Att6_Sample Research Outlines.docx

Sample Research Outlines and Elective Options Sample Research Outlines Research Outline I: Peer Review of a Chronic Study (1 species)

This study is for a chemical administered by inhalation to HSD: Sprague Dawley SD rats at 3 exposure concentrations plus a control group. Each group contains 50 animals/sex with a total of 400 rats. The list of protocol required tissues can be found in the DTT Specifications: https://doi.org/10.22427/NIEHS-00.

Offerors shall provide a detailed description of the approach and timeline for completion of a DTT Pathology Peer Review, according to the SOW and Technical Exhibit B, including conduct of the APS, PDR, and QA/PWG. Assume that these hypothetical studies were conducted in compliance with Good Laboratory Practices, (21 CFR Part 582).

Offerors are to describe how they would approach and interpret each stage of the pathology review and comment on how or if any ancillary studies might provide additional benefit to understanding the findings. In this regard, offerors should suggest methods that may further inform the mechanism(s) of action. Such supplementary evaluations may include molecular pathology, immunohistochemistry, histochemistry, step-section studies of kidney or brain, hepatic enzyme induction, further gross or microscopic evaluations, etc., and/or review of pre-chronic data (acute 14 day or 90-day study).

Deliverables for the APS, PDR, QA, and PWG are described throughout Technical Exhibit B of the SOW.

Research Outline II: Peer Review of a Subchronic (3-month) Study (1 species)

This study is for a chemical administered by drinking water to HSD: Sprague Dawley SD rats at 5 exposure concentrations plus a control group. Each group contains 10 animals/sex with a total of 120 rats. The list of protocol required tissues can be found in the DTT Specifications: https://doi.org/10.22427/NIEHS-00.

Offerors shall provide a detailed description of the approach and timeline for completion of a DTT Pathology Peer Review, according to the SOW and Technical Exhibit B, including conduct of the APS, PDR, and QA/PWG. Assume that these hypothetical studies were conducted in compliance with Good Laboratory Practices, (21 CFR Part 582).

Offerors are to describe how they would approach and interpret each stage of the pathology review and comment on how or if any ancillary studies might provide additional benefit to understanding the findings. In this regard, offerors should suggest methods that may further inform the mechanism(s) of action. Such supplementary evaluations may include molecular pathology, immunohistochemistry, histochemistry, step-section studies of kidney or brain, hepatic enzyme induction, further gross or microscopic evaluations, etc., and/or review of pre-chronic data (acute 14 day or 90-day study).

Deliverables for the APS, PDR, QA, and PWG are described throughout Technical Exhibit B of the SOW.

Research Outline III: Peer Review of a 28-day Study (1 species)

This study is for a chemical administered by gavage to HSD: Sprague Dawley SD rats at 5 doses plus a control group. Each group contains 10 animals/sex with a total of 120 rats. The list of protocol required tissues can be found in the DTT Specifications: https://doi.org/10.22427/NIEHS-00.

Offerors shall provide a detailed description of the approach and timeline for completion of a DTT Pathology Peer Review, according to the SOW and Technical Exhibit B, including conduct of the APS, PDR, and QA/PWG. Assume that these hypothetical studies were conducted in compliance with Good Laboratory Practices, (21 CFR Part 582).

Offerors are to describe how they would approach and interpret each stage of the pathology review and comment on how or if any ancillary studies might provide additional benefit for understanding the findings. Relevant for this study, there are 7 related studies on other test agents in the same chemical class, as well as additional data streams from this study including thyroid hormone assessment at 28 days and genomic sequencing data from the liver and kidney at 5 days and 28 days. In this regard, offerors should suggest methods that may further inform the mechanism(s) of action. Such supplementary evaluations may include molecular pathology, immunohistochemistry, histochemistry, step-section studies of kidney or brain, hepatic enzyme induction, further gross or microscopic evaluations.

Deliverables for the APS, PDR, QA, and PWG are described throughout Technical Exhibit B of the SOW.

Research Outline IV: Lead Pathologist - DTT Technical Report Preparation

DTT has conducted a chronic toxicity study of adult HSD: Sprague Dawley SD rats exposed by inhalation to a volatile industrial chemical. The study findings will be published in an DTT Technical Report. Assume this pathology peer review is being conducted on a locked study and reconciliation with the Study Pathologist is not required. Offerors shall provide a detailed description of how qualified personnel will serve in the role as the Lead Pathologist to support the pathology peer review and reporting of a DTT chronic toxicity study. Below is a description of the major milestones and schedule for report preparation:

During pathology peer review:

· Pathology Data Review (PDR): Review available study data for identification of target tissues and consideration of what should be evaluated by the Quality Assessment Pathologist (QAP). Review draft reports of the Pathology Data Review for alignment of need for the Quality Assessment review. Assume that review of three drafts are required before reaching a final report.

· Quality Assessment Pathology Review (QA): Meet with the QAP to review lesions and clarify preferred terminology. Review draft reports of the Quality Assessment Review. Assume that review of three drafts are required before reaching a final report.

· Pathology Working Group (PWG): With the QAP, discuss expertise and consultants to serve on the PWG. Discuss preparation of and review meeting materials prepared by the QAP for the slides and lesions to be reviewed, along with specific questions for each slide.

· Resolution of Audit Findings: Following an independent audit of the updated pathology data following PWG, the Lead Pathologist shall review the findings and make recommendations for, if additional changes are needed.

Following pathology peer review based on availability of final data:

· Prepare a Powerpoint presentation of histopathological treatment-related findings for a DTT data review. This should include key correlative findings with other data streams and capture important information from prior studies or studies of related chemicals. The Lead Pathologist will need to coordinate with the DTT Project Lead as well as other discipline leads for the study design and findings, as applicable. The Lead Pathologist is also responsible for acquiring images of unique and target lesions/treatment-related lesions from the study slides for inclusion in the data review presentation.

· Two weeks after the data review, a written summary of the histopathological treatment-related findings shall be submitted to the DTT Project Lead for incorporation into the Draft 1 report materials. Representative images of unusual findings from study animals shall also be acquired and submitted with the text.

· The Lead Pathologist shall review draft 1 of the NTP Technical Report and respond to comments from the report preparation support contractors and carefully review Draft 1 which includes all sections of the report except the Abstract and Discussion. Draft 1 will be reviewed in a group forum and the Lead Pathologist shall attend the draft review meeting and address comments related to the histopathology narrative. Following the Draft 1 review meeting, the Lead Pathologist shall work with the DTT Project Lead to finalize Draft 1 edits within 2 weeks of the draft review meeting.

· The Lead Pathologist shall review Drafts 2 and 3 of the NTP Technical Report and respond to comments from the report preparation support contractors and carefully review the overall Drafts 2 and 3 which include all sections of the report. Drafts 2 and 3 will be reviewed in forum and the Lead Pathologist shall attend the draft review meeting and address comments related to the histopathology narrative and overall interpretation. Following the draft review meetings, the Lead Pathologist shall work with the DTT Project Lead to finalize Drafts 2 and 3 edits within 2 weeks of the respective draft review meetings.

· Following external peer review of the draft report, the Lead Pathologist shall work with the DTT Project Lead to respond to peer review comments and finalize edits to the report.

For the purposes of costing, assume that all of the above activities are completed within a 12-month period.

Research Outline V: Histology Performed at Contractor Facility

NIEHS has conducted a short-term gavage study in B6C3F1 mice and collected tissues at necropsy as described in the DTT Specifications - https://doi.org/10.22427/NIEHS-00. Wet tissues from 25 mice/sex (40 tissues per mouse) will be shipped to the contractor facility. The Contractor shall prepare histologic slides of Hematoxylin & Eosin-stained tissue sections of all tissues based on guidance described in the DTT Specifications.

Research Outline VI: Histopathology Evaluation

NIEHS has conducted a short-term gavage study in B6C3F1 mice (25 mice/sex) and collected tissues at necropsy as described in the DTT Specifications. Hematoxylin & Eosin- stained tissue sections from all mice (40 slides per mouse) will be submitted for histopathological evaluation, in addition to tissue sections of the lungs stained with the Masson’s Trichrome histochemical stain and tissue sections of the liver stained with Periodic Acid Schiff’s (PAS) for protein from all mice.

The Contractor shall perform histopathological evaluation on all slides and devise a grading scheme for the findings observed in the lungs.

The Contractor shall prepare a histopathology report that includes individual and summary data tables and interpretation of the pathology data in the report. The report shall include a descriptive narrative of the salient findings with supporting results in tabulated format, and color images, and a discussion/conclusion of the histopathological findings.

Research Outline VII: Global Toxicologic Pathology Training Program

As directed by the COR, the Contractor shall generate publicly available training modules for publishing on the NIEHS hosted GTPTP website in three categories relevant to toxicologic pathology: 1) systems-based modules, 2) agent-based modules, and practice-based modules. These modules will be developed to target a trainee-level audience and shall require sufficient explanation of images/figures and data to be clear to an international audience.

For this Research Outline, NIEHS requires that the Contractor develop a system-based histopathology training module for pathology of the rodent tissue X. The module shall include:

1) Illustrations and annotated images of tissue trimming techniques with the appropriate figure legends

2) Annotated illustrations and images of normal histologic anatomy of the tissue X captured at the appropriate magnifications to demonstrate salient histologic anatomy with appropriate figure legends

3) Annotated images of non-neoplastic and neoplastic lesions captured at appropriate magnifications to demonstrate the salient histopathologic features with appropriate figure legends.

Requirements will include sourcing of photomicrographs, digital images, and/or whole-slide images and preparing descriptive pathology narratives. The Contractor shall work with NIEHS staff and external toxicologic pathologists to review and edit the modules and provide peer review.

The required deliverable shall be a 508 compliant training module in Powerpoint format.