Botanical Drug Product Development in the U.S.A.: Importance of Genotoxicity Testing

Genotoxicity testing (GT) is an important part of preclinical safety assessment of new drugs and is required prior to Phase I/II clinical trials. GT is designed to detect genetic damage such as gene mutations and chromosomal aberration, which may be reflected in teratogenic and tumorigenic potential of the drug. Botanical new drugs in the U.S. are entitled to a waiver for preclinical Pharm/Tox studies, including GT, in support of an initial clinical trial under IND, contingent on previous human experience. Recently, ethical concerns have been raised over conducting Phase I/II clinical trials of new drug with positive GT findings in healthy volunteers. Although the relevance of this issue depends on drug's indication, duration of treatment, and specific findings related to GT, the regulatory view toward it has been to not expose patients to genotoxic compounds unnecessarily in clinical trials. This philosophy may impact on herbal supplement marketing and botanical drug development, in that GT data are often lacking while consumers are exposed to the herbal supplement, or healthy volunteers are tested in an initial Phase I/II clinical trial on the botanical drug. Granted that GT is comparably cost‐efficient (relative to animal toxicity studies), has high statistical power, and is highly reproducible, botanical drug sponsors should be encouraged to prioritize obtaining this information in their product development.