Pathology Peer Review in
Nonclinical Toxicology
Studies: Questions andAnswers
Guidance for Industry
DRAFT GUIDANCEThis guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit writtencomments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
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For questions regarding this draft document, contact (CDER) Office of Study Integrity and
Surveillance at CDER-OSIS-GLP@fda.hhs.gov or 240-402-6002, (CBER) Office ofCommunication, Outreach, and Development at 800-835-4709 or 240-402-8010, (CDRH) Officeof Device Evaluation at 301-796-5550, (CVM) Office of New Animal Drug Evaluation at
CVMONADEPolicyTeam2@cvm.fda.gov, (CFSAN) Office of Center Director at
CFSANBIMO@fda.hhs.gov, (CTP) Small Business Assistance at 1-877-287-1373.
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)
July 2019Pharmacology/Toxicology

Pathology Peer Review in
Nonclinical Toxicology
Studies: Questions andAnswers
Guidance for Industry
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Center for Biologics Evaluation and Research (CBER)
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Center for Veterinary Medicine (CVM)
Center for Food Safety and Applied Nutrition (CFSAN)
Center for Tobacco Products (CTP)

July 2019Pharmacology/Toxicology

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TABLE OF CONTENTSI.

INTRODUCTION............................................................................................................. 1II.

BACKGROUND ............................................................................................................... 1

III.

QUESTIONS AND ANSWERS ....................................................................................... 2

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Pathology Peer Review in Nonclinical Toxicology Studies: Questions
and Answers
Guidance for Industry1
This draft guidance, when finalized, will represent the current thinking of the Food and Drug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 notbinding on FDA or the public. You can use an alternative approach if it satisfies the requirements of theapplicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
for this guidance as listed on the title page.

I.

INTRODUCTION

This guidance provides information to sponsors and nonclinical laboratory staff regarding themanagement and conduct of pathology peer review performed during good laboratory practice(GLP)-compliant toxicology studies. When conducted, pathology peer review should be welldocumented. However, documentation practices during pathology peer review have not beenclearly defined and vary among nonclinical testing facilities. This question-and-answer
document is intended to clarify FDA’s recommendations concerning the management, conduct,and documentation of pathology peer review.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and 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

The histopathological assessment of tissue samples is a key component of GLP-compliant
toxicology studies (referred to as GLP studies). The histopathological assessment includes aninitial read of tissue slides by the study pathologist and may include a subsequent review(referred to as pathology peer review) by a second, or peer-review pathologist. Pathology peer
review can be particularly useful in situations where unique or unexpected findings are noted orwhen the peer-review pathologist has a particular expertise with a class of compounds.

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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 Devices and Radiological Health, Center for Biologics
Evaluation and Research, Center for Veterinary Medicine, Center for Food Safety and Nutrition, and Center for
Tobacco Products at the Food and Drug Administration.

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21 CFR part 58 (GLP regulations) includes general requirements for histopathology evaluation(for example, it requires written standard operating procedures for histopathology). Whilepathology peer review can be valuable when performed during the conduct of a GLP study,
pathology peer review is not specifically addressed in the GLP regulations. This guidance isintended to provide information to sponsors and nonclinical laboratory staff who choose toundertake pathology peer review during the conduct of a GLP study.

III.

QUESTIONS AND ANSWERS

Q1: What constitutes pathology peer review?
A1: Pathology peer review is the process by which the findings of the pathologist assigned to a
study (study pathologist) are subjected to review by another pathologist (peer-review
pathologist) or group of pathologists (peer-review pathologists). Interpretations ofhistopathological changes are made using expert scientific and medical judgment resulting in
output that is mostly qualitative and therefore subjective. Pathology peer review can help toensure the quality and accuracy of histopathological diagnoses and interpretations.
Casual discussions, consultations, opinion exchange, and mentoring among pathologists do notconstitute formal pathology peer review and are not covered by this guidance document.
Q2: Who should conduct a pathology peer review?
A2: The peer-review pathologist should have a combination of appropriate education, training,and experience to be qualified to render opinions on the study pathologist’s histologicaldescriptions. In addition, the peer-review pathologist should have experience with the route ofadministration of the test article, species and strains of animals being tested, and duration anddesign of the study.2 Furthermore, it can also be beneficial for the peer-review pathologist to
have knowledge of the mechanism of action of the test article and knowledge of the results oftest article administration at other dose levels or in other species.3
Q3: When can the pathology peer-review process occur?
A3: A pathology peer review can occur before or after finalization of the study pathologist’sreport (i.e., signed and dated pathology report).
Pathology peer review that occurs before finalization of the study pathologist’s report isconsidered prospective peer review. When pathology peer review occurs prospectively, the study
pathologist should complete the analysis of all slides and prepare a draft pathology report before
the prospective peer review occurs.

2

Morton, D, R Sellers, E Barale-Thomas, B Bolon, C George, JF Hardisty, A Irizarry, J McKay, M Odin, and M
Teranishi, 2010, Recommendations for Pathology Peer Review, Toxicol Pathol, 38(7):1118–1127.
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Boorman, GA, DC Wolf, S Francke-Carroll, and RR Maronpot, 2010, Pathology Peer Review, Toxicol Pathol,38(7):1009–1010.

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Pathology peer review that occurs after finalization of the pathology report is consideredretrospective peer review. When pathology peer review occurs retrospectively, the study
pathologist should document any changes to the conclusions of the study that result from theretrospective peer-review process in an amendment to the final pathology report.
Q4: Can pathology peer review be conducted at a non-GLP‐compliant site for a GLPcompliant study?
A4: Yes, it is possible to conduct a pathology peer review outside of a GLP-compliant site for a
GLP-compliant study provided certain safeguards are in place to protect the integrity of study
data. It is preferable that the peer-review pathologist perform the review at the GLP-compliant
testing facility after receiving the appropriate training on GLP principles and relevant internal
standard operating procedures (SOPs); however, if the peer review is conducted at a non-GLPcompliant site, that fact should be recorded and justified within the study protocol and final study
report. Regardless of where the peer review is conducted, the name, affiliation, and location (i.e.,address) of the peer-review pathologist should be clearly stated in the final study report. Also,
the name, qualifications (including GLP training), affiliations, and address of the peer-review
pathologist should be documented in the study file.
The portions of the study that were not conducted under GLP compliance should be explicitly
stated in a study director-signed GLP compliance statement and included in the final study
report.
Q5: How should the nonclinical laboratory staff document the peer review, and whatshould be included in the peer-review statement?
A5: When pathology peer review is part of a GLP study, the activity should be included in the
study protocol or protocol amendment, and it is important that the peer-review process be well
documented and transparent. The process should be guided by written procedures to establish theextent of the review and ensure the integrity of the study data. Because the study pathologist is
responsible for the overall interpretation of the pathology data, the final pathology report willreflect the study pathologist’s best scientific opinion and judgment regarding the diagnoses andpathological interpretations.
A formal pathology peer review should be planned, conducted, documented, and reported inaccordance with established procedures. These procedures should be documented and available
to the peer-review pathologist before initiation of the peer review and should be clearly describedin the study protocol or study protocol amendments and in SOPs pertaining to the GLP studies.
The peer-review pathologist should generate a signed and dated peer-review statement(document, report, memorandum, or certificate) for inclusion in the permanent study files andfinal 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.
An SOP and GLP study protocol (or protocol amendments) should include a description of thepeer-review procedure, including selected target tissues, the dose groups to be examined, the3

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number of specimens to be examined in each group, and whether the peer review should be
conducted in a blinded fashion. Relevant SOPs can be referenced where appropriate.
The peer-review statement should include the following information:Who performed the peer review

When, where, and under what conditions (i.e., GLP- or non-GLP-compliant) the peer
review was conductedWhat tissues were examined microscopically

A statement on whether the terminology and findings used in the pathology report wereagreed upon by both the study and peer-review pathologist4

For prospective peer review, a statement of whether the draft pathology report was sharedwith the peer-review pathologistPeer-review pathologist’s dated signature

If the peer-review pathologist concurs with the study pathologist’s diagnoses and interpretations,the peer-review statement might not include a comprehensive analysis of the outcome of the peer
review. Under these conditions, a statement that a peer review was conducted and that the final
pathology report reflects the consensus opinions of the study pathologist and peer-review
pathologist would suffice.
Any changes to the overall study interpretations by the study pathologist because of aprospective peer-review process should be documented in the peer-review statement anddiscussed in the final pathology report, as applicable.
Any changes to the interpretations by the study pathologist as a result of a retrospective peerreview process should be documented in an amended final pathology report.
Unresolved differences in interpretation from the final or draft pathology report should be clearly
identified in the peer-review statement. Resolution of any differences should be discussed in the
final pathology report or in an amendment to the final pathology report, and the process ofresolution should be documented (discussed further in Q8 and Q9).
Q6: When should the peer-review statement be signed, and should the peer-review
pathologist sign the pathology report?
A6: The peer-review statement can be signed by the peer-review pathologist before or after the
finalization of the pathology report. The pathology report is the sole responsibility of the study
4Mann, PC, 1996, Pathology Peer Review From the Perspective of an External Peer Review Pathologist, Toxicol
Pathol, 24(5):650–653.

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pathologist, and the peer-review pathologist should not sign the final pathology report. Anychanges made to a final pathology report resulting from a retrospective pathology peer review
should be documented in an amendment to the final pathology 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 as an appendix to the final study
report and should also be included as part of the study file (see Q1).
Q8: How can the Agency be assured that the study pathologist’s interpretive findings are
not unduly influenced during the pathology peer-review process?
A8: As discussed in the preamble to the 1987 GLP final rule, “. . . only the signed and dated final
report of the pathologist comprises raw data respecting the histopathological evaluation of tissue
specimens.”5 The signed and dated pathology report (raw data) is critical in facilitating athorough review of the histopathology data and characterizing the toxicology or toxicologic
potential of a specific investigational product. The pathology report is the responsibility of thestudy pathologist and reflects that individual’s interpretation of the histopathological findings.
Therefore, 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 changes that might result from a pathology peer review.
Such procedures can include the implementation of an audit trail.
The Agency acknowledges that pathology peer review is an iterative process and the draft
pathology report is subject to change until the report is signed and dated by the study pathologist.
The process of conducting pathology peer review involves communication between the study
pathologist, peer-review pathologist, sponsor, testing facility management, study director(s),sponsor-delegated representative, and test site management (if applicable). Records ofcommunications pertinent to the process of slide evaluation and meeting summaries (e.g.,
meeting minutes) relevant to the pathology peer review should be retained in the study file.
Transparency is important to protect the integrity of prospective peer review because the process
occurs during the period of histopathological evaluation―which by its nature is subjective,
iterative, collaborative, and open to influence. To best ensure transparency, documents (e.g.,worksheets, electronic files) that record peer-review events and changes to the study
pathologist’s findings should be retained in the study records. One option to ensure transparency
is to fix or lock the database of pathology findings before the start of the peer-review process toensure that changes to the pathology findings will be recorded in an audit trail.
If the draft pathology report is shared with the peer-review pathologist, this should be reflected in
the peer-review statement. Also, the peer-review statement should clearly identify changes
resulting from the peer-review process that affect the study pathologist’s interpretations.

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Final rule, “Good Laboratory Practice Regulations,” September 4, 1987 (52 FR 33768).

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Q9: How are differences in interpretation between the study pathologist and peer-review
pathologist resolved?
A9: The study pathologist is the individual responsible for the overall analysis and interpretationof the pathology data. If the peer-review pathologist does not concur with the study pathologist’s
interpretations, then changes to the interpretations might be made by the study pathologist toreflect consensus with the peer-review pathologist. The difference in interpretation should be
documented by the peer-review pathologist before engaging in a dialogue to resolve theinterpretative differences. If no resolution can be reached, the study pathologist and peer-review
pathologist should carefully follow a transparent and unbiased process that is clearly describedin the testing facility’s SOPs for resolving interpretative differences during pathology peer
review.
Depending upon the directives of the SOPs, consensus may be achieved through consultation
with additional experienced pathologists. Records of communications pertinent to the process of
slide evaluation and records of meeting summaries (e.g., meeting minutes) relevant to thepathology peer review should be retained in the study file.

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