title: Scientific and Regulatory Policy Committee: Recommended ("Best") Practices for Determining, Communicating, and Using Adverse Effect Data from Nonclinical Studies.
abstract: Recommendations (best practices) are provided by the Society of Toxicologic Pathology's Adversity Working Group for making consistent interpretations of test article-related effects as "adverse" and assigning a "no observed adverse effect level" (NOAEL) in nonclinical toxicity studies. Adverse is a term indicating "harm" to the test animal, while nonadverse indicates lack of harm. Adverse findings in the study reports should be defined in relation to effects on the test species used and within the context of the given study. Test article-related effects should be described on their own merits, and decisions to consider them as adverse or nonadverse should be justified. Related effects may be discussed together; in particular, markers of toxicity that are not in and of themselves adverse ideally should be discussed in conjunction with the causal toxicity to determine adversity. Adverse findings should be identified in subreports (clinical data, pathology data, etc.) if sufficient information is available, and/or in the final study report as individual or grouped findings, but study NOAELs should be established at the level of the overall study report. Interpretations such as "not biologically relevant" or "not toxicologically important" should be avoided unless defined and supported by scientific rationale. Decisions defining adverse findings and the NOAEL in final study reports should combine the expertise of all contributing scientific disciplines. Where possible, use of NOAELs in data tables should be linked to explanatory text that places them in context. Ideally, in nonclinical summary documents, NOAELs from multiple studies are considered together in defining the most important adverse responses in the most sensitive species. These responses are then considered along with an understanding of their likely mechanisms, as well as other information such as variability in species sensitivity, comparative pathology, reversibility and progression, kinetics, and metabolism of the test substance to help assess human risk.
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, Connecticut, USA roy.l.kerlin@pfizer.com.
authors.forename: Roy
authors.initials: R
authors.lastname: Kerlin
authors.affiliation: GEMpath Inc., Longmont, Colorado, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Bolon
authors.affiliation: Preclinical Safety, AbbVie Research and Development, North Chicago, Illinois, USA.
authors.forename: John
authors.initials: J
authors.lastname: Burkhardt
authors.affiliation: US FDA/CFSAN, College Park, Maryland, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Francke
authors.affiliation: Department of Cancer Studies, Leicester Royal Infirmary, Leicester, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Greaves
authors.affiliation: Covance Laboratories Inc., Madison, Wisconsin, USA.
authors.forename: Vince
authors.initials: V
authors.lastname: Meador
authors.affiliation: Stratoxon LLC, Lancaster, Pennsylvania, USA.
authors.forename: James
authors.initials: J
authors.lastname: Popp
mesh_terms: D000818:Animals; D006801:Humans; D019055:No-Observed-Adverse-Effect Level; D012107:Research Design; D018570:Risk Assessment / Q000331:legislation & jurisprudence / Q000379:methods / Q000592:standards; D018675:Toxicity Tests / Q000379:methods / Q000592:standards
keywords: NOAEL; adversity; nonclinical; risk assessment; toxicity study