Table 1.

Nonclinical Regulatory Guidelines/Documents Relevant to mRNA Modalities.

Prophylactic vaccines
WHO	Evaluation of the quality, safety, and efficacy of messenger RNA vaccines for the prevention of infectious diseases: regulatory considerations, Annex 3, 2022 37 Guidelines on the nonclinical evaluation of vaccine adjuvants and adjuvanted vaccines, 2013 38 Guidelines on the nonclinical evaluation of vaccines, 2005 39
EMA	Guideline on Vaccine Adjuvants for Human Use (dormant and no longer being updated), 2005 10
FDA	Considerations for Developmental Toxicity Studies for Preventive and Therapeutic Vaccines for Infectious Disease Indications, 2006 11
ICH	ICH S5(R3): Detection of Reproductive and Developmental toxicity for Human Pharmaceuticals, 2020 20 (does not include prophylactic vaccine exception for male fertility and F1 post-weaning studies [previous versions had a prophylactic vaccine exception])
Therapeutic vaccines
FDA	Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products 2013 12 Considerations for Developmental Toxicity Studies for Preventive and Therapeutic Vaccines for Infectious Disease Indications, 2006 11
Gene therapy
FDA	Human Gene Therapy Products Incorporating Human Genome Editing, Guidance for Industry, 2024 14 Human Gene Therapy for Rare Diseases, Guidance for Industry, 2020 13 Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products 2013 12
EMA	Draft Guideline on quality, nonclinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials, 2024 8 Guideline on the quality, nonclinical and clinical aspects of gene therapy medicinal products, 2018 9
ICH	ICH S12: Guideline on nonclinical biodistribution considerations for gene therapy products, Step 5, 2024 21

Abbreviations: EMA, European Medicines Authority; FDA, Food and Drug Administration; ICH, International Council for Harmonization; WHO, World Health Organization.