As nonclinical safety toxicology consultants, we are often brought into programs at varying stages. Sometimes we get involved early on, near the discovery phase, and get to be involved in many of the discussions leading up to candidate selection. Sometimes we are engaged once the candidate is selected and the sponsor is ready to begin the IND-enabling studies. Other times we become involved later, once IND-enabling toxicology studies have already been conducted, or when unexpected findings are identified.
When getting acquainted with a nonclinical program, there is some basic information that we like to get oriented. Dose route, clinical indication, and clinical trial design are all common questions that come up, as well as species selection. It is important that there is a solid rationale for the determination of which species the nonclinical program is conducted in. Typically, for small molecules, the nonclinical studies are conducted in one rodent and one nonrodent species. There are times when we have begun to review data generated from 28‑day studies in nonhuman primates and we end up asking the question, how did you select nonhuman primates as your nonclinical nonrodent species? (Hint: “because they required less test article for dosing” is not an appropriate rationale!)
The Symposium Session “Species Relevance: Approaches to Determine the Most Relevant Species for Safety Assessment of Pharmaceutical Products” on Tuesday afternoon during the SOT 58th Annual Meeting and ToxExpo did a very good job of discussing options for species selection and gave several case studies for when species selection for a particular program was not very straightforward. There are many variables to take into consideration when selecting nonclinical species to conduct repeat-dose toxicology studies with, including anatomy, physiology, or metabolism differences, pharmacological relevance, or pharmacokinetic profile. The talk by John Dubinion (US Food and Drug Administration) about species selection for biologic programs was very informative. The goals of nonclinical toxicology studies, regardless of if it is a biologic or a small molecule, are to identify possible human risk as well as determine a safe starting dose in humans. When feasible, it is preferred that the nonclinical safety studies are conducted in two pharmacologically relevant species (rodent and nonrodent). However, with biologics, this often is not possible since humans may be the only species that actually express the target.
With the many new pharmaceuticals and biologics being developed, there is a need for flexibility of nonclinical program design, including species selection and species relevance. It is important that the hazards that are identified in the nonclinical safety studies are as relevant to humans as possible.
This blog was prepared by an SOT Reporter. SOT Reporters are SOT members who volunteer to write about sessions and events they attend during the SOT Annual Meeting and ToxExpo. If you are interested in participating in the SOT Reporter program in the future, please email Giuliana Macaluso.