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

Abstract

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. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1058-1066 SIGNIFICANCETo 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.

Therapeutic Potential of Repeated Intravenous Transplantation of Human Adipose-Derived Stem Cells in Subchronic MPTP-Induced Parkinson’s Disease Mouse Model

“…Preclinical studies have demonstrated that dopamine neurons recovered and motor function improved when hASCs were transplanted into neurotoxin-induced PD models [17,18,25]. Based on these studies, considerations for cell-based clinical trials for PD are currently being discussed [26][27][28][29]. However, most studies only reported a short-term effect following ASC administration, once or twice and intravenously or directly in the SN.…”

Regenerating Eye Tissues to Preserve and Restore Vision

“…characteristics that ensure the desired product quality, is difficult for cell products, which are highly complex, change over time, and can be affected by minor changes in the many molecules used in manufacturing. Currently, cell products are defined by a limited number of markers to reflect identity, purity, and potency, but there is recognition that this level of characterization may be inadequate (Barazzetti et al, 2016). We look ahead to improved phenotyping methods, such as single cell-level characterization that better define cell product composition.…”

Readiness for First-In-Human Neuromodulatory Interventions

“…[2][3][4][5] Well-established benchmarks of acceptable levels of preclinical data in pharmaceutical development enable translation on that landscape to proceed ethically. 6 Even so, Phase 1 clinical trials are the riskiest given the inherent lack of pre-existing data necessary for the ethical justification of research with human subjects. 7,8 Furthermore, phase 1 FIH trials are designed to test for safety and tolerability, not efficacy.…”