SOWAugust222014.pdf

STATEMENT OF WORK

PATHOLOGY PEER REVIEW AND PATHOLOGY SUPPORT FOR THE DIVISIONS

OF THE NATIONAL TOXICOLOGY PROGRAM (NTP) AND INTRAMURAL

RESEARCH (DIR) AT THE NATIONAL INSTITUTE OF ENVIRONMENTAL

HEALTH SCIENCES (NIEHS) DATED AUGUST 22, 2014

Background and Significance The National Toxicology Program (NTP), a Division of the National Institute of Environmental Health Sciences (NIEHS), evaluates the toxicity and carcinogenicity of agents of environmental concern by exposing rats and mice by appropriate routes (feed, water, inhalation, dermal, etc.) to various doses of the agents. These are conducted by a variety of testing laboratories under contract to the NTP. This interagency program comprises one of the world's largest scientific data resources in animal toxicity and carcinogenicity.

Since pathology results are crucial endpoints for most NTP studies, and a program of the magnitude and diversification of the NTP requires cooperation and collaboration of numerous testing laboratories throughout the nation, there is a need for assessment of uniformity, consistency, and accuracy of pathology data, diagnostic criteria, and procedures. The NTP Pathology peer-review process has been in place for over 30 years and is viewed as the international gold standard by agencies such as EPA, FDA, NIOSH, and IARC. It is a rigorous and integral part of providing high quality pathology data for NTP studies. Its goal is to verify and establish consistency in pathology results by using standardized criteria and review by experts. Peer review of the pathology data improves the quality of the data from NTP studies in multiple ways including; (1) correcting erroneous or inconsistent data, (2) improving initial evaluations resulting from feedback provided to laboratory pathologists, (3) improving study design by NTP personnel, and (4) identifying special pathology issues for which further studies are needed to more clearly characterize the toxicity and/or carcinogenicity of the chemical under study.

The NTP also provides pathology peer review for studies done by the National Center for Toxicologic Research (NCTR) in Jefferson, Arkansas (near Little Rock) through its pathology support contracts. These studies are similar in quantity and magnitude to chronic and subchronic studies done by the NTP.

Pathology support for other projects, within both the NTP and the Division of Intramural Research (DIR) at the NIEHS is also necessary. Pathology support for these other projects refers to the evaluation of histologically prepared tissue (including special stains), immunohistochemistry, electron microscopy, interpretation of molecular pathology data, or the measurement of cell replication and apoptosis or other special procedures.

Types of Studies Performed by the NTP which may require peer review and other pathology support The NTP performs many types of toxicity studies as described below (for more detailed information, refer to the NTP website). NTP studies are conducted according to Good Laboratory Practices (GLP). The study types performed by the NTP include, but are not limited to :

Chronic Studies: These studies are usually 2-year exposure studies. The default chronic rat study begins with perinatal exposure, but some studies may start with 6-8 week old animals (typical mouse studies begin with 6-8 week old animals). Some studies may include interim sacrifice groups or stop exposure groups. Chronic studies (those without interim or stop exposure groups) generally have at least 400 animals (usually 3 dose groups plus one control group, 50 animals per group, both sexes). Typically, chronic studies are done on both rats and mice for a given test article. Each study produces an average of 20 slides per animal with about 40 tissues per animal, for a total of approximately 15,000 tissues with a range upwards to 8,500 slides..

Subchronic Studies: These are usually 90-day exposures but may be more or less depending on program needs. Each study typically includes 5 dose groups and a control group with 10 animals per group, both sexes. Typically, subchronic studies are done on both rats and mice for a given test article. Each study produces an average of 11 slides per animal, or a total of approximately 1,300 slides per study.

Reproductive Assessment by Continuous Breeding (RACB) Studies: RACB studies usually include 3 exposure groups plus a control group. Only one species (usually rats) are used. There are 3 litters per breeding pair and up to 4 or 5 generations (usually 2 or 3). The tissue list for histopathological examination is generally limited to reproductive tissues plus a few major organs, usually from the F0, F1c, and possibly F2c animals.

These studies can have several thousand of slides including about 5,000 H&E slides, in addition to vaginal cytology slides for estrus staging and evaluation of mammary gland whole mounts.

Modified One-Generation (MOG) Studies: This is a new study design in which the offspring from the F0 generation (with exposure beginning in utero) are assigned to up to 5 cohort studies. The most likely cohorts include a reproductive or fertility study, a teratology study, a subchronic toxicity study, an immunotoxicity study, or developmental neurotoxicity study, but other possible cohorts include a chronic study, an RACB study, or any other type of study deemed necessary by the NTP. Depending on the number and type of cohorts utilized, the number of slides for review in these studies will range from several hundred to potentially around ten thousand slides.

Immunotoxicity Studies: The NTP has developed an expanded review for special immunotoxicity studies (see Immunotoxicity Study Pathology Specifications in Appendix

1) that includes a detailed, enhanced review of the lymphoid system (spleen, thymus, lymph nodes, bone marrow, and mucosa-associated lymphoid tissue). These studies generally include 5 exposure groups and positive and negative control groups with at least 8 animals per group, one species (typically mice), one sex (usually females), for a minimum of 56 animals per study. Occasionally, additional species (rats) or strains, or males may also be tested, so the number of animals per study may vary. The tissue list is also limited, but each tissue requires an in depth review.

For easy reference a table defining abbreviations has been generated (see Table 1)

Table 1. Abbreviations/definitions ACVP American College of Veterinary Pathologists APS Audit of Pathology Specimens CMPB Cellular and Molecular Pathology Branch (a branch of the Division of the National Toxicology Program, NIEHS) COR Contracting Officer’s Representative (previously known as Project

Officer or PO) DCU NTP Data Coordination Unit DIR Division of Intramural Research (a division of the NIEHS) GMM Studies utilizing Genetically Modified animal Models MOG Modified One-Generation Reproductive study with multiple cohorts NCTR National Center for Toxicological Research, Little Rock, Arkansas NIEHS National Institute of Environmental Health Sciences, RTP, NC NTP National Toxicology Program, NIEHS, RTP, NC NTP pathologist The pathologist at NTP assigned to the study who is ultimately responsible for defending the diagnoses and interpretation of the pathology data

PDR preQA pathology data review PPR Pathology Peer Review; The peer review process in general and the meeting and consensus of 3-5 pathologists; a smaller, more focused version of a PWG; generally applied to 90-day and other subchronic or special studies

QA Quality Assessment; an independent review and verification of the pathology materials and data. This was formerly called a PQA or Pathology Quality Assessement.

PWG Pathology Working Group; a panel of pathologists that each independently review slides to arrive at a consensus about the pathology diagnoses in order to achieve consistency of data within and between NTP studies

PWGC The pathologist who coordinates, conducts and organizes a PWG QAP The pathologist responsible for conducting the QA; sometimes called the reviewing pathologist (or RP) RACB Reproductive assessment by continuous breeding; a multigenerational study designed to evaluate the adverse effects of a test article on reproduction

Study Laboratory The contract laboratory that conducted the original study SP The pathologist from the original study lab who performed the original pathology evaluation at the laboratory where the study was conducted

General description of required objectives There are 2 major objectives to the contract:

1. Provide ongoing and recurring support for pathology peer review of NTP studies. Peer review includes evaluation of pathology records, evaluation of the pathology diagnoses and comparison with the histological material, and evaluation of clinical pathology specimens and clinical pathology data. It is anticipated that each contractor will peer review up to 30 studies per year, including chronic, subchronic, RACB, MOG, immunotoxicity, GMM, developmental neurotoxicity, and other studies.

2. Provide ongoing and recurring support for pathology evaluations for the Divisions of NTP (DNTP) and Intramural Research (DIR) projects: Pathology support projects include providing on-site staffing, necropsy services, histology services, special techniques (such as special tissue handling, histochemistry and immunohistochemistry), obtaining digital images, electron microscopy services (including electromicrograph evaluation), interpretation of molecular pathology data, training, assistance with manuscript preparation, and histopathology evaluation for NTP and NIEHS investigations. The contractor shall provide education to the investigators regarding issues identified during the study and pathology review. Each contractor will perform up to 30 support projects per year for NTP and DIR.

Detailed description of the technical requirements

Independently, and not as an agent of the Government, the Contractor(s) shall furnish all services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government under the terms of this contract to provide pathology support for peer review of NTP toxicity and carcinogenicity studies, as well as for NTP and DIR investigational and special studies.

All the activities described below shall be performed in compliance with Good Laboratory Practices (GLP). The type and amount of work will vary from year to year depending on the needs of the NTP. The following is expected:

1. General

The Contractor shall:

a. Develop Standard Operating Procedures (SOPs)

The Contractor shall develop a complete set of SOPs for all defined procedures specific for this contract. These will be reviewed by NTP prior to use.

b. Communication In order to facilitate thoughtful input into NIEHS and NTP research programs, and ensure that the needs of NIEHS and NTP investigators are clearly understood by contract staff with which they are working, it is essential to encourage regular interaction between the Contractor’s staff and NIEHS and NTP investigators. The Contractor’s staff shall attend meetings with NIEHS or NTP staff, as needed, to discuss collaborative projects in which they are involved.

c. Assignment, Tracking, and Reporting of Projects

The contractor shall conduct tasks for administration of this contract including, but not limited to, the preparation cost estimates, milestone schedules and reports, tracking of periods of performance and costs, preparation of monthly, quarterly, annual, or other reports that are submitted to the COR and CO, and meetings with the COR or CO.

2. Pathology Peer Review

a. Pre-QA Pathology Data Review (PDR).

A PDR review will be conducted for chronic, subchronic, RACB, MOG, immunotoxicity, GMM, developmental neurotoxicity, and other select studies (see sample PDR report in Appendix 2). The Contractor shall:

(i) Review pathology data for deviations from historical control data, duplications of diagnoses (using different terms for morphologic variants of the same lesion), inappropriate use of topographies in the diagnoses, and tissues with low tissue accountability. During this review, the pathologists shall identify all positive, negative or unusual trends in the occurrence of potentially treatment-related changes (statistical analysis of the data will not be available, so the pathologist should include all lesions that may be treatment related). The data submitted shall be compared with the narrative prepared by the study pathologist to determine if the pathologist addressed all relevant issues. A portion of the in-life reports, necropsy and histology records, and individual animal pathology records as determined by the COR shall also be reviewed for completeness, accuracy and internal consistency of the information present in these pathology records.

(ii) Prepare a draft PDR report and submit it to the data coordination unit (DCU) at the NIEHS. The report shall contain recommendations for tissue/lesion review and beneficial special studies. The report must also include representative excerpts from the study laboratory’s pathology narrative as a summary of the original findings. The first draft shall be submitted to the DCU not more than 30 calendar days after receipt of all pathology records from the study laboratory.

(iii) Convene a PDR meeting with NTP staff to review the draft PDR report and the pathology findings of the study. Following this meeting, a second draft of the PDR report will be drafted by the contract PDR pathologist and submitted to the

DCU.

(iv) Submit a final PDR report after approval by the NTP pathologist. The submission shall include an electronic version in an NTP specified format and color-print hard copy that is submitted to the NTP DCU and the NTP pathologist, with an email notice to the COR. The PDR pathologist will finalize the tissue review list and select animals to be reviewed in the audit of pathology materials.

The final report of the PDR shall be completed not more than 20 calendar days, after the PDR meeting.

b. Audit of Pathology Specimens (APS).

An APS will be performed for all chronic, subchronic, RACB, MOG, immunotoxicity, GMM, developmental neurotoxicity, and other select studies (see sample APS report in Appendix 3). The Contractor shall:

(i) Examine the residual formalin fixed wet tissues, paraffin blocks and microscope slides from randomly selected animals (usually 10%) as well as from animals identified during the PDR meeting or by NTP personnel. The NTP pathologist may request the examination of additional materials.

(ii) Examine the residual formalin-fixed tissues to evaluate the accuracy of animal identification, the adequacy of the necropsy and gross trimming of the tissues, and the possible presence of gross lesions which were not described at necropsy or trimmed for microscopic examination.

(iii) Examine the microscope slides to determine that they are labeled according to the NTP specifications for toxicity and carcinogenicity studies (Specifications For The Conduct Of Studies To Evaluate The Toxic And Carcinogenic Potential Of Chemical, Biological And Physical Agents In Laboratory Animals For The National Toxicology Program (NTP), January 2011; and any revisions, and the NTP specifications for reproductive and developmental toxicity studies (Specifications For The Conduct Of Studies To Evaluate The Reproductive And Developmental Toxicity Of Chemical, Biological And Physical Agents In Laboratory Animals For The National Toxicology Program (NTP), May 10, 2011; and any revisions, and to determine if required tissues are present and have been consistently sampled. The slides shall be examined for tissue accountability and for histotechnical quality.

(v) Submit a final APS report within 30 calendar days of completion of the PDR.

c. Pathology Quality Assessment (QA).

QA will be performed on all chronic, subchronic, RACB, MOG, immunotoxicity, GMM, developmental neurotoxicity, and other select studies (see QA Guidelines in Appendix 4 and sample QA report in Appendix 5). The Contractor shall:

(i) Have a means for automating the receipt of pathology data in electronic form and transferring the pathology data to QA tables and QA reports for use in the pathology QA process (for an example QA report with QA tables). Software used to prepare the QA tables and reports can be provided to the contractor.

Also, the NTP designated data management system that allows pathology data to be stored as print files or discs will be made available to the contractor.

(ii) Format and print the QA tables, which will include tumor diagnoses, tissues with potential treatment related lesions, other diagnoses or animals as required by the QA process, and for the PDR.

(iii) Perform microscopic examination of designated tissues/lesions (as designated in the PDR) to evaluate the consistency and accuracy of the histopathological diagnoses and to ensure that all treatment-related effects are reviewed and identified. This may include a review of mammary gland whole mounts for some studies. For subchronic studies, the QA pathologist shall review all histological slides from a percentage (usually 60%) of the high dose and control animals, plus a lower percentage (usually 10% of the animals from the other dose groups.

Also, for tissues in which there are a potential treatment related lesions (positive and negative), the QA pathologist shall review that tissue from all animals in the high dose group and each subsequently lower dose group until a clear no-observed-effect-level is reached. The QA pathologist will prepare an interpretive pathology narrative of the results of this review for submission to the NTP. For 90-day studies the report shall also include a summary of clinical pathology findings.

(iv) Evaluate the histotechnical quality (e.g., the quality of the staining and tissue sectioning) and accuracy of the original tissue counts. Activities include review of all slides for the presence of protocol-required tissues; and tabulating and correlating the data with the original laboratory report. These should adhere to the NTP Specifications 2011 and the specific study protocol.

(v) Prepare a detailed report on the pathology QA. This shall include an introduction detailing the study, types of lesions found, nature and significance of the lesions and a general evaluation of the quality of the slides and original pathology review. The body of the report shall include 1) listing of discrepancies between animal records and computer output, 2) details of histotechnical review, 3) listing of target tissues and discrepancies between study pathologist and QA pathologist, 4) lists and summary tables of original and QA tissue counts, and 5) other data as necessary. It is expected to take one week for the QA pathologist to write the QA narrative.

d. Pathology Working Group (PWG) / Pathology Peer Review (PPR).

A PWG or PPR will be conducted for all chronic, subchronic, RACB, MOG, immunotoxicity, GMM, developmental neurotoxicity, and other select studies (see PWG Guidelines in Appendix 6 and sample PWG report in Appendix 7). Typically, the QA pathologist shall conduct the QA and PWG/PPR reviews of NTP pathology data.

(see Appendix 8 for example). However, if deemed necessary by the NTP, the QA pathologist may be directed to perform only the QA of the pathology data, and a second pathologist from a different contract lab shall perform the PWG/PPR (i.e., separation of the QA and PWG processes). In such situations, the second pathologist will be referred to as the Pathology Working Group Coordinator (PWGC). The Contractor shall be responsible for the following.

(i) The QA pathologist will meet with the NTP pathologist to determine what issues need to be resolved by the PWG. If the PWG process is separated from the QA process, this meeting will take place after the PWGC has reviewed all the data, including the study, PDR, and QA reports, and the PWG slide set. The NTP pathologist and the QA pathologist decide which lesions in specific animals need to be brought to the PWG. The contractor shall generate PWG tables and submit to staff to have specific tissues with lesions pulled and ready.

(ii) The PWG slides shall be scanned (using an Aperio slide scanner or one compatible with the Spectrum software or other as specified by the COR) and uploaded to Spectrum. Once available on Spectrum, the QA pathologist (or PWGC) will annotate the images.

(iii) The PWG worksheets shall be prepared (one set for each participant). These worksheets contain tables listing the animal/slide identification, the diagnostic options available to the participants for each slide, and an area for comments on each slide.

(iv) The QA pathologist (or PWGC) shall prepare a 10-15 minute presentation for the PWG panel (given at the beginning of the PWG) highlighting the study design, findings of other relevant studies, and detailing the issues to be discussed and the relevant pathology data including summary data tables showing the diagnoses made by the SP and QAP.

(v) Conduct (planning, scheduling, inviting participants, leading) the Pathology Working Group (PWG) reviews (usually conducted at the NIEHS) for NTP studies and, as needed, for in-house NIEHS studies according to NTP guidelines.

The NTP pathologist, select expert pathologists, other NTP pathologists, and the QAP (if the there is a separate PWGC) typically attend the PWG. The NTP toxicologist and various trainees and guests of the NTP may also attend the PWG. The study pathologist is also invited and may attend in person, but typically attends via teleconference. NTP staff shall approve all PWG attendees.

(vi) On behalf of and under the direction of the NTP, conduct various administrative activities required for the PWG. This shall include, but may not be limited to various administrative actions relevant to coordinating the PWG,

(vii) The QA pathologist (or PWGC) shall conduct the PWG. The PWG Coordinator distributes the specific slides for review to the PWG participants for evaluation.

The slides are passed from one participant to the next until all participants have viewed all slides. The QA pathologist (or PWGC) shall direct the voting on each slide and record the votes of the voting participants. Once all slides have been reviewed and voted on, and all issues of importance have been discussed the PWG ends (this generally takes less than 8 hours).

(viii) As the result of the PWG findings and recommendations, re-evaluation of tissues or specific lesions already reviewed, or a review of additional tissues may be required as post-PWG action items. These activities will be completed by the QA pathologist (or PWGC).

(ix) After the PWG, the QAP (or PWGC) shall prepare and submit a draft report to the NTP pathologist for review and approval within 2 weeks of the PWG meeting. The report must contain (at a minimum) an introduction, a list of the potential treatment related lesions, a section that describes the conduct of the PWG, the conclusions of the PWG, a list of post-PWG action items, and images of salient lesions.

(x) Prepare and submit a final PWG report within 8 weeks of the PWG meeting for a typical chronic study. This includes completion of the PWG report and update of the data.

(xi) Following the PWG meeting, update the anatomic pathology data stored on NTP/NIEHS designated computerized data management system. The updates shall include and reflect the final corrected histopathological diagnoses that are the consensus of the PWG participants. It is estimated that approximately four

(4) to five (5) days are required to complete post-PWG data entry (including Quality Assurance) for each chronic study.

e. Data Entry

Enter pathology data generated from the initial study pathologist histopathological evaluation of protocol-required tissues from NTP studies, and the peer review (PWG or PPR) of such studies with NTP provided software.. The program is also designed to assist QA Pathologists or PWG Coordinators in organizing the data for presentation at the PWG review and in completing post-PWG tables to be included in the PWG report.

f. Clinical Pathology Data Quality Assessment.

Peer review of clinical chemistry, hematology, and/or vaginal cytology may occasionally be performed. Clinical chemistry and hematology are primarily done on subchronic or special studies, and vaginal cytology is done primarily on subchronic, RACB, and MOG studies. This may include an evaluation of a representative number of clinical pathology cytology slides to confirm that their quality is adequate for proper evaluation and interpretation.

3. Pathology support for the Division of the NTP and Division of Intramural Research

(DIR) projects

a. Initial Histopathological Evaluations for DNTP

The Contractor shall:

Perform initial histopathological evaluation of tissues from selected NTP animal studies and NTP-related studies. The Contractor shall also record findings, prepare summary tables of the histopathological findings and prepare a descriptive and interpretative narrative that summarizes the results of these evaluations for submission to the NTP.

Histopathological interpretations may include acquisition of digital images of microscopic lesions. The Contractor shall routinely use the NTP designated system for terminology and data entry. Typical evaluations may involve 3 to 5 dose groups plus controls, 10 to 15 animals/group, for 1 or 2 sexes with evaluation of 3 to 10 tissues.

b. Supplementary Pathology Reviews for the DNTP These include all slide reviews requested by the NTP either on slides from the original study set, or on new sets of slides prepared from the blocks or residual wet tissues. If additional slides need to be prepared for these reviews, the study lab will be responsible for preparing the slides. The most common of these types of studies, step section reviews of various organs (the most common of which are kidney step section reviews) and ovarian follicle counts are described below, but the NTP may request any type of slide review. All specialized reviews shall include the preparation of a report of the findings.

(i) Step Sections.

The Contractor shall:

Conduct histopathological evaluations on supplementary sections of tissues such as in brain, uterus, oral cavity, or kidney. Step-sections from paraffin-embedded or from residual wet tissues from NTP studies are generally employed when there is weak evidence of a carcinogenic response in that organ. The typical step-section evaluation for kidney may involve review of 6 to 8 sections per animal from 3 dose groups plus controls, 50 animals/group for 1 or 2 sexes. Preparation of step-sections will entail retrieval of residual tissues from tissue bags, embedding in paraffin, sectioning to obtain 6 to 8 sections per animal (3-4 from each kidney with the sections 100 apart) and preparation of Hematoxylin & Eosin-stained tissue slides.

(ii) Ovarian Follicle Counts The Contractor shall:

Conduct quantitative assessment of the ovarian follicles from selected reproductive or developmental toxicity studies. Ovarian follicle counts will typically be performed on control and high dose groups, but may be required on mid and low dose groups in some cases to determine a dose response or NOEL (No Observed Effect Level). Step sections of the right and left ovaries are prepared from 10 randomly selected animals per treatment group (in some cases, the COR may request more animals per group). The sections shall be collected at 100 m intervals and a minimum of 5, longitudinal (sectioned parallel to the long axis of the ovary) sections must be collected from each ovary. The sections are processed, mounted on slides, and stained with hematoxylin and eosin. The total number of primordial, growing (primary and secondary; preantral), and antral follicles and corpora lutea shall be recorded for each ovary by animal number.

Data from such counts shall be provided in an NTP specified electronic format that can be used in statistical analysis or other reporting.

c. Necropsy

Conduct complete necropsies at designated laboratories or at Government installations as the need arises. This includes necropsy support for NIEHS and NTP investigators on approved protocols. Necropsy procedures may include blood collection, whole body or organ perfusion for ultrastructural examinations, rapid freezing of various tissues, radiography and acquisition of digital images of gross lesions. The number of animals necropsied and the extent of the necropsies for individual projects will vary. The average necropsy will involve 100 to 160 animals with collection of approximately 50 tissues per animal (as described in the NTP Specifications 2011). Necropsy assistance may also entail post-fixation trimming of collected tissue samples, tissue processing, paraffin embedding and preparation of histological slides.

d. Histology

Provide a variety of histological services. Histology requirements shall include the following: tissue trimming, processing (fixation, dehydration, clearing and infiltration) and paraffin embedding, microtomy and histochemical staining of rodent or other tissues to produce high-quality tissue sections mounted on glass histology slides. The extent of the histology project assignments will vary to include: the preparation of paraffin or plastic tissue blocks, the preparation of stained (Hematoxylin and Eosin or special stains) and/or unstained tissue sections from wet tissue, trimmed tissues in cassettes or paraffin-embedded tissue blocks.

e. Histopathological Evaluations for the Division of Intramural Research

Perform initial histopathological evaluation of tissues from NIEHS intramural (DIR) studies. The Contractor shall also record findings, prepare summary tables of the histopathological findings and prepare a descriptive and interpretative narrative that summarizes the results of these evaluations for submission to the COR and NIEHS principle investigator (PI). Histopathological interpretations may include acquisition of digital images of microscopic lesions. The size and scope of these studies varies greatly, from 5 or 10 animals up to several hundred.

f. Specialized Pathology Evaluations

(i) Perform a variety of more specialized and sophisticated techniques on pathological specimens. These services shall include, characterization of non-neoplastic and neoplastic lesions by special stain techniques, ultrastructural examination, or routine immunohistochemistry, such as for the determination of cell proliferation indices using bromodeoxyuridine (BrdU) or Ki-67 or proliferation cell nuclear antigen (PCNA) immunohistochemistry, and the adaptation of new immunohistochemical methods for evaluation of pathology specimens using formalin-fixed, paraffin embedded sections and/or frozen tissue.

(ii) Interpret molecular pathology data or consult with NTP or NIEHS investigators on matters regarding molecular pathology study design [e.g., selection of molecular targets, method of investigation (e.g., rt-PCR, microarray, DNA sequencing, and more recent techniques), tissue collection methods, and other aspects of study design as requested by the COR.

(iii) Record and prepare a report of findings that includes methods, tables, a descriptive narrative and any visuals pertinent to the interpretation of the data.

(iv) Provide training and/or consultation for these and other specialized techniques.

In addition, the Contractor may be required to send its technical personnel to a laboratory to learn a new technique or instruct personnel in that laboratory in specialized techniques or a technique developed under this contract. This is anticipated to occur about once every other year and involve small groups of 2-5 people for about 5 days.

g. Data Entry

Enter histopathologic or other data from special studies (as part of an NTP study), or from smaller, in-house NTP or NIEHS studies, or other studies into an NTP designated system or into electronic file using an NTP designated format as directed by the COR.

4. Other requirements

a. Provide full time Veterinary Anatomic Pathology support , preferably ACVP-certified, on site at NIEHS to coordinate and accomplish the technical aspects of various projects.

The on-site support will shall provide serve as staff expert(s) expertise and consultant(s) in research and investigations relating to pathology, electron microscopy, toxicology and carcinogenesis. Further, the Contractor shall will manage the evaluation of the pathology and toxicology research data from NTP toxicity studies performed through contract laboratories and in-house studies for clarity, accuracy, and identification of target tissues and determination of the most appropriate descriptive terminology. Involvement in the pathology peer reviews; interpretation and reporting of the data; identification and pursuit of special projects that would advance the understanding of various biological endpoints are also expected. The appropriate subject matter expert will be involved in various areas of scientific investigation including general toxicological pathology, developmental and reproductive toxicology, immunopathology, molecular pathology, ultrastructural pathology, carcinogenesis, and neurotoxicology. Office space, microscope, printer, computer, digital camera and office supplies will be furnished by the NTP.

b. Provide technicians to work on-site at NIEHS in the DCU. These technicians will be responsible for the following activities: 1) serve as the Clinical Pathology Data Coordinators, 2) correct and verify pathology data updates, 3) review PDR, QA, and PWG reports, and 4) coordinate various aspects of NTP studies (tracking studies, managing data, coordinating the activities in the peer review process, etc.). The appropriate contractor personnel shall coordinate receipt of unaudited clinical pathology data for NTP and about 100-200 NIEHS animal studies (usually up to 100 samples each); review blood and bone marrow smears for acceptability of identification, preparation and staining; provide quality assessment evaluation of clinical pathology data, maintain the computerized storage of the information for the NTP and NIEHS, assist in the compilation of clinical pathology results for rats and mice based on data from contract laboratories and the NIEHS Clinical Pathology Laboratory, and any other activities deemed necessary by the COR. Office space, computer, printer and office supplies will be furnished by the NTP.

c. Provide qualified staff with appropriate trianing in histology and immunohistology on-site at NIEHS facilities, on an as-needed basis as determined by the COR, to perform.

all aspects of preparing high quality histologic and immunohistochemical slides from rodent tissues including tissue trimming, processing (fixation, dehydration, clearing and infiltration), embedding, microtomy, histochemical staining (including special stains), and cover slipping. They shall also perform all aspects of immunohistochemical slide preparation including tissue trimming, processing (fixation, dehydration, clearing and infiltration), embedding, microtomy, immunohistochemical staining (antigen retrieval, antibody preparation, primary and secondary antibody application, blocking, chromagen application, and counterstaining) and cover slipping. Proposed staff must also be able to develop, optimize, and troubleshoot staining protocols.

d. Provide administrative and technical support for laboratory animal medicine within the

Cellular and Molecular Pathology Branch. Personnel fulfilling this task may be required to be on-site.

e. Provide training in the NTP’s peer review process for new NTP and contract pathologists evaluating NTP studies by providing 4-8 hour instructional programs. This will include an overview of the peer review process, QA procedures, PWG procedures, and methods for improving pathological reviews and reporting. It is anticipated that this will take place at the contractor's facility.

f. Make frequent (once or twice daily) courier service trips to the NTP Archive and to the

NIEHS for the delivery and pickup of pathology slides, data, and other materials. All materials must be transported as described in the NTP specifications for toxicity and carcinogenicity studies (Specifications For The Conduct Of Studies To Evaluate The Toxic And Carcinogenic Potential Of Chemical, Biological And Physical Agents In Laboratory Animals For The National Toxicology Program (NTP), January 2011) and the NTP specifications for reproductive and developmental toxicity studies (Specifications For The Conduct Of Studies To Evaluate The Reproductive And Developmental Toxicity Of Chemical, Biological And Physical Agents In Laboratory Animals For The National Toxicology Program (NTP), May 10, 2011).

g. Have the contractors’ pathologists attend Pathology Working Group (PWG) meetings held at NIEHS (about 1-3 attendees at each of about 15 PWGs per year).

h. Assist with the preparation of manuscripts, scientific posters, and educational materials such as atlases, informational DVDs, or documents on the NTP peer review process.

Activities may include identifying or preparing images, writing portions of the text, or performing literature searches or reviews. Anticipate 5-10 such projects per year.

i. The Contractor’s pathology staff shall regularly attend and participate in the weekly

Cellular and Molecular Pathology Branch (CMPB) seminar series. This includes preparation and presentation of scientific studies or other topics by the Contractor as requested by the NIEHS or NTP. Regular attendance will keep the Contract pathologists up to date on the research activities of the NTP and NIEHS and will serve as continuing education, providing information on new research methods and techniques used by the NTP and NIEHS.

j. Investigate emerging technologies or techniques that advance pathology evaluations as requested by the COR. Such technologies may include new equipment, new software programs, new histological techniques (e.g., new fixatives), new sectioning protocols, or any other new technologies or techniques that may enhance pathology evaluations or peer reviews.

k. Visit the NIEHS weekly or as needed to meet with the COR to discuss project issues and solve potential problems. These visits shall be made by the Principal Investigator.

5. Travel-related activities as part of the routine work of this contract

The Contractor shall:

a. provide logistical support for invited PWG members (except for Federal Government and contract employees) to include arranging for hotel lodging and assisting PWG members with travel arrangements when required. The Contractor shall reimburse PWG members (except for Federal Government and contract employees) for travel expenses and provide an honorarium for services rendered based on government guidelines.

b. visit NTP-designated contract laboratories to conduct on-site training in necropsy or histotechnique or other specialized procedures as the need arises. Also, to instruct their pathology and QA departments on pathology data problems that can be identified, corrected and prevented at the laboratory. The number of visits is expected to be about 1-2 per year for lab visits. Possible locations for site visits include Columbus, OH, Chicago, IL, Birmingham, AL, and Research Triangle Park, NC. It is estimated that one to two trips of 2 to 3 days each for 1-2 individuals may be assigned.

c. have contractors’ pathologists attend periodic continuing education symposia held at

NIEHS or in the immediate vicinity. At the request of the NTP COR, one or more SPs may be invited and, if so, travel, lodging and per diem shall be paid by the contract. It is anticipated that there will be about 2-3 visits every two years. Travel, lodging and per diem are paid through the contract.

d. have qualified personnel make presentations at various NTP-sponsored symposia, workshops, etc. as requested by the NTP COR. If the personnel are located more than 100 miles from the Research Triangle Park area, their travel, lodging, and per diem will be paid through the contract. These workshops are held sporadically, but there are generally 1-2 workshops every 5 years.

e. On behalf of and under the direction of the NTP, manage and coordinate continuing education minisymposia for NTP and contract personnel. Activities may include booking a facility selected by the NTP, arranging AV equipment and support, preparing written materials, providing refreshments for the attendees, preparing and disseminating promotional materials, and inviting speakers and arranging their travel, lodging, and honoraria. This will be done on an as-needed basis (approximately 1-2 minisymposia every other year) as requested by NTP COR. It is estimated yearly travels will involve approximately 5 travelers. Travel, lodging and per diem are paid by the contract.

6. Deliverables / Reports

a. All final reports must be 508 compliant and in an NTP specified format.

b. Standard specific operating procedures (SOP) – An SOP for all defined procedures and tasks for this contract shall be submitted to the COR within 60 days after start of the contract.

c. Pathology specimens in the form of blocks, stained tissue sections, formalin-fixed tissues, frozen tissues, electron micrographs, and related tissues are to be returned either to the DIR PI or the NTP archives.

d. Report Types

1. Pathology Reports

i. Audit of Pathology Specimens (APS) Reports The APS report will be submitted to finalize the review of wet tissues, blocks and slides and list all discrepancies in animal identification, the adequacy of the necropsy and gross trimming of the tissues, and the possible presence of gross lesions which were not described at necropsy or trimmed for microscopic examination.

ii. PreQA Data Review (PDR) Reports

The PDR report will be submitted to finalize the tissue review list and select animals to be reviewed in the audit of pathology specimens.

iii. Pathology Quality Assessment (QA) Reports

The report shall include an introduction summarizing the findings and stating a conclusion regarding slide quality, quality of original pathology evaluation, significance of compound related lesions and suggestions for further review if deemed necessary. A separate bound and electronic copy of the clinical pathology findings shall be sent to the COR, DCU, NTP pathologist and NTP clinical pathologist. These shall be submitted within two weeks of completion of the Pathology QA.

iv. Pathology Working Group (PWG) or Peer Review (PPR) Reports

Subchronic, chronic, GMM, immunotoxicity, RACB, and MOG PWG/PPR reports shall consist of the PWG/PPR Coordinator’s Slide Review Worksheets, the pathology narrative, and any required appendices. The PWG Coordinator’s narrative shall include summaries that accurately reflect the conduct of the PWG including PWG discussions, the PWG conclusions on the issues discussed, chemical-related toxicity and/or carcinogenicity, and morphologic descriptions of chemical-related neoplastic, non-neoplastic, reproductive, or developmental effects. General comments by the PWG on histotechnique quality or recommendations for additional review shall be included in the report. See Deliverables Table on page 32 for required format, number of copies, and timeline.

v. Pathology Reports for Special Projects.

Reports are to be descriptive, including data in tabular, graphic and/or photographic form, using clear and concise statements of progress, problems, and anticipated activities in the next reporting period. Included in the data shall be such items as:

Introduction Background Objective(s) Design Number of tissues prepared Type of preparation Results Discussion

2. Administrative Reports

i. Monthly Reports A brief monthly report shall summarize the activities performed for each Task Assignment. This shall include the project (study) name, the identity of the initiator (NIEHS investigator), date assigned and completed. For pathologists, the number of hours dedicated to each Task Assignment shall be listed. When a project is completed it shall not be included in subsequent monthly reports but shall be listed in the annual report.

ii. Quarterly Reports

A quarterly report shall summarize all work completed by project (study) name, pathologist assigned, tissue(s) evaluated, tissues and slides prepared, and reports completed. A discussion of any problems encountered and statements of progress shall also be included. In addition, the report shall include under separate copy, a listing in tabulated form, indicating the project, the identity of the initiator (NIEHS/NTP investigator), materials submitted (wet tissue, blocks, slides), the actual level of effort (professional, technical land administrative/clerical hours), and the costs incurred.

iii. Annual Reports

An annual report shall summarize all work completed by project (study name, NIEHS/NTP investigator and pathologist assigned. The report shall include a listing of the tissues evaluated, tissues and slides prepared, and reports completed. In addition, the report shall include under separate copy, a listing in tabulated form, indicating the project, the identity of the initiator (NIEHS/NTP investigator), materials evaluated or prepared, the actual level of effort (professional, technical land administrative/clerical hours), and the costs incurred. The comprehensive annual report shall include an inventory of photomicrographs on file. A discussion of any problems encountered and statements of progress shall also be included. No annual report is required for the final year of contract performance.

iv. NTP/DIR Monthly Expenditure Reports

A report, in tabular form, shall be submitted on a quarterly basis (unless requested more frequently) that lists the projects assigned to the contractor.

The shall be grouped according to whether the project originated within the NTP or within DIR and shall provide monthly expenditures for each project and projects give a final total. At a minimum, the project number, principal investigator, and a brief description shall also be provided for each project.

For NTP projects, the NTP study number shall also be provided.

v. Site-Visit Reports

The contractor shall submit one original and one electronic copy to the contract officer and COR. This report will summarize the findings and detail the steps necessary by the contract laboratory or NTP to improve any deficiencies found. The report is due no later than two weeks after completion of the site visit.

vi. Final Report

This report shall contain a summary of the work completed under the contract.

e. Major Deliverables Table The table below lists the number and format for all report submissions and the due dates for each report type. All final electronic documents shall be section 508 compliant. All NTP pathology reports shall be delivered to the DCU. All non-NTP pathology reports shall be delivered to the COR and the assigned NTP Pathologist. All monthly, quarterly, annual, and NTP/DIR administrative reports shall be sent to the COR. Draft and final site visit reports and draft and final versions of the final report shall be sent to the COR and the contract officer.

DESCRIPTION QUANTITY DUE DATE

(a) Pathology Reports

(i) APS Reports

Draft One (1) original and two (2) hard copies; One (1) electronic copy in an NTP-specified electronic format

Within twenty (20) days of finalization of the PDR report.

Final One (1) original and two (2) hard copies; One (1) electronic copy in an NTP-specified electronic format

Within thirty (30) days of finalization of the PDR report.

(ii) PreQA PDR Reports

Draft One (1) original and two (2) hard Within thirty (30) days of an NTP-specified electronic format receipt of all pathology records from the study lab an NTP-specified electronic format

Within twenty (20) days of the PDR meeting

(iii) QA Reports

Draft One (1) original and two (2) hard copies; One (1) electronic copy in an NTP-specified electronic format

Not more than four (4) months after finalization of the PDR report an NTP-specified electronic format

Within two (2) weeks of receipt of the draft review comments from the NTP pathologist

(iv) PWG or PPR Reports

Draft One (1) original and two (2) hard an NTP-specified electronic format

Seven (7) days after the PWG meeting an NTP-specified electronic format

Seven (7) days after receipt of the draft review comments from the NTP pathologist

(v) Pathology Reports for Special Projects

Draft One (1) copy in an electronic format specified by the COR As specified by the COR

Final Two (2) copies in an electronic

As specified by the COR

(b) Administrative Reports

(1) Monthly Reports One (1) in an NTP-specified electronic format

Within two (2) weeks of the end of each month

(ii) Quarterly Reports One (1) in an NTP-specified electronic format Within two (2) weeks of the end of each quarter

(iii) Annual Reports One (1) in an NTP-specified electronic format Within sixty (60) days of the end of each contract year

(iv) NTP/DIR Monthly

Expenditure Reports

One (1) in an NTP-specified electronic format

Within two (2) weeks of the end of each quarter or as requested by the COR

(v) Site Visit Reports

Draft One (1) copy in an NTP-specified electronic format Within thirty (30) days of the end of the site visit

Final Two (2) copies in an electronic

Within two (2) weeks of receipt of the draft review comments from the COR

(vi) Final Report

Draft One (1) copy in an NTP-specified electronic format Sixty (60) days prior to contract expiration an NTP-specified electronic format

On or before contract expiration

All reports/deliverables shall be delivered to the COR at the address cited below. In addition, one copy of the Final Report shall be delivered to the Contracting Officer at the address cited below:

COR Contracting Officer COR, NIEHS Contracting Officer, NIEHS P. O. Box 12233 P. O. Box 12874 Research Triangle Park, NC 27709 Research Triangle Park, NC 27709

Web…