Adapting Preclinical Benchmarks for First-in-Human Trials of Human Embryonic Stem Cell-Based Therapies

• Published in: Stem cells translational medicine Vol. 5; no. 8; pp. 1058 - 1066
• Main Authors: Barazzetti, Gaia, Hurst, Samia A., Mauron, Alexandre
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.08.2016; AlphaMed Press
• Subjects: Benchmarking - ethics; Benchmarking - legislation & jurisprudence; Cell Differentiation; Cell Lineage; Cell Survival; Clinical trials; Clinical Trials as Topic - ethics; Clinical Trials as Topic - legislation & jurisprudence; Embryo cells; Embryonic Stem Cells - transplantation; Ethics; First-in-human trials; Good Manufacturing Practice; Human embryonic stem cells; Human subjects; Humans; Manufacturing; Models, Animal; Movement disorders; Neurodegenerative diseases; Parkinson Disease - diagnosis; Parkinson Disease - surgery; Parkinson's disease; Patient Safety; Pharmaceuticals; Phenotype; Policy Making; Preclinical benchmarks; Principles; Quality; Research Design - legislation & jurisprudence; Research ethics; Risk Assessment; Standards, Policies, Protocols, and Regulations for Cell-Based Therapies; Stem Cell Transplantation - adverse effects; Stem Cell Transplantation - ethics; Stem Cell Transplantation - legislation & jurisprudence; Stem Cell Transplantation - methods; Stem cells; Translational research; Translational Research, Biomedical - ethics; Translational Research, Biomedical - legislation & jurisprudence; United States > US; Europe; Human embryonic stem cells; Preclinical benchmarks; First-in-human trials; Research ethics; Translational research
• DOI: 10.5966/sctm.2015-0222
• ISSN: 2157-6564

: As research on human embryonic stem cell (hESC)-based therapies is moving from the laboratory to the clinic, there is an urgent need to assess when it can be ethically justified to make the step from preclinical studies to the first protocols involving human subjects. We examined existing regulatory frameworks stating preclinical requirements relevant to the move to first-in-human (FIH) trials and assessed how they may be applied in the context of hESC-based interventions to best protect research participants. Our findings show that some preclinical benchmarks require rethinking (i.e., identity, purity), while others need to be specified (i.e., potency, viability), owing to the distinctive dynamic heterogeneity of hESC-based products, which increases uncertainty and persistence of safety risks and allows for limited predictions of effects in vivo. Rethinking or adaptation of how to apply preclinical benchmarks in specific cases will be required repeatedly for different hESC-based products. This process would benefit from mutual learning if researchers included these components in the description of their methods in publications. To design translational research with an eye to protecting human participants in early trials, researchers and regulators need to start their efforts at the preclinical stage. Existing regulatory frameworks for preclinical research, however, are not really adapted to this in the case of stem cell translational medicine. This article reviews existing regulatory frameworks for preclinical requirements and assesses how their underlying principles may best be applied in the context of human embryonic stem cell-based interventions for the therapy of Parkinson's disease. This research will help to address the question of when it is ethically justified to start first-in-human trials in stem cell translational medicine.