Thank you for joining us for another episode of the Guidance Recap Podcast. My name is Kylie Haskins, and I am today’s host. In this episode, I am excited to be talking with Dr. Lynda Lanning, a toxicologic pathologist in CDER’s Office of Study Integrity and Surveillance. Dr. Lanning will be sharing some thoughts with us on the newly published final guidance titled, “Pathology Peer Review in Nonclinical Toxicology Studies: Questions and Answers.” Welcome, Dr. Lanning! Thank you for speaking with us today.

Can you provide a description of pathology peer review for listeners less familiar with this area?

Sure, I’d be happy to. First, I should take a step back and explain that nonclinical toxicology studies are designed to evaluate potential toxicities and adverse effects of a compound on a model system to assess possible side effects that could occur in humans. These studies almost always include a histopathological assessment of tissue slides by a study pathologist. Pathology peer review is a formally documented, subsequent histopathological assessment of the tissue slides performed by a second pathologist referred to as the peer-review pathologist. Pathology peer review is not required or even mentioned in Good Laboratory Practice regulations (also called GLP regulations), but it can be helpful when unusual or unexpected results are found or when a peer-review pathologist has a specific expertise with a class of compounds. Pathology peer review can be requested by the testing facility, sponsor, or other entity for a variety of reasons by following established procedures and can help to ensure the quality and accuracy of histopathological diagnoses and interpretations. It is a formal, documented process that is conducted according to the study protocol or protocol amendment (for GLP studies), as well as the Testing Facility’s standard operating procedures. Casual discussions, opinion exchange, and mentoring among pathologists does not constitute pathology peer review.

What are some of the reasons that the FDA issued this Guidance?

FDA issued this guidance to define what constitutes pathology peer review and communicate the Agency’s expectations about conducting and documenting the process. As I previously mentioned, pathology peer review is not included in GLP regulations, and prior to this guidance, the FDA had not provided expectations to industry for conducting and documenting the process. As a result, the pathology peer review process was not performed in a consistent manner across industry, and sufficient documentation was not always available to describe how the pathology peer review was performed and also provide transparency to ensure that the study pathologist’s interpretive findings were not unduly influenced. In this guidance, FDA is providing industry with best practices for performing and documenting pathology peer review. As stated in the guidance, pathology peer review should be planned, conducted, documented, and reported in accordance with established procedures that are documented and available to the peer-review pathologist before initiation of the peer review. The peer-review pathologist should generate a signed and dated peer-review statement for inclusion in the permanent study files and the final study report. The testing facility management should implement appropriate measures to ensure independence of the study pathologist and enforce procedures to track all changes to a study pathologist’s interpretations, including an audit trail, when appropriate.

This guidance is being issued by seven FDA centers and the Office of Regulatory Affairs. Are the expectations for pathology peer review consistent across the Agency?

The expectations for performing pathology peer review and submitting documentation to the FDA, as described in this guidance, are consistent across the agency. Each center regulates different products, and aspects of nonclinical toxicology studies, including the pathology requirements, can vary for each product to best evaluate the potential toxicities and adverse effects. For example, a nonclinical toxicology study testing an orally administered drug vs a nonclinical toxicology study testing an injectable vaccine would have different testing criteria and pathology requirements tailored to the product’s specific characteristics, including route of administration; pharmacokinetics; known toxicological risks; and the product’s absorption, distribution, metabolism, and excretion (collectively known as ADME). While the testing criteria and pathology components might differ for the products in this example, FDA’s expectations for performing and documenting pathology peer review remain the same.

When can pathology peer review occur?

Pathology peer review can occur before or after finalization of the study pathologist’s report. Pathology peer review that occurs before finalization of the study pathologist’s report is considered contemporaneous peer review. Pathology peer review that occurs after finalization of the study pathologist’s report is considered retrospective peer review. Many factors determine the timing of pathology peer review. Some contract research organizations have contemporaneous pathology peer review included in their study design. This can be particularly helpful in identifying diagnostic drift, which occurs when a study pathologist over time interprets the severity of a finding, for example, to be greater/lesser than previous slides with the same characteristics. Retrospective pathology peer review can also be a standard business process, but more often, it occurs on a case by case basis. There is no time limit on performing a retrospective pathology peer review. When pathology peer review occurs before the finalization of the study pathologist’s report, the study pathologist should prepare a written narrative that describes the diagnoses and interpretations of available slides before the contemporaneous peer review occurs. When pathology peer review occurs after finalization of the study report, the study pathologist should document any changes to the diagnoses and interpretations that result from the retrospective peer review process in an amendment to the pathology report, and the study director should amend the final study report as necessary to reflect changes in histopathology diagnoses and interpretations.

How are interpretive differences between the study pathologist and peer review pathologist(s) resolved?

First, the study pathologist and peer-review pathologist should have collegial discussions and try to resolve the differences. If no resolution can be reached, a formal study procedure should be followed and documented. Procedures for resolution of differences can be described in a standard operating procedure, study protocol, or study protocol amendment. The procedure will provide directions for conducting a transparent and unbiased process. One common method is to consult with additional experienced pathologists. Regardless of the process followed, this guidance focuses on how a laboratory can ensure transparency through detailed documentation. Records of all communications should be included in the study file, and the consensus findings should be documented in a report separate from the study pathologist’s report and should be appended to the final study report.

For our final question, are there a couple of key items from the guidance that you especially want listeners to remember?

Yes, I’d like listeners to know that there is flexibility around the timing for pathology peer review, as it can occur before or after finalization of the pathology report. Pathology peer review that occurs before finalization of the study pathology report is considered contemporaneous. Pathology peer review that occurs after finalization of the pathology report is considered retrospective. FDA accepts both, and the documentation provided should provide a detailed description of peer-review process, including the timing.

This leads me to my second item; it is important that the peer-review process is well documented and transparent. The pathology peer-review process should be planned, conducted, documented, and reported in accordance with established, written study procedures. The peer-review pathologist should generate a signed and dated peer-review statement for inclusion in the final study report. The peer-review statement might be referred to as a peer review document, report, memorandum, or certificate. All peer-review pathologists’ signature blocks (including identity and affiliation) should be included in the peer-review statement that is contained in the final study report. Documentation for pathology peer review was previously highly variable, and a major reason that FDA issued this guidance is to provide best practices that support consistency.

My last key item is that the peer-review process should be transparent and free from undue influence. Pathology peer review is intended to ensure the quality and accuracy of histopathological findings and should not bias the results. Facilities should have processes in place to ensure that peer-review process is transparent, independent, and free from undue influence that could impact the conclusions of the studies.

Dr. Lanning, thank you for speaking with us today about the final guidance on pathology peer review in nonclinical toxicology studies. We have learned so much from your informative discussion on the document. We would also like to thank the guidance working group for writing and publishing this final guidance.

To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the guidance.