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Regenerative Medicine - from Protocol to Patient pp 51–82Cite as

Guidelines for Preclinical Development

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Abstract

Preclinical development encompasses the set of activities required to initiate testing for safety and efficacy in humans. These requirements are defined by national and international regulations, and are generally focused on definition of drug composition and safety as well as scientific rationale and establishing a proposed dose regimen. The preclinical regulatory requirements for cell therapies broadly parallel those for small molecules and proteins, but the complexity of cells can bring additional challenges to the definition of potency, composition, immunogenicity, and toxicity. As a consequence of their pluripotent origins, stem cell therapies require additional preclinical considerations related to potential tumorigenicity and genetic/epigenetic stability. The first FDA approved stem cell therapy study initiated clinical trial in 2010. Thus, the field is young and there are few completed studies to provide precedents for planned preclinical development of novel stem cell approaches. Rather, the field must draw practical lessons from other somatic cell therapies. The evolution and harmonization of regulatory guidances for stem cells must also contend with a growing number of unregulated sites around the world that offer unproven stem cell treatments. It takes time for any new technology to identify safety and efficacy barriers to clinical application, and to develop strategies to overcome them. As current research and clinical experience guide the next generation of stem cell therapies in preclinical development, the establishment of validated assays based on cells differentiated from human stem cells may revolutionize the preclinical safety testing for all classes of drugs.

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Abbreviations

ADMET:

absorption distribution, metabolism, excretion, toxicity

AM:

ancillary material

ASCs:

adult stem cells

ATM:

ataxia telangiectasia mutated

ATMP:

Advanced Therapy Medicinal Products

BDNF:

brain derived neurotrophic factor

BSE:

bovine spongiform encephalitis

CAT:

Committee on Advanced Therapies

CBER:

Center for Biologics Evaluation & Research

CDER:

Center for Drug Evaluation & Research

CFR:

Code of Federal Regulations

CGMP:

Current Good Manufacturing Practice

CGT:

Cellular and Gene Therapy

CGTP:

Current Good Tissue Practice

CM:

cardiomyocyte

CMC:

Chemistry Manufacturing, and Control

CNS:

central nervous system

CRO:

contract research organization

CTA:

Clinical Trial Authorisation

CTP:

cellular therapy products

CYP450:

cytochrome P450

DCEPT:

Division of Clinical Evaluation and Pharmacology/Toxicology

DCGT:

Division of Cellular and Gene Therapies

DHHS:

Department of Health and Human Services

DHT:

Division of Human Tissues

ECVAM:

European Center for the Validation of Alternative Methods

EMA:

European Medicines Agency

ESNATS:

embryonic stem cell-derived novel alternative test systems

ESC:

embryonic stem cells

FCS:

fetal calf serum

FDA:

Food and Drug Administration

FETAX:

frog embryo teratogenesis assay

FGF:

fibroblast growth factor

FPD:

field potential duration

GDNF:

glial cell-derived neurotrophic factor

GFP:

green fluorescent protein

GVHD:

graft versus host disease

HCT/P:

human cells tissues, and cellular and tissue-based products

hERG:

human Ether-a-go-go-Related Gene

hESCs:

human embryonic stem cells

hiPSC:

human induced pluripotent stem cells

hiPSC-CMs:

human induced stem cell-derived cardiomyocytes

HSCs:

hematopoietic stem cells

HLA:

human leukocyte antigens

IBMIR:

instant blood mediated inflammatory reaction

ICH:

International Conference on Harmonisation

iPSC:

induced pluripotent stem cells

iPSC-HCs:

induced pluripotent stem cell-derived hepatocytes

IDO:

indoleamine 2,3-dioxygenase

IFN-γ:

interferon-gamma

IND:

Investigational New Drug

ISCT:

International Society for Cellular Therapy

LC-MS:

liquid chromatography- mass spectrometry

MEA:

microelectrode array

mEST:

mouse embryonic stem cell test

MHC:

major histocompatibility complex

MM:

micromass

MOA:

mechanism of action

MSC:

mesenchymal stem cell

NDA:

New Drug Application

NSC:

neural stem cell

OCTGT:

Office of Cellular Tissue & Gene Therapy

OKSM:

OCT4, SOX2, KLF4, MYC

PHH:

primary human hepatocytes

PHSA:

Public Health Safety Act

PK/PD:

pharmacokinetics / pharmacodynamics

PSC:

pluripotent stem cell

ROS:

reactive oxygen species

SCDI:

stearoyl-CoA desaturase-1

SCID:

severe combined immunodeficiency

SR-GVHD:

steroid-refractory acute graft versus host disease

TdP:

Torsade de Pointes

TGF-β:

transforming growth factor beta

WEC:

whole embryo culture

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  1. Vector Preclinical Consulting, Sunnyvale, CA, USA

    Edward Spack Ph.D.

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  1. KIlinik und Poliklinik für Herzchirurgie, Universitätsmedizin Rostock, Rostock, Mecklenburg-Vorpomm., Germany

    Gustav Steinhoff

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Spack, E. (2016). Guidelines for Preclinical Development. In: Steinhoff, G. (eds) Regenerative Medicine - from Protocol to Patient. Springer, Cham. https://doi.org/10.1007/978-3-319-28293-0_4

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