Overview of nonclinical testing of novel compounds

All new compounds under development as therapeutics undergo a series of toxicity studies prior to testing in human clinical trials. Requirements for such testing are determined by regulatory bodies.

Prior to initiating clinical trials, the following nonclinical safety studies are conducted:

  • Single- and repeat-dose toxicity studies
    • Evaluate the potential for acute and repeated dose toxicities including target organ toxicity; and
    • Identify the no-observed-adverse-effect level (NOAEL), used to establish a safe starting dose for first-in-human trials.
  • Safety pharmacology studies
    • Evaluate potential adverse effects on vital organ function (cardiovascular, respiratory, and central nervous systems).
  • Genotoxicity studies
    • Evaluate the potential to directly or indirectly damage genetic material in a battery of in vitro and in vivo studies.

 

DART studies are another essential component of nonclinical safety testing of new compounds. DART studies are designed to determine the risk from exposure to a novel compound to: (1) fertility (both sexes), (2) pregnant women, (3) fetus, and (4) subsequent offspring. DART studies are typically performed using animals from two mammalian species and are performed in four stages:

1. Fertility and early embryonic development (FEED)

FEED studies detect abnormalities in mating (males and females) and in conception and implantation (females only). This includes:

  • fertility
  • mating behaviour
  • maturation of gametes
  • effects on estrous cycle and tubal transport (females)
  • functional effects such as epididymal sperm maturation (males)
  • early developmental effects (e.g., viable implantation and preimplantation development of embryos).

2. Embryo–fetal development (EFD)

EFD studies detect adverse effects on pregnant females, embryo and fetal survival, intrauterine growth and development during the period of organogenesis. This includes:

  • maternal toxicity (clinical signs, body weight, food consumption)
  • evaluation of maternal corpora lutea, implantation sites, placenta, early and late resorptions, live and dead conceptuses
  • fetal evaluation (survival, weight, sex, external fetal abnormalities, and detection of soft tissue and skeletal abnormalities).

3. Pre- and postnatal development (PPND)

PPND studies evaluate maternal toxicity during late gestation (after closure of the hard palate) through the end of pregnancy, parturition, and lactation, as well as pre- and postnatal endpoints of offspring during pre- and postweaning periods, through sexual maturity and reproduction. This includes:

  • maternal toxicity (clinical signs, body weight, food consumption)
  • effects on offspring (i.e., F1 generation) exposed during gestation and lactation during the preweaning period (survival, development landmarks and reflexes)
  • effects on F1 generation postweaning (sexual maturation, sensory and motor function, learning and memory, body weight, food consumption, clinical observations, reproductive performance including pregnancy and subsequent evaluation of corpora lutea, number of implantations, and status of implantations [early/late resorptions, live/dead embryos]).

4. Enhanced pre- and postnatal development (ePPND)

ePPND studies are a combination of EFD and PPND studies performed from day 20 of gestation through delivery in non-human primates. They are performed only if non-human primates are the only pharmacologically relevant species (e.g., antibody-based biological therapies).