Scientific and Regulatory Policy Committee Points to Consider: Review of the United States Food and Drug Administration (FDA) Guidance on Pathology Peer Review in Nonclinical Toxicology Studies

Review of the FDA Guidance

This review is structured in sections that correlate with the contents and questions posed and answered in the FDA Guidance for Industry titled Pathology Peer Review in Nonclinical Toxicology Studies: Questions and Answers. The language used directly in the FDA guidance, including the questions posed and answered, is included below in italic font and is followed by commentary or discussion by the STP working group, occasionally indicated with square bullets or numbered lists. Comparative aspects of content between the FDA and Organisation for Economic Co-operation and Development (OECD) documents are presented and discussed when relevant. For the purposes of this discussion on pathology peer review, references to microscopic evaluation of tissue slides applies equally to both glass slides and whole slide images (WSIs).

Casual discussions, opinion exchange, and mentoring among pathologists do not constitute pathology peer review and are not covered by this guidance document.

STP working group response: We concur. Although generally not required in global GLP regulations, the practice of pathology peer review serves as an important protocol-driven data quality exercise to increase confidence in the accuracy of the pathology diagnoses and their interpretations.^5,6 The evaluation and diagnosis of microscopic changes and interpretation of these changes during pathology peer review is a collaborative exercise between the study pathologist and the peer review pathologist(s), and the discussions are intended to arrive at a consensus based on available information. The pathology content for review is generally detailed in an institutional Standard Operating Procedure (SOP) and/or study protocol. As acknowledged directly in the guidance document, casual discussions, opinion exchange, and mentoring among pathology colleagues, including possibly between the study and peer review pathologist(s), may take place during the study pathologist’s evaluation of study materials (including tissue slides) and interpretation (including written narrative) prior to the completion of the protocol-directed pathology peer review.

In the industry setting, a peer review conducted by PWG is uncommon but is one mechanism to resolve irreconcilable difference(s) between the study pathologist and peer review pathologist(s). This concept is addressed further in the comments under Question/Answer 9 below.

STP working group response: We concur. A pathology peer review should be conducted by a pathologist(s) with appropriate training and experience, ⁶ and the peer review pathologist(s) should be clearly identified in the study protocol and may be affiliated with the test facility, sponsoring institution, or a third party.

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.

STP working group response: We concur with the concepts described regarding the use and conduct of retrospective pathology peer review. For a contemporaneous peer review, the FDA guidance states that the study pathologist should prepare a written narrative that describes the diagnoses and interpretations of available tissue slides before the contemporaneous peer review occurs. This could be fulfilled via various written formats ranging from a simple concise e-mail summary to a draft pathology report, including key diagnostic information (e.g., individual animal tabular findings) and interpretation. This recommendation is already typically implemented in many toxicology studies as the draft pathology report is provided at the time of the contemporaneous peer review. However, there are various scenarios in which this is not feasible, including carcinogenicity studies when statistical analysis is not complete, studies in which one sex is evaluated at a time, or studies that are otherwise partitioned for evaluation. Therefore, it is acceptable for the peer review of microscopic findings (i.e., tissue slide or WSI evaluation) to initiate before a written narrative is available. This allows the study and peer review pathologist(s) to align on terminology, diagnoses and study findings even when a written narrative is not yet available. In cases where the peer review pathologist starts the review prior to the availability of a draft written narrative, it is imperative that the draft narrative be reviewed by the peer review pathologist(s) prior to completion of the peer review.

There are also additional important aspects of study evaluation that may be discussed or communicated during the peer review. These aspects may include:

It is also important to remember that informal discussions between the study pathologist and peer review pathologist(s) may take place during the study pathologist’s evaluation of study materials before initiation of the protocol-directed pathology peer review.

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:

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 pathologist’s report.

The STP working group agrees with all the concepts in the guidance document answer to this question, including inclusion of the pathology peer review statement in the final toxicology study report. Regarding the specific line-item information that is recommended to be included in the peer review statement (i.e., the bulleted list of informational items included above in Answer 4), we agree that including this information provides additional clarity and improves consistency of practices. Additional detail is provided for each of these points below.

STP working group response: We concur that the peer review statement should identify who performed the peer review. The date(s) it was performed can be interpreted differently by individual institutions. Some institutions may consider peer review date(s) to only indicate the dates that tissue slides were reviewed, but more generally the peer review dates are considered to include the date(s) during which there was a review of any pathology data, tissue slides, and draft pathology report. The definition of dates of performance of the pathology peer review can either be included in the relevant institutional SOP(s), or the meaning of the peer review date(s) clearly detailed in the peer review statement. Acceptable approaches may include, for example, the start date being the first day that the peer review pathologist starts reviewing any study-related pathology data (e.g., macroscopic and organ weight data, histology records, and tissue slides) or ancillary data (e.g., clinical observations, clinical pathology tables, TK, or anti-drug antibodies [ADAs] data), or the date that the peer review pathologist starts reviewing tissue slides. The date for the end of the peer review may include, for example, the last date of reviewing tissue slides, the date the draft peer review statement is submitted following verbal agreement on diagnoses and draft report interpretations, or the date at which the peer review pathologist signs the peer review statement indicating agreement with the finalized pathology report.

STP working group response: We concur.

STP working group response: This guidance requirement suggests a Yes or No answer to this question and should be addressed in the peer review statement. This can only be answered by the organization responsible for the individual conducting the peer review; each organization will determine whether the peer review processes they follow are GLP compliant. There are certain key elements that make the peer review GLP compliant, which include:

Audit of the peer review statement by a quality assurance (QA) group is not required for GLP compliance (see additional discussion on GLP compliance under Question/Answer 5 below).

STP working group response: The basis for preselection of specific animals to be reviewed in entirety should be determined by the SOP being followed by the peer review pathologist(s). An acceptable basis for animal or tissue selection can therefore simply be in accordance with the institutional SOP. If other methods of animal or tissue selection were used, then the method of selection in study documentation (e.g., directed peer review by protocol or protocol amendment, etc.) should be detailed.

The pathology peer review process should allow for flexibility, such as the evaluation of additional slides and other study data, to ensure that all potential target tissues are thoroughly evaluated and all compound-related findings (expected or unexpected) are properly identified, including concurrence regarding the dose levels affected. In essence, the peer review pathologist needs to have the latitude to be able to increase the scope of the review as the peer review unfolds to fulfill these objectives. ³

STP working group response: We concur. Including the format used is necessary due to the increasing use of WSIs in lieu of glass slides for peer review and is consistent with the STP position paper on use of WSIs for primary evaluation and peer review. ⁴

STP working group response: We concur. The single overriding principle of the pathology peer review process is that it should facilitate “direct interaction between the original and the reviewing pathologists” to produce agreement regarding the nature and interpretation of the pathology data and the final pathology report. ⁶

The terminology, diagnoses, and interpretations of the study pathologist are provided in the final pathology report. By signing the pathology report, the study pathologist affirms the terminology, diagnoses, and interpretations in the final pathology report. The peer review pathologist demonstrates their agreement by signing a pathology peer review statement. When the peer review pathologist issues a statement of agreement about terminology, diagnoses, and interpretations, it should be based on the contents in the final pathology report, which is considered the raw data. If, however, there are substantive areas of disagreement that impact the overall interpretation of the study that have not been resolved by other means (see Question/Answer 9 below), these should be detailed in the peer review statement.

STP working-group response: In most instances, this will occur during the pathology peer review. Review of any study-related material typically indicates that the peer review has been initiated and is ongoing, and therefore, narrative review occurs during the peer review. However, review of a draft written narrative may be prior to, or occasionally after, review of the tissue slides has begun, which is one component of the overall peer review process. Best practice includes that the peer review pathologist(s) review the most complete version of the final pathology report during peer review conduct, assuming this is consistent with institutional SOPs, and includes documentation of this in their peer review statement.

STP working group response: We concur. As noted above, during a pathology peer review, study materials beyond the tissue slides are reviewed, often including macroscopic data, organ weights, key diagnostic information (e.g., individual animal tabular findings) and draft written narratives, and this is generally detailed in the institutional pathology peer review SOP(s), allowing for flexibility in review of additional materials, where relevant. ³ Additional ancillary data (e.g., clinical observations, clinical pathology data, TK, ADA) may also contribute to supporting the overall interpretations and conclusions of the pathology evaluation. Particularly, in instances where ancillary data were critical to the overall pathology conclusions and is not overtly listed in the institutional SOPs or included in the pathology report, it should be documented in the peer review statement.

STP working group response: We concur. It is noteworthy that these recommendations are in principle in line with expectations formulated in the Guidance on the GLP Requirements for Peer Review of Histopathology (Number 16), issued 2014 by the OECD. ⁷ However, given the subtle differences in practices and definition between regulatory authorities in the United States (FDA), and other national regulatory authorities’ country regulations requiring full OECD principles’ compliance, certain test facilities are confronted with varying expectations on the conditions to be fulfilled to claim GLP compliance for a peer review. In Europe (under OECD, see below), the location of a peer review needs to be GLP certified by a national authority to fulfill requirements for claiming GLP compliance, in addition to the key elements stated above under Question/Answer 4. ^{7 (p10)} A lack of that certification ultimately results in the peer review process not being in compliance with the OECD GLP framework. However, assuming other key elements are fulfilled, and the study director is satisfied that the peer review process is well managed, a pathology peer review under these non-GLP conditions is fully acceptable.^3,7(p10)

The OECD GLP Working Party assists countries in harmonizing GLP; it is not a regulatory agency, and does not conduct inspections or verify GLP compliance of studies. OECD GLP Principles are a harmonized international standard agreed to by OECD member countries and have no legal status unless adopted as regulation by a national government. The European Union (EU) requires member countries to adopt OECD principles; other countries or firms may choose to additionally claim compliance to OECD, along with their national regulations.

GLP compliance for each country is governed by their national regulations. There are several equally compliant ways of conducting a pathology peer review; a brief explanation follows.

Ultimately, this STP working group recommends that the test facility (i.e., site of study conduct) ensures access for study directors and QA/auditors to the relevant and actual information on a peer reviewer, regardless of the GLP status of the peer review, via a training file or electronic repository (e.g., name, affiliations, work address, qualifications, GLP training and [if applicable] facility certificate).

STP working group response: We concur. If the peer review pathologist(s) chooses to document agreement with a draft report (i.e., signs prior to finalization of the pathology report) this can be stated in the peer review statement.

STP working group response: We concur. As clearly stated in the answer above, the best practice should be to have the peer review statement included as an appendix in the study report, giving more information and transparency into the process.

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 pathologist’s 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).

STP working group response: In this question/answer, the FDA asks for appropriate clarity (or transparency) into the processes by which the study pathologist and peer review pathologist(s) reach consensus. There is a particular emphasis on the need for test facility management to implement measures to protect against “undue influence” on the study pathologist during the pathology peer review process that impact the conclusions of the study; as a minimum this oversight is accomplished through employee training and institutional SOP(s), with test facility management typically responsible for ensuring completion of such training. “Undue influence” is not defined in the Q&A guidance document. However, for the purposes of this review, it is assumed that it means inappropriate pressure on the study pathologist (by the peer review pathologist[s]) regarding diagnoses and interpretations that impact the conclusions of the study. Recognizing and clearly defining that inappropriate pressure is not always clear. Frequently, the peer review pathologist will request changes due to legitimate scientific disagreements on the interpretation and even the existence of test article-related findings. These requests lead to discussions between the study and peer review pathologist(s) with, ultimately and normally, consensus on the final determination. These changes can have impacts, such as raising or lowering of the effect levels or even adding or removing target organs of toxicity. These are entirely appropriate when based on scientific judgments and interpretations of the involved pathologists. However, in cases where a disagreement persists, a robust process for resolution of non-consensus (see discussion under Question 9) is an effective and transparent tool to mitigate undue influence by the peer reviewer.

The guidance states that measures should be in place to ensure the independence of the study pathologist and the peer review pathologist(s). The guidance has some suggestions for ensuring independence and transparency but is flexible. It states the following:

Measures to ensure transparency can include, among other options [emphasis added], the implementation of an audit trail, or conducting contemporaneous peer review after the study pathologist’s diagnoses are fixed or locked in an electronic system.

We agree that multiple options may be considered to provide additional transparency and the approach taken by an individual laboratory can vary based on established practices and SOPs in those individual organizations/firms. The purpose of the following section is to provide further description of some of the available options and their implications.

Raw data are clearly defined in the US Code of Federal Regulations (CFR) Title 21 Parts 58.3(k) and 130(e), with the definition of histopathology raw data being added in the 1987 preamble as the signed and dated final pathology report. ¹⁰ Some histopathology data collection software “audit trails” track pathologist’s initial entries with the diagnosis, individual’s name, and date and time, without forcing a reason for change. Some histopathology data collection software does not track pathologist’s initial entries in an “audit trail.” Implementation of an audit trail where it does not already exist or locking the data in an electronic system to force a complete audit trail, including a reason for change, in the study pathologist’s initial entries as the result of peer review is not the preferable process. By definition, the histopathology data at the inception of contemporaneous pathology peer review is still in preliminary or draft form and is not raw data, so that, the forcing of a complete audit trail is not appropriate. In addition, implementing a complete audit trail at this early stage for every study, which generally requires a documented reason for every change, could add considerable inefficiency and administrative burden. This burden would fall principally on the study pathologist as the accountable principal investigator/individual scientist.

The guidance offers flexibility to explore other options to increase transparency. In most test facilities, Pathology Peer Review SOPs should have clear processes for resolution of irreconcilable disagreements on substantive differences between the study pathologist and peer review pathologist(s). However, detailed processes are generally not in place for the most common situation where the study pathologist and peer review pathologist(s) are in agreement, or when any differences are not substantive (e.g., not affecting overall study interpretation of test item-related findings) and peer review consensus is achieved through discussion or informal means (e.g., casual discussion with other pathologists).

The STP working group offers the following suggestions for other possible options that add minimal additional administrative burden to the peer review process but increase transparency for instances where there is consensus between the study pathologist and peer review pathologist(s) without the implementation of an audit trail. Any of these alone or in combination may be helpful to provide additional transparency on a case by case basis and as deemed necessary, but individual organizations should have the flexibility to choose to adopt or not adopt any of these options: retention of peer review correspondence (e-mail, other communications) in the study file, retention of study pathologist’s draft incidence tables prior to peer review in the study file, retention of a separate abbreviated peer review summary document (in addition to the peer review statement) in the study file, retention of peer review notes in the study file, or additional signature of the study pathologist on the peer review statement. It should be noted that the optional documentation measures listed above and described below may add information to the study file, but they are not specifically designed to prevent undue influence.

Traditionally, with the exception of the peer review statement, these notes or summaries, informal communications, and preliminary tables are not routinely retained, because they fit the definition of pathology working notes, as mentioned in the FDA Preamble to the GLP Final Rule. ¹⁰ However, retention of these peer review notes, summaries, correspondence, or draft tables in the study file can increase transparency and the understanding of the pathologists’ interactions and collaborations during peer review. Retention of these optional records in the study file, which would be classified as peer review notes or correspondence (supporting documentation) and not raw data, would be in addition to the pathology peer review statement included in the final study report.

Retention of Peer Review Correspondence (e-mail, Other Communications) in the Study File

Pathology peer review correspondence includes communications that reflect the processes, plans, expectations, and outcomes directly linked to the study material used in the peer review that are not captured in other study communications. Examples can include correspondence on the process involved in the selection of the tissues for review, the selection of animals for full tissue review, and the review of additional potential target tissues. Any communication that is deemed relevant by the study or peer review pathologist(s) should be retained in the study file as peer review correspondence. Sharing relevant e-mail communication with the study director to ensure retention in the study file has become a standard practice in many test facilities, since it is a valuable tool to track and document e-mail discussions with the peer review pathologist and other sponsor-related individuals involved with the study (e.g., sponsor study monitors, project/development leads). Moreover, since large portions of communication among the different parties during the peer review process often occurs via e-mail, the decision by the study pathologist to share specific communications with the study director (and consequently to add those to the study file) has proven to be an effective and powerful tool to increase transparency, and to ultimately mitigate undue influence.

Furthermore, the OECD has advised that “All correspondence regarding the histopathological evaluation of the slides used for peer review between the sponsor and representatives of the test facility and the peer review pathologist should be retained in the study file. . . .” ^{7 (p9)} The STP has previously commented that while not “all” correspondence needs to be retained, ³ identification and retention of relevant correspondence by the study pathologist can function as an effective feature of the institutional peer review process and be included in the institutional SOP(s) and employee training. In addition to written mail or e-mail correspondence, other forms of communication may include transcription, voicemail, and phone or video call notes or summaries.

Retention of Study Pathologist Draft Incidence Tables Prior to Peer Review in the Study File

Following this practice would enable direct comparison of original diagnoses included in draft incidence tables prior to peer review activity with the final diagnoses included in incidence tables contained in the final pathology report.

Retention of a Separate Abbreviated Peer Review Summary Document (in Addition to the Peer Review Statement) in the Study File

Some peer review pathologists generate a brief written summary of the overall findings of a peer review, separate from the specific peer review comments on the draft data tables, to guide the peer review discussion with the study pathologist. The format of this summary varies but could be notes generated when the pathologists are face-to-face, an e-mail correspondence, or a separate document. Such documents are not expected to be signed and are not raw data.

Such summaries generally include the peer review pathologist’s overall impression of the key findings in the study pathologist’s draft data tables and draft written narrative (if the draft written narrative is available), and whether the peer review pathologist is in agreement or if there are some disagreements to be resolved regarding substantial key findings. Substantial key findings in any peer review would include the completeness of the study pathologist’s review (all test article-related target tissues were identified), the doses that are affected (i.e., correct assignment of the NOEL), appropriate nomenclature of findings, consistent application of severity grades, appropriate interpretations particularly around the test article relationship of the findings (vs. spontaneous or procedure-related findings), confirming cause of death or moribundity (when applicable), and designating the adversity/non-adversity of test article-related findings. Which substantial key findings are included in the peer review summary document is at the discretion of the peer review pathologist and generally based on where there may be a substantial difference of opinion with the study pathologist.

Retention of Peer Review Notes in the Study File

Many pathologists will perform a contemporaneous peer review in a traditional way of recording their findings on paper. As an illustrative example, the peer review pathologist may start by printing specific pages from the summary and individual animal tables. These tables provide virtually everything the peer review pathologist needs regarding microscopic examination of the tissues. From the individual animal tables, generally only the pages for the full tissue animals preselected to be evaluated will be printed. In addition, information for the unscheduled death animals is often also printed from these tables. From the pathology diagnoses or histopathology cross-reference table, generally only the target organs of interest are printed out. If these can be generated ad hoc at the time of peer review to include only the tissue of interest to the peer review pathologist, this will make the peer review evaluation more efficient. Once tables are in hand, the pathologist will look at animals requiring full tissue examination and check off lesions as to agreement or will make notations on the sheets for any disagreements or comments. Like the target tissues, the pathologist can easily check off the findings, shown with severity grades, to note agreement, or strikeout and write in the grade that the peer review pathologist thinks is appropriate. If a different diagnosis is added, for a finding that the peer review pathologist thinks that the study pathologist may have missed, it is simple to write in the diagnosis and appropriate severity grade for each animal.

When the evaluation of the histopathology diagnosis(es) is complete, the choice can be made to add notes to the front page or an additional page that expands on the peer review pathologist’s thoughts (similar to the option described above for retention of a separate abbreviated peer review summary document). These may include:

After completing this portion of the peer review, the peer review pathologist’s notes are provided to the study pathologist for discussion and consensus building. Once consensus is reached, it is a simple matter to archive the peer review pathologist’s notes with the study file. This can easily demonstrate and reconstruct the thought processes that occurred by preserving the original diagnoses of the study pathologist on the pages from the tables that are printed out, preserving the thoughts of the peer review pathologist from those notes on those printed sheets, and by comparing these, if needed, to the final version of the pathology tables that are appended to the finalized pathology report. Also, the peer review statement demonstrates that the peer review pathologist ultimately agrees with the study pathologist regarding diagnoses and study interpretation in the final pathology report.

If appropriate tables are readily available from which the desired information can be printed, this approach can be efficient for both the study pathologist and the peer review pathologist(s), has minimal cost, and maintains the ability to track the process of the histopathology diagnosis(es) in a contemporaneous pathology peer review. It also avoids the audit trailing or locking of preliminary data, which can at times be onerous for the study pathologist and may add significant time and expense.

Additional Signature of the Study Pathologist on the Peer Review Statement

The FDA guidance document clearly defines what is to be included in the peer review statement. Traditionally, the peer review statement is signed only by the peer review pathologist. In consideration of the need to demonstrate the absence of undue influence by the peer review pathologist on the study pathologist, documentation of consensus can be strengthened by the additional signature of the study pathologist on the peer review statement. In such cases, it is advisable to construct the peer review statement, such that, the specific wording or portion signed by the study pathologist is limited to the statement that “the data in the final pathology report reflect the consensus opinions of the study pathologist and peer review pathologist.”

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 pathologist’s report and should be appended to the final study report.

STP working group response: The working group agrees that the methods employed to resolve substantive differences in diagnoses and interpretations should be transparent and unbiased. It is important to distinguish between substantive and non-substantive differences. As described by Morton et al, ⁶ “it is not necessary to agree on every diagnosis or every severity classification if these discrepancies do not significantly alter the overall interpretation of the pathology data.” Pathologists refer to these as non-substantive differences and there is no expectation to document and resolve these minor differences. In contrast, every effort should be sought to resolve substantive differences of opinion so there is a single unified pathology data set for the study. SOPs directing peer review activity should provide clear description of the approaches that can be followed in the event substantive differences of opinion remain after peer review. There may also be situations where there is uncertainty on the part of both the study pathologist and peer review pathologist(s) that requires additional review by an additional subject matter expert or experts.

There are a variety of approaches to resolving differences of opinion.^3,5-7(p9) As described by Morton et al, ⁶ “When differences of opinion regarding pathology findings or interpretations exist that could affect risk assessment, informal consultations and/or formal (documented) consultations with additional experienced pathologists and/or subject matter experts often lead to resolution of discrepancies.” Determining which approach to use should be based on the nature of the study and the specific issue being addressed. Potential approaches that have been reviewed in the publications cited above include:

In addition to either a contemporaneous or retrospective pathology peer review, there are other situations (e.g., business due diligence) where tissue slides are examined microscopically, and histopathological review occurs that is not relevant to the FDA Peer Review Guidance. ⁵ This working group is also aware that there are instances when a sponsor chooses to have a pathology evaluation performed and report generated by a third party or independent pathologist, and this review is conducted outside of the study protocol and study report. While this practice is outside of the scope of the pathology peer review, this working group does not consider this a best practice as it can lead to confusion as to the most appropriate pathology data set to use for safety assessment. Best practice in this situation would be a fully documented retrospective peer review, so that, there remains a single set of microscopic pathology data.