Draft Statement of Work.pdf

Section 1. Contract Objectives and Scope

1.1. Definitions of Terms

Refer to the Specifications for Chemistry Support Contractors (DTT Chemistry Specifications) for definitions of terms and acronyms used throughout this Statement of Work. DTT Chemistry Specifications can be found at the following link:

https://ntp.niehs.nih.gov/go/SS_chemistryspecs.

1.2. Contract Objectives

The contract will provide chemistry services in support of DTT research. The type and extent of the support provided by this contract will be tailored to specific DTT research needs. Chemistry services will typically be provided by the contractor on a per-test article basis to provide key pieces of information at each step of the DTT toxicological evaluation process. Because many of the DTT research programs study the same test articles, this approach will allow chemistry services to be applied to multiple studies conducted at different times in various DTT programs. This approach has been selected because it is the most cost-effective means of providing support for the various DTT research programs.

1.3. Scope

Independently, and not as an agent of the Government, the Contractor shall, in accordance with the terms and conditions set forth herein, furnish all qualified personnel, facilities, materials, and equipment (other than those furnished by the Government as specified herein), necessary to perform the chemistry services for a period of performance of ten years. An additional optional period of performance of six months is anticipated at the end of ten-year period.

Performance of this contract will involve Program Management procedures and technical activities in up to 9 Functional Areas as given below. Functional Activities under Functional Areas may be performed individually or in one or more combinations (see Functional Area 6, Special Studies). The Contractor is responsible for determining the level of effort required to perform the requirements defined by the Statement of Work, Section 2.

Contract Requirements (below). The Contractor, at a minimum is expected to perform Functional Areas 1 through 6 under the Base Contract and Options 1 and 2. The Contractor may elect to perform activities under Functional Areas 7 to 9 under Options 3 to 5. Detailed requirements for Functional Areas and Functional Activities are given in the DTT Chemistry Specifications.

https://ntp.niehs.nih.gov/go/SS_chemistryspecs

1.4. Program Management

Program management includes but is not limited to an effective quality program, an effective health and safety program, appropriate animal facilities management, effective communication between the contractor and the DTT, accurate and timely reporting of financial data, administrative data, and technical data, and appropriate usage of staff expertise and facilities as described under Statement of Work, Section 2. Contract Requirements (below).

1.5. Functional Areas

1.5.1. Logistics and Handling (Functional Area 1)

Logistics and Handling includes all activities pertaining to procurement, handling, and shipment of test articles and samples produced in support of all DTT research. Activities in this area include, but are not limited to, the Functional Activities described in Section

2.1 of the DTT Chemistry Specifications and shall be performed in accordance with the requirements set forth there.

Logistics and Handling typically involves performing any or all of the following activities:

1. Procure test articles, analytical standards, or samples (e.g., rodent plasma) from commercial and/or non-commercial sources.

2. Handle activities include, but are not limited to repackaging, milling, blending, storing, aliquoting, homogenizing, or photographing of procured material.

3. Ship and/or arranging for shipment of analytical standards, test articles, or samples to DTT-designated research facilities.

4. Receive analytical standards, test articles, or samples from DTT-designated laboratories.

5. Develop protocols for chemical handling and reanalysis, and dose formulation and analysis.

1.5.2. Characterization (Functional Area 2)

Characterization includes all activities related to establishing the identity and determining the purity of test articles, including developing methods needed to perform the analysis. Activities in this area include, but are not limited to, the Functional Activities described in Section 2.2 of the DTT Chemistry Specifications and shall be performed in accordance with the requirements set forth there.

Characterization typically involves performing any or all of the following activities:

1. Determine physical properties (e.g., melting point, color, optical rotation)

2. Establish identity and/or structure

3. Establish purity

4. Determine long-term storage stability

1.5.3. Formulation (Functional Area 3)

Formulation includes all activities related to preparation, mixing, and analysis of dose formulations containing one or more test articles in a vehicle (e.g., corn oil, water, feed).

Activities in this area include, but are not limited to, the Functional Activities described in Section 2.3 of the DTT Chemistry Specifications and shall be performed in accordance with the requirements set forth there.

Formulation typically involves performing any or all of the following activities:

1. Determine solubility, suspendability, and/or syringeability of a test article in a vehicle or vehicles designated by the COR.

2. Develop methods for the formulation of a test article in a vehicle. For similar chemicals (e.g., a chemical class), a common preparation method shall be considered.

3. Develop, qualify, and/or validate methods needed to perform an analysis of a formulation for test article concentration. For similar chemicals (e.g., a chemical class), a common analysis method shall be considered.

4. Evaluate physical and chemical properties of a formulation, e.g., pH.

5. Evaluate the homogeneity of formulations that are not solutions.

6. Evaluate the stability of a formulation under several storage regimes, e.g., ambient temperature, refrigerator, and/or freezer conditions.

7. Evaluate the stability of a formulation under conditions of dosing.

8. Prepare and/or analyze formulations using qualified and/or validated analytical methods. Formulations to be analyzed may be prepared by the Contractor or supplied to the Contractor from a DTT-designated laboratory.

9. Analyze vehicles used in formulations for conformance to DTT, US Pharmacopeia (USP), or other specified requirements.

10. Prepare, analyze and/or ship prepared dose formulations to a DTT-designated laboratory, as directed by the COR.

1.5.4. Biosample Analysis (Functional Area 4)

Biosample analysis includes all activities related to determination of the concentration of an analyte (e.g., test article, a metabolite of the test article, DNA adduct, endogenous analyte) in a variety of matrices (e.g., blood, plasma, tissue). Activities in this area include, but are not limited to, the Functional Activities described in Section 2.4 of the DTT Chemistry Specifications and shall be performed in accordance with the requirements set forth there.

Biosample analysis typically involves performing any or all of the following activities:

1. Develop, qualify, and/or validate methods needed to perform the analyses.

2. Evaluate the stability of the analyte in the matrix during storage.

3. Determine the concentration of an analyte in one or more matrices.

1.5.5. Animal Studies (Functional Area 5)

To support animal studies, Functional Activities in Functional Areas 1-4 shall be conducted as described above or as directed by the COR.

Animal studies include all activities related to determining palatability; absorption, distribution, metabolism, and excretion (ADME) parameters; and/or toxicokinetic (TK) parameters of a test article administered to animals, typically rodents, via a route or routes of interest (e.g., oral gavage, drinking water, feed, and/or intravenous). All animal studies require a signed study protocol, which has been reviewed and approved by the Contractor’s Institutional Animal Care and Use Committee (or equivalent) and the DTT COR. All activities in this category shall be performed in accordance with the requirements set forth in the DTT Chemistry Specifications. Animal studies include the Functional Areas described in Section 2.5 of the DTT Chemistry Specifications and shall be performed in accordance with the requirements set forth there.

Animal studies typically involve performing any or all of the following activities:

1. Palatability Studies

a. Typically use non-radiolabeled test article.

b. Palatability is typically measured by comparing consumption of dosed feed and/or water, and animal body weights after up to 14 days of dosing, to control animals administered undosed feed and/or water.

2. TK Studies

a. Typically use non-radiolabeled test article. The test article may be administered following single or repeated exposure via the route(s) of interest.

b. Consist typically of preliminary and definitive studies with numbers of animals < 100 per species.

c. Typically measure concentration of analyte(s) (e.g., test article, metabolites) in a matrix (e.g., plasma, serum, tissues) over time following administration of test article.

d. Preliminary studies are typically limited to one animal per time point, in 2 species, both sexes, and up to 2 doses.

e. Results of preliminary studies may be used to establish time points for definitive studies, and, if needed, analyte concentration ranges to be validated in the biosample analysis method.

f. Definitive studies typically obtain samples from multiple animals (e.g., 3) per time point. Definitive studies typically utilize up to 3 doses, 2 species, and both sexes following single or repeated exposure via the route of interest.

g. Analysis of data and determination of TK parameters from analyte concentration versus time course data are described in the DTT Chemistry Specifications.

3. ADME Studies

a. Typically use radiolabeled test article. The test article may be administered following single or repeated exposure via the route(s) of interest.

b. Typically consist of studies with numbers of animals < 100 per species.

c. Studies typically utilize up to 3 doses, 2 species, and both sexes and obtain samples from multiple animals (e.g., 3) per end point.

d. Typically measure radiolabel equivalents (e.g., total, bound test article) in blood, excreta, and tissues, over the study duration.

e. Qualitatively and/or quantitatively determine the test article-specific metabolites or products in blood, plasma, serum, tissues, or urine, as directed by the COR.

f. ADME parameters determined are described in the DTT Chemistry Specifications

1.5.6. Special Studies (Functional Area 6)

Special studies include activities that are part of the overall scope of the contract but may or may not be contained within a single functional activity or represent only a portion of a functional activity. Activities in this category include, but are not limited to, the Functional Activities described in Section 2.6 of the DTT Chemistry Specifications and shall be performed in accordance with the requirements set forth there.

Special studies include, but are not limited to, performing any or all of the following activities:

1. Performance of a portion or subset of any functional activity. For example, only determining the stability of the formulation would be a special task, because the formulation development and validation activity requirement includes developing and validating a formulation development and analysis method, in addition to determining stability.

2. Performance of a combination of several portions or subsets of two or more functional activities as a single activity. For example, determining the test article identity and purity and formulation preparation and analysis is a combination of parts of the characterization and formulation analysis activities.

3. Performance of activities such as extraction and analysis of samples other than biological matrices (e.g., PM2.5 filters), nontargeted analysis of mixtures (e.g., botanical dietary supplements), identification of a metabolite of a test article in a biological matrix, partition coefficient determination of an analyte between two matrices, protein binding of an analyte, and inhalation feasibility studies conducted in a small chamber to determine the ability of a chemical or test article to be generated as a uniform atmosphere in an inhalation chamber.

4. Performance of activities to determine enzyme activity using probe substrates (e.g., use of midazolam to determine CYP 3A4 activity) and enzyme inhibition or induction following exposure to a test article (e.g., induction of CYP 1A1 following exposure to benzo(a)pyrene).

5. Performance of the annual water analysis required to confirm the acceptability of water supplied to animals under study in the Contractor’s animal facility.

6. Drafting of manuscripts and/or meeting abstracts and presentations for submittal to peer reviewed journals or presentations for scientific conferences. All manuscript and presentation work must be initiated by DTT via the COR.

1.5.7. Omics (Functional Area 7)

Omics include, but are not limited to, exposomics, proteomics, and/or metabolomics analyses, using state-of-the-art techniques, in biological matrices (e.g., cell lysates, urine, plasma) and/or environmental samples (e.g., water). Activities in this category include, but are not limited to, the Functional Activities described in Section 2.7 of the DTT Chemistry Specifications and shall be performed in accordance with the requirements set forth there. Omics analyses are anticipated to be performed under Option 3, Omics, and typically involve performing any or all of the following activities:

1. Performance of state-of-the-art nontargeted analysis approaches (e.g., high resolution mass spectrometry) to identify and/or quantify environmental chemicals in biological or environmental matrices (e.g., exposomics), as directed by the COR

2. Utilizing nontargeted analysis approaches to identify and/or quantify perturbations in the endogenous metabolome (i.e., metabolomics) or proteome (i.e., proteomics) following an insult (e.g., exposure to a test article), as directed by the COR.

1.5.8. In Vitro Assays (Functional Area 8)

In vitro assays include all activities related to determining in vitro ADME/toxicity (ADMET) of a test article typically in in vitro rodent and human models, as directed by the COR. Activities in this category include, but are not limited to, the Functional Activities described in Section 2.8 of the DTT Chemistry Specifications and shall be performed in accordance with the requirements set forth there. In vitro assays are anticipated to be performed under Option 4, In Vitro Assays. Examples of activities that fall under this Functional Area include, but not limited to:

1. Performance of assay(s) using suitable model(s) to determine absorption of a test article (e.g., Caco-2 monolayer model to determine intestinal absorption).

2. Performance of assay(s) using suitable model(s) to identify transporters responsible for ADME of a test article (e.g., Pgp GloTM assay to determine Pgp substrates).

3. Performance of assay(s) using suitable model(s) to determine clearance and metabolism of a test article (e.g., cryopreserved primary rodent hepatocytes to determine hepatic clearance and metabolism).

4. Performance of assay(s) using suitable model(s) to determine bioaccumulation of a test article following repeated exposure (e.g., HepatoPac or plateable hepatocyte model to determine bioaccumulation).

1.5.9. Medium to High Throughput Screen (MHTS) Activities (Functional Area 9)

MHTS activities include any of the activities that are part of the overall scope of the contract when performed in support of DTT research programs that involve testing of multiple test articles in medium (e.g., zebrafish) to high (e.g., cell-based) throughput assays. Activities in this category include, but are not limited to, the Functional Activities described in Sections 2.9 of the DTT Chemistry Specifications and shall be conducted in accordance with the requirements set forth there or as directed by the COR. These activities are anticipated to be performed under Option 5, Medium to High Throughput Screen (MHTS) Activities and involve:

1. Test Article-Related Activities

a. Procure and/or receive multiple test articles (typically < 100 g each).

b. Perform handling to receive and/or repackage chemicals.

c. Characterize test articles on receipt and periodically while in storage, including, but not limited to, determining identity and purity.

d. Prepare solutions of each test article in a solvent (e.g., dimethyl sulfoxide, DMSO) designated by the COR at concentrations typically < 200 mM.

e. Aliquot prepared solutions into vials, 96- or 384-well plates, and/or another container as required by the supported assay.

f. Ship prepared vials or plates to a researcher or laboratory designated by the

COR.

2. MHTS Chemical Inventory

a. Maintain all MHTS test articles under appropriate storage conditions.

b. Update and maintain a searchable inventory of all test articles stored for this program.

i. Inventory shall include metadata described in the DTT Chemistry Specifications.

ii. Inventory shall be searchable by DTT staff who obtain access credentials.

c. Create Excel files for groups or lists of test articles sent to researchers.

i. Excel files shall contain tabs for metadata and test article information as described in the DTT Chemistry Specifications.

ii. Excel files for each shipment shall be submitted to the Chemical Effects in Biological Systems (CEBS) List Matrix database hosted by the DTT.

Section 2. Contract Requirements

It is anticipated that a severable services, cost plus fixed fee, level of effort type contract will be awarded.

2.1. Project Management

The Contractor shall comply with the Project Management requirements described below and in Section 1 of the DTT Chemistry Specifications during performance of all work under this contract and apply appropriate staff expertise and facilities to ensure that assigned work is completed in a timely and cost-effective manner.

2.1.1. Contract Servicing

1. To ensure timely start-up of contract work, the Contractor shall:

a. Ensure that all proposed staff are in place within 60 days after contract award.

b. Ensure that all the proposed management documents are in place, including but not limited to, the IT Security Plan, the Health and Safety Plan (HASP) and the Quality Management Plan (QMP) within 30 days after award. All management documents shall conform to the requirements, including delivery requirements, set forth in the DTT Chemistry Specifications.

c. Ensure that facilities are as proposed and in good working order within 15 calendar days after contract award.

2. Coordination and Continuity of Services

a. The Contractor shall provide for effective and efficient coordination of contract performance with DTT personnel and other DTT-designated contractors.

3. Travel Requirements

a. Under this contract, travel is authorized for activities pursuant to contract requirements, in accordance with the Office of Management and Budget (OMB) Memo, M-12-12. Travel is authorized, with prior approval of the COR, to professional meetings for the purpose of presenting work conducted under this contract, for meetings with DTT staff, or as specified by the COR.

2.1.2. Scheduling and Information Management

1. The Contractor’s work in this area shall comply with the requirements described in the DTT Chemistry Specifications.

2. The Contractor shall use a DTT electronic information management system (IMS) (DTT IMS) specified by the Government to document assignments, including, but not limited to, assignment descriptions and activities under the contract; and to communicate with the COR regarding the status of ongoing assignments. DTT will provide access to this system. The Contractor shall provide the computer hardware and a high-speed internet connection to access these systems.

3. The Contractor shall employ an internal IMS to track the work performed under the contract. This system shall:

a. Monitor the status of all on-going work, including schedule, hours, and costs.

b. Serve as a Master Schedule for all assignments performed under U.S. Food and Drug Administration (FDA) Good Laboratory Practice (GLP) compliance requirements.

4. The Contractor shall provide schedules and assignment cost estimates that accurately reflect the work to be performed for all assigned work. The Contractor shall update the estimated assignment costs and schedules in their internal IMS and the DTT IMS when there are changes to cost and/or schedule (e.g., assignments that do not proceed as planned or assignment priorities change).

5. The Contractor shall develop and implement an IT security plan that demonstrates compliance of their data management systems and practices with the Federal Information Security Management Act of 2002 (FISMA). A DTT approved IT Security Plan is required prior to any work commencing under the contract and a copy of the proposed IT Security Plan shall be included in the contract proposal.

6. The Contractor shall comply with all applicable NIEHS/DTT Data Management Plans when submitting data to or holding/archiving data for the Government.

2.1.3. Quality Program

1. All work performed under this contract by the Contractor or any Subcontractor for any assignment that directly supports a DTT GLP study (e.g., Toxicology study) shall comply with Food and Drug Administration Good Laboratory Practices for Nonclinical Laboratory Studies (FDA GLP Regulations; Federal Register, 12/22/78, Part II et seq. (CFR Code of Federal Regulations Title 21) unless specifically authorized by the COR or specifically excluded in the DTT Chemistry Specifications.

2. The Contractor shall establish an effective Quality Program, which addresses the requirements described below for any assignment that directly supports a DTT GLP study, including for work performed by any Subcontractor.

3. The Contractor’s quality program shall:

a. Conform to the requirements set forth in the DTT Chemistry Specifications.

b. Implement a comprehensive quality management plan (QMP), which addresses the requirements of the DTT Chemistry Specifications (see Section 1, Part 4.

Quality Program for QMP requirements). A DTT approved QMP is required prior to commencement of any work under the contract and a copy of the proposed QMP must be included in the contract proposal.

c. Establish an effective quality control (QC) program to ensure that data obtained under this contract is of high quality.

d. Establish an independent Quality Assurance Unit headed by a qualified Quality Assurance Officer.

e. Establish SOPs for all activities performed under this contract, as required by the DTT Chemistry Specifications.

f. Provide appropriate, ongoing staff training to ensure that all work conforms to contract requirements, DTT Chemistry Specifications, and where appropriate, to FDA GLP requirements.

2.1.4. Health and Safety

1. The Contractor shall establish procedures to protect the health and safety of contract personnel performing work under this contract and provide staff with on-going training to ensure that they are aware of any potential hazards. Refer to the DTT Chemistry Specifications for a complete discussion of health and safety requirements.

2. The Contractor’s Health and Safety Program shall:

a. Conform to the requirements set forth in the DTT Chemistry Specifications, Section 3.

b. Provide a qualified Health and Safety Officer.

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=58

c. Obtain and maintain full Drug Enforcement Agency (DEA) licensing (Schedules 1-

5) that provides for procurement, receipt, storage, and shipment of Schedule 1-5 substances.

d. Develop and implement a detailed health and safety plan (HASP) that demonstrates compliance with the Occupational Safety and Health Act (Public Law 91-596 84 STAT 1590 1970, amended 2004) and applicable state and local safety and health codes, standards, and regulations. A DTT approved Health and Safety Plan is required prior to any work commencing under the contract and a copy of the proposed HASP shall be included in the contract proposal.

e. Safely dispose of hazardous wastes.

3. The Contractor shall comply with all federal, state, and local regulations for receipt, storage, handling, and shipping of hazardous chemicals, and with the National Cancer Institute (NCI) Safety Standards for Research Involving Chemical Carcinogens, DHEW Publication no. (NIH) 77-900 (1975), and subsequent revisions; and the NIH Guidelines for the Laboratory Use of Chemical Carcinogens, NIH Publication no 81- 2385 (May 1981), and subsequent revisions.

4. All shipments must comply with Department of Transportation (DOT) regulations and the DTT Specifications requirements for chemical shipments.

2.1.5. Animal Care and Use

1. The contract shall be conducted in compliance with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals, the Animal Welfare Act Regulations, the current edition of the Guide for the Care and Use of Laboratory Animals (the Guide), and all local, state or federal regulations and policies; and all animal care policies described in the DTT Chemistry Specifications.

2. The Contractor shall have an approved animal welfare assurance statement on file with the NIH Office of Laboratory Animal Welfare (OLAW) at the time of contract award.

(Note: A contractor that does not have an OLAW-approved Animal Welfare Assurance may be selected but the Contracting Officer will have to initiate the process of obtaining an assurance from OLAW; contract funds may not be expended for animal work until the assurance has been approved).

3. The Contractor shall be accredited by the AAALAC.

4. If animal species regulated by the U.S. Department of Agriculture are involved in the contract, 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.

5. The Contractor and all contract facilities shall have a functional Institutional Animal Care and Use Committee (IACUC). All proposals for use of animals must be described in Animal Study Protocols that have been approved by the IACUC.

6. Animal experimental protocols, approved by the contractor’s IACUC, shall be deliverables to the COR prior to the commencement of work. These contractor-approved protocols shall also be available to the NIEHS ACUC.

7. The Contractor shall utilize a qualified Laboratory Animal Veterinarian to supervise the care and health of the animals.

2.2. Technical Activities

2.2.1. General Requirements

1. 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. Ongoing, recurring chemistry services are assigned as required to support DTT research activities. The Contractor shall perform each assignment according to the requirements described at the time of assignment, and in compliance with the requirements of the DTT Chemistry Specifications for each Functional Activity. The requirements described by the DTT Chemistry Specifications for each functional activity are typical of the work to be performed. Occasionally, subsections of a functional activity may be omitted for a particular assignment, or an assignment may combine aspects of more than one functional activity (see Special Studies of the DTT Chemistry Specifications) per COR direction.

2. The Contractor shall have a working facility and have on their staff experienced key personnel to conduct the work described herein. An on-site evaluation of facilities and equipment may be made prior to award. The Principal Investigator, Deputy Principal Investigator, Discipline/Task Leaders (e.g., staff person leading a Functional Area), and the Health and Safety and Quality Assurance Officers shall be employees (i.e., not consultants or subcontractors). Any subcontracted Functional Area (i.g., animal studies) must have a responsible discipline leader at the prime contract who will oversee activities at the subcontractor. Subcontractors shall have a designated project manager to serve as the point of contact for the discipline leader.

2.2.2. Management of Technical Assignments

1. The day-to-day work performed under this contract will be managed as assignments, governed by assignment memos describing the work to be performed. Assignments shall be initiated by the COR to perform on one or more of the Functional Activities described in the DTT Chemistry Specifications. The assignment description shall be provided by the COR to the Contractor, who shall document the assignment scope and description in the DTT IMS as described below:

a. The Contractor shall consult with the COR to develop a schedule for the proposed work that includes, at minimum, the following milestones:

i. The estimated start date of work for the assignment.

ii. The estimated completion date of lab work for the assignment. If no lab work is involved, the estimated lab work completed date will reflect the date the data package will be completed and work on the draft report will begin.

iii. The estimated date of issuance of the Draft Final report. The reporting requirements can be found in Section 4 of the DTT Chemistry Specifications.

iv. The Contractor shall enter the agreed milestones into the DTT IMS.

b. The Contractor shall provide an estimated cost and hours budget, based on the work to be performed and post the estimated hours and cost to the DTT IMS.

c. The Contractor may not proceed with work on an assignment until the COR has reviewed and approved the proposed schedule and estimated cost in the IMS.

2. During performance of an assignment, the Contractor shall develop and follow assignment- or test article-specific SOPs for all work that employs validated analysis methods.

a. As work on an assignment proceeds, the Contractor shall update the DTT IMS with actual milestone dates as they are completed and revise estimated milestones when necessary. The Contractor’s intention to revise milestone dates must be communicated to the COR, who must approve any change to a milestone date.

b. As work on an assignment proceeds, the Contractor shall update the DTT IMS with cost and hours budget on a regular basis and/or requested by the COR. The Contractor’s intention to revise cost and hours budget for an assignment must be communicated to the COR.

c. The Contractor shall update the assignment workflow (e.g., status flag updated from ‘lab work in progress’ to ‘lab work complete’) in the DTT IMS when an assignment’s status changes. Specific status flags corresponding to assignment milestones will be established in the DTT IMS for all assignments.

d. The Contractor shall provide to the COR updated information on progress and/or changes in approach during the performance of each assignment.

i. Updates shall be posted to the DTT IMS in the form of threaded discussions as they occur or at least weekly, whichever is more frequent.

ii. Updates may also be required by the COR via other communication methods as needed (e.g., telephone). The Contractor shall summarize these communications in the DTT IMS.

iii. Updates shall include data, when applicable, in the form of tables, graphs, spreadsheets, and/or other documents.

3. The Contractor shall update the assignment workflow as work proceeds, compile all data supporting the assignment, and prepare and submit a Draft Final report according to the requirements set forth in the DTT Chemistry Specifications. If changes are requested by the COR after review of the Draft Final report, the Contractor shall make the changes and submit a revised Draft Final report.

4. Once the COR has approved the Draft Final report or subsequent revisions, the Contractor shall submit a signed Final Report according to the requirements set forth in the DTT Chemistry Specifications.

2.2.3. Ongoing Activities

The Contractor, at a minimum, is expected to perform activities under base and options 1 and 2. The contractor may elect to propose to perform activities under one or more of the elective optional functional areas 3, 4, and 5.

1. Base and Options 1 and 2

Ongoing activities for the Base Contract (Year 1), base contract option years (Option Years 1 through 9), and Options 1 and 2 may include any or all activities of the Functional Areas 1 through 6. The Contractor shall provide Program Management and Chemistry services in Functional Areas: Logistics and Handling, Characterization, Formulation, Biosample Analysis, Animal Studies, Special Studies. Requirements for each Functional Area are described in detail in the DTT Chemistry Specifications.

a. Under the Base Contract and all Option Years, assignments may vary from year to year, but typical annual assignment numbers for each Functional Activity included in the Base Contract are given in Table 1.

b. Option 1 for additional work (supplemental studies), if required, may include any Functional Activity or combination of Functional Activities covered by the Base Contract and Option Years. The requirements for Option 1 will therefore vary each time Option 1 is exercised.

c. Option 2 for a 6-month period of performance after Option Year 9 includes all of the chemistry services in Functional Areas 1-6 supplied under the base contract

2. Elective Options 3, 4, and 5

a. If included in the Contract, ongoing activities for Options 3, 4, and 5 may include any or all of the activities described in Functional Areas 7 (Omics), 8 (In Vitro

Assays), and 9 (MHTS Activities), respectively, in the DTT Chemistry Specifications. The Contractor shall provide relevant Program Management and Chemistry services in these Functional Areas.

b. Option 3 for Omics activities includes all Functional Activities described in Section 2.7 (Omics) of the DTT Chemistry Specifications. Assignments may vary from year to year, but typical annual assignment numbers for each Functional Activity included in Option 3 are given in Table 2.

c. Option 4 for In Vitro Assays-related activities includes all Functional Activities described in Section 2.8 (In Vitro Assays) of the DTT Chemistry Specifications.

Assignments may vary from year to year, but typical annual assignment numbers for each Functional Activity included in Option 4 are given in Table 3.

d. Option 5 for MHTS activities includes all Functional Activities found in Sections

2.1 (Logistics and Handling) and 2.9 MHTS Studies and the Chemical Identity and Purity Screen from Section 2.2 described in the DTT Chemistry Specifications.

Assignments may vary from year to year, but typical annual assignment numbers for each Functional Activity applicable to Option 5 are given in Table 4.

Table 1 - Anticipated Annual Functional Activities for Base Contract (per award)

Functional Activity Number of

Assignments Logistics and Handling – Section 2.1 DTT Chemistry Specifications

Chemical Handling (CH) 5 Chemical Procurement (CP) 5 Chemical Storage (CS) 3 Preliminary Chemical Studies (PCS) 1 Shipment (SHIP) 14 Multiple Chemical Handling (MCH)1 1 Multiple Chemical Procurement (MCP)1 1

Characterization – Section 2.2 DTT Chemistry Specifications Comprehensive Chemical Analysis (CCA) 3 Chemical Identity and Purity Screen (CIPS) 3 Chemical Reanalysis (CRA) 3 Protocols Development (PD) 1 Multiple Chemical Identity and Purity (MIPS)1

Formulation – Section 2.3 DTT Chemistry Specifications Formulation Analysis (FA) 1 Formulation Development and Qualification (FDQ) 1 Formulation Development and Validation (FDV) 3 Formulation Preparation and Analysis (FPA) 1 Formulation Preparation, Analysis, and Shipment (FPAS) 5 Vehicle Analysis (VA) 3

Biosample Analysis – Section 2.4 DTT Chemistry Specifications Biosample Method Development and Qualification (BMDQ) 2 Biosample Method Development and Validation (BMDV) 2 Biosample Analysis (BSA) 4 Extended Stability Study (EXS) 1 In Vitro Studies (IVS) 1

Animal Studies – Section 2.5 DTT Chemistry Specifications Toxicokinetic Study (TKS) 2 Absorption, Distribution, Metabolism, and Distribution Study (ADMES) 1

Special Studies – Section 2.6 DTT Chemistry Specifications Annual Water Analysis (AWA) 1 Publication Preparation (PUB) 1 Special Chemical Activity (SCA) 4

1 Functional Activity description and requirements are found in Section 2.9 MHTS of the DTT Chemistry Specifications.

Table 2 - Anticipated Annual Functional Activities for Option 3 Omics (per award)

Functional Area/Activity

Number of Assignments per Exercise

Omics – Section 2.7 DTT Chemistry Specifications Omics Studies (OMICS) 4

Table 3 – Anticipated Annual Functional Activities for Option 4 In Vitro Assays (per award)

Functional Area/Activity

Number of Assignments per Exercise

In Vitro Assays – Section 2.8 DTT Chemistry Specifications In Vitro Assays (IVA) 4

Table 4 - Anticipated Annual Functional Activities for Option 5 MHTS Activities (per award)

Functional Area/Activity

Number of Assignments per Exercise

MHTS Activities – Section 2.9 DTT Chemistry Specifications HTS Chemical Handling (HCH) 1 HTS Chemical Identity and Purity Screen (HIPS) 1 HTS Chemical Procurement (HCP) 1 Multiple Chemical Handling (MCH) 4 Multiple Chemical Identity and Purity Screen (MIPS) 3 Multiple Chemical Procurement (MCP) 3

Logistics and Handling – Section 2.1 DTT Chemistry Specifications Chemical Handling (CH) 5 Chemical Procurement (CP) 5 Chemical Storage (CS) 6

Characterization – Section 2.2 DTT Chemistry Specifications Chemical Identity and Purity Screen (CIPS) 2

2.2.6. Reporting Requirements

The Contractor shall provide accurate, timely reporting of financial and administrative data, and results of all work done on the contract, in accordance with the contract requirements found in Attachment 4. Deliverables and the DTT Chemistry Specifications Section 4 Reporting Requirements