Practical Considerations in Determining Adversity and the No-Observed-Adverse-Effect-Level (NOAEL) in Nonclinical Safety Studies: Challenges, Perspectives and Case Studies

Abstract

Determining the adverse nature of findings from nonclinical safety studies often poses a challenge for the key stakeholders responsible for interpreting the results of definitive toxicity studies in support of pharmaceutical product development. Although there are instances in which responses to treatment clearly indicate intolerability or tissue injury associated with dysfunction; in practice, more often there is uncertainty in characterizing an effect of drug treatment as adverse or not. This is due to the inherent variability in responses of biological test systems to toxicological insults, leaving the ultimate analyses of adversity to individual interpretation and subjectivity. This article is a follow-up to the workshop entitled, “Adverse or Not Adverse?: Thinking process behind adversity determination during nonclinical drug development,” conducted at the 58th Annual Meeting of the Society of Toxicology, March 2019 in Baltimore, MD. In this paper, we further discuss and incorporate the perspectives of authors representing different roles, such as Study Director, Study Pathologist, Pharmacology/Toxicology Reviewer (U.S. Food and Drug Administration), and Sponsor in the determination and use of adversity. We also present a practical stepwise approach as an aid in this assessment, and further apply these principles to discuss 10 case studies with different therapeutic modalities and unique challenges.

How important are concurrent vehicle control groups in (sub)chronic non-human primate toxicity studies conducted in pharmaceutical development? An opportunity to reduce animal numbers

“…Subsequently, concordance with the original interpretation was evaluated and differences or challenges in the interpretation without concurrent control groups were highlighted. The analysis followed general recommendations on determining adversity and the NOAEL in nonclinical safety studies [15] and was conducted with particular emphasis on the following aspects: Timing of effect and development over time Magnitude of the effect and dependence on dose level Number of individual animals demonstrating the effect Comparison of measurements under dosing with those obtained before dosing Comparison of measurements under dosing with reference data obtained from previously used control animals …”

“…Subsequently, concordance with the original interpretation was evaluated and differences or challenges in the interpretation without concurrent control groups were highlighted. The analysis followed general recommendations on determining adversity and the NOAEL in nonclinical safety studies [15] and was conducted with particular emphasis on the following aspects:…”

“…; https://doi.org/10.1101/2023.02. 15.528719 doi: bioRxiv preprint 4 With the aim to reduce the number of animals used in regulatory toxicity studies, the concept of virtual control groups has been introduced into nonclinical safety assessment [11]. Virtual control groups are supposed to replace concurrent control groups, which represent up to 25% of the animals in a regulatory toxicology study [12].…”

“…(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is madeThe copyright holder for this preprint this version postedFebruary 16, 2023. ; https://doi.org/10.1101/2023.02 15…”

How important are concurrent vehicle control groups in (sub)chronic non-human primate toxicity studies conducted in pharmaceutical development? An opportunity to reduce animal numbers

“…Subsequently, concordance with the original interpretation was evaluated and differences or challenges in the interpretation without concurrent control groups were highlighted. The analysis followed general recommendations on determining adversity and the NOAEL in nonclinical safety studies [ 17 ] and was conducted with particular emphasis on the following aspects:…”