Pathology Peer Review in 
Nonclinical Toxicology 
Studies: Questions and 
Answers 
 
Guidance for Industry
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER)  
Center for Devices and Radiological Health (CDRH)  
Center for Veterinary Medicine (CVM) 
Center for Food Safety and Applied Nutrition (CFSAN)  
Center for Tobacco Products (CTP) 
Office of Regulatory Affairs (ORA) 
 
December 2021 
Pharmacology/Toxicology 
 
    
Pathology Peer Review in 
Nonclinical Toxicology 
Studies: Questions and 
Answers 
Guidance for Industry 
 
 
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U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER)  
Center for Devices and Radiological Health (CDRH)  
Center for Veterinary Medicine (CVM) 
Center for Food Safety and Applied Nutrition (CFSAN)  
Center for Tobacco Products (CTP) 
Office of Regulatory Affairs (ORA) 
 
 
 December 2021 
Pharmacology/Toxicology 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  QUESTIONS AND ANSWERS ....................................................................................... 2 
i  Contains Nonbinding Recommendations 
 
Pathology Peer Review in Nonclinical Toxicology Studies: Questions 
and Answers 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can 
use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To 
discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title 
page.  
 
 
 
 
I.  INTRODUCTION  
 
This guidance provides 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. 
When conducted, pathology peer review should be well-documented. However, documentation 
practices during pathology peer review have not been clearly defined and vary among nonclinical 
testing facilities. This question-and-answer document is intended to clarify FDAs 
recommendations concerning the management, conduct, and documentation of pathology peer 
review.  
 
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract. This document is intended 
only to provide clarity to the public regarding existing requirements under the law. FDA 
guidance documents, including this guidance, should be viewed only as recommendations, unless 
specific regulatory or statutory requirements are cited. The use of the word should in Agency 
guidances means that something is suggested or recommended, but not required.  
 
 
II.  BACKGROUND 
 
Histopathological assessment is a key component of some in vivo nonclinical toxicology studies. 
The histopathological assessment includes diagnoses and interpretations by the study pathologist 
and can also include a subsequent review (referred to as pathology peer review) by another 
pathologist (peer-review pathologist), or group of pathologists (peer-review pathologists), or a 
pathology working group (PWG). Pathology peer review can be particularly useful, for example, 
 
1 This guidance has been prepared by the Office of Study Integrity and Surveillance in the Center for Drug 
Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research, Center for Devices 
and Radiological Health, Center for Veterinary Medicine, Center for Food Safety and Applied Nutrition, Center for 
Tobacco Products, and the Office of Regulatory Affairs at the Food and Drug Administration.  
  1  Contains Nonbinding Recommendations 
 
in situations where unique or unexpected findings are noted or when the peer-review pathologist 
has a particular expertise relevant to the study. 
 
21 CFR part 58 (GLP regulations for Nonclinical Laboratory Studies) includes general 
requirements for histopathology (for example, it requires written standard operating procedures 
(SOPs) for histopathology); however, pathology peer review is not specifically addressed in the 
GLP regulations. This guidance is intended to provide information to sponsors, applicants, and 
nonclinical laboratory personnel who choose to undertake pathology peer review during the 
conduct of a nonclinical toxicology study under GLP (referred to as a GLP toxicology study). 
Casual discussions, opinion exchange, and mentoring among pathologists are not covered by this 
guidance document.  
 
FDA acknowledges the need for interactions between the sponsor or applicant and study 
personnel during the conduct of a nonclinical toxicology study under GLP. Sponsors or 
applicants and persons2 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)3 and retrospective 
pathology peer review. 
 
 
III.  QUESTIONS AND ANSWERS 
 
Q1: What constitutes pathology peer review? 
 
A1: Pathology peer review is 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. Pathology peer review can help to ensure the quality and 
accuracy of histopathological diagnoses and interpretations. 
 
Casual discussions, opinion exchange, and mentoring among pathologists do not constitute 
pathology peer review and are not covered by this guidance document.  
 
Q2: Who should conduct a pathology peer review? 
 
A2: A peer-review pathologist should have a combination of appropriate education, training, and 
experience to be qualified to render opinions on the study pathologists histological descriptions. 
It can be beneficial for a peer-review pathologist to have experience with the route of 
administration, contact type and duration of the test article, species and strains of animals being 
tested, and duration and design of the study. It can also be beneficial for a peer-review 
pathologist to have knowledge of the mechanism of action of the test article and knowledge of 
the results of test article administration at other dose levels or in other species.  
 
 
2 Under 21 CFR 10.3 the term person includes an individual, partnership, corporation, association, scientific or 
academic establishment, government agency, or organizational unit thereof, and any other legal entity. 
3 In the context of pathology peer review the terms contemporaneous and prospective can be used 
interchangeably. The term contemporaneous will be used in this guidance. 
  2  Contains Nonbinding Recommendations 
 
Q3: When can pathology peer review occur? 
 
A3: Pathology peer review can occur before finalization (contemporaneous) or after finalization 
(retrospective) of the study pathologists report (i.e., signed and dated pathology report). 
Pathology peer review that occurs before finalization of the study pathologists report is 
considered contemporaneous peer review. When pathology peer review occurs before the 
finalization of the study pathologists report, the study pathologist should prepare a written 
narrative that describes the diagnoses and interpretations of available slides before the 
contemporaneous peer review occurs. 
 
Pathology peer review that occurs after finalization of the pathology report is considered 
retrospective peer review. When pathology peer review occurs retrospectively, 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. When pathology 
peer review occurs after the final study report is signed, the study director should amend the final 
study report as necessary to reflect changes in histopathology diagnoses and interpretations. 
 
Q4: How should pathology peer review be documented, and what should be included in the 
peer-review statement? 
 
A4: It is important that the peer-review process be well documented and transparent. When 
either a contemporaneous or a retrospective pathology peer review is part of a GLP toxicology 
study, the activity should be included in the study protocol or protocol amendment. The process 
should be guided by written procedures to establish the extent of the review and ensure the 
integrity of the study. Because the study pathologist is responsible for the overall pathology data, 
the pathology report will reflect the study pathologists best scientific opinion and judgment 
regarding the diagnoses and pathological interpretations. 
 
Pathology peer review should be planned, conducted, documented, and reported in accordance 
with established written procedures. These written procedures should be available to the peer-
review pathologist(s) prior to the initiation of peer review as SOPs, or in the study protocol or 
study-protocol amendment.  
 
The peer-review pathologist(s) should generate a signed and dated peer-review statement 
(document, report, memorandum, or certificate) for inclusion in the final study report. All peer-
review pathologists signature blocks (identity and affiliation) should be included in the peer-
review statement that is contained in the final study report. 
 
The peer-review statement should be signed and dated by the peer-review pathologist(s) and 
include the following information: 
  Who performed the peer-review and the date(s) it was performed 
  Whether the peer-review was performed contemporaneously or retrospectively 
  Whether the peer-review was conducted in compliance with GLP regulations 
  What tissues were examined microscopically, corresponding animal identification 
number, dose/treatment group, and the basis for their selection 
  What format (e.g., glass slides or whole slide images) was used 
  3  Contains Nonbinding Recommendations 
 
  Whether the terminology, diagnoses, and interpretations used in the pathology report 
were agreed upon by both the study and peer-review pathologist(s)  
  Whether a narrative report prepared by the study pathologist was reviewed either 
prior to or during peer review (for contemporaneous review only) 
  What data and documents were utilized during the peer review (a listing) 
 
If the peer-review pathologist concurs with the diagnoses and interpretations of the study 
pathologist, the peer-review statement might not include a comprehensive analysis of the 
outcome of the peer review. Under these conditions, sponsors or applicants can submit a 
statement explaining that a peer review was conducted, and the final pathology report reflects the 
consensus opinions of the study pathologist and peer-review pathologist(s). If no resolution of 
differences in diagnoses and interpretations can be reached during pathology peer review, the 
study pathologist and peer-review pathologist should carefully follow a transparent and unbiased 
process that is clearly described in written procedures (i.e., SOPs, study protocol, or study 
protocol amendment) for addressing diagnostic and interpretative differences during pathology 
peer review (as discussed further in Q9). 
 
Any changes to the diagnoses and interpretations by the study pathologist as a result of a 
contemporaneous peer review do not need to be documented in the study pathology report, as 
contemporaneous peer review is considered part of the iterative diagnostic pathology process. 
Any changes to the diagnoses and interpretations by the study pathologist as a result of a 
retrospective peer-review should be documented in the peer-review statement and in an 
amendment to the study pathologists report. 
 
Q5: Can pathology peer review for a GLP toxicology study be conducted at a site that does 
not have an established quality system that complies with GLP regulations? 
 
A5: Yes, it is possible to conduct the pathology peer review for a GLP toxicology study at a site 
that does not have an established quality system that complies with GLP regulations provided the 
integrity of the study is protected. It is preferable that the peer-review pathologist(s) perform the 
peer review under a GLP-compliant quality system after receiving training on GLP regulations 
and relevant SOPs. If the pathology peer review is not conducted under a GLP-compliant quality 
system, that fact should be recorded within the study protocol and final study report. The name, 
affiliation, and work address of the peer-review pathologist(s) should be included in the final 
study report. Also, the name, qualifications (including GLP training), affiliations, and work 
address of the peer-review pathologist(s) should be documented in the peer-review pathologists 
training files and retained at the testing facility. 
 
Q6: When should the peer-review statement be signed, and should the peer-review 
pathologist sign the pathology report? 
 
A6: The peer-review statement for a contemporaneous review can be signed by the peer-review 
pathologist before or after the study pathologists report is signed. The peer-review statement for 
a retrospective review is by definition signed by the peer-review pathologist(s) after the study 
pathologist report is signed. The pathology report is the sole responsibility of the study 
pathologist, and the peer-review pathologist(s) should not sign the final pathology report. Any 
  4  Contains Nonbinding Recommendations 
 
changes to a study pathologists report resulting from a retrospective pathology peer-review 
should be documented in an amendment to the study pathologists report. 
 
Q7: Should the signed peer-review statement be included in the final study report? 
 
A7: Yes, the signed peer-review statement should be included in the final study report. 
 
Q8: How can the Agency be assured that the study pathologists diagnoses and 
interpretations are free from undue influence during the pathology peer-review process? 
 
A8: The pathology report is the responsibility of the study pathologist and reflects that 
individuals diagnoses and interpretations. The signed and dated pathology report (raw data)4 is 
critical in facilitating a thorough review of the toxicologic potential of a specific investigational 
product.  
 
Testing facility management should implement appropriate measures to ensure that the conduct 
of all phases of GLP toxicology studies, including the generation of the pathology report, is free 
from undue influence impacting the conclusions of the studies. Regarding pathology peer review, 
the independence of both the study pathologist and the peer-review pathologist(s) throughout the 
process should be ensured by both the management of the nonclinical testing facility and the 
sponsor or the applicant. Measures to ensure transparency can include, among other options, the 
implementation of an audit trail, or conducting contemporaneous peer review after the study 
pathologists diagnoses are fixed or locked in an electronic system.  
 
Diverging diagnoses, interpretations, or conclusions between the study pathologist and peer-
review pathologist(s) should be addressed using a transparent and unbiased process that is clearly 
described in written procedures (see Q9).  
 
Q9: How are differences in interpretation that result from pathology peer review 
addressed? 
 
A9: If no resolution of differences in diagnoses and interpretations can be reached during 
pathology peer review, the study pathologist and peer-review pathologist should carefully follow 
a transparent and unbiased process that is clearly described in written procedures (i.e., SOPs, 
study protocol, or study protocol amendment) for addressing diagnostic and interpretative 
differences during pathology peer review. 
 
Depending upon the directives of the written procedures, consensus could be achieved through 
consultation with additional experienced pathologists (e.g., PWG). Records of communications 
pertinent to differences of opinion relevant to the pathology peer review, including but not 
limited to records of meetings (e.g., meeting minutes), should be retained in the study file. 
Adherence to written procedures should be documented. Consensus diagnoses and 
interpretations should be documented in a report (e.g., PWG report) separate from the study 
pathologists report and should be appended to the final study report. 
 
4 The final rule, Good Laboratory Practice Regulations, published September 4, 1987 (21 CFR Part 58). 
 
  5