NAMs for Assessing Developmental Toxicity of Pharmaceuticals: Moving the Needle Forward
Scientist from various prestigious organizations, including Toxys CSO Amer Jamalpoor, recently published “New approach methodologies for assessing developmental toxicity of pharmaceuticals: Case examples and future directions” in Reproductive Toxicology. Below, we share highlights from this publication, which can be accessed here.
This manuscript is part of a Health and Environmental Sciences Institute’s Developmental and Reproductive Toxicology (HESI DART) series investigating the general, chemical, and pharmaceutical utility of NAMs for reduction and replacement of in vivo mammalian embryo-fetal developmental toxicity studies.
ICH S5 (R3) guidelines
New approach methodologies (NAMs) for assessing the developmental toxicity (Dev Tox) of substances have been in use by pharmaceutical companies for more than 20 years. Although there have been challenges regarding the regulatory adoption of these NAMs due to the dynamic interactions between the substance, the mother’s physiology, and the embryo-fetal development, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Safety Guidelines for Reproductive Toxicology revision 3 (ICH S5(R3)) provides a guideline to qualify Dev Tox NAMs for regulatory decision making.
ICH S5(R3) identifies several scenarios in which an appropriately qualified Dev Tox NAM can be used to support pharmaceutical development:
- In cases where there is a high likelihood that a pharmaceutical will adversely affect embryo-fetal development
- In cases where the pharmaceutical is being developed for certain severely debilitating or life-threatening diseases, or late-life onset diseases
- When toxicity in the animal species precludes attaining systemic exposures relevant to humans under conditions of clinical use
- As support for Weight-of-Evidence (WoE) when animal data are equivocal.
Current state of DART NAMs used by pharma companies
Results from a recent survey of HESI DART public and private committee members showed that the current predominant use of Dev Tox NAMs consists of screening candidate compounds early in development when the target population is of reproductive age or pregnant. Both regulators and industry sponsors agreed that robust comparative data supporting regulatory acceptance of Dev Tox NAMs equivalence to embryo-fetal development studies in standard species was needed for Dev Tox NAMs to ultimately replace in vivo testing.
The Dev Tox NAMs currently used in pharmaceutical safety testing within HESI DART pharmaceutical sponsor companies were as given in below table.
| Screening | Prioritization | Mechanistic Study | Regulatory use/ animal replacement | |
| Zebrafish Embryo Developmental Toxicity Assay | Yes | Yes | No | No |
| Stemina Dev Tox, quickPredict, Human | Yes | Yes | No | No |
| Toxys, ReproTracker, Human | Yes | Yes | Yes | No |
| Mouse Embryonic Stem Cell Test | Yes | Yes | No | No |
| Human Embryonic Stem Cell Test | Yes | Yes | No | No |
| Rat Whole Embryo Culture | Yes | Yes | Yes | No |
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