot release testing
  • 5.2.2.7 - Summary
  • 5.2.3 - Challenges
  • 5.2.3.1 - Assembly of the team
  • 5.2.3.2 - Funding
  • 5.2.3.3 - Balancing workload
  • 5.2.3.4 - Other challenges
  • 5.2.4 - Opportunities
  • 5.3 - Conclusion
  • Abbreviations
  • References
  • Chapter 6 - Bioreactor for Scale-Up: Process Control
  • 6.1 - Introduction
  • 6.2 - Seed train
  • 6.3 - Considerations for microcarrier selection
  • 6.3.1 - Experimental Strategies for Microcarrier Selection
  • 6.4 - In-process culture control: options and components
  • 6.4.1 - Offline Measuring Methods
  • 6.4.2 - Automated Sampling Systems
  • 6.4.3 - Online Measuring Methods
  • 6.5 - Platform components
  • 6.5.1 - Growth Medium
  • 6.5.2 - Vessel
  • 6.5.2.1 - Mechanically driven bioreactors
  • 6.5.2.1.1 - Stirred-tank bioreactors
  • 6.5.2.1.2 - Rocker bioreactors
  • 6.5.2.2 - Hydraulically driven bioreactors
  • 6.5.2.2.1 - Pall Xpansion multiplate bioreactor system
  • 6.5.2.2.2 - Fixed-bed bioreactors
  • 6.5.2.2.3 - Hollow fiber bioreactors
  • 6.5.3 - Controller
  • 6.6 - Scalability/comparability
  • 6.7 - Downstream processing
  • 6.7.1 - Cell Detachment
  • 6.7.2 - Microcarrier Removal
  • 6.7.3 - Cell Washing and Concentration
  • 6.7.3.1 - Tangential flow filtration
  • 6.7.3.2 - Centrifugation
  • 6.7.4 - Fill
  • 6.7.5 - Visual Inspection
  • 6.8 - Process optimization
  • 6.9 - Feeding control
  • 6.9.1 - Batch Versus Fed-Batch Versus Continuous Perfusion
  • 6.10 - Conclusion
  • References
  • Chapter 7 - GMP Requirements
  • 7.1 - Introduction
  • 7.2 - The elements of cGMP
  • 7.3 - Quality
  • 7.4 - Staff qualifications
  • 7.5 - Facilities
  • 7.6 - Materials management
  • 7.7 - Manufacturing activities
  • 7.8 - Release testing
  • 7.9 - Testing resources
  • 7.10 - The chemistry, manufacturing, and control section of the IND
  • 7.11 - Documentation
  • 7.12 - Audits
  • 7.13 - Post-CMC manufacturing changes
  • 7.14 - Summary
  • Acknowledgments
  • References
  • Chapter 8 - Mesenchymal Stromal Cells and the Approach to Clinical Trial Design: Lessons Learned From Graft Versus Host ...
  • 8.1 - Introduction
  • 8.2 - MSCs and GVHD
  • 8.2.1 - Diagnosis and Immunobiology of Acute GVHD
  • 8.2.2 - Current Preemptive Strategies
  • 8.2.3 - Current Therapeutic Strategies
  • 8.2.4 - MSCs in GVHD
  • 8.3 - Translational challenges of MSCs for GVHD
  • 8.3.1 - Relevance of Preclinical Studies of MSCs in GVHD
  • 8.3.2 - Source of MSCs and Donor Selection in GVHD
  • 8.3.3 - Fresh or Frozen?
  • 8.3.4 - Potency and Release Criteria
  • 8.3.5 - Biodistribution, Fate, and Longevity
  • 8.3.6 - Intellectual Property and Funding
  • 8.3.7 - Clinical Trial Parameters
  • 8.3.8 - Control Arm
  • 8.3.9 - Patient Eligibility
  • 8.3.10 - Endpoint Selection
  • 8.3.11 - Stratification
  • 8.4 - Overcoming translational pitfalls
  • 8.5 - Conclusions
  • References
  • Chapter 9 - Regulatory Pathway for Mesenchymal Stromal Cell-Based Therapy in the United States
  • 9.1 - Introduction
  • 9.2 - Regulatory plan
  • 9.3 - Regulatory pathway
  • 9.3.1 - Interactions With CBER and OCTGT
  • 9.4 - Pre-IND meeting
  • 9.5 - IND submission
  • 9.6 - IND content-chemistry, manufacturing, and controls
  • 9.7 - IND content-pharmacology and toxicology
  • 9.8 - Cross-referencing
  • 9.9 - FDA action on an IND application
  • 9.10 - IND maintenance
  • 9.11 - Moving to a clinical trial
  • 9.12 - Trial design considerations
  • 9.13 - Data and adverse event monitoring
  • 9.14 - Conclusions
  • Suggested Reading
  • References
  • Chapter 10 - Global Regulatory Perspective for MSCs
  • 10.1 - Introduction
  • 10.2 - Medicinal product legislation applicable to mesenchymal stromal cell products
  • 10.2.1 - United States
  • 10.2.2 - European Union
  • 10.2.3 - Japan
  • 10.2.4 - Australia
  • 10.2.5 - Canada
  • 10.2.6 - Korea
  • 10.2.7 - Use of Medicinal Products Prior to Marketing Authorization
  • 10.3 - Product development: from nonclinical studies to clinical trials to marketing authorization
  • 10.3.1 - Guidance on Achieving Quality, Safety, and Efficacy When Developing Mesenchymal Stromal Cell Products
  • 10.3.2 - The Common Technical Document
  • 10.4 - CMC and quality development
  • 10.4.1 - Good Manufacturing Practice
  • 10.5 - Safety studies and nonclinical development
  • 10.5.1 - Good Laboratory Practice
  • 10.6 - Clinical development
  • 10.6.1 - Good Clinical Practice
  • 10.7 - Incentives and accelerated approval schemes applicable to mesenchymal stromal cell products
  • 10.7.1 - United States
  • 10.7.1.1 - Orphan drug designation
  • 10.7.1.2 - Expedited programs for serious conditions
  • 10.7.2 - European Union
  • 10.7.2.1 - Orphan designation
  • 10.7.2.2 - Alternative routes to marketing authorization
  • 10.7.2.2.1 - Conditional marketing authorisation
  • 10.7.2.2.2 - Marketing authorisation under exceptional circumstances
  • 10.7.2.3 - Accelerated assessment
  • 10.7.2.4 - Adaptive Pathways
  • 10.7.3 - Japan
  • 10.7.3.1 - Orphan drugs
  • 10.7.3.2 - Expedited conditional approval of regenerative medicinal products
  • 10.8 - Conclusions
  • Glossary
  • Abbreviations
  • References
  • Chapter 11 - The Health Economics for Regenerative Medicine: How Payers Think and What That Means for Developers
  • 11.1 - Introduction
  • 11.2 - Health technology assessment and appraisal
  • 11.3 - Cost effectiveness analysis
  • 11.4 - Cost effectiveness analysis in health technology appraisal
  • 11.5 - Understanding the value of research in the presence of HTA market access hurdles
  • 11.6 - Considering value assessment in translational research: the value engineered translation framework
  • 11.7 - Potential challenges to novel cell therapy technologies in achieving reimbursement
  • 11.8 - Summary
  • References
  • Chapter 12 - Mesenchymal Stromal Cells: Clinical Experience, Challenges, and Future Directions
  • 12.1 - Introduction
  • 12.2 - Clinical experience with MSCs
  • 12.3 - Clinical considerations in use of MSCs
  • 12.3.1 - Intended Mode of Action: Tissue Regeneration Versus Immune Modulation
  • 12.3.2 - Donor Source of MSCs
  • 12.3.3 - Tissue Source for MSCs
  • 12.3.4 - Cell Dose, Timing, and Frequency
  • 12.3.5 - Route of Administration
  • 12.3.6 - Combination of MSCs with Other Agents Including Immunosuppressive Drugs
  • 12.3.7 - Immunogenicity of the Cells
  • 12.3.8 - Safety Issues
  • 12.3.9 - Relevance of Preclinical Models
  • 12.3.10 - Choice of Potency Assays
  • 12.4 - Manufacturing considerations for clinical use
  • 12.4.1 - Isolation and Culture Medium for MSCs
  • 12.4.2 - Cell Density, Oxygen Tension, and Culture Devices
  • 12.4.3 - Storage and Cryopreservation
  • 12.5 - Conclusions
  • References
  • Index
  • Back cover

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