Drug Development for Rare Diseases

Cover
Half Title
Series Page
Title Page
Copyright Page
Table of Contents
Editors
Contributors
1. Introduction to Rare Disease Therapy Development
	1.1 Introduction
	1.2 Definitions
	1.3 Differences in Clinical Setting for Rare Diseases
		1.3.1 Understanding of the Disease
		1.3.2 Identification and Diagnosis of Patients
		1.3.3 Funding Challenges
		1.3.4 Regulatory Uncertainties
		1.3.5 Privacy Considerations
		1.3.6 Pediatric Focus
	1.4 Scope
	References
2. Challenges and Opportunities in Rare Disease Drug Development
	2.1 Introduction
	2.2 Focused Recruitment Efforts
	2.3 Use of Innovative Study Designs and Analyses
	2.4 Use of Data External to Clinical Trials
	2.5 Strong Incorporation of Biomarkers
	2.6 M&S Input to Development Choices
	2.7 Expanded Regulatory Options
	2.8 The Desire for Transformative Therapies
	References
3. Developing Drugs for Rare Diseases: Regulatory Strategies and Considerations
	3.1 Introduction
	3.2 Expedited Programs and Accelerated Review Pathways of the US FDA
		3.2.1 US FDA Orphan Drug Designation (ODD)
		3.2.2 US FDA Breakthrough Therapy Designation (BTD)
		3.2.3 US FDA Regenerative Medicine Advanced Therapy (RMAT) Designation
		3.2.4 US FDA Priority Review (PR)
		3.2.5 US FDA Accelerated Approval (AA)
		3.2.6 US FDA Fast Track (FT)
		3.2.7 US Rare Pediatric Disease Priority Review Vouchers
		3.2.8 FDA Guidance for Drug Development on Specific Topics in Rare Disease
	3.3 EMA Guidance and Tools for Drug Development in Rare Disease
		3.3.1 EMA Orphan Designation
		3.3.2 EMA PRIority MEdicines (PRIME) Scheme
		3.3.3 EMA Advanced Therapies
		3.3.4 EU Centralized Procedure and Accelerated Assessment
		3.3.5 EU Conditional Marketing Authorization
	3.4 Other Global Regulatory Considerations in Drug Development for Rare and Orphan Diseases
		3.4.1 Compassionate Use
		3.4.2 Pediatric Rare Disease
			3.4.2.1 US Pediatric Drug Development
			3.4.2.2 EU Pediatric Drug Development
	3.5 Overall Considerations in Rare Disease Drug Development
4. Clinical Trial Design and Analysis Considerations for Rare Diseases
	4.1 General Considerations
	4.2 Some Considerations on Endpoint Selection in Rare Disease Trials
	4.3 Design and Analysis of Clinical Trials for Rare Diseases
		4.3.1 Group Sequential and Sample Size Reestimation Designs for Rare Disease Trials
			4.3.1.1 Introduction
			4.3.1.2 Exact Group Sequential Design for a Clinical Trial in Sickle Cell Disease
			4.3.1.3 Sample Size Re-Estimation Design for Clinical Trials in Takayasu Arteritis
		4.3.2 Seamless Phase II/III Designs with Treatment Selection
		4.3.3 Master Protocol Designs
			4.3.3.1 Umbrella/Platform Trials
			4.3.3.2 Basket Trial
		4.3.4 Crossover Design
			4.3.4.1 AB/BA Design
			4.3.4.2 Optimal Design for Two Treatments
			4.3.4.3 Complete Block Designs for Three or More Treatments
			4.3.4.4 Incomplete Block Designs
		4.3.5 The n of 1 Trial Designs
		4.3.6 Population Enrichment Design
			4.3.6.1 Enrichment Design to Decrease Variability
			4.3.6.2 Prognostic Enrichment Design
			4.3.6.3 Predictive Enrichment Design
			4.3.6.4 Adaptive Enrichment Design
		4.3.7 Randomized Withdrawal Design
			4.3.7.1 Randomized Withdrawal Design Case Study 1: The ICE Trial in Chronic Inflammatory Demyelinating Polyneuropathy
			4.3.7.2 Randomized Withdrawal Design Case Study 2: The VALO Trial in Pachyonychia Congenita
		4.3.8 Totality of Evidence Analysis of Clinical Trials of Rare Diseases
			4.3.8.1 Combining Endpoints for Totality-of-Evidence Analyses
			4.3.8.2 Selected Approaches to Multiple-Endpoint Analyses
			4.3.8.3 Simulations
			4.3.8.4 Discussion
	References
5. Use of Real-World Evidence to Support Drug Development
	5.1 Introduction: Value of RWE across the Rare Disease Drug Development Stages
		5.1.1 RWD and RWE Definitions
		5.1.2 Role of RWE across the Lifecycle of Rare Disease Drug Development
	5.2 RWD Collection Approaches in Rare Disease Research
		5.2.1 Secondary Use of Data Collected by Existing Rare Disease Registries
		5.2.2 Secondary Use of Healthcare Record Databases and Multi-Database Studies
		5.2.3 Primary Data Collection
	5.3 RWE in Early Stages of Drug Development for Rare Disease
		5.3.1 Quantifying Target Patient Population
		5.3.2 Evaluating Burden of Illness/Natural History of Disease
	5.4 RWE in Later Stages of Drug Development for Rare Disease
		5.4.1 RWE as an External Control Arm
		5.4.2 RWE to Contextualize Potential Safety Concerns Arising during the Course of Rare Disease Product Development
	5.5 RWE for Post-Marketing Safety and Effectiveness Evaluations of Rare Disease Therapies
	5.6 RWE for Label Expansions
	5.7 Conclusion
	References
6. Clinical Development of Pediatric Program within Rare Diseases
	6.1 Motivating Examples and Background
		6.1.1 Motivating Examples
		6.1.2 Regulatory Consideration for Pediatric Program and Approvals
			6.1.2.1 Background
			6.1.2.2 Pediatric Rule
			6.1.2.3 PREA
			6.1.2.4 The Research to Accelerate Cure and Equity (RACE) for Children Act
			6.1.2.5 BPCA
			6.1.2.6 Regulations in Europe and Key Comparisons to US Regulations
			6.1.2.7 Global Implications and International Collaboration
		6.1.3 Patient Advocacy and Natural History
		6.1.4 Preclinical and Nonclinical Models
	6.2 Pediatric Extrapolation
	6.3 Trial Design Considerations When No Extrapolation or Partial Extrapolation are Used in Efficacy Add Evaluation
		6.3.1 Adaptive Design
		6.3.2 Multi-arm Designs/Master Protocol
		6.3.3 Historical Control
		6.3.4 Enrichment Strategies
		6.3.5 Efficacy Endpoints
		6.3.6 Dose Selection
	6.4 Application of Modeling and Simulations in the Pediatric Drug Development for Rare Disease
		6.4.1 Dose Selection and Extrapolation
		6.4.2 Dose Optimization
		6.4.3 Clinical Trial Design
		6.4.4 Summary
	6.5 Bayesian Approach
		6.5.1 Background on Bayesian Statistics
		6.5.2 General Methods
			6.5.2.1 Noninformative Priors
			6.5.2.2 Informative Priors
		6.5.3 Effective Sample Size
		6.5.4 Operating Characteristics
		6.5.5 Decision Rule
		6.5.6 Case Example
	6.6 Other Aspects and Discussions
		6.6.1 Neonates and Preterm Babies
		6.6.2 Data Quality, Collection, and Sharing
		6.6.3 Animal Rule
	Acknowledgment
	References
7. Use of Modeling and Simulation in Support of Drug Development for Rare Diseases
	7.1 Introduction to Modeling and Simulation in Rare Diseases
	7.2 Modeling Methodologies Suited to Rare Diseases
	7.3 Application to Rare Diseases
	7.4 Future Opportunities for Modeling in Rare Diseases
	References
8. Case Studies of Rare Disease Drug Development
	8.1 Use of Natural History Studies for Drug Approval: A Case Study of Zolgensma® (Onasemnogene Abeparvovec-Xioi)
		8.1.1 Background
		8.1.2 Spinal Muscular Atrophy
		8.1.3 Natural History Studies of SMA
		8.1.4 Case Study of Zolgensma
			8.1.4.1 Overview
			8.1.4.2 The AVXS-101-CL-303 Phase 3 Trial
			8.1.4.3 The AVXS-101-CL-101 Phase 1 Trial
		8.1.5 Other Approved Drugs for SMA
		8.1.6 Discussion
	References
	8.2 Use of Electronic Health Records for Drug Approval: A Case Study of Xpovio® (Selinexor)
		8.2.1 Background
		8.2.2 Case Study of Xpovio® (Selinexor)
			8.2.2.1 Biases or Issues Identified
			8.2.2.2 Additional Analyses Recommended
		8.2.3 Discussion
	References
	8.3 Use of Basket Trial: A Case Study of VITRAKVI® (Larotrectinib)
		8.3.1 Background
		8.3.2 Case Study on Tissue-Agnostic Type Approval
			8.3.2.1 Larotrectinib
			8.3.2.2 Other Tissue-Agnostic Approvals
		8.3.3 Summary and Discussion
	References
	8.4 Use of Biomarker as Surrogate Endpoint for Accelerated Approval: A Case Study of VYONDYS 53 (Golodirsen)
		8.4.1 Background about Accelerated Approval
		8.4.2 Case Study on Accelerated-Type Approvals Based on Biomarkers
			8.4.2.1 VYONDYS 53 (Golodirsen)
			8.4.2.2 Other Accelerated Approvals by the FDA
		8.4.3 Summary and Discussion
	References
Index