The article addresses the key points related to the pathology peer review for a specific type of nonclinical investigation.

The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to pathology peer review in nonclinical toxicology studies. The guidance is structured as a questions-and-answers document and provides answers to the most important questions raised by the industry. It is also important to mention that FDA guidance documents are non-binding in their legal nature, nor are intended to introduce new rules or impose new obligations, but rather to provide additional clarifications with respect to the existing regulatory requirements, as well as recommendations to be followed in order to ensure compliance thereto. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the existing legislation and has been agreed with the authority in advance. The document represents the current thinking of the authority and, consequently, could be subject to changes, should such changes be reasonably necessary to reflect corresponding amendments to the underlying regulations.

Regulatory Background

As it is stated by the authority, the document is intended to provide information to sponsors, applicants, and nonclinical laboratory personnel regarding the management and conduct of histopathology peer review as part of nonclinical toxicology studies conducted in compliance with Good Laboratory Practice (GLP) regulations. The authority further emphasizes the importance of ensuring that the pathology peer review is duly documented. At the same time, provisions of the existing legislation do not clearly define the requirements for such documentation, so the actual practices followed by various testing facilities could differ significantly. The purpose of the present document is to provide recommendations developed by the authority, ensuring the unified approach is followed. As it was already mentioned before, provisions of the guidance are merely descriptive in their nature, so the implementation of the approach described in the document will not result in additional regulatory burdens for the parties involved.

According to the guidance, histopathological assessment constitutes the most important component of some in vivo nonclinical toxicology studies. The authority further explains that the histopathological assessment includes diagnoses and interoperation by the study pathologist and can also include a subsequent review (referred to as pathology peer review) by another pathologist (peer-review pathologist), or a group of pathologists (peer-review pathologists), or a pathology working group (PWG). As further explained by the authority, such a review could be needed in cases when there are unique or unexpected findings.

The general requirements for histopathology are set forth in 21 CFR part 58 (GLP regulations for Nonclinical Laboratory Studies). The said regulation covers the aspects related to the standard operating procedures to be followed. At the same time, pathology peer review is not something explicitly described in the aforementioned regulations. Nor the regulation addresses the aspects related to casual discussions, opinion exchange, and mentoring among pathologists – these matters are falling outside the scope of the present guidance since they do not constitute pathology peer review.

The authority acknowledges the importance of the efficient interactions between the party responsible for a medical device (study sponsor or applicant for marketing approval) and study personnel in the course of a nonclinical toxicology study conducted under GPL. In this respect, the FDA states that sponsors or applicants and persons performing study-related activities should have processes in place to ensure that the studies are transparent and free from undue influence that could impact the conclusions of the studies, including during contemporaneous (prospective) and retrospective pathology peer review. 


Pathology Peer Review: Key Points

First of all, the authority describes the concept of a pathology peer review. The document defines it as the process by which the diagnoses and interpretations of the pathologist assigned to a study (study pathologist) are subjected to review by one or more peer-review pathologist(s) or a PWG. As explained by the FDA, the said review is important for ensuring the accuracy of the diagnoses and interpretations, as well as their proper quality.

The document further outlines the requirements for a peer-review pathologist. According to the guidance, they include the appropriate education, training, and also experience necessary to provide opinions with respect to the histological description. It is also stated that the experience with the appropriate route of administration and contact type will be beneficial, as well as the knowledge of the mechanism of action of the test article.


As explained by the authority, the review described herein can take place either before finalization or after the finalization of the pathologist’s report. The one taking place before the finalization of the said report will be considered a “contemporaneous peer review”. In such a case, the study pathologist should prepare a written narrative that describes the diagnoses and interpretations of available slides before the contemporaneous peer review occurs. 

Should the pathology peer review take place after the finalization of the appropriate report, it will be considered a retrospective peer review – in such a case, any changes to the diagnoses and interpretations resulting from the retrospective peer-review process should be duly documented. Furthermore, this will require a study report to be amended accordingly in order to reflect the said changes. 

In summary, the present FDA questions-and-answers document provides an overview of the regulatory requirements for pathology peer review in the context of nonclinical toxicology studies. The document highlights the key points to be considered by the study sponsors and provides recommendations to be followed in the course of a study in order to ensure it is properly documented.




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