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

Area of Science:

• Drug development
• Pharmacology
• Toxicology

Background:

• Investigator Brochures (IBs) are critical documents for early-phase drug development.
• Nonclinical studies form the basis for determining safe starting doses in human trials.
• Both small molecules and biopharmaceuticals undergo rigorous preclinical evaluation.

Purpose of the Study:

• To compare the extent and nature of nonclinical studies for small molecules versus biopharmaceuticals in First-In-Human (FIH) studies.
• To analyze the distribution of pharmacology, ADME, and toxicology studies for different drug types.
• To examine the methods used for calculating safe starting doses based on nonclinical data.

Main Methods:

• Content analysis of 35 Investigator Brochures for small molecules and 11 for biopharmaceuticals from 2014-2016.
• Quantification of the number of nonclinical studies per molecule.
• Categorization of studies into pharmacology, ADME (Absorption, Distribution, Metabolism, and Excretion), and toxicology.

Main Results:

• Small molecules underwent a mean of 37 nonclinical studies, with pharmacology (43%), ADME (32%), and toxicology (24%) as major components.
• Biopharmaceuticals underwent a mean of 17 nonclinical studies, with pharmacology (82%) dominating, and limited ADME (6%) and toxicology (12%).
• Despite similar pharmacology study numbers, biopharmaceuticals had ~50% fewer studies overall due to reduced ADME and toxicology testing.

Conclusions:

• Biopharmaceuticals require significantly fewer nonclinical studies than small molecules, primarily due to less extensive ADME and toxicology testing.
• While regulatory guidance exists, diverse approaches are used to calculate safe starting doses, with NOAEL (No Observed Adverse Effect Level) remaining crucial.
• Pharmacology and PK data play a key role in establishing safety margins for biopharmaceuticals in the absence of extensive toxicology studies.