Getting a molecule into the clinic: Nonclinical testing and starting dose considerations

Examination of content of 35 Investigator Brochures (IBs) for small molecules (including some for oncology) used to support First-In-Human studies over a 2 year period (2014-2016) showed that a mean of 37 nonclinical studies were performed per molecule with pharmacology, ADME and toxicology testing contributing 43%, 32% and 24% of the studies, respectively. Examination of 11 IBs for biopharmaceuticals (monoclonal antibodies) over the same time frame showed that the mean number of nonclinical studies was 17 studies per molecule with pharmacology, ADME and toxicology testing contributing 82%, 6% and 12% of the studies, respectively. For both types of molecule, similar numbers of pharmacology studies were performed but the approximately 50% fewer studies for biopharmaceuticals was due to considerably limited ADME and toxicology testing. Despite available regulatory guidance to allow calculation of a safe clinical starting dose, examination of how this occurred in the examined IBs showed that a variety of approaches are in practice, although reference to the NOAEL in toxicology testing is still key, whether in calculation of a Maximum Recommended Starting Dose (small molecules), or after use of pharmacology and/or PK data (especially for biopharmaceuticals) to show acceptable safety margins over doses used/exposure seen in toxicology studies.