REGULATORY CONSIDERATIONS FOR OLIGONUCLEOTIDE DRUGS - UPDATED RECOMMENDATIONS FOR PHARMACOLOGY AND TOXICOLOGY STUDIES

This article describes pharmacology and toxicity studies for oligonucl eotide drugs that are recommended for inclusion in the initial Investi gational New Drug Application (IND), a first request to use an investi gational drug in clinical trials. Recent observations of non-sequence- dependent cardiovascular toxicity and deaths in monkeys following intr avenous infusions of phosphorothioates have raised a potential safety concern for oligonucleotide drugs. This concern should be considered b y drug sponsors in designing pre-IND nonclinical development programs and Phase 1 clinical protocols. Pre-IND conduct of pharmacodynamic car diovascular screening is highly recommended for defining safe clinical dosing regimens for phosphorothioate (and, possibly, other charged-ba ckbone) oligomers. Additionally, drug sponsors are encouraged to (1) c onduct research into the mechanisms responsible for this dose-limiting toxicity, (2) institute liberal publication policies for research con ducted under industrial sponsorship, and (3) communicate with reviewin g divisions at FDA for updated guidance in this field when planning pr e-IND safety studies. Recommendations for nonclinical studies during d evelopment of oligonucleotides will be modified as new information reg arding the biological properties of oligonucleotides becomes available .