Solicitation_NIHES2016089_-_Amendment_2.pdf

Amendment 2 - Questions and Answers to RFP No. NIHES2016089

Title: Conduct of studies to Evaluate the Toxicologic Potential of Selected Test Agents for the National Toxicology Program (NTP)

1) Reference Attachment 8, Page 14 and Attachment 20, Page 1: The Additional Business

Proposal Instructions (Attachment 20) for Sample Study Assignment 4 state that the study will include thyroid assays (T3, T4, TSH), cytochrome P450, and collection and analysis of sperm and vaginal cytology (SCVCE) but the Sample Study Assignment 4 (Attachment 8) does not include these items. Please confirm that these items should be included in the Study Design and Business Proposal.

Response: For Sample Study Assignment 4, the study will not include thyroid assays

(T3, T4, TSH) or collection and analysis of sperm and vaginal cytology (SCVCE). It was inadvertently included in the Additional Business Proposal Instructions (Attachment 20). However, the study will include collection and analysis of cytochrome P450.

Sample Study Assignment 5 states (Attachment 8) that the study will include thyroid assays (T3, T4, TSH) and cholinesterase inhibition activity (AChE and BuChE)) but the Additional Business Proposal Instructions (Attachment 20) do not include these items.

Please confirm that these items should be included in the Study Design and Business Proposal.

Response: The Additional Business Proposal Instructions (Attachment 20) should have included thyroid assays (T3, T4, TSH) and cholinesterase inhibition activity (AChE and BuChE) for Sample Study Assignment 5.

2) Reference Attachment 3, Page 3; Attachment 8, Pages 5-7; and Attachment 20, Page 1:

Please confirm that for Sample Study Assignments 3 and 4 (reference Attachment 8 and Attachment 20) it should be assumed that test agents will be provided by the Government, these test agents will have been evaluated for identity and purity prior to shipment, and that the bulk chemical reanalysis methods (identity and purity) and dose formulation and analysis methods will be provided to the contractor (Attachment 3) therefore the contractor will only be required to demonstrate method performance as part of the work assignment and prior to initiation of the studies.

Response: Yes, this assumption is correct.

3) As a general comment, offerors are reminded that Sample Study Assignment #1 will not be part of the technical evaluation, but will only be evaluated as part of the business proposal for costing purposes.

*Amended versions of the Additional Business Proposal Instructions (Attachment 20) and the Additional Technical Proposal Instructions (Attachment 21) are attached.

Attachment 21

Additional Technical Proposal Instructions

Amended 11/15/2016 Amended language provided in italics

These Technical Proposal instructions reflect the requirement of the RFP and provide additional instructions for the preparation of the Technical Proposal. While Section L of the RFP provides a generic set of Technical Proposal instructions, these additional instructions are tailored to the specific requirements of the RFP.

Offerors are advised to give careful consideration to all aspects of the Statement of Work (SOW), the Mandatory Qualification Criteria, the Technical Evaluation Criteria, and the RFP as a whole in the development of their proposal. The offeror may include additional pertinent information within the guidelines listed below. The offeror shall refer to all referenced documents in the RFP and attachments.

Submission Instructions

The proposal, including appendices, shall include a detailed table of contents, be formatted by sections, and be cross-referenced to the Technical Evaluation Criteria. Offerors shall submit FIVE (5) full paper copies of the technical proposal and TWO (2) USB Flash drives containing electronic copies (password protected; use password TOX2016) of the technical proposal including appendices in a PDF searchable format. Proposals should NOT include links to Internet website addresses or otherwise direct readers/reviewers to alternate sources of information.

The offeror shall submit a detailed plan indicating how each aspect of the SOW is to be accomplished.

The Technical Proposal shall include information on how the project is to be organized, staffed, and managed.

Information should be provided to demonstrate the understanding of management of time frames for planning and accomplishing the work.

The Technical Proposal shall be in as much detail as necessary to explain the proposed methods and rationale, and should reflect a clear understanding of the nature of the work being undertaken.

The Technical Proposal shall include unique arrangements, facilities, equipment, or other factors that the offeror deems advantageous to the project.

The offeror shall include all information and supporting documentation addressing the mandatory qualification criteria in one clearly marked section of the Technical Proposal.

In order to facilitate efficient preparation and review of proposals and reduce paperwork burden, the following page limits shall apply to the technical proposal. Additionally, the total proposal including appendices shall not exceed 275 MB.

Aspect Page limit* Project Management and Coordination 25 pages Aspect Page limit* Toxicology 100 pages Analytical Chemistry 100 pages

Performance of Pathology Evaluations 50 pages

Performance of Clinical Pathology Evaluations

25 pages

Performance of Laboratory Animal Management

25 pages

GLP Compliance and Quality Assurance

25 pages

Health and Safety 25 pages

Personnel Position Description 2 pages for PI and critical staff;

½ page for other professional personnel, and 2 pages by job function (e.g. animal care technicians) for technical personnel.

Tables summarizing personnel and years of experience are not limited.

Environment – Facilities and Equipment

No page limit

Appendices Sample Study Assignments 50 pages/assignment

Quality Management Plan 50 pages

Health and Safety Chemical Hygiene Plan

50 pages

DRAFT Information Technology Security Plan

50 pages

Biographical sketches** 5 pages/person

*The total proposal including appendices shall not exceed 275 MB.

**Required for all personnel with a Master’s or Doctorate degree, or the equivalent in experience and/or responsibility.

Mandatory Qualification Criteria

The Offeror should include all information that documents and/or supports the mandatory qualification criteria in one clearly marked section of the technical proposal. This section related to the Mandatory Qualification Criteria must be listed in the Table of Contents with a page reference.

Technical Discussions

Statement of Work

For the statement of work (SOW) provided at Attachment 1, a detailed work plan shall be submitted indicating how each aspect of the SOW is to be accomplished. The Technical Proposal should be in as much detail as necessary to explain the proposed methods and rationale, and should reflect a clear understanding of the nature of the work being undertaken.

The Technical Proposal shall also include information on how the project is to be organized, staffed, and managed. Information should be provided to demonstrate the understanding of management of time frames for planning and accomplishing the work.

The offeror is referred to 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 thereof) 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):

https://ntp.niehs.nih.gov/ntp/test_info/finalntp_reprospecsmay2011_508.pdf

Specific study designs (or portions thereof) may also require the use of the “National Toxicology Program Neurobehavioral Testing Specifications” dated June 2015:

http://ntp.niehs.nih.gov/testing/types/neuro/index.html

Each offeror shall submit the following items as part of the technical proposal:

1) Demonstration of Understanding: Provide a brief overview to demonstrate an understanding the work outlined in the Statement of Work, potential biological effects, and how this information relates to study design, including route of administration and any differences in study outcome depending on route of exposure.

2) Personnel: Provide a functional organization chart for the project. Provide a list of personnel that will work on these studies (including but not limited to the Principal Investigator; Discipline Leaders for Toxicology, Developmental and Reproductive Toxicology, Neruotoxicology, Chemistry, Laboratory Animal Management, Pathology, Health and Safety and Quality Assurance; Study Directors, Pathologists, Laboratory Animal Veterinarians, Alternative animal model biologists/toxicologists, Clinical Pathologists, Cell/Molecular biologists; Toxciology, Clinical Pathology, Necropsy and Histopathology, Chemistry, Animal Care, Health and Safety, and Quality Assurance technical staffs, including their years of experience, availability to the project, and the number of hours committed to the project for each staff person. List additional personnel and include all information relevant to document individual training, education, experience, qualifications, and expertise necessary for the successful completion of all contract requirements. Clearly identify who is to be assigned as Key Personnel and Critical Staff. If Key Personnel or Critical Staff are committed to other government- supported projects, please include their time commitment to these projects.

Provide a biographical sketch for all personnel (in an appendix) with a Master’s or Doctorate degree, or the equivalent in experience and/or responsibility. Use the biographical sketch form in Attachment 22. Include information to document relevant training, experience, scientific expertise (professional staff only), and competency including selected references for publications relevant to the scope of the project (limited to 5 pages), necessary for the successful completion of all contract requirements.

The Principal Investigator and discipline leaders for Toxicology, Developmental and Reproductive Toxicology, Neurotoxicology, Chemistry, Laboratory Animal Management, Health and Safety and Quality Assurance, shall be employees (e.g.

not consultants or subcontractors). The Neurotoxicologists, Molecular/cell biologists and Study Directors shall also be employees (i.e., not consultants or subcontractors).

The daily interaction and constant coordination of efforts needed amongst these discipline areas throughout the in-life portion of the studies makes it critical that they be physically and organizationally together.

i) Quality Management Plan: Provide a Quality Management Plan. A QMP identifies the organizational structure, policy and procedures, functional responsibilities of management and staff, lines of authority, and its processes for planning, implementing, documenting, and assessing all activities conducted under the organization's quality system. Discuss within the QMP a process for assessing possible conflicts of interest.

For additional information on QMPs, see http://www.epa.gov/quality/qmps.html.

3) Health and Safety: Provide a Health and Safety Chemical Hygiene Plan. Document the approach and procedures for health and safety aspects to minimize/prevent exposure to potentially harmful situations and hazardous materials, including personal protection procedures/equipment, and monitoring methods and strategy. Document the locations of health and safety equipment. Document relevant training, experience, and competency of the proposed Health and Safety Officer (as demonstrated in the biographical sketch) and support staff, including proposed specific duties and effort on the project.

4) Facility and Equipment: Provide evidence of having a working laboratory in place for a sufficient length of time to demonstrate experience in conducting the required types of studies. A working laboratory means that the facility has in place essential features necessary to conduct GLP toxicity studies of environmental agents involving large groups of rats and mice (i.e., environmentally controlled animal rooms, analytical laboratories, clinical laboratory, necropsy room, histology facility, etc.) and staff with appropriate expertise to expose, care for, and process large numbers of animals (e.g., toxicologists, exposure/engineering personnel, pathologists, clinical pathologist, chemists, laboratory animal veterinarian, animal care technicians, prosectors, histologists, quality assurance group, etc.).

Provide detailed facility floor plans for all discipline areas (for example, chemistry, pathology, etc.) with clear labels as to function, equipment, and health and safety devices.

Animal facility floor plans shall include airflow direction and corridor system/traffic flow for personnel as well as animals, equipment and supplies through the facility(ies) proposed for use. All rooms are to be labeled as to use. Information on the air handling system and back-up generator and other pertinent features shall be included. The offeror shall have all the equipment necessary to accomplish the studies, including but not limited to, animal racks and caging, microscopes, centrifuges, cage washers, hazardous chemical storage cabinets and refrigerators, pathology equipment such microtomes, dose formulation equipment, laboratory and analytical chemistry equipment. The laboratory shall have or have access to appropriate terminal and computer facilities and equipment for data collection and storage.

5) SOPs: Provide a list of Standard Operating Procedures (SOPs) to be used in the management and technical conduct of the project.

6) Historical Control Data: Provide relevant historical control data for clinical pathology parameters included in the Specifications.

7) Gavage: Provide gavage proficiency data, including dosing of pre-weaned animals.

8) Subcontracting: If subcontractors/consultants are proposed, the offeror must clearly define how any proposed subcontract/consultant arrangements would meet program needs. A letter of commitment from the subcontractor/consultant must be provided. If subcontracting is suggested, details must be given as to how this would be structured, organized, managed and monitored. Information similar to items above must be provided for the subcontractor (including qualifications, historical control, proficiency data, list of SOPs and other information).

Sample Study Assignments

The following 5 Sample Study Assignments will be technically evaluated. A detailed copy of each is provided at Attachment 8.

*Please note that Sample Study Assignment #1 will NOT be part of the technical evaluation, but will only be evaluated as part of the business proposal for costing purposes.

1) Sample Study Assignment #2 for five-day studies in HSD rats by gavage for five chemicals in each study for the TGMX evaluation with the collection of liver and kidney for RNA preparation and microarray analysis, histopathology evaluations of liver and kidney, clinical pathology evaluations (clinical chemistry, and hematology). Assume one study per year.

2) Sample Study Assignment #3 for One 14-day study using B6C3F1 mouse and Harlan

Sprague Dawley rats by dermal route as described in the NTP specifications and the protocol outline provided. Assume that test agents will be provided by the Government, these test agents will have been evaluated for identity and purity prior to shipment, and bulk chemical reanalysis methods and dose formulation and analysis methods will be provided to the contractor. Assume one study per year.

3) Sample Study Assignment #4 for One 28-day study in HSD rats by gavage with prestart chemistry. Assume that test agents will be provided by the Government, these test agents will have been evaluated for identity and purity prior to shipment, and bulk chemical reanalysis methods and dose formulation and analysis methods will be provided to the contractor. The offeror shall revalidate the method and prepare formulations. The study will include clinical chemistry, hematology, thyroid assays (T3, T4, TSH), cytochrome P450, collection and analysis of sperm and vaginal cytology (SCVCE) and histopathology. Collect and send micronuclei samples to NTP designated contractor. Assume one study per year.

4) Sample Study Assignment #5 for One Perinatal Extended dose range finding study for a

Modified One Generation study (duration up to PND 56 days) in HSD rats, with detailed clinical observations, BPS, nipple retention, and gait analysis. The study will include thyroid assays (T3, T4, TSH) and cholinesterase inhibition activity (AChE and BuChE).

Refer to the NTP Repro Specs. Assume one study per year.

5) Sample Study Assignment #6 for in vitro evaluation of twenty test articles. The offerors are asked to propose assays for hepatotoxicity, neprotoxicity, neurotoxicity, cardiotoxicity screening. Provide separate cost for each assay you are proposing (see Additional Business Proposal Instructions). The contractor may do these studies in-house or have these studies done by sub-contract. If done by subcontract, give details of the arrangements, cost and time to complete the studies. Assume one study per year.

These Sample Study Assignments have been included to assess each Offeror’s capabilities.

Test agents are not identified in the sample study assignments (except assignment #5) because the focus shall be only on the Offeror’s capability to perform the type of activity included in the protocol. For each of these sample study assignments, describe the technical approach and provide a brief overview to demonstrate an understanding of the sample assignment. Include a discussion of any potential biological effects and how this relates to study design, including route of administration, and any differences in study outcome depending on route of exposure. Include detail on how the sample assignment is to be organized (i.e. staffed and managed) and conducted. Also, include details for the submission of all deliverables; include dates for critical events, QA audit/inspection schedule, and submission of all reports/deliverables. Include detail on all aspects of the work to be performed by contractor staff and any proposed subcontractors/consultants. Finally, identify potential problems or issues with the conduct of these assignments and proposed solutions to these problems or issues.

Attachment 20

Additional Business Proposal Instructions

Amended 11/15/2016

Amended language provided in italics

The business proposal shall be submitted as a separate volume from the technical proposal.

The following information should be used to assist offerors in preparing the business proposal.

Submission Instructions

The business proposal shall include a detailed table of contents and be clearly labeled. Offerors shall submit TWO (2) full paper copies of the business proposal and TWO (2) USB Flash drives containing electronic copies (password protected; use password TOX2016) of the business proposal. Please submit electronic copies of Excel spreadsheets in additional to the PDF copy of the business proposal. Proposals should NOT include links to Internet website addresses or otherwise direct readers/reviewers to alternate sources of information.

Base and Option Structure

The contract shall be proposed as a cost plus fixed fee, level of effort type contract and shall consist of one (1) base year + nine (9) optional years to extend for a total performance period of ten (10) years. In addition, Option 2 may be exercised to add additional level of effort and may be exercised multiple times each year up to 100% of the base level of effort for that year.

Cost Assumptions

In order to estimate the total effort and cost for each year of the contract, offerors are to assume a starting date of May 1, 2017 and shall assume that each year of the contract the following studies will be conducted:

1. Administrative Assignment #1 - the administrative assignment is to be used for activities such as the preparation of study-specific responses, calculation of test article needs, preparation of monthly reports, and water analysis/reporting. Ongoing throughout the year based on the number and types of study protocols.

2. Sample Study Assignment #2 - five day studies in HSD rats by gavage for five chemicals in each study for the TGMX evaluation with the collection of liver and kidney for RNA preparation and microarray analysis, histopathology evaluations of liver and kidney, clinical pathology evaluations (clinical chemistry, and hematology). Conducted 1x year.

3. Sample Study Assignment #3 - One 14-day study using B6C3F1 mouse by dermal route as described in the NTP specifications. Assume that test agents will be provided by the Government, these test agents will have been evaluated for identity and purity prior to shipment, and bulk chemical reanalysis methods and dose formulation and analysis methods will be provided to the contractor. Conducted 1x year.

4. Sample Study Assignment #4 - One 28-day study in HSD rats by gavage with prestart chemistry. Assume that test agents will be provided by the Government, these test agents will have been evaluated for identity and purity prior to shipment, and bulk chemical reanalysis methods and dose formulation and analysis methods will be provided to the contractor. The offeror shall revalidate the method and prepare formulations. The study will include clinical chemistry, hematology, thyroid assays (T3, T4, TSH) cytochrome P450, collection and analysis of sperm and vaginal cytology (SCVCE) and histopathology. Collect and send micronuclei samples to NTP designated contractor. Conducted 1x year.

5. Sample Study Assignment #5 - One Perinatal Extended dose range finding study for a Modified One Generation study (duration to PND 56 days) in HSD rats, with detailed clinical observations, BPS, VO, nipple retention, and gait analysis. Refer to the NTP Repro Specs. The study will include thyroid assays (T3, T4, TSH) and cholinesterase inhibition activity (AChE and BuChE). Conducted 1x year.

6. Sample Study Assignment #6 for in vitro evaluation of twenty (20) test articles. The offerors are asked to propose assays for hepatotoxicity, neprotoxicity, neurotoxicity, cardiotoxicity screening. Provide cost for each assay. *Note - When estimating the overall total yearly cost (a, b, d, and e below), only include the cost for hepatotoxicity and cardiotoxicity assays. Conducted 1x year.

Business Proposal Format

Offerors must provide a separate itemized effort and cost breakdown to include a detailed breakdown of direct labor hours (to include labor classification, professional vs technical), labor category, individual hourly rate, material cost, indirect rates, travel, subcontracting, and proposed fee.

The yearly total estimated cost/level of effort of the Contract can be estimated by taking the sum of the cost/level of effort of all six assignments provided above. This yearly total assumes that each optional year (Option 1) is exercised and Option 2 is exercised once each year to increase the level of effort by 100% each year.

Costs should be presented as follows:

(a) Base Years Cost Estimate (base year and each of the 9 option years) – provide a cost estimate for the base year and each successive year.

(b) Overall Cost Estimate (base + 9 option years + Option 2 at 100% each year) – provide a cost estimate for the base year and each successive year which also includes Option 2.

(c) Study Protocol Estimate – provide a separate itemized effort and cost breakdown associated with each sample assignment (1 – 6) listed above.

(d) Summary Cost Estimate (base + 9 option years + Option 2 at 100% each year) - Provide an overall summary cost estimate for all years.

(e) Option for 6-month extension estimate (see description below)

Note that when the actual contract award is made, for each contract year, the type and number of studies may vary from the Sample Protocols and options may be unilaterally exercised by the Government at any time during the contract.

Optional 6-month extension under FAR 52.217-8

If necessary, a separate option may be exercised in accordance with FAR 52.217-8 at the end of the contract to extend the period of performance for six months beyond year ten (10) of the contract. Please provide a separate cost spreadsheet for this 6-month extension at the same rates in existence for Year 10 (assuming that Option 2 is exercised in Year 10).