Attachment No. 3 Statement of Work.pdf

ATTACHMENT No. 3 3/22/2021

Pharmacology and Toxicology for Therapeutics Program (PTTP) Statement of Work

1. Introduction/Background The National Institute of Neurological Disorders and Stroke (NINDS) and the NIH Blueprint Neurotherapeutics Network (BPN) (http://neuroscienceblueprint.nih.gov/bpdrugs/index.htm) have established a ‘virtual pharma’ network of contract service providers and consultants with extensive industry experience to enable therapeutic (e.g., small molecule, peptide, biologic) development in the NIH research community. The Network, similar NINDS and NIH programs offer researchers access to a range of industry-style therapeutic development services and expertise, including medicinal chemistry, IND-enabling studies, and Phase I clinical trial infrastructure, with the goal of supporting efforts to advance compounds successfully through Phase I clinical testing. Projects may utilize some or all of the BPN infrastructure. The PTTP contract will support all preclinical pharmacology and toxicology testing needed to inform lead discovery, the selection of a clinical candidate, and comprehensive studies needed for regulatory filings, such as an Investigational New Drug (IND) application to the FDA, to allow for clinical evaluation of the candidates. This contract will serve as part of the NIH Blueprint Neurotherapeutics Network and will also be utilized for individual development projects outside of the Blueprint Network.

2. Contract Type and Ordering Mechanism

This contract is a multiple-award (MAC), indefinite delivery/indefinite quantity (IDIQ) type contract award. This contract will be administered and funded via approved task orders (TO). The MAC IDIQ Contractors shall then compete for future pharmacology and toxicology studies as requirements become available.

The Contractor shall perform work as directed in awarded Task Orders. Task Order awards will cover the following performance areas:

a. Performance Area 1: Management and Operations Support - will cover the effort needed for contract start-up and project management, consultation and communication with NIH and other components of the Blueprint Neurotherapeutics Network or other programs, implementation and maintenance of data management functions and components, preparation and deliver of both administrative and technical reports, and development of a potential transition plan.

b. Performance Area 2: Pharmacology and Toxicology Studies. Task orders for individual pharmacology and toxicology studies of investigational agents/therapeutics will be competed through a Task Order Request for Proposal (TORFP) process under Performance Area 2. It is anticipated that these task orders will be cost-reimbursement, completion and/or level of effort type orders, or fixed-price, and will have variable periods of performance. The http://neuroscienceblueprint.nih.gov/bpdrugs/index.htm

ATTACHMENT No. 1

Government anticipates the possibility of issuing 8-10 TORFPs under Performance Area 2 during each year of the contract. The actual number of TORFPs issued will depend upon programmatic needs and funding availability, and may vary from year to year. Due to changes in priorities within NINDS, the projected workload cannot be precisely described for each year. The Contractor shall initiate work only when authorized by issuance of an approved task order.

c. Project Capacity Estimate: The NINDS anticipates requiring non-GLP

ADMET services (e.g., in vitro ADMET, pharmacokinetic studies, dose range finding toxicity studies) for up to 10 projects in the lead optimization stage per year and GLP IND-directed ADMET services (e.g., toxicity and safety pharmacology studies) for up to 5 projects per year. Multiple studies may be required for each project. It is anticipated that multiple projects and studies will be conducted simultaneously (e.g., concurrent studies for 2-3 lead optimization stage projects and 2-3 IND-stage projects).

3. Goals and Objectives The goal of the PTTP is to assess the pharmacokinetics, toxicology and safety of promising candidates to support their eventual use as therapeutics. It is anticipated that NIH-approved samples will be submitted from a variety of sources including NIH-funded research programs, pharmaceutical companies, biotechnology companies, or other sources. Pharmacology, toxicology and safety data generated from this program may be used by investigators in support of an Investigational New Drug (IND) application.

Studies to be performed may include, but are not limited to:

• Development and validation of the analytical methods for quantitating drug/biologic concentrations in dosing solutions, biological fluids, and tissues, as required

• In vivo pharmacokinetic studies through various routes of administration

• Preclinical acute toxicity evaluations on lead compounds or therapeutics

• Subacute, subchronic, and/or long-term toxicity evaluations in rodents and non-rodent species

• Safety Pharmacology Studies in rodent and non-rodent species (e.g., cardiovascular, pulmonary, CNS)

• Genotoxicity assessments using a battery of appropriate assays and carcinogenicity assessments

• In vitro predictive ADMET assays, including metabolic stability studies, hepatotoxicity, permeability studies, cytochrome P450 assays, plasma protein binding, and cytotoxicity assays

4. Specific Technical Requirements

a. General Description

The Contractor shall conduct pharmacology and toxicology studies in accordance with the complete protocol requirements for each agent developed by the Contractor and approved by the NINDS Contracting Officer’s Representative (COR) and submitting investigator, in conformance with the requirements of the FDA. The types of studies conducted and the protocols used will vary based on the needs of each compound, taking into account data on the agent’s in vitro activity, biochemistry, mechanism of action, and schedule dependence, as well as in vivo activity.

The types of studies to be performed include, but are not limited to:

1. Development and validation of analytical methods for quantitating sample concentrations in dosing solutions, biological fluids, and tissues, as required. Determination of plasma levels in animals administered the agent under study, and calculation of pharmacokinetic parameters derived from this data.

2. In vivo pharmacokinetic studies of the drug through various routes of administration. Determination of bioavailability after different routes of administration, including oral, intravenous (i.v.), subcutaneous (s.c.), intramuscular (i.m.), or intraperitoneal (i.p.), as needed. Calculation of the pharmacokinetic parameters from the derived data.

3. Preclinical acute toxicity evaluations on lead candidates, evaluating clinical observations, body weights, clinical pathology, histopathology, and plasma drug/biologic levels in rodents and non-rodent species. Other toxicology endpoints may be selected if needed.

4. Sub-acute, sub-chronic, and/or long-term toxicity evaluations in rodents and non-rodent species, evaluating clinical observations, body weights, clinical pathology, and histopathology.

5. Safety pharmacology studies, including the assessment of effects on vital functions, such as cardiovascular, central nervous system, and respiratory systems. These may be conducted as part of an existing study or in a separate study.

6. Genotoxicity assessments using a battery of appropriate assays and carcinogenicity assessments.

7. Predictive ADMET assays, including in vitro metabolic stability studies, in vitro permeability studies, Cytochrome P450 inhibition assays, plasma protein binding, and in vitro cytotoxicity studies.

b. Regulatory Compliances and Safety Requirements

1. The Contractor shall develop experimental protocols in consultation with the COR, the submitting investigator, and/or FDA staff and conduct studies using established techniques, study parameters, and statistical methods of data analysis in accordance with current FDA GLP regulations for nonclinical laboratory studies (21 CFR Part 58) and International Conference on Harmonisation (ICH) Guidelines.

Investigators will use the technical reports as part of an IND or RDRC application for human studies. As such, it is required that the format and content of the technical report conform to the highest scientific standards.

2. It is expected that during the contract term, the Contractor shall maintain compliance with current GLP regulations, and provide documentation to the COR of any FDA data audits and inspections (i.e., reports and responses to issues raised) in a timely manner. If it is determined that problems are encountered with the assays or documentation because GLP conditions were not met or maintained, the Contractor shall repeat the assay at no additional cost to the Government.

3. In the event that data quality issues arise in any of the tests performed under the NINDS contract due to Contractor performance issues or negligence, the Contractor shall cooperate fully with the COR to resolve the issues, and if necessary repeat specified tests or data analyses at no additional cost to the Government. In the event that compound quality control or assurance issues in a given experimental study cannot be resolved between the Contractor and COR, a scientific advisory group, comprised of Government staff and expert consultants chosen by the COR shall be asked to review the data and make recommendations to resolve the issues.

4. The Contractor is expected to have available the following species for use in the in vivo studies: rodents (rats or mice), dogs (purpose bred Beagle dogs), rabbits, non-human primates, and other animal models (as appropriate). The animals shall be obtained from an AAALAC-accredited registered breeder (Association for Assessment, Accreditation, and Laboratory Animal Care, U.S. Department of Agriculture (USDA).

5. The Contractor shall obtain, prior to the start of any work under this contract, an approved Animal Welfare Assurance from the Office of Extramural Research (OER), Office of Laboratory Animal Welfare (OLAW) (http://grants.nih.gov/grants/olaw/olaw.htm), Office of the Director, NIH, as required by Section I-43-30 of the Public Health Service Policy on Humane Care and Use of Laboratory Animals.

6. The Contractor shall maintain such assurance for the duration of this http://grants.nih.gov/grants/olaw/olaw.htm contract, and any subcontractors performing work under this contract involving the use of animals shall also obtain and maintain an approved Animal Welfare Assurance. The Contractor shall also be fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International. Information about AAALAC accreditation is available at www.aaalac.org. The Contractor’s Institutional Animal Care and Use Committee (IACUC) shall approve all animal procedures under this contract.

7. All candidate therapeutics and any known human safety data for storage and handling shall be supplied to the Contractor directly by the sponsor or through the COR. Obtaining any other equipment, chemicals, or other materials shall be the responsibility of the Contractor.

8. Each agent will be considered potentially hazardous. Therefore, all necessary precautions must be taken to protect personnel and the environment against possible exposure to the agents being tested. The Contractor shall perform all work associated with this contract in accordance with all applicable Federal, State and local regulations including transportation and disposal of hazardous waste.

c. Confidentiality and Intellectual Property Requirements

1. The Contractor shall protect the confidentiality of all data provided to the Contractor and developed by the Contractor under this contract. The data to be treated confidentially is associated not only with the certain “discreet” compounds which are not available to the public, but with all agents submitted for testing through the program. Under no circumstances are samples or any information associated with these samples, including the data generated under this contract, to be released or divulged to the public without prior written approval of the Contracting Officer’s Representative (COR) and Contracting Officer (CO).

2. The Government requires that all data accumulated under this contract be immediately available for its review and that provision be made to maintain confidentiality of all data. Authority to release data may be granted only by the CO together with the COR and must be in writing.

3. The Contractor shall use drug/biologic samples supplied by investigators under this contract for only contract-related research. The Contractor shall not publish any data generated from investigators’ compounds submitted for testing under the contract, without written approval of the COR and CO. Since the investigator is supplying the compounds, the toxicity and safety data for compounds shall be disclosed only to the http://www.aaalac.org/

COR and to the investigator.

4. The compound supplier may also request the Contractor to sign agreements like those found at: https://www.ott.nih.gov/forms-model-agreements.

d. Description of Performance Areas

The Contractor shall carry out the scope of work and activities defined in each task order awarded under the following two performance areas:

Performance Area 1: Management and Operations Support

The Contractor shall perform activities related to the overall management and operational support for implementation of Performance Area 2, Pharmacology and Toxicology Studies, including but not limited to: project start-up and management ; communication and consultation with the NIH and other components of the Blueprint Neurotherapeutics Network or other programs, implementation and maintenance of data management functions and components; preparation and delivery of both administrative and technical reports; ongoing archival of completed study data/information and development of a transition plan.

• Communication

The Contractor shall be expected to participate in regular conference calls with the NIH, its therapeutics development consultants, other Blueprint Neurotherapeutics Contractors, and the Investigator/Sponsor on a regular basis (typically bi-weekly or monthly) for each ongoing project. The Contractor may be requested to provide written summaries of study progress to support these discussions. It is anticipated that the Contractor will participate in one annual in-person Blueprint Neurotherapeutics Network meeting (in the Washington, DC metro area).

• Consultation

The Contractor shall provide ongoing consultation and advice directly to NIH or to NIH-approved investigators regarding appropriate development plans and testing protocols for potential candidate therapeutics.

• Data Management

The Contractor shall develop, implement, and maintain a data management system for all data/information created, collected and https://www.ott.nih.gov/forms-model-agreements https://www.ott.nih.gov/forms-model-agreements processed for all pharmacology and toxicology studies conducted under the contract. Work under the contract shall require the Contractor to (1) develop, (2) have the ability to access, and (3) host and/or maintain a Federal Information System. This data management system shall be implemented and maintained in accordance with the terms and conditions as specified in Article H, Information and Physical Access Security, and all applicable portions of the Federal Information Security Management Act of 2002 (FISMA), Title III. E-Government Act of 2002, Pub.L. No. 107-347 (Dec. 17, 2002). It is anticipated that data from non-GLP studies will be maintained for a period of twelve (12) months from study completion. Data from GLP studies must be maintained according to current GLP requirements.

The Contractor shall maintain a secure, cumulative electronic project database of compounds evaluated in toxicity and safety tests in Microsoft Excel for PCs. When a compound is approved for testing, the following entries shall be made: 1) compound identification number or name; 2) source of compound (investigator name affiliation, phone, fax, and e-mail); 3) date of receipt; 4) storage and handling requirements; 5) tests authorized; 6) date protocol was approved; 7) date study was initiated; 8) date study was completed; and 9) date data, draft, and final reports are sent to COR.

• Transition plan

The Contractor shall provide the COR with a proposed Transition Plan for complete transition/relocation of the contract resource to a successor Contractor or to the NINDS. The Plan shall provide list of all specimens and data, including laboratory records, protocols, specimens, raw data from experimental studies, reports, data collection forms, and compound databases developed under the contract. Upon written direction by the Government, the Contractor shall transfer all the above Government furnished materials as directed, and fully cooperate with any successor Contractor and the NINDS to ensure an efficient transfer.

Performance Area 2: Pharmacology and Toxicology Studies

NINDS will issue Task Order Request for Proposals (TORFPs) for all individual task orders under Performance Area 2. Performance Area 2 activities are defined below and are to be considered general technical requirements that will be executed following issuance of individual Performance Area 2 task order awards. Performance Area 2 task order awards will define the specific technical specifications and requirements for that task order Statement of Work.

Under Performance Area 2, the types of studies conducted and their associated protocols will vary based on the needs of each project, taking into account data on the agent’s in vitro activity, biochemistry, mechanism of action, and schedule dependence as well as in vivo activity. Work under this performance area will also study related sample storage, and preparation and delivery of specific study reports. The Contractor shall be required to perform all activities associated with the conduct of Pharmacology and Toxicology Studies as specified below:

1) Assay / Study Types

This contract specifically focuses on the evaluation of the toxicology of potential therapeutics. The Contractor shall perform, as directed by a task order (TO) and according to approved protocols, all types of pharmacokinetic and toxicology studies required for advancing an agent into clinical testing. Studies will be conducted in rodent and/or non-rodent species, and may include but are not limited to the following:

pharmacokinetics and/or bioavailability studies; single-dose and dose range finding toxicity studies; expanded acute toxicity studies; multi-day toxicity studies (up to 9 months); safety pharmacology studies (CNS, cardiovascular, pulmonary, etc); and genotoxicity/mutagenicity studies.

Depending on the specific protocol, hematological and clinical chemistry parameters, urinalysis, ophthalmological examination, necropsy, microscopic examination of tissues, and pharmacokinetic analysis may be carried out. The final protocols shall be approved in writing by the COR and will be made part of any task order award.

As some of the studies performed under this contract will be used in the filing of the IND application by the sponsor of the candidate therapeutic, the Contractor shall possess and maintain an intimate knowledge of the Food and Drug Administration's Good Laboratory Practices (GLP) regulations and be able to conduct and report these studies accordingly.

The Contractor's facilities shall be accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

International and maintain that accreditation for the life of the contract.

The Contractor shall also comply with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals and conduct work in compliance with recommendations established in the Guide for the Care and Use of Laboratory Animals.

Within Performance Area 2, the general types of studies that the Contractor shall be required to perform include, but are not limited to, the following:

a) Pharmacology o Develop (or adapt) and validate appropriate analytical methodology which is sufficiently sensitive, specific, and reproducible to allow measurement and quantitation of assigned test agents (e.g., small molecules, biologics) and metabolites in body fluids and/or tissues of animals at therapeutic and/or toxic concentrations.

o Conduct pharmacokinetic studies in animals (e.g., mice, rats, optionally larger animals) using various routes of administration (e.g., intravenous, oral, intraperitoneal, subcutaneous, continuous infusion, etc.). Studies will include collection of multiple blood samples by suitable methods to obtain plasma or serum and, in some studies, collection of urine, feces, and tissue samples, including brain.

Studies may be for administration of a single compound or for administration of multiple compounds in a cassette dosing format.

o Utilize suitable analytical methods to determine concentrations of test agents in biological samples (e.g., plasma, urine, bile, saliva, brain and other tissues).

o Use modern modeling software to fit concentration vs. time data (for plasma, brain and possibly tissues) to appropriate pharmacokinetic models and calculate relevant pharmacokinetic parameters (e.g., half-life, volume of distribution, area under the curve, clearance, brain to plasma ratio, etc.) for a given agent and route of administration.

Calculate systemic bioavailability for various routes (e.g., oral, ip, sc) and determine if bioavailability is dose-dependent. Calculate mass-balance parameters if sufficient data are collected.

o Determine the solubilities of test agents as required in solvents and other formulations suitable for parenteral and/or non-parenteral administration to animals.

o Conduct in vitro plasma protein binding and stability studies of test agents in biological fluids, model systems, and tissues.

o Determine the structures of metabolites and/or degradation products of test agents present in blood, plasma, urine, and/or other fluids.

Characterize the plasma and tissue pharmacokinetics of major metabolites.

o Determine the ability of a drug/biologic to cross the blood-brain barrier in rodent and/or non-rodent species.

b) Toxicity and Safety Evaluations o Analytical: Drug identity analysis (e.g., IR, NMR, MP, MS, or other emergent assay methodology designated by the COR), development and/or validation of procedures for dose concentration analyses and validation of the requisite methodology for assay of test article in biological fluids.

o Dose-Range Finding: For each test article, establish relative toxicity in two species (usually one rodent species and beagle dogs) or as NIH specifies. The use of non-human primates or other animal models as alternative species may be required for certain agents under evaluation. The types of studies required in this phase shall be decided by the COR, may be non-GLP and may include single or multiple dose range-finding studies in rodents, beagle dogs, non-human primates or other species.

o Acute/Expanded Acute Toxicity: Establish toxicity and safety using single or multiple daily dose schedules (e.g., control and 3-dose paradigm, control and single-dose paradigm). If so directed by NIH, studies shall comply with GLP regulations. Doses may be determined based on the no-observed-adverse-effect level (NOAEL) information for the compound or as a multiple of the maximal expected human dose for very low dose compounds (e.g., low dose of 100x maximal expected human dose, mid dose of 1000x, and high dose of 10,000x).

o Subacute, Subchronic, or Long-term toxicity: Repeated administration of drug/biologic to rodents, beagle dogs and/or non-human primates or other species, typically 14 or 28 day study durations, but may require studies of up to 9 months duration.

o Safety pharmacology studies including the assessment of effects on vital functions, such as cardiovascular, central nervous, renal, gastrointestinal, hepatic, and respiratory systems. These evaluations may be conducted as part of an existing study or in a separate study and must comply with ICH Guidelines.

o Mutagenicity/Genotoxicity studies including the Salmonella Reverse Phase Mutation Assay (Ames test), Mouse Lymphoma Gene and Chromosomal Mutation assay, CHO Cytogenetic Assay, Mouse Micronucleus Assay, and/or Unscheduled DNA synthesis.

Long-term rodent carcinogenicity studies may also be required.

These evaluations must comply with ICH Guidelines.

o Predictive Absorption, Distribution, Metabolism, and Toxicity (ADMET) assays to provide early assessment of lead compounds.

A standard battery will typically include bacterial mutagenicity tests, in vitro metabolic stability studies (multiple species), in vitro permeability studies (Caco-2, PAMPA), Cytochrome P450 assays, plasma protein binding assessment, and in vitro cytotoxicity studies. The Contractor may also be asked to provide in vitro target profiling (e.g. GPCRs, kinases), hERG interaction (non-GLP and GLP), plasma stability, lipophilicity, and solubility assessment.

2) Incorporation of Novel Techniques and Technologies

The Contractor shall maintain awareness of new tools, techniques, and regulatory requirements in areas applicable to this program. Novel technologies may be adopted and incorporated into the program as they are validated.

3) Study Timelines

While individual study timelines will be determined on a task order by task order basis, it is anticipated that the Contractor shall utilize all efforts to complete studies as expeditiously as possible. For studies to support lead optimization (e.g., in vitro ADMET, pharmacokinetics), rapid turnaround is essential. It is anticipated that these studies will be non-GLP, will use a minimal number of animals, and require rapid development of a ‘screening’ bioanalytical method, rather than the fully validated method needed to support later stage development. For in vitro and rodent studies, study initiation is expected within one (1) week of receipt of the test article. Data reports should be available within one

(1) week of end of in-life. Additional time may be needed in non-rodent studies due to quarantine requirements, however it is expected that all efforts will be made to expedite these studies to the extent possible.

4) Study Related Sample Storage

The Contractor shall store study related samples as specified by the task order award. The Contractor shall prepare batches of the test formulation as frequently as is necessitated by available stability data. In most cases, stability data will not be available for the studies, in which case, the Contractor shall prepare the test formulation not more than one working day prior to evaluation. The Good Laboratory Practice regulation requires that analysis of the dose formulation, usually a suspension or solution, be done several times during each study for purity and identity.

The methods of analysis will typically be supplied by the submitting investigator.

5. Reporting Requirements and Deliverables

a. Technical Reports

Performance Area 1 - The Contractor shall be required to prepare and deliver the following reports during the base year of the initial task order award for Performance Area 1, and for each subsequent option year if so exercised:

• Quarterly Technical Progress Report

These reports shall address, at a minimum, a summary of the work accomplished during the period reported upon; a summary of all activities conducted for each active and completed task order; summary of any performance difficulties and their resolution; performance activities related to implementation and maintanence of FISMA requirements; staff training and updates; copies of minutes from meetings, teleconferences, webinars and site visits occurring during the reporting period; list of all archived data sets for studies performed under the contract. Quarterly technical progress reports are due five (5) calendar days after months 3, 6, and 9 of each contract year. The report covering the last quarterly period of each year is due on or before the completion and/or termination date of the task order (TO) award.

• Final Contract Report.

At the conclusion of the TO for Performance Area 1, the Contractor shall submit a Final Contract Report, on or before the final day of the contract period of performance, which documents and summarizes the results of all the task orders for the entire contract period of performance. This report shall be in sufficient detail to explain comprehensively the results achieved and shall contain a summary (not to exceed 200 words) of the salient results achieved during the performance of the contract.

Performance Area 2 - Technical reporting requirements will be specified in each task order award made under this performance area. Examples of reports that may be required include:

(1) Task Order Data Reports: The data and results from each protocol in which a particular agent is studied shall be submitted to the COR within a period of time defined in the individual task order. This report may omit final histopathological evaluations because of the potential delay in submission if these data are mandated. However, the report must include as much raw and summarized data as has been generated in the study, including data from interim sacrifice or sampling points, drug/biologic level evaluations and pharmacokinetics parameters, and shall give a realistic target date for submission of supporting histopathologic data. Format may follow that suggested for Study Reports, or may follow any reasonable and logical reporting format routinely utilized by the Contractor.

(2) Task Order Study Reports: The data and results from all protocols in which a given agent was evaluated, including microscopic pathology, shall be submitted to the COR as a separate draft report, due within the time frame specified in the Task Order. Each final Study Report shall be due as specified in the Task Order.

For GLP studies, the study report must be submitted in a format approved by the COR for submission of the report to the Food and Drug Administration for filing of an Investigational New Drug application or similar regulatory filing. Final Study Reports shall accurately and completely describe study design, procedures, and findings, and present an analysis and summary of the data followed by conclusions derived from the analysis. Data generated in the course of the studies should be separated by protocol and should be presented in an easily followed and understood tabular and graphic form.

a) The report shall include:

i. A cover page which shall include title, contract number, author(s), laboratory address, dates of initiation and completion, and sponsor;

ii. Comprehensive summary to be placed after the cover page;

iii. Data from each individual animal in each study, as well as a tabular summary of data for each treatment group, compared with a tabular presentation of ranges of historical control values presented in the context of individual control animals from the study;

iv. An evaluation of the meaning and significance of the data, particularly as they relate to potential effects of the agent in human therapy;

v. The signature of the Contractor's authorized representative and any others deemed necessary;

vi. A table of contents;

vii. A statement prepared and signed by the Contractor's Quality

Assurance Unit which will refer to all phases of the study and indicate where the raw data records, reports, and samples are stored.

The following items are examples of data that may be required for inclusion in the report.

b) Experimental Design and Methods

i. Drug/biologic compound information

Identity data Lot number History (dates received, on test and study completed) Stability

ii. Animal history (source, sex, age, weight, immunization, procedure used for unique identification, etc.)

iii. Baseline data (pre-test)

iv. Control animals

v. Vehicle controls (if requested)

vi. Dose formulation information

vii. Route of administration

viii. Rate of injection

ix. Method of blood collection

x. Urinalysis data, if specifically requested

xi. Methodologies of all test procedures

xii. Days and method of sacrifice

xiii. Time period from death to necropsy

xiv. Rationale and documentation of all deviations from protocol

c) Results

i. Mortality

ii. Clinical Observations (appearance, behavior, signs of toxicity and pharmacologic effects)

iii. Body weights and food consumption

iv. Clinical laboratory studies

v. Gross and microscopic pathology

vi. Histopathology

vii. Ophthalmoscopic findings

viii. Organ weights and organ/body weight ratios

d) Statistical Analysis: Appropriate statistical analyses for comparing treatment groups to the control group as well as any other relevant statistical analyses needed to evaluate the data.

e) Statistical Evaluation

i. Cumulative mortality rate if appropriate

ii. Body weight and body weight changes

iii. Microscopic lesions if appropriate

iv. Clinical laboratory values

v. Total food consumption

vi. Organ weights and organ/body weight ratios

f) Tables

i. Cumulative mortality rates

ii. Mean body weights and food consumption

iii. Mean clinical laboratory values

iv. Summary incidence of gross pathology findings

v. Summary incidence of histopathology findings

vi. Summary of incidence of ophthalmoscopic findings

vii. Toxic, pharmacologic and behavioral effects for each test group to include a list of each sign and number of animals affected

g) Graphs

i. Mean weekly bodyweight and food consumption

ii. Survival if appropriate

h) Appendices

i. Toxic, pharmacologic and behavioral effect for each animal to include: date of observation of each sign, a description of each sign, and its subsequent course

ii. Clinical pathology reference ranges (when available)

iii. Individual ophthalmoscopic findings

iv. Analytical chemistry methods and results

v. Individual gross pathology findings

vi. References for clinical laboratory and statistical methods

vii. Week of death for each animal

viii. Individual clinical laboratory values

ix. Individual histopathology findings

x. Individual organ weights and organ/body weight ratios

i) Additional items may be required per Principal Investigator/COR discussions. In studies specified as GLP, all portions of the studies and reports must be in compliance with the GLP regulations. Corrections or additions to reports shall be submitted in form of amendment clearly identifying that part of the report being added to or corrected, reasons for addition or correction, and dated signature of person responsible.

The report shall be reviewed, assured for quality control, contain a statement certifying that the studies were conducted in compliance with current GLP regulations, approved, signed, and dated by the Study Director.

(3) Report of Unexpected Event: This is a report of an unexpected adverse event, observed at any stage of the study, which would jeopardize the progress of the study. It shall be sent to the COR as soon as practicable after the adverse event.

b. Other Report Requirements

The Contractor shall prepare and deliver the reports specified below as part of their work effort under Performance Area 1. These reports, which are in addition to the “Technical Reports” specified above, are required by FAR clauses that are applicable to and made a part of this contract.

The Contractor shall submit all reports in electronic format. All electronic reports submitted shall be compliant with Section 508 of the Rehabilitation Act of 1973 (29 U.S.C. 794d), as amended by the Worforce Investment Act of 1998 and the "Electronic and Information Technology Accessibility Provisions" set forth by the Architectural and Transportation Barriers Compliance Board (also referred to as the "Access Board") in 36 CFR part 1194. Additionally, 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 can be found at http://www.hhs.gov/web/section-508/.

Any paper/hardcopy documents/reports submitted under this contract shall be printed or copied, double-sided, on at least 30 percent post consumer fiber paper, whenever practicable, in accordance with FAR 4.302(b).

1) Information Security and Physical Access Reports

To satisfy FISMA requirements, the contractor shall submit all FISMA deliverables to an NINDS secured, provisioned website. The contractor must maintain a current list of each contract staff who will be accessing this website. For access to the NINDS provisioned website, the contractor must implement NIH sponsored, or NIH approved, Federated login solutions. Some NIH approved solutions include no-cost social media solutions, and upon request, NINDS can provide a current list of the sponsored and/or approved solutions. The contractor will be responsible for the setup and support of the chosen Federated login solution.

The Contractor shall submit the following reports as required by the INFORMATION AND PHYSICAL ACCESS SECURITY Article in SECTION H of the contract.

Document Section Deliverable Title/Description Due Date

2 – Roster and Personnel Security Responsibilities

Roster Changes

• Onboarding

• Offboarding

Onboarding- Prior to performing any work on behalf of NIH/NINDS, and monthly thereafter.

http://www.hhs.gov/web/section-508/

List of Personnel with defined roles and responsibilities

Offboarding-documentation, equipment and badge when leaving contract within 3 business days

2 – Background Investigation

Onboarding documentation when beginning contract.

Prior to performing any work on behalf of

NIH/NINDS

2 – Contractor Employee Non- Disclosure Agreement (NDA)

Contractor Employee Non- Disclosure Agreement

(NDA)

Prior to performing any work on behalf of

NIH/NINDS

2 – Training Records

Copy of NIH training records for all mandatory training

In conjunction with contract award and annually thereafter or upon request

2 – Rules of Behavior

Signed ROB for all employees

Initiation of contract and at least annually thereafter

2 – Incident Response

Incident Report (as incidents or breaches occur)

NIH/NINDS policy states as soon as possible or no later than 1 hour of discovery

2 – Incident Response

Incident and Breach Response Plan

Upon request from government

2 - Certification of Sanitization of Government and Government Activity- Related Files, Information, and Devices.

Form or deliverables required by NIH

NIH/NINDS requires NIH Form NH270 Certification:

Removal of Data and Software

2 – Contract Initiation and Expiration

If the procurement involves a system or cloud service, additional documentation

At contract expiration.

will be required, such as Disposition/Decommission Plan

4 – Security Assessment and Authorization

(SA&A)

SA&A Package

• SSP

• SAR

• POA&M

• Authorization Letter

• CP and CPT Report

• E-Auth (if applicable)

• PTA/PIA (if applicable)

• Interconnection/Data

Use Agreements (if applicable)

• Authorization Letter

• Configuratio n Managemen t

Plan (if applicable)

• Configuration Baseline

NIH/NINDS requires the contractor to complete the SA&A package within 90 days of initial contract award.

This includes the delivery of the following items within 30 days of contract award.

• SSP

• PIA

5 – Protection of Information in a Cloud Environment

Contract expiration NIH/NINDS requires this within 2 weeks.

5 – FedRAMP (applicable if the product/service meets the NIST definition of a

CSP)

FedRamp Authorization NIH/NINDS requires FedRAMP Authorization due prior to using product.

5 – Reporting and Continuous Monitoring

POA&M updates;

Revised security documentation/Agreemen ts, vulnerability and application scans

Monthly/as requested by NINDS

ISSO

6 – Other IT Procurements (Non- Commercial and Open Source Computer Software Procurement s)

Computer software, including the source code.

Prior to performing any work on behalf of

NIH/NINDS

i. Roster of Employees Requiring Suitability Investigations (Monthly IT Roster)

The Contractor shall submit a roster, by name, position, e-mail address, phone number and responsibility, of all staff (including subcontractor staff) working under the contract who will develop, have the ability to access, or host and/or maintain a Federal Information System(s). The initial roster shall be submitted to the COR, with a copy to the CO, within 14 calendar days after contract award. Monthly IT Roster reports shall be submitted thereafter.

The monthly IT roster reports are due 5 calendar days after the end of each montly reporting period. (Reference subparagraph a.4. of the INFORMATION AND PHYSICAL ACCESS SECURITY Article in SECTION H of the contract.)

ii. IT Security Plan (IT-SP)

The Contractor shall submit the IT-SP within thirty (30) days after contract award. (Reference subparagraph d.3.a). of the

SECTION H of the contract.)

iii. IT Risk Assessment (IT-RA)

The Contractor shall submit the IT-RA within thirty (30) days after contract award. (Reference subparagraph d.3.b). of the

iv. FIPS 199 Assessment

The Contractor shall submit a FIPS 199 Assessment within thirty

(30) days after contract award. (Reference subparagraph d.3.c). of the INFORMATION AND PHYSICAL ACCESS SECURITY Article in SECITON H of the contract.

v. IT Security Certification and Accreditation (IT-SC&A)

The Contractor shall submit written proof to the Contracting Officer that an IT-SC&A was performed within three (3) months after contract award. (Reference subparagraph d.3.d). of the

vi. Contractor-Employee Non-Disclosure Agreement(s) The

Contractor shall complete and submit a signed and witnessed "Commitment to Protect Non-Public Information - Contractor Agreement" form for each Contractor and Subcontractor employee who may have access to non-public Department information under the contract. (Reference subparagraph E.3.d. of the

vii. Vulnerability Scanning Reports: The Contractor shall report results of monthly vulnerability scans within 10 calendar days following the end of each monthly report period. The first report shall cover the first full month of contract performance and is due 40 days after contract award. (Reference subparagraph E.5. of the

2) Section 508 Annual Report

The Contractor shall submit an annual Section 508 report in accordance with the schedule set forth in Article F.2. and ELECTRONIC AND INFORMATION TECHNOLOGY ACCESSIBILITY Article in SECTION H of the contract. The Section 508 Report Template and Instructions for completing the report are available at: http://www.hhs.gov/web/508/contracting/technology/vendors.html under "Vendor Information and Documents."

3) Invention Reporting Requirement

All reports and documentation required by FAR Clause 52.227-11, Patent http://www.hhs.gov/web/508/contracting/technology/vendors.html http://www.hhs.gov/web/508/contracting/technology/vendors.html

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, OPERA, NIH, 6705 Rockledge Drive, Suite 310, MSC 7980, Bethesda, Maryland 20892-7980 (Telephone: 301-435-1986). One copy of each annual utilization report shall be submitted as an e-copy to the CO on or before each anniversary date of the contract. The final invention statement (see FAR 27.303(b)(2)(ii)) shall be submitted as an e-copy to the CO on or before the expiration date of the contract, listing all subject inventions or stating that there were none.

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 CO.

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 encouraged 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 Division of Extramural Inventions and Technology Resources, OPERA, NIH.

4) Subcontracting Reports

The Contractor shall submit the individual and summary subcontract reports as required and as set forth in Section H. These reports shall be submitted via the "electronic Subcontracting Reporting System (eSRS) at http://www.esrs.gov .

5) 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/cgi-bin/textidx?

c=ecfr&SID=0af84ca649a74846f102aaf664da1623&rgn=div5&view=text &node=45:1.0.1.1.51&idno=45.See%20Part%2094.5, Management and http://www.esrs.gov/ http://www.esrs.gov/ reporting of financial conflicts of interest for complete information on reporting requirement

(Reference subparagraph g. of the INSTITUTIONAL RESPONSIBILITY

REGARDING INVESTIGATOR FINANCIAL CONFLICTS OF INTEREST

Article in SECTION H of this contract.)

6) Service Contract Reporting Requirements for Indefinite-Delivery

Contracts

In accordance with FAR 52.204-14, “Service Contract Reporting Requirements”, contained in full text in Article I.4. of the contract, the Contractor shall report annually by October 31, for services performed under this contract during the preceding Government fiscal year (October 1 – September 30) the following information to http://www.sam.gov, with an electronic copy to the Contracting Officer:

i. Contract number and, as applicable, order number.

ii. The total dollar amount invoiced for services performed during the previous Government fiscal year under the contract.

iii. The number of Contractor direct labor hours expended on the services performed during the previous Government fiscal year.

iv. Data reported by subcontractors [if applicable] under paragraph (f) of the subject clause (see full text of clause FAR 52.204-14, “Service Contract Reporting Requirements” in Article I.4. of the contract).

Task Order Requirements

Contract Kickoff Conference Call

Sample Task Order 1(a)

The Contractor’s Key Personnel shall participate in a virtual contract kickoff meeting.

The meeting shall be between 30-60 minutes and not exceed 60 minutes. The conference call shall be scheduled at a date and time mutually agreed upon by the Government and Contractor that is within sixty (60) days of the base IDIQ effective date. The Government will provide a brief agenda before the meeting and there will be time for questions and answers (Q&As) regarding the contract and its related projects. It is anticipated that award of this task order will be made on a firm-fixed-price basis.

Performance Area 1 - Management and Operations Support

Sample Task Order 1(b)

NOTE:

The NINDS anticipates awarding a Task Order under Performance Area 1 concurrently with award of a Task Order under Performance Area 2, “Pharmacology and Toxicology Studies”. There will be no more than one Task Order under Performance Area 1, “Management and Operations Support,” at one time. Offerors are to include as a part of their technical proposal, a full and complete technical response that addresses all aspects of their approach, methods, resources and capabilities as to how they will carry out, perform and meet all aspects of Performance Area 1 requirements as set forth in the Statement of Work. The Statement of Work and Reporting Requirement/Deliverables for the Performance Area 1 Task Order will be as stated in Articles C.1. and C.2. of Section C – Description/Specifications/Work Statement of the RFP.

It is anticipated that award of this task order will be made on a fixed-price basis.

Performance Area 2 – Pharmacology and Toxicology Studies

Sample Task Orders 2(a) through 2(g)

NOTE: The following sample Task Orders are provided to assess the offeror’s capabilities to conduct and fulfill all of the requirements of the Statement of Work for pharmacology and toxicology studies of the same or similar size and scope anticipated to be issued under the contract. These sample Task Orders will NOT be executed nor will awards be issued for them. Offerors are to include in their proposals a response that specifies the methods by which each sample Task Order will be fulfilled (including sample study protocols) with associated costs.

This Performance Area includes the conduct of all types of pharmacology and toxicology and studies outlined in the Statement of Work, including the specific reporting requirements associated with each respective study.

Information to be Provided with Technical Proposal:

Offerors are to provide, as part of their overall technical proposal, separate responses including timelines for the execution of each of the sample tasks specified below. You may include separate sections in the technical proposal that address each of the seven (7) sample tasks. Your response must be prepared in a manner and provide sufficient information to demonstrate your understanding, knowledge and experience with the types of studies to be performed as presented in the Statement of Work. Responses for each sample task should include timelines for study completion, from study initiation to availability of a data report and then to completion of a final report.

For Sample Task 2f (IND-Directed Studies) and Sample Task 2g (in vitro ADMET), the Technical Proposal should include an overview and study/assay protocol for each study within the task. A per study and overall task timeline should be provided.

Note: Study design outlines are provided…