general comments on pathology peer review in nonclinical toxicology … · 2019. 10. 9. ·...

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IQ CONSORTIUM COMMENTS ON FDA-2019-D-2330

PATHOLOGY PEER REVIEW IN NONCLINICAL TOXICOLOGY STUDIES:

QUESTIONS AND ANSWERS; GUIDANCE FOR INDUSTRY; DRAFT GUIDANCE

We are pleased to offer the following comments, developed by the DruSafe Leadership Group

(with input from the Quality Leadership Group) of the International Consortium for Innovation

and Quality in Pharmaceutical Development (www.iqconsortium.org). The IQ Consortium is a

not-for-profit organization of pharmaceutical and biotechnology companies with a mission of

advancing science and technology to augment the capability of member companies to develop

transformational solutions that benefit patients, regulators and the broader research and

development community.

The IQ Consortium and DruSafe Leadership Group appreciate the opportunity to review the

draft guidance and to share detailed feedback below. First, general comments on the current

draft guidance’s text are presented. In the table that follows, specific comments and proposed

revisions are provided for your consideration.

The IQ Consortium hopes this feedback will assist the Agency in their efforts. If you require

clarification of any of these comments, please contact Dr. Ann Marie Stanley at the IQ

Consortium Secretariat:

IQ Consortium Secretariat*

1500 K Street NW

Washington DC 20005

Telephone: (202) 230-5158

Fax: (202) 842-8465

Web: www.iqconsortium.org

Email: [email protected]

*Secretariat, Drinker Biddle & Reath LLP

GENERAL COMMENTS ON PATHOLOGY PEER REVIEW IN NONCLINICAL

TOXICOLOGY STUDIES: QUESTIONS AND ANSWERS DRAFT GUIDANCE

FOR INDUSTRY

The goal of the pathology peer review is to assist the study pathologist with the creation of the

best, most accurate set of histopathology data and interpretations of those data to describe the

toxicity of the test article in the test system under the conditions of the nonclinical study. Some

details outlined in the draft guidance, particularly as they pertain to how the process of peer review

is recorded, appear to jeopardize the main goal and collaborative benefit of performing a peer

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review. There is fundamental disagreement on what should be included in the peer review

statement (A5) and how differences in interpretation between the pathologist and the peer review

pathologist should be recorded (A9). The area of greatest concern is the lack of trust in the integrity

of pathologists to perform their job role (Q8). The remainder of the discussion and detailed

comments in the table are recommendations intended to increase the clarity in the guidance and

drive consistency throughout the industry.

DruSafe agrees with the FDA position that “Casual discussions, consultations, opinion exchange,

and mentoring among pathologists do not constitute formal pathology peer review and are not

covered by this guidance document.” However, each organization’s interpretation of these aspects

of communication versus what constitutes a formal peer review are expected to result in substantial

differences in detailed documentation. In addition, the iterative process of communication between

the primary pathologist and peer review pathologist would be made cumbersome if documentation

and justification are required along the way. The current philosophy of the industry is that the

retention of interim information, working notes, communications to reconcile differences of

opinions or draft versions of narrative reports from prospective/contemporaneous peer reviews is

not essential for the reconstruction and understanding of the pathology section of the final study

report, and do not require an audit trail or retention after the pathology report is finalized (Morton

et al, 2010; US FDA 1987).

The expectation of an audit trail initiation in between the study pathologist and peer review

pathologist analysis appears to change the definition of pathology raw data. In addition, the

initiation of an audit trail on interim data poses a burden to both study conduct and quality

assurance units to manage this information for data which is not considered final, as identified in

the 1987 GLP Final Rule1. It is strongly recommended that the expectation of an audit trail

initiation prior to the peer review pathologist analysis be removed from the draft guidance prior to

finalization.

Regarding ‘undue influence’, it is not in any Sponsor’s best interest of patient safety to

mischaracterize a nonclinical hazard. The essential correspondence to retain as part of peer review

activities are communications that reflect the process, plans and expectations directly linked to the

slides used in peer review (Fikes et al, 2015). Examples include correspondence on the process

involved in the selection of slides for review, the selection of animals for full slide review, and the

selection of potential target tissues for review in remaining animals. However, communications

regarding preliminary pathology observations prior to final database lock and the generation of

histopathology raw data by the study pathologist’s signature of the narrative report are not needed

for reconstruction of the histopathology portion of the study and would not be required to be

maintained, in accordance with FDA, OECD and Japanese Ministry of Health Labour and Welfare

guidance (US FDA 1987, OECD guidance no. 16, 2014, and Japanese MHW 1997). In addition to

the ability to reconstruct the pathology section of the study, additional safeguards are the retention

of specimens, allowing a third party or FDA to evaluate the slides themselves, in the rare event

that a concern arises for unethical practice.

Finally, DruSafe has the consensus opinion that FDA and OECD need to be harmonized in

practices that drive a quality product but are also straightforward and easy to be consistent across

the industry. Avoiding unnecessary regulations that are prone to variability in execution will not

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drive alignment and will likely result in confusion and misinterpretation which could delay our

main goal of getting new medicines to patients. We would like to take this opportunity to thank

FDA for considering DruSafe’s opinion and input on this draft guidance.

SPECIFIC COMMENTS ON PATHOLOGY PEER REVIEW IN NONCLINICAL

TOXICOLOGY STUDIES: QUESTIONS AND ANSWERS DRAFT GUIDANCE

FOR INDUSTRY

Lines-

FDA

Guidance text Comment

General The intent of comment is

to provide an overarching

statement that

acknowledges that while

some of the principles

articulated in the draft

reflect best practices in

toxicologic pathology,

there are major points of

concern regarding

Questions 5 and 8 related

to the degree of

documentation of

differences for

prospective peer review

which appears to conflict

with the definition of

pathology raw data as

stipulated in the federal

rule.

As the introduction of the draft guidance notes,

documentation of practices during peer review have not been

clearly defined and vary among testing facilities. While it is

true that these practices have not been codified in regulatory

guidance, it is important to note that the toxicologic

pathology community has carefully considered both

scientific and compliance aspects of pathology review and

published documents related to pathology peer review (Fikes

et al, Toxicologic Pathology 2015; Morton et al, Toxicologic

Pathology 2010; STP, Toxicologic Pathology 1997; and

Ward et al, Toxicologic Pathology 1995). These documents

were prepared by expert panels of pathologists and IQ

DruSafe suggests that the principles in these publications

provide a strong scientific basis for both the scientific

conduct of a peer review as well as appropriate

documentation practices to allow study reconstruction.

The current draft guidance references several of these

publications and we appreciate that in many of the questions

(Q1-4, and 6-7) portions of these practices have been

adopted. Our primary concern regards statements in Q 5

and 7 related to the nature of documentation required in

prospective peer review of any differences between the

primary and peer review pathologist. While we appreciate

the agency’s desire to be assured that primary pathologists

are not unduly influenced during the peer review process, the

report practices suggested for prospective peer review in this

draft guidance will not guarantee undue influence, will add a

notable and cumbersome addition to the reporting process,

and will likely result in pathology narratives which may be

unclear and confusing to non-pathologists. More detailed

comments are described below.

General

Lines

34/35

53

55

57

Definitions:

Histopathological

assessment (lines 34/35)

Findings (53)

Interpretations (55)

Output (57)

Terminology around the conduct of the histopathology phase

of a toxicology study and pathology peer review used

throughout this document (e.g. histopathological assessment,

findings, interpretations, and output) is confusing. It would

be helpful to more clearly define these terms in the

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introduction and use them consistently throughout the

document.

Line 36

(Backgr

ound)

….includes an initial read

of tissue slides by the

study pathologist….

Recommend changing colloquial term “read” to “evaluate”

to take into account the pathologist’s training, experience

and understanding of the range of normal tissue

morphologies, background observations and

pathophysiology.

Lines

37-39

Pathology peer review can

be particularly useful in

situations where unique or

unexpected findings are

noted or when the peer-

review pathologist has a

particular expertise with a

class of compounds.

The scope of pathology peer review is broader than

described here; it is not just for unique or unexpected

findings and is intended as a quality control measure to

ensure accuracy of diagnoses, consistency of terminology,

and appropriate interpretation of pathology findings.

Lines

43-44


be valuable when

performed during the

conduct of a GLP study,

pathology peer review is

not specifically addressed

in GLP regulations.

The expectation of initiating an audit trail on interim

microscopic data in between the study pathologist and peer

review pathologist reviews adds a level of complexity and

confusion to the dataset without added benefit. Given that

the signed and dated pathology report is considered

pathology raw data, the added burden to administer a process

which is not a regulatory requirement may prompt some

entities to discontinue the peer review process. This would

weaken the GLP quality management system.

Line 53

(A1)

Pathology peer review is

the process by which the

findings of the pathologist

It is unclear here what ”the findings” means and if the

expectation is that a peer review pathologist reviews both the

recorded morphologic diagnoses and the interpretation of

these within the context of the study. Recommend clarifying

in this section.

Line 55 ….or group of

pathologists (peer-review

pathologists).

Add pathology working group as follows:

“… or group of pathologists (peer review pathologists or a

pathology working group, PWG).”

Lines

56-57

Interpretations of

histopathological changes

are made using expert

scientific and medical

judgment resulting in

output that is mostly

qualitative and therefore

subjective

Recommend deleting “and therefore subjective”

Lines

57-58


help to ensure the quality

and accuracy of

histopathological

diagnoses and

interpretations

Consistency should be mentioned as well, as this is a key

element of the pathologist’s work.

Lines

60-61

Casual discussions,

consultations, opinion

exchange, and mentoring

Clarify and/or define what is meant by a “formal pathology

peer review” as compared to “casual discussions,

consultations, opinion exchange and mentoring” and who

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among pathologists do not

constitute formal

pathology peer review and

are not covered by this

guidance document

may or may not be included in the definitions of pathologists

in these roles.

Suggest replacing “casual” with “informal” and delete

“opinion exchange”. The types of interactions described

here are critical components of the iterative process of

arriving at a diagnosis in both the experimental and

diagnostic pathology arenas. We fully support that both

these interactions, as well as the exchange of information

between the primary and peer review pathologist that occurs

as part of study preparation are not necessary for study

reconstruction and are out of scope of the guidance.

Lines

65-67

(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 histological

descriptions.

“Sufficient knowledge” may be more appropriate

terminology than “experience” in the first sentence.

Lines

67-69

(A2)

In addition, the peer-

review pathologist should

have experience with the

route of administration of

the test article, species

and strains of animals

being tested, and duration

and design of the study

Appropriate experience to perform the peer review does not

always require specific expertise in all of these aspects.

Lines

69-71

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

of test article

administration at other

dose levels or in other

species.

Change the word “can” to “is” – “Furthermore it is also

beneficial….”

Lines

78-79

(A3)

Pathology peer review

that occurs before

finalization of the study

pathologist’s report is

considered prospective

peer review

“Prospective” corresponds to “contemporaneous” I OECD

Guideline. Recommend harmonization.

Lines

80-81

pathologist should

complete the analysis of

all slides and prepare a

draft pathology report

Recommend changing “prepare a draft pathology report” to

“prepare study pathologist interpretation.”

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before the prospective

peer review occurs.

We concur that it is optimal for the draft pathology report to

be prepared prior to the initiation of the prospective

pathology peer review; however, as written, the text is not

sufficiently flexible to accommodate many study designs

and reporting processes. Specifically, in order to

accommodate pathologist scheduling and efficient

evaluation and reporting it is necessary for both the primary

and peer review process to be divided into multiple phases.

For example, certain tissues or special techniques may have

significantly longer processing times and it may be most

efficient to have all “routine” tissues processed, evaluated,

and peer reviewed and then the additional tissues evaluated

when they are available. In addition, for 2-year

carcinogenicity studies it is most efficient for the study

pathologist to begin reviewing early sacrifice animals prior

to the end of the live phase. In these cases, flexibility should

be allowed to provide for a phase of peer review covering

the early sacrifice animals. In all of these instances, neither

the primary or peer review evaluation would be complete

until all protocol-specified tissues have been reviewed and

the various phases of peer review would be documented in

the peer review statement.

Recommendation: We suggest removing the language

suggested all tissues must be evaluated prior to the start of

the peer review and retain the language that the draft

pathology interpretation should be available prior to peer

review as follows:

“When pathology peer review occurs prospectively, the

study pathologist should complete the analysis of all slides

and prepare a draft pathology interpretation before the

prospective peer review occurs. In those cases where the

primary or peer review occurs in multiple phases, the draft

pathology interpretation which covers the relevant

phase/tissues should generally be available during the peer

review”

While this practice is generally agreed to, there are cases (eg,

peer review conducted in several phases and/or early deaths

occur that require early evaluation and peer review to

support changes to the study protocol) when the full draft

interpretation cannot be available at the start of the peer

review. Recommend including flexibility to take these

possibilities into consideration.

Lines

83-86

Pathology peer review

that occurs after

finalization of the

pathology report is

considered retrospective

peer review. When

Please clarify if retrospective peer review could be applied

for the peer review conducted many years after fixation

without original study pathologist, as described in OECD

guidance No. 16. Please clarify if an independent report for

peer review that occurred after finalization of final report is

acceptable.

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pathology peer review

occurs retrospectively, the

study pathologist should

document any changes to

the conclusions of the

study that result from the

retrospective peer-review

process in an amendment

to the final pathology

report.

Because question 3 is focused on timing and not

documentation we suggest the following revisions.

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

conclusions of the study that result from the retrospective

peer-review process in an amendment to the final pathology

report. Refer to question 5 regarding differences in

documentation practices for prospective and retrospective

peer review.

Lines

88-89

(Q4)

Can pathology peer

review be conducted at a

non-GLP‐compliant site for a GLP compliant

study?

Consider alignment with OECD 16 and 20.

Lines

91-93

(A4)

It is possible to conduct a


outside of a GLP-

compliant site for a GLP-

compliant study provided

certain safeguards are in

place to protect the

integrity of study data.

Recommend inclusion of chain of custody documentation

(condition at arrival, confirmation of arrival to study director

etc.). Secure retention of the GLP slides at a non-GLP site is

to be ensured.

Clarify archiving recommendation for peer reviewer

documentation

Remove the word “data” in this section: “….to protect the

integrity of the study.”

Recommend replacing the term “safeguards” with

“appropriate procedures and documentation”

Lines

93-95

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

Clarification requested: if the peer reviewer has received

adequate training on GLP and internal SOP, we consider that

he/she is operating under the umbrella of the test facility and

is GLP-compliant.

Lines

95-96

…however, if the peer

review is conducted at a

non-GLP-compliant site,

that fact should be

recorded and justified

within the study protocol

and final study report

Recommend removing the word ‘justified” as it implies

requirements exist for choosing a non-GLP compliant site

for peer review.

Please clarify that the justification referred to is ensuring

appropriate GLP training and documentation practices of the

peer review pathologist.

Suggest deleting the sentence specifying the documentation

practices as this is covered in Q5 and this may create

confusion. We suggest the following revision:

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“Regardless of where the peer review is conducted, the

name, affiliation, and location (i.e., address) of the peer-

review pathologist study director should follow the

documentation practices described in Q5 of this

guidance”

Lines

93-97

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-GLP- compliant

site, that fact should be

recorded and justified

within the study protocol

and final study report.

In an environment where global systems enable successful

deployment of GLP compliant business, a GLP peer review

can easily be supported by global GLP training and SOP

systems, but the site as a whole not conduct other GLP

activities. Recommend this section be revised as follows:

It is preferable that the peer-review pathologist perform the

review at a 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 remotely to a GLP- compliant

site, appropriate measures and documentation must be

undertaken to ensure that the peer review was GLP

compliant. If the peer review was conducted non-GLP, that

fact should be recorded within the study protocol and final

study report.

We contend that if the peer reviewer is GLP trained and the

pathologist is conducting the peer review in a GLP standard

manner, the GLP accreditation of the facility where it is

done is not critical.

Lines

98-100

Also, the name,

qualifications (including

GLP training), affiliations,

and address of the peer-


be documented in the

study file

As an alternative option a centralized process (not study

related documentation) at the test facility could be

considered (if defined within a respective SOP)

For privacy reasons, it may be more appropriate to list only

the city name or to use the affiliated business address for the

peer review pathologist. Home addresses can be kept in test

facility records.

Lines

102-104

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.

Clarify if this exception would include any pathology peer

reviews conducted in a GLP-compliant manner at a non-

GLP compliant site.

Lines

111-112

(A5)

The process should be

guided by written

procedures to establish the

extent of the review and

ensure the integrity of the

study data.

Since no data is produced during a pathology peer review,

and all data is safely protected within the data capture

system under the control of the study pathologist, how could

study data integrity be affected by peer review, unless FDA

are redefining the definition of histopathology raw data.

Suggest removing the word data: “….to ensure the integrity

of the study.”

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Lines

116-119

A formal pathology peer

review should be planned,

conducted, documented,

and reported in

accordance 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 described in the

study protocol or study

protocol amendments and

in SOPs pertaining to the

GLP studies.

Peer review procedures are typically described in SOPs.

The peer review statement can be used to document the

detailed activities of the peer review and to state the overall

results (i.e., that consensus was reached).

Lines

118-120

and

126-129

“An SOP and GLP study

protocol (or protocol

amendments) should

include a description of

the peer-review

procedure, including

selected target tissues, the

dose groups to be

examined, the 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.”

Potential or suspected target tissue selection can occur at the

time of prospective peer review and having to provide a

protocol amendment with such detail will result in delays to

the completion of the process, or a study deviation rather

than an amendment if the peer review is time-critical. It is

considered more appropriate to include the target tissues and

other details of what was evaluated (specimens, animals,

etc.) in the peer review statement rather than requiring them

to be decided a priori within the protocol or having to

provide a protocol amendment/deviation.

In GLP studies, details from SOPs are not also repeated in

Study Protocols; this is a long established GLP practice and

this guidance, as written would inappropriately replicate the

purpose of an SOP. Since formal Peer Review details

including target organs, which dose groups, the number of

specimens examined, and blinding aspects cannot be

accurately determined until primary pathology read is

complete, they cannot be included in the protocol. While

the SOP describes the standard expectations, it is not able to

provide the specific Peer Review details. The SOP does

outline which doses, groups and animals should be reviewed,

but allows the pathologist to use scientific judgement in the

evaluation. Adding the information from the SOP to the

protocol is repetitive and more specific target organ detail is

not known at the time of protocol generation. The scope of

the peer review often includes additional material not

foreseen ahead of time. As written, this will require

generating abundant protocol amendments which are not the

appropriate means of documenting prior events. The detailed

information is included in the peer review memo, where

information is better explained in context of the study.

Blinding is also specifically mentioned in the draft guidance

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as requiring prior documentation in the SOP, Protocol or

Protocol Amendments. Blinding is not routinely done

during peer reviews. Toxicologic pathology is not conducted

blindly in practice in GLP toxicity studies except in rare

circumstances, as described in multiple publications (Rouse

et al., 2015; Neef et al., 2012; Holland et al., 2011).

Blind examination is usually triggered by perceived subtle

differences between control and treated animals; it is an

unbiased way to confirm that a suspected target organ is

indeed a target organ.

Therefore, the recommendation would be to reword the

sentence, and state: "slide review during the peer review

process may include blind examinations”

Change “number of specimens to be examined in each

group” to “the number of animals and/or tissues examined”.

Counting and documenting how many slides/specimens

were evaluated is not value-added. It is more meaningful to

document which animals and tissues were evaluated.

Lines

121-123

(A5)

Lines

177-178

(A7)

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 and the study report.

… 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).

This seems duplicitous and should not be required within the

study report since documentation of data verification and

review processes are not typically included in study reports.

However, it should be retained in the study file for a

reviewer. The study report should confirm that a peer review

was conducted and that there was alignment between

pathologists. GLP study documents maintained in the study

file with similar or greater impact include Note to File,

Protocol Deviations, SOP Deviations, and raw data. The

value of publishing the peer review statement within the

report is not evident in comparison to these other documents.

Of note, the need to include the peer review statement in the

final study report is not required in OECD guideline.

Line

127

…peer-review procedure,

including selected target

tissues, the dose groups to

be examined, th

“selected target tissues” should read “selection of tissues for

peer review” as target tissues cannot be selected.

Line

129

“Relevant SOPs can be

referenced when

appropriate”

Suggest deleting line 129 reference to SOPs. Listing of all

SOPs related to a study is not standard practice in other areas

so it is not clear why this option would be provided for peer

review. SOPs are available for inspection as part of the audit

process.

Line

135

When, where, and under

what conditions (i.e.,

GLP- or non-GLP-

compliant) the peer

review was conducted

Suggested clarification, ‘when, where, and whether the peer-

review was conducted as GLP-compliant or not.’

Indication of the GLP-status is most appropriate in the

compliance exception statement of the overall report and it is

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not clear that this is needed in the actual peer review

certificate. If retained, instead of indicating “and under what

conditions”, revise to “and indicate the GLP-compliance

status of the peer review location”.

Lines

140-141

A statement on whether

the terminology and

findings used in the

pathology report were

agreed upon by both the

study and peer-review

pathologist

Does this mean that the peer review statement needs to

confirm agreement on all and any findings reported,

including terminology used for spontaneous findings known

as background changes? Recommend deletion of this

sentence

Lines

148-156

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. (lines 148-152)

Any changes to the

overall study

interpretations by the

study pathologist because

of a prospective peer-

review process should be

documented in the peer-

review statement and

discussed in the final

pathology report, as

applicable. (lines 154-

156)

If consensus is reached during the peer review process,

we agree with recommendations put forth in lines 148-

152 and recommend deletion of lines 154-156. We do not

agree that documentation of changes occurring prior to

consensus is appropriate. We recommend that changes

to diagnosis and terminology associated with changes to

overall study interpretation do not need to be detailed in

the peer review statement. More context provided below.

In accordance with the 1987 FDA GLP Final Rule (US FDA

1987), only the finalized pathology report represents raw

data. For this reason, the study pathologist’s “original

interpretation” of the raw data is the point of creation of the

microscopic pathology raw data and its integrated

interpretation with other study-related data indicative of the

overall survival and health of the animals such as

macroscopic necropsy observations, organ weight

differences, and in-life observations such as clinical signs,

effects on body weight and food consumption, and clinical

laboratory tests (i.e., hematology, clinical chemistry,

coagulation tests, urinalysis and urine chemistry).

Additionally, the U.S. EPA and the U.S. FDA consider that

interim notes are not essential for the reconstruction and

evaluation of the pathology report because of the availability

of the tissue sections from which reconstruction could be

accomplished if necessary. Prior to finalization of the

pathology report, the study pathologist can therefore modify

pathology data without documentation until finalization.

After the finalization of the study report which should

include the locking of the pathology data capturing system,

any modification of the pathology data would result in the

production of an audit trail.

The peer review pathologist provides an additional set of

eyes, as a means of promoting consensus between

independent observers. This approach has been the mainstay

of Peer Review for decades to help reduce individual

observer bias. The Peer Review of available study materials,

including in-life results, clinical pathology findings, organ

weights, and toxicokinetic exposure data, along with

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preliminary findings from the study pathologist, enhances

the thorough interpretation of data. Language in the FDA

draft guidance recommending documenting all discussions

will encourage greater discord than what actually occurs in

pathology peer review practice-- which is consultative,

collegial and constructive. The inclusion of peer review

suggestions or notes into the file indicates that there is raw

data generated prior to the signing of the pathology report

and is thus in opposition to the Final Rule. Adding an audit

trail to preliminary findings is an unnecessary exercise

imposed on the data generation process. Creating this type

of audit trail, or retention of original draft interpretations are

unnecessary forms of documentation which themselves open

an environment of adversarial approach, which is entirely

contrary to the practice and purpose of peer review.

Comparing preliminary versions to final versions will also

create an assessment of competency, and this environment

will build defensive postures that are not conducive to

consultation, consensus, and collegiality. In practice,

differences between pathologists that are unresolvable are

quite rare. It is not in any Sponsor’s best interest of patient

safety to mischaracterize nonclinical hazard. Consequently,

the new proposed forms of documentations in this draft

guideline impose a hurdle and not a value to the

pharmaceutical drug development process while offering no

assurance of patient safeguards.

As written, it will be open to interpretation to determine

which “changes to the overall study interpretations by the

study pathologist” are in scope regarding what

communication to document. This could be viewed as a new

target organ or change to an effect level or recovery

interpretation, or even a slight change to severity score, or all

of the above. Ambiguous language in regulation creates

confusion, promotes disparate interpretations in the quality

assurance community, and delivers burdensome processes

that do not avert any real risk. Much of these discussions

have historically been handled as professional

communications without further disclosure or retention, and

while the aim is to diminish undue influence, logistically it

will be difficult and resource intensive to ensure every

change to a study table is documented above just an audit

trail based on locked data. The peer review is an iterative

process that requires input from both parties to reach a

scientific consensus, and thus including all communications

would be voluminous in many cases.

We recommend this not be adopted as written nor

documented by the peer review pathologist. However, any

documentation performed should be within the study

of 20

pathologist responsibility since they hold ultimate authority

and responsibility over the raw data (final signed report)

There is also confusion if the level of detail being requested

includes specific recorded observations or interpretation of

those observations. For example, this may apply when only

changes to severity grades and/or terminology used to record

an observation across the board without any impact on

criteria or “diagnosis”, or only if nothing is changed at all.

Lines

169 –

170

(A6)

The peer review statement

can be signed by the peer


or after the finalization of

the pathology report.

No changes to suggest. We agree and appreciate the agency

clarifying this point. We are aware of audits which have

appeared to suggest a requirement for peer review statement

timing which is not consistent with the GLPs and which can,

in some reporting systems, created undue burden on the

reporting process and unnecessary report delays. This

section appropriately affirms that the pathology report is the

sole responsibility of the study pathologist and as such the

timing of the signing of the peer review statement is not

relevant to study reconstruction.

The statement should clearly indicate what was part of the

peer review process; if it is signed prior to the finalization of

the pathology report, it should state that the diagnoses and

interpretation were reviewed.

Lines

180-181

(Q8)

How can the Agency be

assured that the study

pathologist’s interpretive

findings are not unduly

influenced during the

pathology peer-review

process?

We understand that the agency’s desire is to minimize the

potential for undue influence on the primary pathologist;

however, several factors should be considered:

If implemented as suggested in the current draft guidance, it will still not be possible for an

independent reviewer, whether pathologist or non-

pathologist, to determine if the changes were a

legitimate change based on a more accurate

diagnosis/interpretation or if the change was brought

about due to undue influence of either a peer

reviewer or a report reviewer. Only a third

inspection of the microscopic slides by a pathologist,

or panel of pathologists, will allow this.

Potential unintended implications of the current guidance include inconsistency with the definition of

raw data in the regulations and multiple

datasets/interpretations resulting in confusion around

the final dataset and decreasing confidence in

providing a well-defined, high-quality consensus

data set.

The current set of peer review practices which adhere to the

OECD guidance on pathology peer review have served the

profession well. We are not aware of any examples where

fraud has been demonstrated in the conduct of pathology

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peer review or where pathology peer review issues have led

to implications for patient safety. As such, we urge caution

in implementing cumbersome documentation practices that

will detract from the overall quality of the study report and

still not achieve the stated goal of limited undue influence

during pathology evaluations.

Lines

189-192

(A8)

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 results

from a pathology peer

review. Such procedures

can include the

implementation of an

audit trail.

Remove reference to “audit trail” or specify that this refers

to retrospective peer reviews.

For prospective peer reviews, our position is that this is not

necessary as the interpretation is in draft form and is being

refined by casual consultations and peer review. Tracking all

changes is unnecessary, will result in unnecessary

documentation burden, and will result in unnecessarily

complex data tables.

This statement should pertain to retrospective peer review

activities. A retrospective peer review occurring after the

anatomic pathology report has been finalized has the

potential to alter histopathology raw data and interpretations

derived from those data. Under those conditions,

implementation of procedures to document all changes such

as implementation of an audit trail is appropriate and

consistent with GLP requirements.

However, in the conduct of a prospective or

contemporaneous peer review, the study pathologist’s

“original interpretation” of the raw data is the point of

creation of the microscopic pathology raw data and its

integrated interpretation with other study-related data, which

per the 1987 FDA GLP Final Rule (US FDA 1987) is the

point at which the pathology report is signed and finalized.

There are no changes to overall study interpretations to be

discussed or documented through procedures such as an

audit trail.

It should be remembered that the goal of pathology peer

review is to assist the study pathologist with the creation of

the best, most accurate set of histopathology data and

interpretations of those data to describe the toxicity of the

test article in the test system under the conditions of the

nonclinical study. The study pathologist has the sole

responsibility for the final histopathology diagnoses and

final interpretation of data as indicated by his or her

signature on the final anatomic pathology narrative report.

The only necessary record of that activity is a short

document indicating what was evaluated by the peer review

pathologist in order to come to that consensus opinion.

Generation of an audit trail as part of a prospective peer

review prior to the generation of raw data creates the

appearance of a second primary evaluation of the

of 20

microscope slides with a subsequent reconciliation step

between multiple sets of preliminary diagnoses that are not

raw data according to the 1987 FDA GLP Final Rule.

Documentation of these interim steps prior to the generation

of histopathology raw data is of little value for the purpose

of producing the most accurate description and interpretation

of the effects of the test article under the conditions of the

study.

The essential processes to document and correspondences to

retain as part of a prospective peer review are the

communications and documentation that reflect the process,

plan and expectations linked to the specimens used for peer

review—the microscope slides. However, the retention of

interim information, working notes, communications to

reconcile differences of opinions or draft versions of

narrative reports from prospective, contemporaneous peer

reviews is not essential for the reconstruction and evaluation

of the pathology section of the final study report, and do not

require an audit trail or retention after the pathology report is

finalized (Morton et al, 2010; US FDA 1987).

The initiation of an audit trail on interim data poses a burden

to both study conduct and quality assurance units to manage

this information for data which is not considered final, as

identified in the 1987 GLP Final Rule. Highly recommend

the expectation of audit trail initiation between study and

peer review pathologist analysis be removed from the

document

Lines

193-199

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 of

communications pertinent

The study pathologist and peer review pathologist often have

informal discussions and communications regarding findings

and study interpretation. These informal communications

need not be retained because they are not raw data. Such

extensive documentation requirements may reduce and/or

interfere with the scientific interactions between the study

pathologist and peer review pathologist. Along with the Peer

Review Statement, the final pathology report (containing

final conclusions) is the only documentation necessary to

reconstruct this phase of a study. Specimens (wet tissues,

tissue blocks, tissue slides) are retained and can contribute to

reconstruction of the study, if necessary.

of 20

to the process of slide

evaluation and meeting

summaries (e.g., meeting

minutes) relevant to the


should be retained in the

study file.

Lines

198-200

Records of



evaluation and meeting

summaries (e.g., meeting

minutes) relevant to the



study file.

Some clarity as to the level of detail expected and what the

documentation should include would be helpful. We would

hope that FDA would reflect the position of Fikes et all,

2015 in their proposed interpretation of the OECD 16.

Section 2.5. Difference of interpretation could result in wide

variability in communication retention eg clinical pathology

data discussion or mode of action of the test article as it

pertains to the findings.

Recommend change “should” to “can be”. If changes are

appropriately recorded and peer review statement includes

the overall result of the process, retention of evaluation and

meeting summary will not be needed.

The specific study files for retention of such records should

be clarified (i.e. the ones of the primary pathologist, peer

review pathologist or the test facility)

Lines

204-206

To best ensure

transparency, documents

(e.g.,

worksheets, electronic

files) that record peer-

review events and

changes to the study

pathologist’s findings


study records.

The iterative process of communication between the primary

pathologist and peer review pathologist is made difficult

when documentation and justification is required along the

way. The requirement to save pathologist worksheets, draft

reports, preliminary diagnoses and study pathologists notes

is not consistent with current best practices as described in

Morton et.al, 2010 nor is it consistent with retention of pre-

“raw data” records elsewhere in GLP regulations.

The critical outcome of anatomic pathology evaluation and

peer review of nonclinical studies is to achieve the best,

most accurate set of tables of diagnoses, and to interpret

these findings to accurately describe the toxicity of the test

article in the test species as part of hazard identification and

risk assessment. This requires achieving the best possible

scientific understanding of the data. It is not uncommon for

the study pathologist to be a generalist in toxicologic

pathology employed by a contract research organization,

with limited to no prior specific knowledge, experience or

specialized in the novel biological mechanism of action or

specific chemical/biological classes of novel therapeutic

agents. This may mean that the most relevant expertise to

leverage in support of the study pathologist’s activities

resides with peer review pathologists selected or employed

by the Sponsor. The only necessary record of prospective

peer review prior to raw data generation is a short document

describing the materials evaluated by the peer review

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pathologist and a statement of consensus with the study

pathologist’s diagnoses and interpretations as provided in the

final signed narrative report. Locking the database of interim

histopathology findings before the start of pathology peer

review does not alleviate the subjective nature of a

collaborative process. Instead, it creates the appearance of a

second primary-read of the microscope slides that may

require a subsequent reconciliation step of potentially

multiple data sets that are not considered raw data according

to the 1987 FDA GLP Final Rule. Only the final tables

reflect the “correct” diagnosis—by consensus agreement--at

the time raw data is generated upon report signature by the

study pathologist. It serves no purpose of record-keeping for

the reconstruction of the study to document multiple

preliminary diagnoses. Anatomic pathology evaluation of

nonclinical studies remains a subjective, iterative scientific

process, and is strengthened by aligned industry

recommendations for pathology peer review (Morton et.al,

2010; Fikes et al, 2015). The goal of anatomic pathology

evaluation and prospective peer review of nonclinical studies

is to achieve the best, most accurate set of tables of

diagnoses, and to interpret these findings to accurately

describe the toxicity of the test article in the test species as

part of hazard identification and risk assessment. That is not

accomplished by locking databases before raw data is

generated and the pathology report is signed or retaining

working notes related to parallel sets of incorrect findings.

The relevant information regarding peer review events

should be captured in the peer review statement and as such,

retaining interim notes in the study file does not add

transparency to the process, but merely adds bulk to the

study files.

Lines

206-208

One option to ensure

transparency is to fix or

lock the database of

pathology findings before

the start of the peer-

review process to ensure

that changes to the

pathology findings will be

recorded in an audit trail.

This recommendation is in conflict with the US FDA’s

definition of pathology raw data as the final signed

pathology report. While an audit trail is critical for

recording changes to raw data it is labor intensive and

impedes iterative processes like pathology assessment

with prospective peer review.

While this is offered as “one option” it would be helpful if

the guidance would propose additional options for ensuring

transparency.

We would prefer the removal of any reference to using an

audit trail as a method to record changes made by a

pathologist prior to the final signed report (i.e. the currently

defined presence of raw data).

Lines

210-212

If the draft pathology

report is shared with the

Recommend removing ‘The peer-review statement should

clearly identify changes resulting from the peer-review

of 20

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

process that affect the study pathologist’s interpretations."

and replace this with: "The peer review statement needs to

include a statement on agreement and/or disagreement

between study pathologist and peer reviewer."

As per the response to Q5, line 154-156, this requires

duplication of record-keeping and puts the emphasis

(inappropriately) on the peer review pathologist to keep

records of changes made by the study pathologist. It is not

the peer review pathologist which is directly capable of

making any changes to the observations and/or

interpretation, and as such, the peer review pathologist

should not be responsible for recording what changes are

made. It is the responsibility of the study pathologist to make

any changes with full accountability for them.

The peer review statement should not have to include

detailed changes if both pathologists are in agreement at the

time of pathology report finalization when it becomes raw

data. Line 140-141 indicates that the peer review memo will

include a statement that the terminology and conclusions

were agreed upon. If everything is agreed upon, then it

seems unnecessary to record all the iterations of the data that

lead up to this point?

Lines

221-222

(A9)

“The difference in

interpretation should be

documented by the peer-


engaging in a dialogue to

resolve the interpretative

differences.”

This new requirement is not suited to the collegial and

consultative process that comprise peer review, and it further

creates undue burden and documentation which adds no

value. Quite often, the difference in interpretation is worked

out very quickly once a discussion takes place. These

discussions between the peer review pathologist and study

pathologist are often occurring in real time, with the peer

review pathologist asking questions or raising concerns

about slides he/she has just examined. Proposing this

regimented documentation for these questions and

interactions prior to receiving clarification from the study

pathologist or while discussing differences in opinion that

rest on the experience of one over another creates an

unnecessary step in the peer review process and like the

suggestion in Q5 regarding documenting study notes, runs

counter to other FDA guidance. If peer reviewing

pathologist’s opinions prior to peer review are recorded or

documented, it is treating them as raw data, which they are

not. Any notations or questions on terminology, severity

grade, missed findings, or findings considered consistent

with normal background made by the peer review

pathologist are considered working notes and not retained,

aligned with OECD guidelines and STP best practices for

peer review. Just as the study pathologist notes, they are not

required to be recorded or included in the study file or

documented in the final report. It is critical that this practice

of not retaining working notes is consistent with industry

of 20

best practices and OECD peer review guidelines. FDA and

OECD should be harmonized to prevent confusion,

misinterpretation, and potentially delay bringing new

medicines to patients that accompany unnecessary

regulation.

Please clarify what is meant by the statement “differences in

interpretation should be documented …… before engaging

in a dialogue….” and what the expectation is as to how and

where this would be documented.

Lines

222-225

If no resolution can be

reached, the study

pathologist and peer-


carefully follow a

transparent and unbiased

process that is clearly

described in the testing

facility’s SOPs for

resolving interpretative

differences during

pathology peer review.

Suggest changing to: “….follow a transparent and unbiased

process for resolving interpretative differences during

pathology peer review that is clearly described in the SOP’s

under which the peer review is performed.”

Lines

227-230

Depending upon the

directives of the SOPs,

consensus may be

achieved through

consultation with

additional experienced

pathologists. Records of



evaluation and records of

meeting summaries (e.g.,

meeting minutes) relevant

to the pathology peer

review should be retained

in the study file.

The essential correspondence to retain as part of peer review

activities are communications that reflect the process, plans

and expectations directly linked to the slides used in peer

review (Fikes et al, 2015). Examples include

correspondence on the process involved in the selection of

slides for review, the selection of animals for full slide

review, and the selection of potential target tissues for

review in remaining animals. However, communications

regarding preliminary pathology observations prior to final

database lock and the generation of histopathology raw data

by the study pathologist’s signature of the narrative report

are not needed for reconstruction of the histopathology

portion of the study and would not be required to be

maintained, in accordance with FDA, OECD and Japanese

Ministry of Health Labour and Welfare guidance (US FDA

1987, OECD guidance no. 16, 2014, and Japanese MHW

1997).

We are not aware of a single facility that takes minutes of

peer review or that create summaries of discussions to

include in either the peer review memo or final reports or

study files. This is burdensome, cumbersome, and doesn’t

aid the interpretation of a study. Such discussions constitute

nothing more than “working notes” as described in OECD

Peer Review Guidelines and the official STP/ESTP/

BSTP/JSTP response (Fikes et al., 2015), and working notes

are not retained after the Peer Review.

When additional consultations with experienced pathologists

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

occur, clarification of the expectations of the documentation

process and retention of such documentation would be

beneficial.

general comments on pathology peer review in nonclinical toxicology … · 2019. 10. 9. ·...

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