Maximizing Insights from Preclinical Safety Studies in the context of rising costs and shortages

During the 2023 Safety Pharmacology Society (SPS) Conference in Brussels, scientists from leading preclinical contract organizations (CROs) discussed how traditional IND-enabling studies involving primates and dogs can be complemented (and sometimes even replaced) by alternative models such as mice, rats, rabbits and pigs.

The inclusion of non-traditional models in safety pharmacology studies can help scientists de-risk compounds early on, adapt their project to the context of rising costs, and offer unique biological insights, especially for new modalities such as gene and cellular therapies.

Re-thinking species selection in safety studies

Tracing back to the FDA’s inception in 1937, the guidance required preclinical testing of new drugs and biologicals for pharmacologic activity and acute toxicity in animals prior to their use in clinical trials. The use of two animal species, a rodent and a larger non-rodent mammal, for toxicological studies were established.

Though the recently adopted FDA modernization act no longer mandates animal testing, the use of animal species for IND-enabling studies remains a cornerstone of drug safety.

The selection criteria, guided by the FDA and EMA, encompass animal, environmental and physiological attributes that simulate the clinical setting, with scientific information justifying the appropriateness of the chosen animal model. A comprehensive understanding of the subject’s anatomy, physiology, and baseline values is critical to understand and contextualize the results. The table below provides cardiovascular comparative physiology references:

Expected baseline values for cardiovascular endpoints in different species, compared to human
Table1: Expected baseline values for cardiovascular endpoints in different species, compared to human (*data from IPS Therapeutique)

In the 1960s and 1970s, most drugs developed were chemical entities. Dogs and NHPs were commonly used for drug development due to their availability and cost-effectiveness. They provided effective models for adverse drug effects and yielded vast amounts of scientific reference data.

The rise of complex molecules such as biologics impacts preclinical safety considerations. Indeed, biologics account for over 40% of FDA-approved drugs and there have been over a thousand ongoing clinical studies for cellular and gene therapies in 2023. These new drug modalities present unique challenges for preclinical safety studies, as a single administration can have effects over many months. They also offer reduced toxicological risks compared to small chemical entities. Indeed, small molecule drugs present more off-target effects and toxicological risks than biologics, which are purposefully designed to interact with the immune system. 

Safety Pharmacologists therefore face a unique opportunity to improve the translational value of preclinical assays for biologics, by combining non-traditional animal species with advanced measurement techniques such as implantable telemetry. easyTEL+ implantable telemetry, allows scientists to derive maximal insights (ECG, Blood Pressure, Respiration) from animal studies in a natural, stress-free context, during extended monitoring period of several days or even months.

Today, IND-enabling studies still rely on data from dogs and NHPs, since their close genetic proximity to humans allow them to exhibit target-binding characteristics as well as the associated desired pharmacological effect sought in humans. But alternative models are also being explored. With the increasing costs of preclinical studies and the intensification of ethical concerns associated with the use of companion animals for scientific research, scientists are re-discovering alternative models such as pigs, rats and rabbits to better predict human toxicity. These models are combined with complementary assays such as 3D cell cultures, organoids, organ slices, Novel Alternative Methods (NAMS), and in silico methods, to better inform biomedical research projects.

Species used for different molecule types within the NC3Rs-ABPI Two species working group dataset
Figure 1: Species used for different molecule types within the NC3Rs/ABPI ‘Two species’ working group dataset.
Toxicol Res, Volume 9, Issue 6, December 2020, Pages 758–770,

The articles below summarize some of the key points that were presented during the 2023 Safety Pharmacology Society Partner Talk, in Brussels. They include the video recording of each talk.

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