Cell and gene therapies have become the third major drug modality in pharmaceutical medicine of the 21st century after low molecular weight and antibody drugs. The gene therapy (GTx) field is rapidly advancing, and yet there are still fundamental scientific questions that remain to be answered. Development of GTx products poses unique challenges and opportunities for drug developers. However, there is lack of a systematic exposition of the GTx product development and the pivotal role of the biostatistician in this process. Development of Gene Therapies: Strategic, Scientific, and Regulatory, and Access Considerations attempts to summarize the current state-of-the-art strategic, scientific, statistical, and regulatory aspects of GTx development. Intended to provide an exposition to the GTx new product development through peer-reviewed papers written by subject matter experts in this emerging field, this book will be useful for researchers in gene therapy drug development, biostatisticians, regulators, patient advocates, graduate students, and the finance and business development community .
Key Features:
A collection of papers covering a wide spectrum of topics in gene therapies (GTx), written by leading subject matter experts. An exposition of the core principles of GTx product development, emerging business models, industry standards, best practices, and regulatory pathways. An exposition of statistical and innovative modeling tools for design and analysis of clinical trials of GTx. Insights into commercial models, access hurdles, and health economics of gene therapies. Case studies of successful GTx approvals from core team members that developed the first two FDA-approved AAV gene therapies: Luxturna and Zolgensma. A discussion of potential benefits and hurdles to be overcome for GTx in coming years from a multi-stakeholder perspective.
1. Introduction: The Road to Gene Therapy 2. Driving AAV Drug Design to the Right Place, Right Amount, and Right Time 3. A Practical Guide to the Nonclinical Development of In Vivo Gene Therapies 4. Quantitative Systems Pharmacology Modeling of Adeno-Associated Virus Gene Therapies: Mechanistic Identification of Species-Translation Using Preclinical and Clinical Data 5. Bringing Gene Therapy to Patients: A Clinical Development Perspective Based on Brain and Neuromuscular Diseases 6. The Ethics of Gene Therapy 7. AAV Vector Immunogenicity in Gene Therapy: Mechanisms, Assessment, and Immunomodulation Strategies 8. Prenatal Somatic Cell Gene Therapy 9. Development of Gene Therapies for Ultra-Rare Disease 10. Statistical Innovation for Gene Therapy Development: Clinical Trial Design and Analysis Considerations 11. Biomarkers in Gene Therapy Development for Rare Diseases 12. Manufacturing, Analytical, and Process Comparability Challenges for Recombinant Adeno-Associated Virus (rAAV) Gene Therapy 13. Regulatory Considerations in the Development of Gene Therapy Products 14. Gene Therapy Clinical Safety Considerations: Short- and Long-Term 15. Development of Gene Therapies from an Academic Perspective 16. Commercial Models, Access Hurdles, and Health Economics of Gene Therapies 17. The Zolgensma Journey: A Groundbreaking Therapy for SMA 18. History and Development Story of Luxturna: Scientific and Regulatory Challenges 19. The Future of in vivo rAAV Gene Therapies for Rare Neurological Diseases
Avery McIntosh, Ph.D. is a drug developer working in rare diseases at Pfizer. He received his M.Sc. and Ph.D. in biostatistics from Boston University with a dissertation on Bayesian methods to model household tuberculosis transmission. He has managed teams of statisticians across study phases and in a variety of drug types and disease areas, including neurology, ophthalmology, infectious disease/ global health, hematology, and oncology. He has published peer-reviewed articles on various topics in drug development and biostatistics, including development of cell and gene therapies and qualification of digital endpoints in neurological diseases. Oleksandr Sverdlov, Ph.D. is a Neuroscience Disease Area Statistical Lead at Novartis. He received B.Sc. in Applied Mathematics from V.N. Karazin Kharkiv National University, Ukraine, M.Sc. in Statistics from University of Maryland, Baltimore County (UMBC), and Ph.D. in Information Technology with Concentration in Statistical Science from George Mason University. He has been actively involved in methodological research and applications of innovative statistical approaches in drug development. He has co-authored over forty refereed articles, edited two monographs, and co-authored a book ``Mathematical and Statistical Skills in the Biopharmaceutical Industry: A Pragmatic Approach'' (CRC Press/Chapman \& Hall, 2019). His most recent work involves design and analysis of clinical trials evaluating novel digital technologies.
