Attach_3_SOW_Tox-Carc_FINAL_7_15_13.pdf

ATTACHMENT 3

STATEMENT OF WORK

FOR SUPPORT OF THE RESEARCH EFFORT TO EVALUATE

THE TOXIC AND CARCINOGENIC POTENTIAL

OF TEST AGENTS IN LABORATORY ANIMALS

FOR THE NATIONAL TOXICOLOGY PROGRAM (NTP)

July 2013

STATEMENT OF WORK

FOR SUPPORT OF THE RESEARCH EFFORT

TO EVALUATE THE TOXIC AND CARCINOGENIC POTENTIAL

OF TEST AGENTS

IN LABORATORY ANIMALS

FOR THE NATIONAL TOXICOLOGY PROGRAM (NTP)

GENERAL PROJECT OBJECTIVES AND REQUIREMENTS

The National Toxicology Program (NTP) is responsible for evaluating the toxic and carcinogenic potential of environmental agents that may pose a health hazard to citizens of the United States. The purpose of this contract is to support and assist this ongoing NTP research effort by conducting short-term and long-term studies of a variety of test agents by various routes of exposure. The project is designed to study diverse agents that may include: environmental chemicals; chemicals used in manufacturing or industrial settings; naturally occurring chemicals; food additives, preservatives, colorants or flavorings; pharmaceuticals, botanically- and non botanically-based dietary supplements; herbicides, fungicides, and pesticides; ingredients found in a wide variety of consumer products including soaps, lotions, perfumes and cosmetics; chemicals used in detergents and cleaners, etc.; naturally occurring and synthetic fibers, nanomaterials including carbon nanotubes; metals;

plasticizers; flame retardants; mold or mold components; or other agents not specified at this time.

Study designs and endpoints analyzed will be specific for individual test agents and will be submitted to the contractor as a Work Assignment. Sample Work Assignments are provided for 4 test agents, representing various routes of exposure (whole-body inhalation, nose-only inhalation, dosed feed, gavage) in order to determine contractor capabilities and to standardize costing by offerors. For each contract year, the type and number of studies to be conducted under this contract may vary from the sample Work Assignments and projections provided in the section entitled “Instructions for Preparation of Technical and Business Proposals” as an example. However, the contractor must have the ability to concurrently conduct multiple studies per year under the contract.

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 work set forth below. In general, studies shall be conducted according to the requirements described in the Work Assignment and in the 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 (January 2011 and subsequent revisions;

http://ntp.niehs.nih.gov/ntp/Test_Info/FinalNTP_ToxCarSpecsJan2011.pdf). Specific study designs (or portions

of) may require the use of the NTP 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 (May 2011 and subsequent revisions;

http://ntp.niehs.nih.gov/ntp/Test_Info/FinalNTP_ReproSpecsMay2011_508.pdf); contractors will be directed as to studies or portions of studies that require these specifications.

Work shall be performed in accordance with the Good Laboratory Practice Regulations established by the FDA for Non-clinical Laboratory Studies (http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfr58_01.html) or as most recently updated. The contractor shall have in place a quality management plan. Information on quality management plans can be found at http://www.epa.gov/quality/qmps.html.

http://ntp.niehs.nih.gov/ntp/Test_Info/FinalNTP_ToxCarSpecsJan2011.pdf http://ntp.niehs.nih.gov/ntp/Test_Info/FinalNTP_ReproSpecsMay2011_508.pdf http://www.access.gpo.gov/nara/cfr/waisidx_01/21cfr58_01.html

The Contractor shall be Association for assessment and Accreditation of Laboratory Animal Care (AAALAC) accredited and shall have an approved animal welfare assurance on file with The Office of Laboratory Animal Welfare (OLAW). The contractor shall comply with Public Health Service (PHS) Policy, the Animal Welfare Act and regulations, the Guide for the Care and Use of Laboratory Animals and all local, state or federal regulations.

The Contractor shall have a working facility and have on staff experienced personnel to conduct the work described herein. 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. The Principal Investigator and Discipline Leaders for Toxicology, Exposure/Engineering (inhalation), Chemistry, Laboratory Animal Management, Health and Safety and Quality Assurance, shall be employees (e.g. not consultants or subcontractors). The daily interaction and constant coordination of efforts needed among these disciplines requires that they be physically and organizationally together.

PROJECT MANAGEMENT

It is anticipated that a severable services, cost reimbursement, level of effort type contract will be awarded. The day-to-day work performed under this contract will be managed on a “Work Assignment” basis, with individual Work Assignments prepared for each agent or group of agents to be studied under the contract. Each Work Assignment will be initiated by the Contracting Officer’s Representative (COR), will include a detailed description of the work to be performed, and will be sent directly to the Contractor. The Contractor will be asked to submit a technical proposal outlining the proposed technical approach and a cost proposal describing the proposed costs and effort. During the course of the studies, if the need for support of a particular Work Assignment changes, a “revised” Work Assignment will be submitted by the COR to the Contractor; if the revisions are significant the COR may request a cost proposal for the revision. Further instruction can be found in the section entitled “Instructions for Preparation of Technical and Business Proposals”. When the need for support of a particular Work Assignment has concluded, the Contractor shall submit a summary of milestones, costs and effort associated with the Work Assignment. An Administrative Work Assignment will be issued for the Contractor to use for activities such as preparation and submission of Technical and Cost proposals, periodic reports, and if needed, preliminary estimates of the amount of test agent required to complete the studies.

GENERAL STUDY DESIGNS

Ongoing and recurring evaluations shall be conducted to evaluate the toxicity and carcinogenicity of test agents by various routes of exposure. The design of studies assigned to the contract will vary as needed depending on the individual test agents, route(s) of exposure, and endpoints to be evaluated. Studies will typically utilize Harlan Sprague Dawley rats and B6C3F1/N mice; however, other stocks/strains or other species may be utilized.

Study duration may be from one to a few days up to 2-years or lifetime; exposure may begin in utero or in young animals; the route of administration may be inhalation (whole body or nose only), oral (dosed feed, dosed water, gavage), dermal or parenteral (intraperitoneal, subcutaneous, intravenous, intratracheal). Details for typical study designs and for individual routes of administration are found in the NTP Specifications.

Test agents will typically be provided to the contractor.

For inhalation studies, the contractor shall develop methods for characterizing identity and purity to be conducted prior to the start and during the course of the studies. In addition, methods for exposure generation and monitoring of chamber concentrations shall be developed and validated by the contractor for use prior to and during the course of the studies.

For routes of exposure other than inhalation, test agents will typically have been evaluated for identity and purity prior to shipment to the contractor, and bulk chemical reanalysis methods (identity and purity) and dose formulation and analysis methods will typically be provided to the contractor. The contractor will typically be required to demonstrate method performance prior to starting the studies.

The Contractor shall have an animal disease-screening program that complies with the NTP Specifications. The NTP will provide the address for shipment of samples for disease screening.

The Contractor shall use an electronic data capture system specified by the COR, such as a government owned toxicology data collection system or an NTP-leased system, for collection of study data. Study data shall be entered directly into the system. The Contractor shall not record data on paper (or other means) for which an NTP electronic data capture system is available, unless the server is unavailable. NTP will provide access to the system. The Contractor shall provide the computer hardware and high-speed internet connection (for example Citrix client solution) to access the server. NTP’s version of a leased system is currently under development and the NTP will provide additional information, system support and training for the system. Note: In the case that a leased system is used, it will not be Government owned and the Contractor is not expected to need access to government computer systems.

Ongoing activities and evaluations may include, but are not limited to, the following (all activities except for certain chemical analysis and disease screening activities are considered to be core work):

- chemistry activities typically to be conducted prior to the start of the studies include the 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 (for other routes of administration);

homogeneity and stability; preparation of a prestart chemistry report or prestart data summary that will ultimately be included in a study report

- disease screening

- exposure to test agents by various routes

- for perinatal studies, evaluation of dams for signs of partuition and numbers of implantations/resorptions, determinations of litter parameters such as survival, size, weight, abnormalities, gavage dosing of pups

- in-life chemistry activities during these studies include periodic bulk chemical reanalysis; for inhalation studies, daily monitoring of exposure conditions; for routes other than inhalation, periodic dose formulation preparation and analysis

- other in-life activities may include clinical observations; body weights; food or water consumption;

clinical pathology (hematology, clinical chemistries, urinalysis, hormones, methemoglobin, clotting time, etc.); collection and storage of blood and tissues; collection of excreta using metabolism cages;

bronchioalveolar lavage and evaluation of cytokines, LDH activity, albumin concentration, cell counts and differentials; neurotoxicity endpoints such as functional observation battery

- at sacrifice, necropsies, gross evaluations, organ weights; collection and storage of blood and tissues

- histopathology; cell proliferation

- characterization/fate/reactivity of material in the biological system (for example concentration of test agent or metabolite in blood/tissue/excreta, lung burden, determination of deposition and clearance rates)

- biochemical and molecular assays including, but not limited to measurement of cytochrome P450s, glutathione, alpha-2-globulin, gene expression

- immunotoxicity measurements (typically to involve only collection and shipment of samples to an

NIEHS contractor for evaluation)

- reproductive and developmental endpoints (such as developmental landmarks, sexual maturation, fertility/fecundity, anogenital distance, teratology, etc); sperm and vaginal cytology sample collection and evaluations

- other functional toxicologic assessments (for example, cardiac function, pulmonary function, etc)

- in vitro assays, such as biodurability, cell death, metabolism, mechanistic assay, etc.

- submission of study reports, electronic data, pathology specimens and study files according to milestone and deliverable schedules

GOVERNMENT FURNISHED MATERIALS

- test agents (unless specified otherwise)

- methods for test agent characterization – identity and purity (unless specified otherwise)

- methods for dose formulation and analysis (unless specified otherwise)

- information on storage and stability for test article and dose formulations (unless specified otherwise)

- B6C3F1/N mice

- equipment, software and user manuals for a government owned toxicology data collection system or access to an NTP specified data management system

- information on NTP-designated suppliers for laboratory animals and disease screening will be provided after award

GENERAL INSTRUCTIONS FOR PREPARATION OF TECHNICAL AND BUSINESS PROPOSALS

Four Sample Work Assignments (A, B, C and D) have been included at Attachment 6 in order to provide Offerors examples of study types that might be conducted under this contract. Prestart chemistry work is a component of each sample Work Assignment. In addition, Work Assignment A contains prechronic and chronic nose-only inhalation studies of amosite asbestos, Work Assignment B contains chronic dosed-feed studies of n-nitrosodimethyl amine, Work Assignment C contains prechronic and chronic whole body inhalation studies of hydrogen sulfide, and Work Assignment D contains prechronic and chronic gavage studies of decabromodiphenylethane (Flame Retardant).

Offerors are to provide technical and cost information in their proposal for each of the Sample Work Assignments; technical information shall include identification of potential problems or issues with the conduct of these studies and proposed solutions to these problems or issues.

In order to estimate the total effort and cost over the 10 year period of this contract, Offerors are to assume that Work Assignments will be awarded per contract year (assume a starting date of October 1, 2013) according to the table below. There are 16 Base Sample Work Assignments and 10 Optional Sample Work Assignments for a total of 26 (7 each of A and B; 6 each of C and D). Note that for each contract year, the type and number of studies may vary from the Sample Work Assignments and that options may be unilaterally exercised by the Government at any time during the contract.

Base Contract Year 1

Contract Year 2

Contract Year 3

Contract Year 4

Contract Year 5

Contract Year 6

Contract Year 7

First Quarter A A A A A*

Second Quarter

B B B B B B B

Third Quarter

C C

Fourth Quarter

D D

Options

First Quarter A A

Second

Third

C C C C

Fourth Quarter

D D D D

*for Sample Work Assignment A awarded during year 7, assume that only the prestart and 2-year portions shall be conducted in order to allow sufficient time to complete the studies prior to the end of the contract.

MILESTONES AND DELIVERABLES

General Reporting Requirements

Narrative reports shall include charts, graphs, tabulations and pictures as necessary for explanation or support of the narrative. All final reports shall be dated and signed by the individual(s) responsible and the Quality Assurance Unit (QAU). Information on specific reporting requirements is presented below. All deliverables shall be sent directly to the appropriate recipient as indicated in the table below. Electronic deliverables must be compliant with Section 508 regarding accessibility. In some cases, there may be accommodations for which the COR will provide information annually.

Periodic Reports

Monthly Progress Report A Monthly Progress Report for the previous month shall be mailed by the fifteenth day of each month. Each Monthly Progress Report shall be submitted in the format specified in the NTP Specifications. No QAU audit of this report is required.

Sanitization Methods Report 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 EPA registration number and their chemical constituents if possible. Report any changes in procedures or products used in the appropriate Monthly Progress Report.

Water Analysis Water samples shall be collected for analysis and a report of the results submitted to the Contract Officer’s Representative 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 NTP, a report shall also be submitted within 30 days of contract award.

Health and Safety Chemical Hygiene Plan (General Facility Plan) An NTP approved Health and Safety Plan is required prior to any work commencing under the contract. An updated Health and Safety Plan shall be submitted to the NTP for review and approval every two years and anytime it is modified. Action to correct deficiencies shall be taken within 30 days of notification that such an action is required.

Study Reports

For each test agent evaluated, prestart chemistry data shall be generated and submitted in a prestart chemistry report (see the NTP specifications) according to the Schedule of Milestones and Deliverables included in each Work Assignment or as a study report appendix.

Study Reports shall follow the Report Formats provided in the NTP Specification and be submitted according to the Schedule for Milestones and Deliverables included in each Work Assignment.

Other Reports

Any incident or unforeseeable occurrences not listed in this document, or any physical modifications to the laboratory facilities, as well as any change in personnel which might have an impact on the conduct and results of studies shall be reported immediately to the NTP.

List of Milestones and Deliverables

Note that the information contained in this table may be modified for Actual Work Assignments

PERIODIC SUBMISSIONS FREQUENCY DUE DATES DISTRIBUTION (Number of copies)

Monthly Progress Report 1/month Mail by 15th each month CC (2); CO-Cover page only

Water Analysis Minimum 1/year; 1/prechronic study

CC(2)

PRESTART ACTIVITIES FREQUENCY DUE DATES DISTRIBUTION (Number of copies)

Submission of preliminary chemistry and generator and chamber characterization

1 TBD CC(1)

Submission of Prestart Chemistry Report or Prestart Inhalation Report

1 Within 3 months receipt of test material

CC (1 and DVD), CO-Cover page only

NTP Review and Approval to Proceed to Next Phase

NA Within 4 weeks of receipt of report

PRECHRONIC STUDIES FREQUENCY DUE DATES DISTRIBUTION (Number of copies)

Animal Study Protocol (IACUC approved)

1/Species Prior to study start COR(1)

Start of Study NA 4 Weeks from approval to proceed

Serum Samples for Disease Screening

See SPECS As collected SA-Send samples for evaluation

Clinical Lab Study Data Per Design CC(1), COR(1)

Blood for Micronuclei 1 Within 24 hours of collection MN-Blood and decoding information

MI-Copy of transmittal letter and decoding information

Study Report 1/Species Within 6 (<90 days) or 16 (>90 days) weeks from last day of necropsy

CC (1 and DVD) CO-Cover page only

Electronic Submission of Non- NTP-Specified System Data

1 Within 1 week after approval of report

CC-Transmittal letter and DVD

IANR Forms, Histology Processing Records, Slides, Blocks and Inventory;

Notification of Storage on TDMS

1/Species Within 4 weeks after approval of report

REP

CC, PC, QA-Copy of transmittal letter to include notification of pathology storage on TDMS

Wet Tissues and Inventory 1/Species Same as above REP

CC, PC, QA-Copy of transmittal letter

Archival Records for Study Raw Data and DVDs

1/Species Same as above REP CC-Copy of transmittal letter, inventory and DVDs

NTP Review and Approval to Proceed to Next Phase

NA 4 weeks after approval of report

CHRONIC STUDY FREQUENCY DUE DATES DISTRIBUTION (Number of Copies)

Animal Study Protocol (IACUC approved)

1/Species Prior to study start PO(1)

Start of Study NA 4 Weeks from approval to proceed

Serum Samples for Disease Screening

See SPECS As collected SA-Send samples for evaluation

Study Report 1/Species 30 Weeks from last day of necropsy CC (1 and DVD) CO (Cover page only)

Electronic Submission of Non- NTP-Specified System Data

1 Within 1 week of approval of Study Report

CC-Transmittal letter and DVD

IANR Forms, Histology Processing Records, Slides, Blocks and Inventory;

Notification of Storage on TDMS

1/Species 4 Weeks after submission of Study Report

REP

CC, PC, QA-Copy of transmittal letter to include notification of pathology storage on TDMS

Wet Tissues and Inventory 1/Species Same as above REP

CC, PC, QA-Copy of transmittal letter

Archival Records of Study Raw

Data and DVDs

1/Species Same as above REP

CC-Copy of transmittal letter, inventory and DVDs QA-Copy of transmittal letter

Shipment of 100 g Aliquot and Residual Test Material to Chemistry Contractor

1 At time of final bulk analysis CH CC-Copy of transmittal letter

IANR-Individual Animal Necropsy Record

TDMS-Toxicology Data Management System (also applicable to other NTP-specified data capture system

Abbreviations and General Addresses for Deliverables Exact names and addresses to be provided by the Contract Officer’s Representative SA Sentinel Animal Serum Samples To Be Provided

CC Contracts Coordinator Research Triangle Park, NC 27713

CH Chemistry Contractor To Be Provided

CO Contracting Office NIEHS, Office of Acquisitions Research Triangle Park, NC 27713

MI Micronuclei Decoding Information Research Triangle Park, NC 27709

MN Micronuclei Evaluation To Be Provided

PC Pathology Coordinator Research Triangle Park, NC 27709

COR Contract Officer’s Representative

NIEHS, DNTP, POB

Research Triangle Park, NC 27713

REP Repositories:

Archival Material - Raw Data

OR

Wet Tissues and Blocks Durham, NC 27713

SA Sentinel Animal Serum Samples To Be Provided