A quality preclinical pathology report will include critical analysis and interpretation of histopathological and toxicological data, providing the foundation for making a decision on how best to proceed with your preclinical research. Prior to study initiation, it is crucial to ensure that the study pathologist is up to the task of delivering an accurate and comprehensive pathology report. Although, often incorporated as an appendix to the final study report, the pathology report should constitute a stand-alone document that is ultimately responsible for characterizing the preclinical safety of your compound or biologic.

A superb preclinical pathology report will adequately address the following 3 points:

Compliance: Bear in mind that the report must stand up to thorough audit and review from knowledgeable pathologists and toxicologists within an applicable regulatory agency. This agency should be named and included in the report itself along with a statement of good laboratory practices (GLP). In some cases, including many proof of concept (POC) studies, adherence with GLP will not be possible and a statement reflecting the non-GLP status of the studies must then be included.

As clearly stated in the Code of Federal Regulations, “For each nonclinical laboratory study subject to the [GLP] regulations under part 58, a statement that the study was conducted in compliance with the [GLP] regulations in part 58, or, if the study was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance” must be included in the final study report (21 CFR 312.23(a)(8)(iii)).

Content: The basic contents of a preclinical pathology report are outlined in the STP guidelines. Briefly, they include:

• Table of contents
• Methods
• Data tables
• Narrative description of findings
• Summary
• References
• Signature of the study pathologist(s)

These items must provide a thorough account of 1) how the study was conducted and 2) any notable observations that were recorded.

1. Description of the study design should include: an account of the test system; animal model; control and experimental agents; dose levels; detailed product administration procedures; and all study protocol parameters. Although the prospective study protocol will give clear directives for intended study conduct, it is not infrequent that deviations and amendments to the protocol are made by the test facility throughout the course of the study. These changes must be verified against the raw data to ensure that they are accurate and reflect the final study methods employed.
2. Data tables should reflect all parameters studied and should include both individual animal data and summary tables. The narrative description needs to detail treatment-related findings (and their significance) but also clear justifications for why any specific observations were deemed not related to treatment or not biologically/pathologically relevant. Whenever possible, an integrated analysis and interpretation of the study findings including: mechanism; physiologic and pathologic relationships; and macroscopic-microscopic correlations should be included in the narrative description. Images included as appendices to the study report will augment detailed descriptions of study findings.

Additional GLP-relevant documentation including quality assurance and compliance statements (described above) should also be included in the completed pathology report.

Conclusion: The preclinical pathology report should provide the study director and sponsor’s representative with a concise description of the remarkable (or sometimes unremarkable) study outcomes that were observed microscopically. In addition to discussion of the various macroscopic and microscopic results, the report should also contain a solid conclusion statement, which clearly identifies major pathological findings and includes a risk assessment. This conclusion by the study pathologist will be the basis for making decisions about additional preclinical and clinical studies moving forward. It is therefore essential that the conclusion statement clearly conveys the study pathologist’s interpretation of observed findings and that no misinterpretations are possible. Moreover, the conclusion statement should overtly tie the protocol’s study objective to the summarized histopathology results. The clarity with which the pathologist’s expert interpretation is presented is of the utmost importance. Any ambiguity can lead to misinterpretation of results, which will cost time and money.

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Remember: the quality of and diligence with which the preclinical pathology report is written is a direct reflection of the level of attention with which the study was conducted and therefore of the quality of your results. Regulatory agencies understand this and will be making judgments about your data based on this vital, stand-alone report. Ensure that your study includes a comprehensive and unambiguous preclinical pathology report.