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Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics

DraftCenter for Drug Evaluation and Research11/15/2024

Description

The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics.”  FDA is publishing this draft guidance which, when finalized, will provide recommendations on approaches for the nonclinical safety evaluation of oligonucleotide-based therapeutics (ONTs) to support clinical development and marketing of these products.  ONTs present unique challenges and opportunities in the nonclinical evaluation of safety that differ in many regards from those appropriate for small molecule drugs or therapeutic proteins.

Scope & Applicability

Product Classes

4
Oligonucleotide-Based Therapeutics

Guidance provides recommendations for the nonclinical safety evaluation of these products.; Nonclinical safety assessment of these products; Nonclinical safety assessment of these therapeutics; Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics

Antisense Oligonucleotides

Type of ONT drug product

Small Interfering RNAs

Type of ONT drug product

Aptamers

Type of ONT drug product

Stakeholders

1
Sponsor

Entity responsible for submitting applications under section 524B

Regulatory Context

Attributes

4
Pharmacologically Relevant Species

Species responsive to the clinical candidate or surrogate

Species specificity

Targeting moieties may confer additional species specificity

Tissue Half-life

Prolonged half-life at the site of action

Human Equivalent Dose

Estimated by normalizing animal dose to body surface area

Identified Hazards

Hazards

5
Off-Target Hybridization-Dependent Effects

A safety assessment consideration for ONTs.; Potential to bind to nontargeted RNA or DNA sequences

Mutagenic Impurities

DNA Reactive Impurities in Pharmaceuticals

Tumorigenicity

Risk associated with intended pharmacology or off-target effects

Immunotoxicity

Section XI of the guidance.

Exaggerated Pharmacology

Potential adverse effects resulting from intended PD effect

Related CFR Sections (2)

See Also (8)

Nonclinical Safety Assessment of Oligonucleotide-Based Therapeutics | Guideline Explorer | BioRegHub