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.