Regulatory considerations for oligonucleotide drugs: updated recommendations for pharmacology and toxicology studies.
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.
Black
L E
LE
U.S. Food and Drug Administration, Division of Antiviral Drug Products, Rockville, Maryland 20857.
Farrelly
J G
JG
Cavagnaro
J A
JA
Ahn
C H
CH
DeGeorge
J J
JJ
Taylor
A S
AS
DeFelice
A F
AF
Jordan
A
A
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
D015507:Drugs, Investigational; D009841:Oligonucleotides