Principles for Assessing Adversity in Toxicologic Clinical Pathology.

Area of Science:

• Toxicology
• Biomarker Discovery
• Preclinical Safety Assessment

Background:

• Limited regulatory guidance exists for determining biomarker adversity in preclinical safety studies.
• Clinical pathology (CP) biomarkers are crucial but often lack clear interpretation frameworks for adverse effects.
• Existing literature offers insufficient direction on assessing the significance of CP biomarker changes.

Purpose of the Study:

• To establish a consensus opinion on the principles and approach for assessing adversity of clinical pathology biomarkers in preclinical safety studies.
• To provide guidance for toxicologic pathologists on interpreting CP data within a regulatory context.
• To address the need for a standardized method for evaluating the adverse potential of CP biomarkers.

Main Methods:

• A consensus-building process involving experts from the American Society for Veterinary Clinical Pathology-Regulatory Affairs Committee and the Society of Toxicologic Pathology-Clinical Pathology Interest Group.
• Identification and discussion of key principles, overall approaches, and unique considerations for CP data interpretation.
• Emphasis on pathophysiologic context and a weight-of-evidence approach for assessing biomarker adversity.

Main Results:

• Most clinical pathology biomarkers are not considered adverse in isolation, irrespective of the magnitude of change.
• CP biomarkers often quantify effects, support pathogenetic understanding, and serve as translational biomarkers.
• Adversity is typically determined by a constellation of findings, requiring integrative interpretation with other study data.

Conclusions:

• Clinical pathology biomarker changes should not be interpreted in isolation; contextual and integrative interpretation is essential.
• A weight-of-evidence approach, considering pathophysiologic context, is critical for assessing biomarker adversity.
• Exceptions exist for critical CP changes lacking correlates that signify a health risk in the tested species.