Attachments_75N96023R00009_Tox RFP 10.02.23.pdf

RFP 75N96023R00009 Attachment 1

PACKAGING AND DELIVERY OF PROPOSAL Page 1 of 2

Packaging and Delivery of Proposals for Use with the NIH electronic Contract Proposal Submission (eCPS) Website

I. PROPOSAL SUBMISSION

A. eCPS

1. Proposals must be submitted via the electronic Contract Proposal Submission (eCPS) website at https://ecps.nih.gov.

2. Proposals submitted by facsimile or e-mail will not be accepted.

3. Follow the “How to Submit an Electronic Proposal” instructions provided on the eCPS website at: https://ecps.nih.gov/home/howto. Please note that creating an account to submit may take up to three (3) business days. Please apply for a new account early to allow enough time for the registration process.

4. Offerors are solely responsible for submitting proposals and any modifications or revisions so as to reach the Government office designated above by the date and time specified in the solicitation. If your proposal is not received by the date and time specified in the solicitation, it will be considered a “late proposal,” in accordance with FAR Clause 52.215-1 Instructions to Offerors – Competitive Acquisition..

B. Creating and Naming Files:

1. Create one PDF file of your Technical Proposal, including all attachments. The Technical Proposal should be created in a PDF format that enables word searches to the maximum extent practicable. Forms and/or documents requiring signature(s) may be scanned but must be merged into the Technical Proposal PDF file.

2. Create one PDF file of your Business Proposal, including all attachments:

The Business Proposal should be created in a PDF format that enables word searches to the maximum extent practicable. Forms and/or documents requiring signature(s) may be scanned but must be merged into the Business Proposal PDF file. Additionally, the “Breakdown of Proposed Estimated Costs (plus Fee) with Excel Spreadsheet” (http://oamp.od.nih.gov/sites/default/files/DGS/contracting-forms/spshexcl_dec2012.xlsx) must be included in the Business Proposal.

3. Create your Business Document Excel. The Excel file should be the “Breakdown of Proposed Estimated Costs (plus Fee) with Excel Spreadsheet” (http://oamp.od.nih.gov/sites/default/files/DGS/contracting-forms/spshexcl_dec2012.xlsx) included in the Business Proposal in its original Excel format, not PDF. Multiple Excel files may be included, as necessary.

https://ecps.nih.gov/ https://ecps.nih.gov/home/howto http://oamp.od.nih.gov/sites/default/files/DGS/contracting-forms/spshexcl_dec2012.xlsx http://oamp.od.nih.gov/sites/default/files/DGS/contracting-forms/spshexcl_dec2012.xlsx http://oamp.od.nih.gov/sites/default/files/DGS/contracting-forms/spshexcl_dec2012.xlsx http://oamp.od.nih.gov/sites/default/files/DGS/contracting-forms/spshexcl_dec2012.xlsx

RFP 75N96023R00009 Attachment 1

PACKAGING AND DELIVERY OF PROPOSAL Page 2 of 2

4. Each of the proposals, Technical and Business, must be separate and complete in itself.

Do not reference one proposal in another.

5. File naming convention: It is requested that the filenames for your Technical Proposal, Business Proposal, and Excel Workbook include the name of the offeror, the solicitation number and the type of proposal (i.e., Technical, Business, or Excel Workbook).

Examples:

Technical Proposal: XYZ Company_NIHAI2012001_Technical.pdf Business Proposal: XYZ Company_NIHAI2012001_Business.pdf Excel Workbook: XYZ Company_NIHAI2012001_Business.xlsx

II. FORMATTING AND PAGE LIMITATIONS:

A. Formatting for proposals

1. Proposal page layout shall be letter size 8.5” x 11" for all pages.

2. Proposals shall not include links to internet web site addresses (URLs) or otherwise direct readers to alternate sources of information.

3. Proposals shall not include audio or video files of any type.

4. Font size must be 10 to 12 points.

5. Spacing should be no more than 15 characters per inch. Within a vertical inch, there must be no more than six lines of text.

6. Margins must be at least one-inch on all sides.

7. Failure to adhere to the formatting requirements above may impact whether your proposal is reviewed in its entirety.

B. Page limitations:

1. Please refer to page limitations in the Solicitation Submittal Requirements for each Factor listed in Section M of the RFP.

2. Pages exceeding limitations will be removed from the proposal and will not be considered.

PROPOSAL INTENT RESPONSE FORM

RFP No:

RFP Title:

Please review the Request for Proposal (RFP). Furnish the information requested below and return this page to the Contracting Officer/Contract Specialist identified on Section A-Solicitation/Contract Form by

Your expression of intent is not binding but will greatly assist us in planning for proposal evaluation.

Choose one of the following Options:

Do intend to submit a proposal Do Not intend to submit a proposal

If you are not responding to this RFP, please provide your reason(s):

Please provide the following contact information:

Name (First, Middle Initial, Last):

Title:

Organization:

E-mail:

RFP 75N96023R00009 Attachment 2

RFP-75N96023R00009 Attachment 3

Statement of Work for the Conduct of Toxicological Evaluations for the Division of Translational Toxicology

Revised, April 2023

Table of Contents

Table of Contents

I. Background

II. General Requirements

A. Specifications and Regulatory Compliance

B. In Vivo Study Conduct

C. Facilities and Personnel

1. Facilities

2. Professional Personnel

3. Technical Personnel

III. Program and Project Management

IV. Data Management

V. Study Designs

A. General Overview

B. Operational Requirements

C. Specific Study Elements

4. Biological Models

5. Chemistry

6. In Vitro Studies

7. In Vivo Studies

8. Endpoints for In Vitro and In Vivo Studies

VI. Government Furnished Materials and Information

VII. Appendix A. Contract Milestones and Deliverables

A. General Reporting Requirements

B. Sanitation Methods Report (Recipient: COR)

C. Periodic Reports

1. Monthly Progress Report (Recipient: COR, CO and CS)

2. Water Analysis (Recipient: COR)

4. Quality Management Plan (Recipient: COR)

D. Final Study Reports (Recipient: COR, CO and CS)

E. Budget Summary Report (Recipient COR, CO and CS)

G. Section 508 Compliance Report (Recipient COR, CO and CS)

VIII. Appendix B. Technical Work Plan and Budget

A. Technical work plans shall include (at a minimum)

B. Study budgets shall include (at a minimum)

IX. Appendix C. Sample Protocol Outlines Overview

A. Background

B. Problem Formulation

C. General Information

1. Project Management

2. Phases

3. Government Furnished Materials

D. Phase 1- Prestart Activities

1. Test Article Analyses

2. Development of Exposure System

E. Phase 2- Toxicity Study

1. Exposure

2. Observations

3. Cohort X/Y Assessments

4. Core Assessments

F. Study Schedule and Output Requirements

I. Background The Division of Translational Toxicology (DTT) is an intramural division of the National Institute of Environmental Health Sciences, National Institutes of Health. DTT uses traditional and cutting-edge approaches to better understand how factors in our environment may impact human health. Such approaches include the conduct of toxicology studies on chemical, physical, and biological agents, as well as non-chemical stressors, using in vitro and in vivo models of health and disease.

II. General Requirements Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, procedures, materials, equipment, and facilities not otherwise provided by the Government as needed to perform the studies set forth below. In general, studies shall be conducted according to the requirements described in a Protocol

Outline (see below), which includes the test agent-specific study design and endpoints to be analyzed.

A. Specifications and Regulatory Compliance

• To the greatest extent possible, all studies shall be conducted in accordance with the

Specifications for the Conduct of Toxicity Studies by the Division of Translational

Toxicology at NIEHS (https://ntp.niehs.nih.gov/go/DTT_toxicologyspecs), referred to hereafter as the DTT Specifications.

• When specified by the Protocol Outline, the study shall be performed in accordance with the Good Laboratory Practice (GLP) Regulations established by the U.S. Food and

Drug Administration for Non-clinical Laboratory Studies (21 CFR 58;

https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-58) or as most recently updated.

• The Contractor shall have in place a Quality Management Plan. Information on quality management plans can be found at https://www.epa.gov/quality/epa-qar-2-epa-requirements-quality-management-plans.

• For in vitro studies, the Contractor shall reference and utilize the Guidance Document on Good In Vitro Method Practices (https://www.oecd.org/env/guidance-document-on-good-in-vitro-method-practices-givimp-9789264304796-en.htm)

B. In Vivo Study Conduct

• Test facilities shall be accredited by AAALAC International and shall have an approved

Animal Welfare Assurance on file with the Office of Laboratory Animal Welfare (OLAW).

• Test facilities shall comply with Public Health Service (PHS) Policy, the Animal Welfare

Act and regulations, the current edition of the Guide for the Care and Use of Laboratory

Animals, and all local, state, or federal regulations.

• If animal species regulated by the USDA are involved, the Contractor shall be registered with the Secretary of Agriculture of the United States in accordance with 7 U.S.C 2136 and 9 CFR sections 2.25 through 2.28.

https://ntp.niehs.nih.gov/go/DTT_toxicologyspecs https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-58 https://www.epa.gov/quality/epa-qar-2-epa-requirements-quality-management-plans https://www.epa.gov/quality/epa-qar-2-epa-requirements-quality-management-plans https://www.oecd.org/env/guidance-document-on-good-in-vitro-method-practices-givimp-9789264304796-en.htm https://www.oecd.org/env/guidance-document-on-good-in-vitro-method-practices-givimp-9789264304796-en.htm

• Animal experimental protocols, approved by the Contractor’s institutional animal care and use committee (IACUC), shall be delivered to NIEHS prior to the commencement of a study. These Contractor-approved protocols shall also be available to the NIEHS ACUC.

• The Contractor shall have an animal disease-screening program that complies with the

DTT Specifications, Chapter 6.

C. Facilities and Personnel

1. Facilities Studies performed by the Contractor shall be conducted in a working facility with experienced personnel. A working facility means that the facility has in place essential features and staff with appropriate expertise to fulfill the requirements outlined in this SOW. All personnel described here shall have the requisite experience as described in the DTT Specifications, Chapter 1 (see below).

2. Professional Personnel

The Principal Investigator and Program Manager are both considered key personnel. The Discipline Leaders for Toxicology, Laboratory Animal Medicine, Health and Safety, Quality Assurance, Exposure/Engineering (inhalation), and Chemistry are considered to be critical staff. The daily interaction and constant coordination of efforts needed among these disciplines requires that they be physically and organizationally together.

The anatomic pathology discipline leader may be filled by a subcontracted staff and is also considered critical to the contract. Personnel filling subject matter expert (SME) roles shall be available for consultation and coordination as needed for specific studies.

3. Technical Personnel

Technical Personnel provide total effort to the program by job function.

The above general objectives and requirements apply by extension to any subcontracted work. All work to be performed by subcontract shall occur in a working facility that is fully accredited and compliant with all the above regulations. For critical staff roles under the contract, there shall be respective subcontractor SMEs that are responsible for liaising with the appropriate contract critical staff to ensure compliance with all requirements.

Please reference Chapter 1 of the Specifications (Table 1-1 Professional staff, Table 1-2 Technical staff) for General Personnel Requirements. Examples of personnel can be found at the following link:

https://ntp.niehs.nih.gov/ntp/test_info/toxspecs/chapter1_general_508.pdf ; included in https://doi.org/10.22427/NIEHS-00

III. Program and Project Management The Principal Investigator and Program Manager shall be responsible for the daily management of the contract and serve as points of contact for communication with the Government officials.

Collectively, the Principal Investigator and Program Manager are expected to be knowledgeable and involved in all aspects of the contract, including project status, record keeping, reporting, and detailed analysis of budget for all contract functions.

https://ntp.niehs.nih.gov/ntp/test_info/toxspecs/chapter1_general_508.pdf https://doi.org/10.22427/NIEHS-00

Although the contract, as a whole, shall be for the ongoing and recurring support for DTT toxicology research and testing evaluations, a Protocol Outline will be prepared and issued by the Government for each study and test agent(s) to be studied under the contract.

Each Protocol Outline will include a detailed description of the study(s) to be performed, or an outline of study objectives. In response, the Contractor shall submit a technical work plan outlining the proposed technical approach and a project budget describing the proposed costs and level of effort. Information to be included in the technical work plan and budget are included in Appendix B of this SOW.

In general, a specific study shall begin after the Government has reviewed the technical work plan and budget documents, and any questions have been discussed and resolved between the

Government and Contractor. As needed based on specific changes in a study, updates may be made to these documents after study initiation.

Administrative activities shall be conducted by the Contractor as described in the administrative

Protocol Outline. These activities include general management, periodic reports, or other

Government-approved activities not directly attributable to a specific study.

Submission of Protocol Outlines by the Government and technical work plans and budgets prepared by the Contractor shall be transmitted through a Government furnished program and project management (PPM) software. All substantive communication and decisions throughout the performance of work on a study shall be documented within the software.

IV. Data Management Data management plans for each study shall be reviewed and approved by the Government prior to any data collection. For in vivo data, the Contractor shall use an electronic data capture system specified by the Government for collection of study data, unless the Government has determined that collection of a specific endpoint(s) is/are not feasible. The current toxicology data collection system is a NIEHS-leased system; however, other systems, such as a Government-owned system, may be specified by the Government. Study data shall be entered directly into the system. The Contractor shall not record data on paper (or other means) for which a NIEHS electronic data capture system is available. NIEHS will provide access, system support, and training for the system. In vitro data shall be provided to NIEHS in a format reviewed and approved by the Government and shall be deposited in NIEHS’s database

“Chemical Effects in Biological Systems (CEBS)” with appropriate metadata. Additional data management requirements are included in the DTT Specifications, Chapter 11.

V. Study Designs

A. General Overview The overall research approach employed under this contract is likely to be tiered, with early project phases informing study design of later phases and facilitating timely dissemination of information to the public. Projects may explore health effects and disease-based outcomes or focus on generating screening level information for prioritization. Test agents may include chemical, physical, and biological agents, as well as non-chemical stressors.

For example, a class of data poor test agents may be evaluated in a higher throughput, lower complexity in vitro test system to identify agents with outcomes of higher potency or more diverse biological activity. Results from these studies would then be used to select a smaller group of test agents for more complex in vitro test systems or short term and subchronic in vivo studies. If warranted based on key characteristics identified during initial evaluations, more targeted and hypothesis-driven in vivo testing exploring specific health outcomes (e.g., DART, neurobehavior, cardiac, or pulmonary) or chronic exposures would be conducted. Alternatively, there may be information from a well conducted in vivo study (from DTT or published in the literature) that would lead to the design of a read across bridging study for a larger set of related test agents using in vitro or short-term in vivo models.

Contract personnel shall have the expertise to contribute to problem formulation and study design as required. In these cases, the Contractor shall develop a research plan based on input from the Government, background information and high-level program objectives. In other cases, the Government will provide a detailed Protocol Outline to be followed by the Contractor.

Ongoing and recurring evaluations shall be conducted to evaluate the toxicity and/or carcinogenicity of test agents by various routes of exposure. The design of studies conducted under the contract will vary as needed depending on the individual test agents, classes of test agents, route(s) of exposure, and endpoints to be evaluated. The Contractor shall have the ability to conduct multiple studies in parallel (e.g. 3-5 of varying durations) and accommodate multiple studies per year in different phases (e.g.

complete reporting while another study is on-test) under the Contract.

B. Operational Requirements For in vivo inhalation studies and in vitro exposure studies at the air-liquid interface, the bulk test agent may be provided by the Government or procured by the Contractor. The

Contractor shall develop methods for characterizing identity and purity to be conducted prior to the start of and during a study. In addition, methods for exposure generation and monitoring of chamber concentrations shall be developed and validated by the

Contractor for use prior to the start of and during a study.

For routes of exposure other than inhalation, the bulk test agent will commonly be provided by the Government. Test agents will normally have been comprehensively characterized prior to shipment to the Contractor. Methods to perform identity and purity analysis and dose formulation and analysis will typically be provided to the

Contractor. Standard chemistry support for non-inhalation studies will involve confirmation of identity and purity, demonstration of performance for formulation analysis method, and formulation preparation (based on established protocols) and analysis.

For conduct of in vivo studies, the Contractor shall have an animal disease-screening program that complies with the DTT Specifications. DTT will provide the address for shipment of samples for disease screening.

For information about data management and data capture, please see section IV. Data

Management and the DTT Specifications, Chapter 11. The Contractor shall provide the computer hardware and high-speed internet connection (for example Citrix client solution) necessary to access the server and demonstrate the ability to use the NIEHS-leased system to collect data under GLP regulations for electronic records. The

Contractor is not expected to need a government furnished computer. If access to a system requires use of government furnished computer equipment, the Government shall work with the Contractor to ensure the appropriate network account and equipment are procured.

C. Specific Study Elements

The following study design elements will be frequently encountered in Protocol Outlines. The actual assessments included in a specific study will vary according to the test agents selected and will be defined in the study Protocol Outline. A sample Protocol Outline has been included in Appendix C of this SOW.

4. Biological Models The Contractor will be responsible for the procurement of animals and in vitro test models to be used on study, unless otherwise specified by the Protocol Outline. Studies will typically utilize rodent in vivo models (e.g., Hsd:Sprague Dawley SD rats, B6C3F1/N mice, rodent disease models, diversity outbred models) or human and rodent in vitro test systems. Alternative animal models (e.g., C. elegans, zebrafish, etc.) may also be evaluated. Study durations may range from a few hours or days up to 2 years or lifetime for the test system.

• For in vivo studies, exposure may begin in utero or in young animals and the routes of administration may be inhalation (whole-body or nose-only), oral (e.g., dosed feed, dosed water, gavage), dermal, or parenteral (e.g., intraperitoneal, subcutaneous, intravenous, intratracheal).

• In vitro models may include immortal or primary cells, cell suspensions, cells grown on the air-liquid interface, or 3D complex tissue models including multiple cell types, such as microphysiological systems. Exposure models for in vitro systems may include standard cell culture conditions, exposure at the air-liquid interface, or microfluidic systems.

5. Chemistry As described above in Section V.B., the requirements for inhalation and non-inhalation studies will differ slightly. Specific requirements will be included in the Protocol Outline for a given study. Listed here are capabilities that the contractor may be required to perform on a select study. Detailed capabilities are also described in the DTT

Specifications, Chapter 5.

• Characterization of the bulk material (identity and purity)

• Development and validation of a generation and monitoring system for inhalation studies

• Development and validation of, or evaluation of method performance for, dose formulation and analysis methods and assessment of formulation stability and homogeneity

• Preparation of a prestart chemistry report and prestart data summary for inclusion in the study report

• On-study chemistry activities including periodic bulk test agent reanalysis

• Monitoring of exposure conditions for inhalation studies

• Periodic dose formulation preparation and analysis

6. In Vitro Studies

• Development and maintenance of in vitro biological models including, but not limited to cells grown at the air-liquid interface, cell culture of immortal or primary cells, cell differentiation, co-cultures, 3D tissue models, and microphysiological systems

• Evaluation of in vitro systems following exposure to test agents

• Cell imaging capabilities to evaluate cell morphology with a high throughput capacity (e.g., full plate imaging)

• Liquid handling capabilities and procedures for in vitro studies to reduce manual manipulation and ensure accuracy and reproducibility within and across experiments

• Assays evaluating cell proliferation, viability, and culture integrity (e.g., cytotoxicity, oxidative stress, trans-epithelial electrical resistance)

7. In Vivo Studies

a) In-life Procedures and Evaluations

• Exposure to test agents by various in vivo routes [e.g., inhalation, dosed water, dosed feed, gavage (including direct dosing of pups)]

• Disease screening

• Clinical observations, including evaluation of humane endpoints

(see DTT Specifications, Chapter 6).

• Body weights

• Food or water consumption

• Functional assessments and physiological monitoring (e.g., electrocardiogram, echocardiogram, aortic and left ventricular blood pressures, pulmonary function) using telemetered animals or other remote vital monitoring tools (e.g., video recordings with automated analysis software)

• Evaluation of pregnant animals (signs of parturition and numbers of implantations/resorptions; determinations of litter parameters such as survival, size, weight, abnormalities; determination of fertility/fecundity) and pups (developmental landmarks such as anogenital distance, balanopreputial separation, vaginal opening);

collection and evaluation of vaginal cytology samples

• Neurobehavioral endpoints such as detailed clinical observations (DCO), functional observation battery (FOB), remote physiological monitoring, motor activity, motor function, learning and memory, prepulse startle inhibition, or gait analysis

b) Terminal Assessments and Collections

• Necropsies including gross evaluations; organ weights; collection and storage of blood and tissues

• Collection of excreta using appropriate methods (e.g. using metabolism cages), including appropriate collection for volatile test articles

• Blood (survival and terminal) and tissue collection, including following whole-body perfusion

• Anatomic and clinical pathology

• Pulmonary function, bronchioalveolar lavage and evaluation of cytokines, LDH activity, albumin concentration, cell counts and differentials

• Structural and functional developmental (e.g., teratology) and reproductive (e.g., sperm motility and counts) endpoints

8. Endpoints for In Vitro and In Vivo Studies

• Collection and processing of cells and tissues for RNA isolation

• Gene expression analysis from in vivo and in vitro studies including, but not limited to:

o TempO-Seq or miRNA microarrays to capture small RNA species for microarray or qPCR applications o NanostringTM technologies which would allow Next Generation

Sequencing Gene expression profiling by RNAseq (e.g., mRNA or miRNA) or genomic sequencing (e.g., whole genome, exome sequencing) by DNAseq multiplexing of many transcripts and several samples at once

• Histopathology

• Biochemical and molecular assays including, but not limited to measurement of cytokines, gene expression, thyroid hormone, cytochrome

P450s, metabolomics, proteomics

• Characterization of test agents in the biological system (e.g., concentration of test agent or metabolite in media or biological matrices, lung burden, determination of clearance rates)

VI. Government Furnished Materials and Information Study-specific Government-furnished materials will be specified in the Protocol Outline. In general, the below materials will be provided by the Government:

• Test agents

• Methods for test agent identity and purity determination

• Methods for dose formulation and analysis

• Information on storage and stability for test agents and dose formulations

• Access to Government-specified laboratory information management system (LIMS) (currently an NIEHS-leased version of Provantis)

• Information on government-designated suppliers for laboratory animals and disease screening

• Government-owned rodent models

VII. Appendix A. Contract Milestones and Deliverables

A. General Reporting Requirements

Information on specific reporting requirements is presented below. All final study reports shall be dated and signed by the individual(s) responsible. Electronic deliverables must be compliant with Section 508 regarding accessibility. In some cases, there may be accommodations for which the Government will provide information annually. Formats and additional requirements for monthly reports, prestart chemistry reports, study reports, and study files are described in more detail in the DTT

Specifications.

In addition to the reports mentioned herein, any incidence or unforeseeable occurrence not listed here, including physical modifications to the laboratory facilities and personnel changes which may impact study conduct shall be immediately reported to the Government.

DELIVERABLE REFERENCE DUE/FREQUENCY FORMAT SUBMIT TO

Technical Work

Plan and

Estimated Budget

SOW – Section

III. Program and Project management

Due 3 weeks from

Protocol Outline submission. Due dates may be up to 6 weeks based on individual

Study Protocols assigned.

Electronic COR, CO, and CS

Sanitation

Methods Report

Appendix A – B. Due 90 days after contract award

Electronic COR

Monthly Technical

Progress Report

Appendix A –

C.1.

Due by the 15th of the following month

Electronic COR, CO, and CS

Water Analysis Appendix A –

C.2.

Analysis and a report of the results submitted at least once per year. An analysis is required during the in-life portion of the 13-week study and once each year during the two-year study. For laboratories that are not currently conducting studies for NIEHS, a report shall also be submitted within 30 days of contract award.

Electronic COR

Chemical Hygiene

Report and Health and Safety Plan

Appendix A –

C.3.

Submitted and approved prior to any work commencing.

Electronic COR

Updated reports:

Submitted and approved every two years and anytime it is modified, as described in the

Specifications.

Action to correct deficiencies shall be taken within 30 days of notification.

Quality

Management Plan

(QMP)

Appendix A –

C.4.

QMP - Submitted prior to any work commencing and updated versions submitted at regular intervals (e.g., biannually), or if the plan has been updated substantively, as described in the

Specifications.

Electronic COR

Final Study

Reports and Other

Study-Specific

Deliverables

Appendix A –

D.

Study Reports shall be submitted according to the Schedule for Requirements and Deliverables included in each Protocol Outline.

Electronic COR, CO, and CS

Budget Summary

Report

Appendix A – E. Due by the 15th of the month

MS Excel spreadsheets

(or in other spreadsheet software by agreement)

COR, CO, and CS

IT Security Plan and other IT

Related

Deliverables

Appendix A -

VII.F.

See Appendix A - VII.F. Electronic COR, CO and CS

Annual Section

508 Compliance

Report

Appendix A -

VII.G.

Due 30 days after PoP end

Electronic COR, CO and CS

Reporting Financial Conflicts of Interest

(FCOI)

Appendix A -

VII.H.

In accordance with https://www.ecfr.gov/c urrent/title-45/part-94.

Electronic CO and CS

Invention Reporting Requirements

Appendix A -

VII.I.

First utilization report -30 days after the end of the Fiscal Year

Annual Utilization report - 30th Calendar Day

Electronic

CO and CS

CO and CS https://www.ecfr.gov/current/title-45/part-94 following the reporting period

Final Invention Statement

Contract Financial Report (NIH 2706)

Appendix A -

VII.J.

No later than the 30th working day after the close of reporting period.

Monthly thereafter.

Electronic CO and CS

Subcontracting Report

Appendix A -

VII.K.

April 30th October 30th Expiration Date of Contract

Electronic CO via U.S. Department of Health and Human Services (HHS) Small Business Customer Experience (SBCX) system at https://osdbu.hhs.gov

Property Report Appendix A -

VII.L.

B. Sanitation Methods Report (Recipient: COR) A Sanitization Methods Report shall be due 90 days after contract award and shall describe in detail: the methods being used (and/or proposed for future use) for sanitization of equipment used in the studies to include at least chambers, cages, racks, feeders, watering devices, rooms, walls, halls, and buildings. Describe methods in detail, including commercial products used, their Environmental Protection Agency registration number and their chemical constituents if possible. Report any changes in procedures or products used in the appropriate Monthly Progress Report.

C. Periodic Reports

1. Monthly Progress Report (Recipient: COR, CO and CS) A Monthly Progress Report shall be submitted by the 15th day of the following month. No Quality Assurance Unit audit of this report is required.

2. Water Analysis (Recipient: COR) Water samples shall be collected for analysis and a report of the results submitted at least once per year. An analysis is required during the in-life portion of the 13-week study and once each year during the two-year study. For laboratories that are not currently conducting studies for NIEHS, a report shall also be submitted within 30 days of contract award.

3. Chemical Hygiene Report and Health and Safety Plan (Recipient: COR)

A Chemical Hygiene Report/Health and Safety Plan is required for submission and approval by the Government prior to any work commencing under the contract. An updated report shall be submitted for review and approval every two years and anytime it is modified, as described in the Specifications. Action to correct deficiencies shall be taken within 30 days of notification that such an action is required.

4. Quality Management Plan (Recipient: COR)

A Quality Management Plan (QMP) shall be submitted before performance of https://osdbu.hhs.gov/ work under the contract and updated versions submitted at regular intervals

(e.g., biannually), or if the plan has been updated substantively, as described in the Specifications.

D. Final Study Reports (Recipient: COR, CO and CS) For each test agent evaluated, prestart chemistry data shall be generated and submitted in a prestart chemistry report according to the Schedule of Requirements and Deliverables included in each Protocol Outline or as a study report appendix.

Final Study Reports (and other study-specific deliverables) shall be submitted according to the Schedule for Requirements and Deliverables included in each Protocol Outline.

E. Budget Summary Report (Recipient COR, CO and CS) For each activity separately undertaken, and for the contract, submit a monthly Budget Summary Report. The report must include amounts of each activity budget, total expenditures on the activity for the month, summaries of current contract year and cumulative expenditures, projected expenses to complete each activity. Budget Summary Reports shall be submitted monthly to the COR as MS Excel spreadsheets (or in other spreadsheet software by agreement) and shall be sortable as required by COR.

Budget summary reports must be included as an attachment with the monthly invoices.

Monthly Budget Reports are due by the 15th of each month.

F. IT Security Plan and other IT deliverables (Recipient COR, CO and CS) Refer to Section C, Article TBD of the contract for specific requirements related to IT

Security.

G. Section 508 Compliance Report (Recipient COR, CO and CS) The Contractor shall comply with Section 508 of the Rehabilitation Act of 1973 (29 U.S.C.

794d) which requires Federal agencies to purchase Electronic and Information Technologies (EIT) that meet specific accessibility standards. In order to conform to the Section 508 Electronic and Information Technology Accessibility Standards, the Contractor shall perform all work required under this contract in compliance with the provisions delineated in the Code of Federal Regulations (CFR) Title 36 (36 CFR Part 1194) and outlined below.

All electronic deliverables including reports, data entry, web pages, web applications, audio and video shall be Section 508-compliant; drafts do not need to be compliant.

Detailed data that is meant to be processed by a program and not meant to be read by people does not need to be Section 508 compliant. The following Section 508 accessibility technical standards apply to this SOW:

• E205.1 General Electronic content shall comply with E205.

The Contractor shall submit an annual Section 508 report in accordance with the schedule set forth in the ELECTRONIC AND INFORMATION TECHNOLOGY ACCESSIBILITY Article in SECTION H of the contract. Additional information about testing documents for Section 508 compliance, including guidance and specific checklists, by application, can be found at:

https://www.hhs.gov/web/section-508/index.html https://www.hhs.gov/web/section-508/index.html and at:

https://www.section508.gov/create/documents , "Create Accessible Documents."

Remediation of any materials that do not comply with the applicable provisions of 36 CFR Part 1194 as set forth in the SOW, shall be the responsibility of the Contractor.

H. Reporting of Financial Conflict of Interest (FCOI) All reports and documentation required by 45 CFR Part 94, Responsible Prospective Contractors including, but not limited to, the New FCOI Report, Annual FCOI Report, Revised FCOI Report, and the Mitigation Report, shall be submitted to the Contracting Officer in Electronic format. Thereafter, reports shall be due in accordance with the regulatory compliance requirements in 45 CFR Part 94. 45 CFR Part 94 is available at:

https://www.ecfr.gov/current/title-45/part-94.

See Part 94.5, Responsibilities of Institutions regarding Investigator financial conflicts of interest for complete information on reporting requirements.

(Reference the INSTITUTIONAL RESPONSIBILITY REGARDING INVESTIGATOR FINANCIAL

CONFLICTS OF INTEREST Article in SECTION H of the contract.)

I. INVENTION REPORTING REQUIREMENT

All reports and documentation required by FAR Clause 52.227-11, Patent Rights- Ownership by the Contractor including, but not limited to, the invention disclosure report, the confirmatory license, and the Government support certification, shall be directed to the Division of Extramural Inventions and Technology Resources (DEITR), OPERA, OER, NIH, 6705 Rockledge Drive, Suite 310, MSC 7980, Bethesda, Maryland 20892-7980 (Telephone: 301-435-1986). In addition, one copy of an annual utilization report, and a copy of the final invention statement, shall be submitted to the Contracting Officer. The final invention statement (see FAR 27.303(b)(2)(ii)) shall be submitted to the Contracting Officer on the expiration date of the contract.

The first annual utilization report shall be due on or before 30 days after the end of the fiscal year. Thereafter, reports shall be due on or before the 30th Calendar Day following the reporting period. The final invention statement (see FAR 27.303(b)(2)(ii)) shall be submitted on the expiration date of the contract.

If no invention is disclosed or no activity has occurred on a previously disclosed invention during the applicable reporting period, a negative report shall be submitted to the Contracting Officer.

To assist contractors in complying with invention reporting requirements of the clause, the NIH has developed "Interagency Edison," an electronic invention reporting system.

Use of Interagency Edison is required as it streamlines the reporting process and greatly reduces paperwork. Access to the system is through a secure interactive Web site to ensure that all information submitted is protected. Interagency Edison and information relating to the capabilities of the system can be obtained from the Web ( http://www.iedison.gov), or by contacting the Extramural Inventions and Technology Resources Branch, OPERA, NIH.

J. CONTRACT FINANCIAL REPORT

https://www.section508.gov/create/documents http://www.iedison.gov/

a. Financial reports on the attached Form NIH 2706, Financial Report of Individual Project/Contract, shall be submitted by the Contractor in accordance with the Instructions for Completing Form NIH 2706, which accompany the form, in an original and two copies, not later than the 30th working day after the close of the reporting period. The line entries for subdivisions of work and elements of cost (expenditure categories) which shall be reported within the total contract are listed in Section G of the contract. Subsequent changes and/or additions in the line entries shall be made in writing.

b. Unless otherwise stated in that part of the Instructions for Completing Form NIH 2706, entitled " PREPARATION INSTRUCTIONS," all columns A through J, shall be completed for each report submitted.

c. The first financial report shall cover the period consisting of the first full Calendar Month following the date of the contract, in addition to any fractional part of the initial month. Thereafter, reports will be on a Monthly basis.

d. The Contracting Officer may require the Contractor to submit detailed support for costs contained in one or more interim financial reports.

This clause does not supersede the record retention requirements in FAR Part 4.7.

K. SUBCONTRACTING REPORT

L. PROPERTY REPORT

VIII. Appendix B. Technical Work Plan and Budget

A. Technical work plans shall include (at a minimum):

o Detailed staffing plan, including study director, study pathologist, and applicable

SMEs. If the technical work plan includes staff that have not previously performed work on the contract, the work plan shall be accompanied by the requisite documentation of personnel experience and training.

o Draft protocols for each study, as well as supporting documentation for any new approaches being implemented that demonstrate acceptability.

o Study schedule for major milestones including the duration of the on-test period through to review of draft report by the Government.

o Data management plan describing the electronic submission mechanism and final disposition of all data types generated as part of the study.

B. Study budgets shall include (at a minimum):

o Significant technical assumptions that may impact effort or cost.

o Projected costs of purchased materials, other direct costs, etc.

o Detailed hours broken down by individually-named professional staff and technical staff by category.

o Estimated level of effort must include a detailed breakdown of cost (direct, indirect, and fee) and hours (by labor category) by month for each category and must align with the milestone schedule in the technical work plan and contract period.

o Hours and dollars for any subcontracted work or purchased service shall be accompanied by the subcontractor quote.

IX. Appendix C. Sample Protocol Outlines Overview

Study to Evaluate the Toxicity of [Test Article] in [Species] Following [Route of

Administration] Exposure

A. Background This section provides any critical information that may inform the Contractor’s technical approach (e.g., rationale for conducting the study or information to inform health and safety considerations).

B. Problem Formulation As needed for individual projects, the Government may require the Contractor to perform problem formulation to facilitate development of a project plan.

C. General Information

1. Project Management Studies shall be conducted in accordance with the Specifications for the Conduct of Toxicity

Studies for the Division of Translational Toxicology at NIEHS (DOI). The section will also describe whether the study should be conducted under Good Laboratory Practices.

2. Phases This section describes a high-level overview of the study phases and whether or not they can be performed in parallel or sequentially.

Some studies include multiple phases to be conducted in consecutive order. As an example, in this protocol outline, prestart chemistry work is to be conducted under phase 1 and the study in phase 2 should not be initiated until the Government has reviewed and approved the technical outcomes of phase 1.

3. Government Furnished Materials This section lists materials to be provided to the Contractor by the Government for the purposes of informing the technical approach (e.g., rodent procurement, planning for use of a particular

LIMS).

D. Phase 1- Prestart Activities

1. Test Article Analyses

• Receive the test material.

• Develop identity and purity methods for the test material.

• Conduct identity and purity analysis of the test material using the methods developed.

2. Development of Exposure System NOTE: this sample Protocol Outline describes requirements for a whole-body inhalation study.

The requirements listed here will vary based on route of exposure. For example, a study with feed, water, or gavage exposure would have requirements related to formulation development and validation.

• Develop methods for generation and chamber monitoring at the required concentrations.

• Validate the methods for generation and chamber monitoring

• Conduct 3-day chamber characterization studies.

• Determine measurement limits, specificity, precision, and linearity of the chamber concentration monitoring system.

• Determine T90, T10, chamber homogeneity, aerosol evaluation, and stability of the chamber concentration in all chambers. The stability of the chamber concentration must be established over three days at a daily duration to match that in the protocol outline. All the data must be obtained in the same exposure room and under identical conditions that will be used during the animal exposures.

• Conduct stability studies of the test material in the generator reservoir and chamber.

(Identification of possible degradation products is the responsibility of the Contractor.)

• Develop and test method(s) of effluent treatment during generation runs at the protocol-required concentrations in all chambers under actual animal exposure conditions.

o Demonstrate effectiveness of the exhaust treatment unit immediately after the effluent treatment unit and at the point of exhaust from the building.

o Establish the percent efficiency of the exhaust treatment. The effluent exhaust treatment must be effective in removing the test material to an acceptable concentration (i.e., greater that 90% efficiency of removal by the treatment system and less than 50% of the TLV, if a TLV exists), or written documentation for a waiver from the appropriate air regulatory agencies must be provided.

o Determine lifetime expectancy of any proposed filtration/treatment units and amount of treatment media required. Confirm that none of the exhausted test material is re-entrained.

• Develop and test method(s) of room air monitoring during generation runs at protocol-required concentrations in all chambers under actual animal exposure conditions. Define the lower limit of detection of the monitoring method(s) and document that this level provides an adequate safety margin for personnel.

• Prepare and submit a Prestart Inhalation Report of Phase I chemistry, exposure system, and health and safety activities and procedures to include:

o Description of bulk material identity and purity method development o Confirmatory data on identity, purity, and, if necessary, stability of the bulk material using methods developed, as well as copies of the SOPs for the bulk test agent reanalysis methods o Description of inhalation exposure chamber o Generation system description and approach o Chamber monitoring system description and calibration o Homogeneity of test atmosphere in chambers o Stability of chamber concentration over 3 days o Evaluation for the presence of aerosols o Chamber T90 and T10 o Test material stability studies in generator reservoir and chamber o SOPs for generation of test material, generation maintenance/change out, chamber monitoring system including calibration approach, , bulk material identity and purity and reanalysis, chamber homogeneity determinations, evaluation for the presence of aerosols; other SOPs as appropriate for the specific test material o Description of effluent exhaust treatment and SOPs o Effluent exhaust treatment monitoring data and percent efficiency of the effluent exhaust treatment o Room air monitoring methodology, strategy, SOPs, frequency, and results

• Upon successful completion and approval of Phase 1 (including Government review of the

Prestart Inhalation Report), the Contractor shall conduct work specified as Phase 2.

E. Phase 2- Toxicity Study

1. Exposure This section describes the test model(s) for in vivo studies, the life stage of exposure (adult, juvenile, perinatal), along with the route and duration of exposure. Based on experimental design, the total animal needs are presented. Some examples for these parameters include:

• Test model: species and stock/strain and sexes (e.g., male and female HSD:Sprague

Dawley SD rats), cell culture model(s) or tissue type(s) to replicate if in vitro

• Life stage for in vivo studies: e.g., adult, juvenile, or perinatal (time-mated pregnant) with age and weight requirements at study start

• Route of exposure: e.g., whole-body inhalation, nose-only inhalation, drinking water, feed, oral gavage for in vivo, or air-liquid interface or direct media dosing for in vitro

• Duration of exposure: single dose or one day, up to lifetime of exposure. For inhalation studies, the duration on each exposure day will also be provided (e.g., 6 hours + T90 per day).

• Other details: this section may also include unique study requirements related to diet, housing, enrichment, etc.

Table 1. Example Table Detailing Animal Requirementsa

Animals Species Sexes Groupsb Total

Core Cohort =

Cohort Xc = Cohort Y = Sentinel - =

Total a Columns in the table multiply to determine a total animal requirement for each cohort. For in vitro studies, a similar table would be presented which includes biological and technical replicate requirements and cohorts of tissues to be included.

b Number of exposure groups plus an untreated or vehicle control group.

c Additional cohorts are included if endpoints being assessed are not compatible with those being required in the core cohort.

2. Observations This section describes routine, scheduled activities during the on-test portion of the study. For all in vivo studies, animals will be observed “cage side” twice daily for moribundity and mortality, including holidays and weekends. In addition, “formal” or “out of cage” clinical observations will also be conducted. For short duration studies on test agents of unknown toxicity the frequency of formal clinical observations will be higher (e.g., daily), while longer duration studies with more test compound data may be less frequent (e.g., biweekly, weekly, monthly). In vitro study observations during the on-test period may include cell imaging at multiple times or other similar observations of cell health.

3. Cohort X/Y Assessments This section describes endpoints to be assessed in cohorts other than the core cohort. As described above in the Table 1 footnote, additional cohorts are often included when endpoint assessment is not compatible with the core group. For example, when histopathology must be conducted at an interim timepoint (e.g., 14 days in a 3-month study), or a large (terminal) amount of blood collection is required at a time point prior to the end of the study. The potential endpoints to be included here are detailed in the SOW sections V.C.3, V.C.4 and V.C.5.

4. Core Assessments This section describes endpoints to be assessed in the core cohort. The potential endpoints to be included here are detailed in the SOW sections V.C.3, V.C.4 and V.C.5.

F. Study Schedule and Output Requirements This section describes the required…