title: Regulatory considerations for oligonucleotide drugs: updated recommendations for pharmacology and toxicology studies.
abstract: This article describes pharmacology and toxicity studies for oligonucleotide drugs that are recommended for inclusion in the initial Investigational New Drug Application (IND), a first request to use an investigational drug in clinical trials. Recent observations of non-sequence-dependent cardiovascular toxicity and deaths in monkeys following intravenous infusions of phosphorothioates have raised a potential safety concern for oligonucleotide drugs. This concern should be considered by drug sponsors in designing pre-IND nonclinical development programs and Phase I clinical protocols. Pre-IND conduct of pharmacodynamic cardiovascular screening is highly recommended for defining safe clinical dosing regimens for phosphorothioate (and, possibly, other charged-backbone) oligomers. Additionally, drug sponsors are encouraged to (1) conduct research into-the mechanisms responsible for this dose-limiting toxicity, (2) institute liberal publication policies for research conducted under industrial sponsorship, and (3) communicate with reviewing divisions at FDA for updated guidance in this field when planning pre-IND safety studies. Recommendations for nonclinical studies during development of oligonucleotides will be modified as new information regarding the biological properties of oligonucleotides becomes available.
authors.affiliation: U.S. Food and Drug Administration, Division of Antiviral Drug Products, Rockville, Maryland 20857.
authors.forename: L E
authors.initials: LE
authors.lastname: Black
authors.forename: J G
authors.initials: JG
authors.lastname: Farrelly
authors.forename: J A
authors.initials: JA
authors.lastname: Cavagnaro
authors.forename: C H
authors.initials: CH
authors.lastname: Ahn
authors.forename: J J
authors.initials: JJ
authors.lastname: DeGeorge
authors.forename: A S
authors.initials: AS
authors.lastname: Taylor
authors.forename: A F
authors.initials: AF
authors.lastname: DeFelice
authors.forename: A
authors.initials: A
authors.lastname: Jordan
mesh_terms: D000818:Animals; D015507:Drugs, Investigational / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007275:Injections, Intravenous; D017387:Investigational New Drug Application; D009841:Oligonucleotides / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D015507:Drugs, Investigational; D009841:Oligonucleotides