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.
Since 1937, the Food and Drug Administration (FDA) has required preclinical testing of new drugs and biologicals for pharmacologic activity and acute toxicity in animals prior to their use in clinical trials. In 1962, the Thalidomide tragedy was largely averted in the US thanks to the persistence and steadfastness of Dr. Frances Kelsey. Dr. Kelsey’s diligence was used to help pass rigorous drug approval which set an enduring framework for drug testing. The guidance established the use of two animal species, a rodent and a larger non-rodent mammal, for toxicological studies.
In spite of recent adaptations in the FDA modernization act, the use of animal species for IND-enabling studies remains a cornerstone of drug safety. The selection of the animal species, while flexible, must adhere to the FDA and EMA’s guidance:
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:
In the 1960s and 1970s, most drugs developed were chemical entities. Dogs and NHPs were readily available and relatively inexpensive. Their low body weight meant smaller amounts of test article could be used compared to pig studies (prior to the development of micro-pigs). Selecting dogs and NHPs met the FDA’s “use of non-rodent” requirement. They proved to be effective models of adverse drug effects. The standardization around these translational models yielded vast amounts of scientific reference data, further reinforcing the popularity of these models.
The rise of complex molecules such as biologics impacts preclinical safety considerations. On one hand, the specificity of biologics reduces 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. Biologics therefore enable the selection of non-traditional models for IND-enabling studies and permit more flexible study designs, (e.g. combining safety pharmacology and toxicology studies). On the other hand, the rise of biologics further solidified to importance of primates in drug development 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.
Today, IND-enabling studies still rely primarily on data obtained from dogs and Non-Human Primates. For biologics, single species toxicology packages, often conducted with primates, have become common. Technological advances such as the development of easyTEL+ implanted telemetry system allows scientists to derive maximal insights (ECG, Blood Pressure, Respiration) from increasingly expensive animal studies in a natural, stress-free context. 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 increasingly 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.
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.
Dr. Donald Hodges (CBSET, MA, USA) discussed the history, regulatory framework and other factors influencing species selection in IND-enabling studies.
He outlined how proven translational characteristics and historical data are enabling the wider adoption of swine as an alternative to dogs and Non-Human Primates in the context of shortages and rising costs.
Dr. Michael Stonerook (AmplifyBio, OH, USA) highlighted the benefits and limitations of the rat model for cardiovascular screening assays.
He explained how the rat can play a critical role in cost-effective screening modalities, provided scientists understand the model organism’s anatomy and physiology.
Dr. Dany Salvail (IPST, QC, Canada) explained how experienced pharmacologists rely on alternate models combined with sophisticated measurement techniques that go well beyond the ICH guidelines to help sponsors truly understand and quantify liabilities associated with their lead compounds early on.
IPS’s flexible approach allows their scientists to rapidly adapt study designs and, if needed, conduct complementary safety and efficacy assays at minimal additional cost to better characterize physiological effects of compounds.
When you visit any web site, it may store or retrieve information on your browser, mostly in the form of cookies. Control your personal Cookie Services here.