Pediatric Cancer Therapeutics Development

Contents
1: History of Drug Development for Children with Cancer
	1.1	 Introduction
	1.2	 Initial Progress
	1.3	 Rise of the Cancer Cooperative Groups
	1.4	 Impact of Regulation to Improve Safety and Efficacy Federal Laws Providing a Regulatory Framework for Drug Development in Children
	1.5	 Indications
	1.6	 Summary
	References
2: Targeted Small Molecule Drug Discovery
	2.1	 Introduction
	2.2	 Stage Gating
	2.3	 Phenotypic Drug Discovery
	2.4	 Target-Based Drug Discovery: Considerations for Target Selection/Identification
	2.5	 Target-Based Drug Discovery: Identifying Chemical Starting Points
	2.6	 Hit-to-Lead
	2.7	 Lead Optimization
	2.8	 Candidate Nomination
	References
3: An FDA Oncology Perspective of Juvenile Toxicity Studies to Support Pediatric Drug Development
	3.1	 Introduction
	3.2	 Should a JAS Be Considered?
		3.2.1	 ICH S11: Nonclinical Safety Testing in Support of Development of  Pediatric Medicines
		3.2.2	 ICH S9: Nonclinical Evaluation for Anticancer Pharmaceuticals Questions and Answers
	3.3	 Dinutuximab and Naxitamab
	3.4	 TRK Inhibitors
	3.5	 Conclusion
	References
4: Design and Statistical Considerations for Early Phase Clinical Trials in Pediatric Oncology
	4.1	 Introduction
	4.2	 Rule-Based Designs
		4.2.1	 Traditional 3 + 3 Design
		4.2.2	 Accelerated Titration Design
		4.2.3	 Rolling Six Design
	4.3	 Model-Based Designs
		4.3.1	 Continual Reassessment Method (CRM)
		4.3.2	 EWOC and BLRM
		4.3.3	 TITE-CRM and TITE-EWOC
	4.4	 Model-Assisted Designs
		4.4.1	 Modified Toxicity Probability Interval (mTPI) Design
		4.4.2	 Keyboard Design
		4.4.3	 Bayesian Optimal Interval (BOIN) Design
	4.5	 New Designs
		4.5.1	 Modified 4 + 4 Design
	4.6	 Conclusions
	References
5: Exploratory Clinical Development: From First in Humans to Phase 3 Ready
	5.1	 Introduction
	5.2	 The Therapeutic Hypothesis
	5.3	 Dose and Schedule Determination
	5.4	 Clinical Proof of Concept (PoC)
	5.5	 Putting It All Together: Combined Phase 1–2 Studies
	5.6	 A Role for Pediatric Cancer in Exploratory Drug Development
	References
6: Gene and Cell Therapy: How to Build a BioDrug
	6.1	 Introduction
	6.2	 BioDrug ToolKit: Cells
		6.2.1	 Hematopoietic Stem Cells (HSCs)
		6.2.2	 T Lymphocytes
		6.2.3	 Natural Killer (NK) Cells
		6.2.4	 Macrophages (MΦs)
		6.2.5	 Dendritic Cells (DCs)
		6.2.6	 Mesenchymal Stem Cells (MSCs)
		6.2.7	 Human-Induced Pluripotent Stem Cells (iPSCs)
		6.2.8	 Target Tissues
	6.3	 BioDrug ToolKit: Genetic Material and Gene-Editing Machinery
	6.4	 BioDrug ToolKit: Delivery Systems
		6.4.1	 Viral-Based Delivery Systems
		6.4.2	 Nonviral Delivery Systems
			6.4.2.1	 Chemical Methods of Delivery
			6.4.2.2	 Physical Methods of Delivery
	6.5	 Building a BioDrug
		6.5.1	 Building Gene Therapies: Putting Together Genetic Material, Gene-Editing Machinery, Delivery Systems, and Target Cells
		6.5.2	 Building Gene Therapies: Progress and Challenges
		6.5.3	 Building Cell Therapies: Using the BioDrug ToolKit for Treatment of Malignancy
		6.5.4	 Engineered Cell Therapy: Putting Together Cells, Genetic Material, Gene-Editing Machinery, and Delivery Systems to Target Malignant Cells
			6.5.4.1	 Toxicities of Engineered T cell Therapy
			6.5.4.2	 Building a More Effective T cell BioDrug: Remaining Challenges
	6.6	 Summary
	References
7: The Pharma/Biotech Model for Drug Development: Implications for Pediatric Cancer Therapeutics
	7.1	 The Old: Large Pharma
		7.1.1	 Background and History
		7.1.2	 Profile of a Large Pharma: Merck & Co.
	7.2	 The New: Biotech
		7.2.1	 Biotech Financing: From Birth to Adulthood
	7.3	 The Drive for Pharmaceutical Innovation
	7.4	 Current Trends in Pharmaceutical R&D
		7.4.1	 Open Innovation
		7.4.2	 Small Entrepreneurial Units
		7.4.3	 Virtualization and Outsourcing
	7.5	 Implications for Pediatric Cancer Therapeutics
	References
8: Clinical Research Organizations
	8.1	 Introduction
	8.2	 Business Development
		8.2.1	 CRO Team Members
		8.2.2	 Regulatory Affairs
		8.2.3	 Investigational New Drug (IND)/Investigational Device Exemption (IDE) Application
		8.2.4	 FDA Meetings
		8.2.5	 Investigator’s Brochure (IB)
		8.2.6	 Annual Reporting
		8.2.7	 Protocol Development and Amendments
		8.2.8	 Feasibility
		8.2.9	 Study Start-Up
		8.2.10	 Site Activation
		8.2.11	 Determining the Impact on Timelines
	8.3	 Project Management
		8.3.1	 Medical Monitoring
		8.3.2	 Clinical Monitoring
		8.3.3	 Safety
		8.3.4	 Clinical Data Management (CDM)
		8.3.5	 Statistics
		8.3.6	 Quality Assurance
		8.3.7	 Risk Management/Risk Mitigation
		8.3.8	 Recruitment and Retention
	8.4	 Conclusion
	References
9: Role of Patients and Advocates in Cancer Therapeutics Development
	9.1	 Introduction and Landscape Perspective
	9.2	 A Brief History and the Rise of Advocate Involvement
	9.3	 Defining the Roles of Patients and Advocates
	9.4	 Policy and Regulatory Issues
		9.4.1	 United States
		9.4.2	 Europe
		9.4.3	 Canada
		9.4.4	 Low- and Middle-Income Countries
	9.5	 Support and Learning for Patient Experts
	9.6	 Involving Patient Experts in the Drug Development Life Cycle
		9.6.1	 Setting Research Priorities and Catalyzing New Ideas
		9.6.2	 Basic and Translational Research
		9.6.3	 Tumor Tissue for Preclinical Testing
		9.6.4	 Philanthropic Funding of Early Drug Development
		9.6.5	 Clinical Trial Design and Ethics Review
		9.6.6	 Regulatory Approval and Reimbursement
			9.6.6.1	 FDA
			9.6.6.2	 EMA
			9.6.6.3	 HTAs
	9.7	 Collaboration Among Stakeholders to “ACCELERATE”
		9.7.1	 Pediatric Strategy Forums
	9.8	 Challenges and Opportunities
	9.9	 Recommendations for Academic, Industry, and Regulatory Bodies
	9.10	 Summary and What’s Next?
	References
10: The Role of Regulatory Agencies in Pediatric Cancer Drug Development
	10.1	 Introduction and History of Legislation Affecting Pediatric Drug Development
		10.1.1	 US Regulatory Programs to Expedite Development of Drugs and Biologics
		10.1.2	 European Regulatory Programs to Expedite Development of Drugs and Biologics
		10.1.3	 US Orphan Drug Program
	10.2	 Regulatory Standards for Approval of Drugs and Biologics
	10.3	 Implementation of Pediatric Regulations (Before FDARA)
		10.3.1	 Implementation of Pediatric Regulations in the United States
		10.3.2	 Legislative Requirements for Pediatric Studies
			10.3.2.1	 United States
			10.3.2.2	 European Union
		10.3.3	 Voluntary Incentive Pediatric Development Programs
			10.3.3.1	 United States
			10.3.3.2	 European Union
	10.4	 Impact of US Pediatric Regulations Prior to FDARA on Pediatric Drug Development
	10.5	 Evolving Regulatory Landscape
		10.5.1	 PREA and the RACE for Children Act
	10.6	 Responding to the Changing Cancer Drug Development Paradigm
		10.6.1	 Evolving Cancer Drug Development
	10.7	 International Multi-Stakeholder Collaboration
	10.8	 Prospects for Future Advances
	References
11: Ethical Considerations in Pediatric Cancer Therapeutics Development
	11.1	 Introduction
	11.2	 Ethical Principles Defined by the National Commission and Regulatory Framework for Safeguarding Children Involved in Clinical Investigations
		11.2.1	 Additional Safeguards for Children Involved in Clinical Investigations (21 CFR 50, Subpart D)
	11.3	 Interpreting and Applying the Ethical Principles and Regulatory Framework in Pediatric Cancer Therapeutics Development
		11.3.1	 Scientific Necessity and Pediatric Extrapolation
		11.3.2	 Prospect of Direct Benefit in Pediatric Oncology Trials
			11.3.2.1	 Eligibility Criteria: Considerations for  the Age of Enrollment
			11.3.2.2	 Early-Phase Pediatric Oncology Trials
			11.3.2.3	 Optimizing Prospect of Direct Benefit: Dose Selection and Study Design in the Era of Molecularly Targeted Products
		11.3.3	 Analysis and Minimization of Risk in Pediatric Oncology Trials
	11.4	 Parental Permission and Child Assent
	11.5	 Conclusions
	References
12: Future Directions
	References