Principles for Assessing Adversity in Toxicologic Clinical Pathology

Abstract

There is limited direction in the literature or regulatory guidance on determination of adversity for clinical pathology (CP) biomarkers in preclinical safety studies. Toxicologic clinical pathologists representing the American Society for Veterinary Clinical Pathology-Regulatory Affairs Committee and Society of Toxicologic Pathology-Clinical Pathology Interest Group identified principles, overall approach, and unique considerations for assessing adversity in CP data interpretation to provide a consensus opinion. Emphasized is the need for pathophysiologic context and a weight-of-evidence approach. Most CP biomarkers do not have the potential to be adverse in isolation, regardless of magnitude of change. Rather, they quantify or describe the impact of effects, provide adjunct or supportive information regarding a process or pathogenesis, and provide translational biomarkers of effect. Most often, CP changes are part of a constellation of findings that collectively are adverse. Thus, most CP changes must be interpreted in conjunction with other study findings and require contextual and integrative interpretation. Exceptions include critical CP changes without correlates that indicate a health risk in the tested species. Overall, CP changes should not be interpreted in isolation and their adversity is best addressed with an integrated approach.

Interpretative considerations for clinical pathology findings in nonclinical toxicology studies

“…For a complete review of concepts related to the determination of adversity of clinical pathology findings in nonclinical toxicology studies, readers are referred to the following publications . This section briefly covers some key concepts as related to adversity and the reporting of clinical pathology effects.…”

“…It is preferable to address adversity in the context of the overall effect on an organ or organ system that is deemed to be adverse (at a particular test article dose) using a weight‐of‐evidence approach . In this context, designating individual clinical pathology test results in an itemized fashion as adverse or nonadverse is not advised and is often not even possible.…”

Overview and considerations for the reporting of clinical pathology interpretations in nonclinical toxicology studies

“…For a complete review of concepts related to the determination of adversity of clinical pathology findings in nonclinical toxicology studies, readers are referred to a recent review of this topic . This section briefly covers some key concepts as related to adversity and reporting of clinical pathology.…”

“…Contemporary concepts of adversity indicate that an adverse effect is not limited to a specific clinical pathology value, or microscopic change, but is an overall effect of a test article on an organ or organ system that is deemed to be adverse using a weight‐of‐evidence approach . Therefore, in most cases, the adversity of clinical pathology findings is best addressed as part of a constellation of findings that are collectively deemed adverse at a given dose.…”

“…For clinical pathology reports, it is usually not appropriate to discuss individual findings as adverse or nonadverse in isolation, or in an “itemized” fashion, as most clinical pathology changes are not adverse in and of themselves . Exceptions to this include effects such as severe decreases in platelet count or glucose concentration, for example.…”