RFP Att. 3_IDIQ Contract SOW.pdf

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Attachment #3

SECTION C - STATEMENT OF WORK (SOW) FOR BASE CONTRACT

ARTICLE C.1. – STATEMENT OF WORK

GENERAL INFORMATION

Title of Project:

Manufacturing and Nonclinical Studies Support for Development of Therapeutic Biotechnology Products (Biologics) for Neurological-related Disorders

Background Information and Objectives:

General

The National Institutes of Health (NIH) is the nation’s leading medical research agency and the primary Federal agency whose mission is to seek fundamental knowledge about the nature and behavior of living systems and apply that knowledge to enhance health, lengthen life, reduce illness and disability, and conduct, support, and make medical discoveries that improve people’s health and save lives. The National Institute of Neurological Disorders and Stroke (NINDS) is an institute within the NIH that conducts research into the causes, treatment, and prevention of neurological disorders and stroke. The NINDS mission is to seek fundamental knowledge about the brain and nervous system and use that knowledge to reduce the burden of neurological disease.

The NINDS has a need for current Good Manufacturing Practices (cGMP) manufacturing and Good Laboratory Practice (GLP) nonclinical (preclinical) support services to support translational development of therapeutic biotechnology products (Biologics) for NIH drug discovery and development programs. To that end, several NIH programs are being launched or expanded to provide support for investigators developing medical interventions for neurological disorders. Researchers with a promising Biologic (hereinafter “Contributors”) will be invited to submit investigational agents to the NIH program for drug development, and the Contributors will retain all intellectual property rights. Contributors may come from a variety of sources, including academic institutions, NIH intramural programs, government organizations, sole proprietors, and industry. The NIH has been granted a Determination of Exceptional Circumstances (DEC) to the Federal Acquisition Regulation (FAR) for this contract. The primary goal of the NIH programs is to provide health benefits to patients by bringing new drugs to market. The DEC enables the Contributors to retain control of the intellectual property for investigational agents evaluated through the various NIH programs.

NIH Drug Development Programs Involving Biologics

This contract supports the NIH Biologics development projects for the NIH Blueprint Neurotherapeutics Network Biologics (BPN-Biologics) program, the NINDS Ultra-Rare Gene Therapy (URGenT) program, the Helping to End Addiction Long-term Pain Therapeutics

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Development Program (HEAL-PTDP), and other extramural or intramural NIH drug discovery and development programs.

The NIH Blueprint Neurotherapeutics (BPN) network (https://neuroscienceblueprint.nih.gov/neurotherapeutics/blueprint-neurotherapeutics-bpn-network) is a consortium comprised of the NIH Office of the Director and 14 NIH Institutes and Centers (ICs) that support neuroscience research. BPN provides neuroscience researchers with funding and access to a full range of industry-style drug development services and expertise.

The program, originally focused on small molecules, was launched for projects requiring medicinal chemistry optimization, pharmacokinetics (PK), drug manufacturing and formulation, Investigational New Drug (IND)-enabling toxicological studies support through Phase I clinical testing and it is now being expanded to include the development of biological therapeutics for neurological diseases (BPN-Biologics) (https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics).

The URGenT program (https://www.ninds.nih.gov/Current-Research/Research-Funded- NINDS/Translational-Research/urgent-network) has been established by the NINDS to support the development and clinical evaluation of therapeutics to address ultra-rare genetically based neurological disorders. The network will provide neuroscience researchers with funding and access to a full range of industry-style biologics development services and expertise and in the future may expand to include other NIH institutes. The program is intended to rapidly advance patient-customized therapeutics through manufacturing, preclinical toxicology testing and evaluation in Phase 1 clinical studies.

The HEAL-PTDP program (https://heal.nih.gov/) is a multi-IC initiative that has been established by the NIH to support preclinical optimization and development of safe, effective, and non-addictive biologic therapeutics to treat pain. The goal of the program is to accelerate the optimization and development of promising biologic hits/leads to Phase I clinical trials and readiness for the Early Phase Pain Investigation Clinical Network (EPPIC-Net) or other Phase II clinical studies. Applicants must have a promising Biologic hit/lead, robust biological rationale for the intended approach, and identified assays for optimization of the agent. The scope of this program includes optimization and early development activities, IND-enabling studies, development of a pharmacodynamic (PD)/ target engagement biomarker, assembly and filing of an IND application and Phase I clinical testing. This is a milestone-driven phased cooperative agreement program involving participation of NIH program staff in the development of the project plan and monitoring of research progress. A list of currently funded HEAL projects may be found at the following link: https://heal.nih.gov/funding/awarded.

Ordering Period:

This indefinite-delivery indefinite quantity (IDIQ) contract includes an ordering period through September 29, 2030.

It is anticipated that the period of performance, including options, for some task orders (TOs) will extend multiple years past the end of the IDIQ ordering period. However, under FAR Clause 52.216-22, the Contractor shall not be required to make any deliveries under this contract after three years past the end of the IDIQ ordering period.

https://neuroscienceblueprint.nih.gov/neurotherapeutics/blueprint-neurotherapeutics-bpn-network https://neuroscienceblueprint.nih.gov/neurotherapeutics/blueprint-neurotherapeutics-bpn-network https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/urgent-network https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/urgent-network https://heal.nih.gov/ https://heal.nih.gov/funding/awarded

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SCOPE OF WORK

Scope:

The Contractor shall provide support for both Biologics cGMP manufacturing and GLP nonclinical services, including execution of the studies and completion of study reports and documentation that will enable regulatory filing and evaluation of biological therapeutics in clinical trials for NIH drug development programs. These services may be provided through a combination of internally executed studies and subcontracted work.

Throughout the contract ordering period and awarded TO periods of performance, the Contractor must maintain the technical capabilities, subcontractor network, minimum resources and organizational compliances with which to successfully perform the range of activities under both Task Area 1: Manufacturing and Task Area 2: Nonclinical Studies. Additionally, unless otherwise requested, any assigned research must comply with all current U.S. Food and Drug Administration (FDA) and International Committee on Harmonization (ICH) policies, practices, procedures, guidelines and regulations specific to GLP and cGMP, as may be applicable. Data and documentation shall be prepared in a form acceptable to the FDA for inclusion in a Drug Master File (DMF), IND application, or New Drug Application (NDA).

Technical Requirements:

In its own facilities and/or through its subcontractors, the Contractor shall conduct and/or oversee all manufacturing activities and nonclinical therapeutics evaluation and characterization in appropriate in vitro, in vivo, and/or ex vivo models, including cGMP manufacturing and preclinical IND-enabling and related studies. Nonclinical activities may include, but not are limited to, bioassay development, and/or efficacy studies, and/or absorption, distribution, metabolism, and elimination (ADME) studies, and/or PK and/or PD characterization, and/or GLP toxicology studies or other preclinical IND-enabling studies in support of requirements for IND applications. The Contractor shall provide Chemistry, manufacturing, and controls (CMC) and nonclinical study documentation to enable regulatory interactions, IND filing and evaluation of biological therapeutics in clinical trials for NIH drug development programs.

Independently and not as an agent of the Government, the contract awardee shall furnish all the necessary services, qualified personnel, materials, equipment, and facilities, not otherwise provided by the Government as needed to perform the actions outlined in each of the following Task Areas:

TASK AREA 1 – MANUFACTURING

Manufacturing of biological therapeutic modalities that will be required to support BPN-Biologics, URGenT, HEAL-PTDP, or other NIH Biologics programs includes, but is not limited to, the categories of Biologics listed below.

(1) Oligonucleotides, such as antisense oligonucleotide (ASO), small interfering RNAs (siRNAs), and/or other nucleic acids, such as plasmid DNAs for generating viral gene vectors, etc.

(2) Viral gene delivery vectors, such as adenovirus-associated viruses (AAV), lentiviruses, retroviruses, herpesviruses, adenoviruses, etc.

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(3) Purified proteins, including purification of polypeptides from a variety of expression systems including, prokaryotic, mammalian, avian, yeast, insect, or plant, and may include protein modifications such as bioconjugation, or other protein modifications

(4) Peptides, including those with modified amino acids, structures, or conjugations

(5) Antibody-based Biologics, including antibody–drug conjugates (ADCs), bi- and multi-specific antibodies, peptibodies, nanobodies, antibody fragments, etc.

(6) Cell-based therapeutics such as induced pluripotent stem cells (iPSC) cell line generation, stem cell, mesenchymal stromal cell therapies, ex vivo cellular therapies, chimeric antigen receptor T-cell (CAR-T) modalities, cell banks for bioassays and/or for manufacturing viral vectors, etc.

(7) Novel genome-editing modalities, such as clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, etc.

(8) Formulations of biological therapeutics, including common formulations for biologics, and/or liposomes, micelles, polymers, or solid metallic nanoparticle formulations.

Manufacturing services for the Biologics listed above may include, but are not limited to the following subtasks:

(1) Technology-transfer of an R&D laboratory scale process from a research facility to the Contractor

(2) Biological therapeutics manufacturing process development

(3) Analytical Methods Development

(4) CMC development

(5) Small-scale manufacture, scale-up, engineering runs and/or manufacturing under cGMP

(6) Formulation and Dosage Form Manufacture and Validation

(7) Fill-finish, release testing, stability testing, validation and other associated tasks

The Contractor and/or its subcontractor shall have adequate infrastructure, capacity and expertise to provide other specialized support services that may include, but are not limited to, the following:

(1) Technology transfer, process development, analytical methods development, scale-up and manufacturing of biological therapeutics. Scale-up and manufacture shall be acceptable for support of preclinical studies, IND-enabling toxicology studies, and clinical studies.

(2) Manufacture and qualification under GLP compliant and/or cGMP compliant conditions, as appropriate.

(3) Process development to establish methodologies and processes amenable to scale-up and quality control.

(4) Conduct studies to support the development of formulations and dosage form manufacture of candidate therapeutics.

(5) Fill-finish, label, store, and ship material intended for evaluation in preclinical studies, IND-enabling and related studies, and clinical studies.

(6) Conduct phase appropriate validation studies to support preparation of active pharmaceutical ingredients (API) and dosage form manufacture of candidate therapeutics. The validation studies shall support documentation of the identity, strength, quality, purity, potency and stability of drug substances and drug products.

(7) Assemble information, submit samples, and present data to support analytical methodologies for drug substances and drug products in a form acceptable to the FDA for an IND.

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(8) Prepare data and documentation in a form acceptable to the FDA for inclusion in a DMF, IND application, or NDA.

(9) Perform general administrative and technical activities to support all TOs awarded under this contract.

The Contractor shall:

(1) Ensure delivery of preclinical and clinical lots of biological therapeutics and associated data packages to enable the timely execution of nonclinical studies and clinical trials.

(2) Develop robust and scalable processes for the manufacture of Biologics, with Intellectual property (IP) freedom to operate, if required. These needs may be addressed separately and in parallel, e.g., initial clinical lots may not necessarily be manufactured using IP-free or optimized technology, with technology development continuing while initial lots are manufactured using currently available methods.

(3) Provide GLP and/or cGMP manufacture of nonclinical and/or clinical materials, including product/process development and support activities, technology transfer as needed.

(4) Provide appropriate cGMP compliance throughout the supply chain including cold storage, transportation, and distribution of manufactured biologics

(5) Arrange for site visits and independent audits as requested by the NIH. Audits may be requested to assure Contractor and subcontractor facilities and all planned procedures meet FDA-required drug development (GLP and/or cGMP) standards. Contractors shall ensure all Contractor and subcontractor records and staff are available in response to site visits or study-specific audits and provide interim and final audit reports to the NIH.

All information generated by the Contractor to support manufacture of cGMP drug product shall have 100% quality system review of raw data and transcription.

TASK AREA 2 - NONCLINICAL STUDIES

Nonclinical services include conduct of in vitro, in vivo and/or ex vivo IND-enabling preclinical studies, as well as the completion of associated study reports and documentation that will enable regulatory filing and evaluation of biological therapeutics in clinical trials for NIH drug development programs. Nonclinical studies may include but are not limited to:

(1) GLP or non-GLP efficacy testing in in vitro, in vivo or ex vivo models, including modeling neurological disease using patient derived pluripotent stem cells, or in animal models of disease, or in naïve animals, or in ex vivo tissue or small explant cultures

(2) GLP or non-GLP absorption, distribution, metabolism, and elimination (ADME) studies;

PK and PD characterization; toxicology studies including, but not limited to single-dose and/or repeat dose toxicology studies, and/or reproductive toxicology and/or carcinogenicity studies, and/or neonatal and juvenile toxicology studies in small animal, large animal, and/or non-human primate (NHP) models, and

(3) Bioassay development and/or assay qualification or validation to support nonclinical or clinical studies.

(4) All nonclinical work (GLP and non-GLP) should be conducted in facilities that are GLP capable and compliant, unless a written waiver is given by the Contracting Officer’s Representative (COR) for work to be conducted in a non-GLP capable facility.

The Contractor shall perform in vivo, in vitro or ex vivo characterization studies, including but not limited to, the following:

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(1) The Contractor and/or subcontractors shall perform efforts associated with planning, conducting, and reporting on approved in vitro and/or ex vivo characterization studies and/or in vivo animal studies (non-GLP or GLP), as directed by each individual TO and in accordance with approved protocols. Efficacy testing may include studies with in vitro, in vivo or ex vivo models, including but not limited to, modeling neurological disease using patient derived pluripotent stem cells, and/or in ex vivo tissue or small explant cultures. The Contractor and/or subcontractors shall assist with a broad range of animal efficacy studies to support preclinical research including neurological disease studies in animal models involving species such as NHP, rodent and/or other small or large mammal animal models. Support may include acquisition, housing and care of animals;

health monitoring and surveillance; procedures in high containment areas; imaging;

laboratory animal medicine; sample collection; model development; and immunogenicity, safety and efficacy testing, generate positron emission tomography (PET) and/or other radiolabeled ligands for distribution studies, etc.

(2) The Contractor shall perform, as directed by a TO and according to approved protocols, all types of PK and toxicology studies required for advancing an agent into clinical testing. In vivo general toxicology, safety pharmacology and efficacy studies (via oral, intramuscular (IM), intravenous (IV), subcutaneous (SC), intrathecal (IT), ocular, intraperitoneal (IP), or other routes of administration) for IND/Biologics License Applications (BLA)-enabling nonclinical packages may include, but are not limited to:

a) Non-GLP range finding studies in rodent and non-rodent species

b) Dose ranging and/or maximum tolerable dose (MTD) studies to define the highest dose of a biologic therapeutic that does not cause unacceptable side effects or toxicity.

c) GLP studies in rodent and non-rodent species

d) Single-dose and/or repeat-dose safety pharmacology studies (pulmonary, cardiovascular or other) in relevant species, 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.

e) Reproductive toxicology studies

f) Carcinogenesis studies in rodent and non-rodent models

g) Non-GLP and/or GLP efficacy studies in appropriate animal models of neurological diseases

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

i) Conduct PK studies in animals (e.g. rodent and non-rodent) using various routes of administration (e.g., intravenous, oral, intraperitoneal, subcutaneous, continuous infusion, intracerebroventricular, intralumbar, 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.

j) Use modern modeling software to fit concentration versus time data (for plasma, brain and possibly tissues) to appropriate PK models and calculate relevant PK 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 (including oral, IP, SC, etc.) and determine if bioavailability is dose dependent.

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(3) Bioassay development and/or assay qualification or validation to support nonclinical or clinical studies may include but is not limited to:

a) Neutralizing antibody assays, including assays to measure neutralizing antibodies to viral vectors such as AAVs or other viral vector modalities used in gene-therapy studies.

b) Enzyme-linked immunosorbent assays (ELISA).

c) Relative potency assays to support release testing of manufactured Biologics.

d) Assays that measure the biological activity of a bioactive molecule, including ligand-receptor binding, or signal transduction processes, etc.

e) Human or animal tissue bioassays. (Any data associated with human materials will be de-identified.)

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

Upon completion of a study under Task Area 2, the Government may require that all study documentation including, but not limited to, laboratory notebooks, source documents, monitoring logs, regulatory documents, observations or notations of activities and all reports and records necessary for the evaluation and reconstruction of the research study, as well as databases on disk or tape, be placed in secure storage. This documentation shall be stored throughout the contract ordering period and/or for the length of time required by the FDA and the Contractor’s standard operating procedures. During this period, the Contractor will be responsible for the integrity and organization of the material and its confidentiality. At the end of this period, all reference material, data files, etc. will be transferred or disposed of per instructions of the COR.

All nonclinical work (GLP and non-GLP) should be conducted in facilities that are GLP capable and compliant, unless a written waiver is given by the COR for work to be conducted in a non- GLP capable facility.

The Contractor and/or subcontractor shall have adequate infrastructure, capacity, and expertise to provide other specialized support services that may include, but are not limited to, the following:

(1) Conduct studies under GLP compliant conditions.

(2) Conduct phase appropriate bioassay qualification and/or validation studies to support

GLP IND-enabling studies and/or clinical studies.

(3) Assemble information and present data to support regulatory submissions in a form acceptable to the FDA.

(4) Prepare data and documentation in a form acceptable to the FDA for inclusion in a DMF, IND application, or NDA.

The Contractor shall:

(1) Ensure delivery of preclinical study reports and associated data packages to enable the timely execution of IND submissions and clinical trials

(2) Arrange for site visits and independent audits as requested by the NIH. Audits may be requested to assure Contractor and subcontractor facilities and all planned procedures meet FDA-required drug development GLP standards. Contractors shall ensure all Contractor and subcontractor records and staff are available in response to site visits or study-specific audits and provide interim and final audit reports to the NIH.

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(3) All information generated by the Contractor and/or subcontractors to support IND submissions shall have industry standard quality system review of raw data and transcription.

CONTRACT MANAGEMENT

The Contractor shall effectively and efficiently manage cost, schedule, and performance under this contract by using integrated program management processes across all aspects of performance and in a manner that yields cost savings and/or performance efficiencies throughout the execution of all TOs issued to the Contractor under this SOW.

The Contractor shall provide project management for its own core team to ensure project planning, execution, delivery of reports, and accurate and timely communication with the NIH Contracting Officer (CO), COR, and other stakeholders. The Contractor shall have a designated head Program Manager as the point of contact for the contract. The Contractor shall also provide a project management plan for how subcontracted work will be executed, including but not limited to how qualified subcontractors will be identified, how studies will be scheduled to meet NIH timelines, and how subcontractor work will be managed and overseen. The Contractor shall provide project management support for the overall administration of the contract; and development, tracking and management of all TOs issued under this contract. The Contractor’s project management support staff shall work in coordination with designated federal staff and will be responsible for performing all the non-inherently governmental activities associated with administration of this contract.

The Contractor’s core team leader shall attend program team meetings on an as needed basis (typically no more than one meeting per week) via teleconferencing. During these meetings, the Contractor shall report project progress and provide input and feedback to the program team.

The Contractor shall send the materials needed for these meetings to the NIH at least 24-hours in advance of the meeting. The material needed shall include a status update on all ongoing studies, plans for the next reporting period, data generated and interpretations of data, any quality control issues, and the status of the budget when requested.

Contract Management Plan: The Contractor shall develop and maintain a Contract Management Plan to ensure that the Contractor’s staff (including any subcontractor’s staff) follow individual Project Plans established in support of the work performed under this SOW. The COR will closely monitor the cost and schedule of the work to minimize the potential for cost and/or schedule variance.

The Contractor shall follow the work process flow, methodology, procedures, deliverables and best practices that conform to the standards dictated by the Project Management Body of Knowledge (PMBOK) Guide, and Project Management Life Cycle defined and published by the Project Management Institute (PMI).

The Contract Management Plan shall describe the Contractor’s understanding of its contract management responsibilities and the approach it will use to: 1) keep projects on track; 2) ensure risks are understood and managed; 3) handle changes to scope, 4) communicate in a timely manner with stakeholders, 5) maintain strong oversight of any subcontractor(s) and 6) promptly report to the COR/CO progress/issues for work done under any subcontract(s). The Contract Management Plan shall be kept current and updated throughout the contract period of performance and shall address, but is not limited to, the following:

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(1) Team organization and responsibilities;

(2) Project execution;

(3) Project constraints and assumptions;

(4) Project schedule and milestones;

(5) Project risks identification and management;

(6) Budgeted costs; and

(7) Project monitoring.

Monthly Activity and Financial Status Reports: The Contractor shall provide separate written Monthly Activity and Financial Status Reports that monitor the progress, cost, and projections.

The Contractor shall provide other reports as requested by the COR. Although the activity and financial status reports are due monthly, this shall not relieve the Contractor of the responsibility to pro-actively keep the Government informed of issues or problems as they occur (including technical, cost, or schedule issues). Reports in a computer-readable format of the Contractor’s staff leave schedules are required to enable the Government to be notified of anticipated absences and vacation schedules.

The following conditions must be satisfied:

• Ensure a robust and comprehensive quality control, to include only using quality assurance-approved reagents; guarantee of purity and safety; development of batch production records; and performance of release testing.

• Produce material using standard operating procedures (SOPs) compliant with U.S. FDA regulations and certification testing performance that meets current FDA requirements.

• Perform clinical research quality management activities, to include independent audits, to evaluate prospective outside vendors for approval as a qualified supplier for the NIH.

• At the direction of the COR, the Contractor shall perform other TOs directly relating to Manufacturing and Nonclinical Studies that are within the scope of Task Areas 1 and 2

Transition-Out Plan:

In the event the Government re-competes the requirements of this SOW, the Contractor shall, at the Government’s option, provide the Government with a Transition-Out Plan that shall ensure an orderly and successful transition to a successor Contractor should the incumbent Contractor not be selected during the re-competition.

Special Requirements:

a. CONFIDENTIALITY All data provided to the Contractor and developed by the Contractor under this contract must be treated confidentially. The data to be treated confidentially is associated not only with the certain “discreet” investigational agents which are not available to the public, but with all agents (Materials) submitted for testing through the program. Under no circumstances are chemicals or drugs or any information associated with these chemicals or drugs, including the data generated under this contract, to be released or divulged without prior written approval of the NINDS COR.

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The Government requires that all data accumulated under the contract be immediately available for its review and that provisions are 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.

The Contractor shall use Materials supplied by Contributors under this contract only for contract-related research. The Contractor shall not publish any data generated from Contributor’s Materials submitted for testing under the contract, without written approval of the COR and Contributor. Toxicity and safety data for compounds shall be disclosed only to the COR and may only be disclosed to other parties at the direction of the COR.

b. INTELLECTUAL PROPERTY The testing of agents through this contract may result in intellectual property. To facilitate the Contributors’ further development and eventual commercialization of their investigational agents, the NIH has sought a Determination of Exceptional Circumstances (DEC) to the Federal Acquisition Regulation (FAR) for this contract. The DEC enables the Contributors to retain control of the intellectual property created related to their investigational agents through this contract, thereby increasing the likelihood of commercializing of potential new therapies. The intellectual property policies established under the DEC are described in detail in Department of Health and Human Resources Acquisition Regulation (HHSAR) 352.227-11 Patent Rights— Exceptional Circumstances (Sept. 2014) and HHSAR 352.227-14 Rights in Data—Exceptional Circumstances (Sept. 2014) hereby made a part of any resultant contract in Section I.

To summarize:

Class 1: Subject Inventions that require use of the Material.

Class 2: Subject Inventions that could utilize the Material but are not limited to the Material.

Class 3: Subject Inventions that do not fall into Class 1 or Class 2 above.

The DEC contains the clause HHSAR 352.227-14 Rights in Data-Exceptional Circumstances (Sept. 2014), also made a part of any resultant contract under Section I, to ensure that proprietary data provided to the Contractor are used only for the purpose of the contract, and that data generated under the contract are not disclosed until there has been reasonable time for the applicable party to prepare and file a patent application, if appropriate.

Additional Requirements:

I. ANIMAL FACILITY - shall be accredited by or registered as follows:

1. 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 and/or subcontractors shall possess and maintain an intimate knowledge of the Food and Drug Administration's 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).

2. The Contractor and any subcontractor shall be fully accredited by the AAALAC International or equivalent and maintain that accreditation for the duration of the contract.

Information about AAALAC accreditation is available at www.aaalac.org.

http://www.aaalac.org/

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3. The Contractor shall submit an approved Animal Welfare Assurance for 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. The Contractor shall maintain such assurance for the duration of this contract, and any subcontractors performing work under this contract involving the use of animals shall also obtain and maintain an approved Animal Welfare Assurance.

4. The Contractor and any subcontractor shall comply with the Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/phspol.htm) and conduct work in compliance with recommendations established in the Guide for the Care and Use of Laboratory Animals (http://www.nap.edu/openbook.php?record_id=5140).

5. The Contractor’s Institutional Animal Care and Use Committee (IACUC) shall approve all animal procedures under this contract.

II. ANIMAL REQUIRMENTS:

The Contractor shall comply with the HHSAR clause 352.270(5)(b), Care of Live Vertebrate Animals (Oct 2009). All available animal handling and safety assurances and related laboratory inspections shall be provided to the COR on an annual basis throughout the period of the contract and such assurances must also be accessible when required. Any violations of protocol resulting in issues, warnings, or the need for corrective measures shall be reported immediately in writing to both the COR and CO. All relevant explanations related to the nature of the violation as well as the planned remedy or actions need to accompany the report.

1. Animal Sources and Strains:

Animal species and strains, including but not limited to, mice, rats, rabbits, guinea pigs, minipigs, dogs, or NHPs shall be specified by the COR for each investigational intervention and should be used from the same supplier throughout each study to the greatest extent possible.

Testing in male and/or female animals shall also be required on specified investigational agents as specified by the NINDS COR.

2. Data Integrity and Controls:

The Contractor shall establish controls to ensure consistency of the data. Source of animal supplies shall not be changed without advanced permission of the COR and validation of appropriate drug standards.

3. Animal Facility Treatments:

No insecticides, such as chlorinated hydrocarbons or methylenedioxyphenyl compounds shall be used in animal facilities because of their effects on hepatic drug metabolism enzymes.

Bedding for animal cages shall not contain any substances that alter the animal's microsomal enzymes or that produce other adverse effects.

III. RIGOR:

The Contractor shall refer to Article H.2., of the Contract and the NIH Rigor and Reproducibility http://grants.nih.gov/grants/olaw/olaw.htm http://grants.nih.gov/grants/olaw/references/phspol.htm http://www.nap.edu/openbook.php?record_id=5140

April 15, 2024 Page 12 of 18 webpage (https://www.nih.gov/research-training/rigor-reproducibility) for guidance on implementing enhanced rigor in study designs and data reporting as appropriate or as directed by the NINDS COR.

IV. SUPPLY AND PURITY OF THE INVESTIGATIONAL AGENTS:

1. For some “pain” related studies use of controlled substances such as opioids, morphine, etc. may be required; the Contractor and/or its subcontractor must be licensed by the Drug Enforcement Administration (DEA) to procure, receive and handle schedule II-V compounds. In addition, the Contractor and/or its subcontractor must either possess or demonstrate the ability to obtain a DEA registration for Schedule I controlled substances.

2. At the end of the end of requested studies the Contractor shall transfer any stored investigational agents to a location designated by the COR or shall dispose of it in an approved manner based on industry standards when directed by the COR to do so.

V. DATA SECURITY, STORAGE, ACCESS, TRANSFER TO NINDS, AND SECTION 508

COMPLIANCE:

1. Test Data and Programmatic Information Storage, Access and Data Transfer.

a) Contractors will have access to Sharepoint, or other site, which will allow it to download test orders and upload test results. The mechanism will be supplied and maintained by the Government.

2. Data Security:

a) Access to all investigational therapy, data or other materials provided by the Government as well as all reports, summaries, data descriptions, generated tables and/or testing results derived in performance of this contract shall be restricted pursuant to the terms of HHSAR 352.227-14 Rights in Data—Exceptional Circumstances (Sept. 2014) not this FAR clause. The Contractor is not allowed any internal use or through outside contract to study, manipulate, copy, remove, publish and/or release any information on any data provided by the Government and/or generated under this contract without the prior written approval of the NINDS CO and the COR. Further, any such approvals must be submitted in writing by the Contractor to the COR and CO. When the data are not at the contract site, e.g., when data are being securely transmitted, mailed or delivered to NIH, the Contractor must ensure that the data are covered with the statement, "Privileged Communication of Data -- Property of the U.S. Government” and take appropriate measures to assure safe transmission. The contract number and title shall also be included on such transmissions. Any unexpected or notable observation discovered during evaluation of investigational compounds or resultant from reviews or other summary data collected must be immediately reported to the COR. All such information and conclusions, raw data are deliverables and therefore the sole property of the U.S. Government.

b) All computers, software and databases used by the Contractor in the performance of this Contract shall be FISMA compliant. Computers shall have the latest operating system, web browser, anti-virus software, and security patches installed with automating updating enabled.

c) The Contractor shall store all raw data (i.e. laboratory notebooks, data storage https://www.nih.gov/research-training/rigor-reproducibility

April 15, 2024 Page 13 of 18 media, etc.) for the performance period of the contract. At the end of the performance period of the contract the Contractor shall transfer program data to a location designated by the NINDS COR.

d) 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 shall be responsible for the setup and support of the chosen Federated login solution.

3. 508 Compliance:

HHS Section 508 and Accessibility Standards Section 508 of the Rehabilitation Act, as amended by the Workforce Investment Act of 1998 (P.L. 105-220) requires that when Federal agencies develop, procure, maintain, or use information and communication technology (ICT), it shall be accessible to people with disabilities. Federal employees and members of the public who have disabilities must have access to, and use of, information and data that is comparable to people without disabilities.

All products, platforms and services delivered as part of this work statement that are ICT, or contain ICT, must conform to the Revised 508 Standards, which are located at 36 C.F.R. §

1194.1 & Apps. A, B, C & D, and available at https://www.access-board.gov/ict/.

All requirements are applicable to support services and documentation deliverables. All functional performance criteria apply when using an alternative design or technology that achieves substantially equivalent or greater accessibility and usability by individuals with disabilities, than would be provided by conformance to one or more of the requirements in Chapters 4-6 of the Revised 508 Standards, or when Chapters 4-6 do not address one or more functions of ICT.

The government reserves the right to perform testing on required ICT items to validate their Section 508 conformance. If the government determines that Section 508 conformance does not meet the HHS Section 508 requirements, the government shall, at its option, require the offeror to remediate the item, at no additional cost to the government, to align with the HHS Section 508 conformance requirements prior to acceptance.

References:

• Section 508 Standards: https://www.access-board.gov/ict/

• HHS Policy on Section 508 Compliance and Accessibility of Information and Communications Technology (ICT): https://www.hhs.gov/web/governance/digital-strategy/it-policyarchive/department-of-health-and-human-services-hhs-policy-on-section-508-and-accessibilityof-technology.html

352.239-73(B) ELECTRONIC AND INFORMATION TECHNOLOGY ACCESSIBILITY

(a) Pursuant to Section 508 of the Rehabilitation Act of 1973 (29 U.S.C. 794d), as amended by the Workforce Investment Act of 1998, all electronic and information technology (EIT) products and services developed, acquired, maintained, or used under this contract/order must comply with the "Electronic and Information Technology Accessibility Provisions" set forth by the Architectural and Transportation Barriers Compliance Board (also referred to as the "Access https://www.access-board.gov/ict/ https://www.access-board.gov/ict/ https://www.hhs.gov/web/governance/digital-strategy/it-policyarchive/department-of-health-and-human-services-hhs-policy-on-section-508-and-accessibilityof-technology.html https://www.hhs.gov/web/governance/digital-strategy/it-policyarchive/department-of-health-and-human-services-hhs-policy-on-section-508-and-accessibilityof-technology.html https://www.hhs.gov/web/governance/digital-strategy/it-policyarchive/department-of-health-and-human-services-hhs-policy-on-section-508-and-accessibilityof-technology.html

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Board") in 36 CFR Part 1194. Information about Section 508 is available at http://www.section508.gov/. The complete text of Section 508 Final Provisions can be accessed at https://www.access-board.gov/ict/.

(b) The Section 508 accessibility standards applicable to this contract/order are identified in the Statement of Work. If it is determined by the Government that EIT products and services provided by the Contractor do not conform to the described accessibility standards in the Product Assessment Template, remediation of the products or services will be the responsibility of the Contractor at its own expense.

(c) In the event of a modification(s) to this contract/order, which adds new EIT products or services or revises the type of, or specifications for, products or services the Contractor is to provide, including EIT deliverables such as electronic documents and reports, the Contracting Officer may require that the contractor submit a completed HHS Section 508 Product Assessment Template to assist the Government in determining that the EIT products or services support Section 508 accessibility standards. The Voluntary Product Accessibility Template (available at https://www.itic.org/policy/accessibility/vpat) is the equivalent of the HHS Product Assessment Template.

The contractor shall submit an annual Section 508 report in accordance with the schedule set forth by the Contracting Officer (CO)/Contracting Officer's Representative (COR). The Section 508 Report Template and Instructions for completing the report are available at:

https://www.hhs.gov/web/508/contracting/technology/vendors.html under "Vendor Information and Documents."

The offeror shall ensure thar personnel providing the labor hours possess the knowledge, skills, and ability necessary to address the applicable Revised 508 Standards defined in this contract and shall provide supporting documentation upon request.

When submitting electronic reports and forms the offeror shall ensure they fully conforms to the applicable Revised 508 Standards prior to delivery and before final acceptance.

OTHER CONSIDERATIONS

Government Responsibilities:

The Government does not anticipate providing Government furnished property. Project related data (i.e. Government furnished information) will be provided to the Contractor for performance of work efforts. All data provided to the Contractor must be treated as confidential and shall not be disclosed to any third party without the express permission of the NIH.

Project data will be collected and stored by the NIH, which will provide data as needed to the Contractor each time it requests service. The Contractor may store data for up to 12 months after initially receiving it, after which the Contractor should either delete the data files and sanitize the computer using National Institute of Standards and Technology (NIST) SP 800-88 (or current revision) or, if information is still needed, contact the COR for permission to store the data for a longer period of time.

https://www.access-board.gov/ict/ https://www.itic.org/policy/accessibility/vpat

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Travel:

Site and technical assistance visits as well as general meetings may be required to fulfil the tasks under this contract. The Contractor may be required to attend conferences or meetings to provide a contract deliverable (e.g., a speech, presentation, or poster.)

All travel arrangements must be made in accordance with Federal Travel Regulation (FTR) and must be approved by the COR and authorized by the CO prior to being finalized or invoiced.

Deliverables:

I. TECHNICAL DELIVERABLES

General

1) Comprehensive Project Plan - When tasked to work on a project via a TO, Contractors shall work with the COR, CO, and other stakeholders identified by the COR to deliver a comprehensive project plan, including work breakdown structures, timelines, key milestones and deliverables, Go/No-Go decision points, resource allocation, budget, intellectual property terms, and a risk mitigation plan.

2) Standard Operating Procedures - Contractors shall, upon request by the COR, submit any SOPs, method descriptions, and references to be used in the implementation of the studies. Contractor SOPs will be treated as confidential, and how much detail is revealed and at what time can be discussed.

3) Preliminary Data Reports - After completion of the in-life portion of the study, the Contractor shall prepare a preliminary data report, to be submitted within 5 calendar days from the end of in-life portion of the study. Within 10 calendar days of submission of the data report, the Contractor shall submit a full draft report for review and comment by the COR. After receipt of COR comments, raw data and a final study report shall be delivered and /or transferred to a specified NINDS database.

4) Final Data Reports - The Contractor in coordination with the NINDS data management representative shall coordinate a seamless transfer of raw and analyzed data, statistical and method(s) of analysis into the NINDS database within 1 week of finalization on study reports.

5) Comprehensive Summary Reports – As directed by the NINDS COR, a comprehensive report of all studies completed through this contract shall be completed within 45 days after final test results are submitted for each Investigational Agent. Other less comprehensive summaries for “pilot studies and special projects” shall have a 30-day completion requirement for each separate candidate selected.

6) Quarterly Progress Reports – Quarterly Progress Reports for all testing summaries shall be provided in an approved electronic format to the COR. Quarterly Reports shall comprise a) a summary of all testing performed in the performance period; b) the status of all projects under development (i.e. new model development, pilot studies), problem areas and any performance delays encountered or that may impede future performance;

c) a list of comprehensive summary reports in preparation or completed during the

April 15, 2024 Page 16 of 18 reporting period and d) Solutions to identified problems encountered during the reporting period if any. The first reporting period consists of the first full three months of performance including any fractional part of the initial month. Thereafter, the reporting period shall consist of three full calendar months. Reports shall be due on or before the 10th calendar day following each reporting period. The Contractor shall send two copies of the Quarterly Progress Reports, one to the COR and one copy to the CO.

7) Conference Call Summaries- The Contractor shall be required to generate and deliver summaries of all conference calls conducted in performance of work under the contract.

The summary shall consist of a bulleted list of decisions made and action items identified on the call. These summaries shall be sent via e-mail to all participants within 48 hours of each call. The exact number and timing for such calls will depend on the specifics and circumstances surrounding each individual project.

8) Final Progress Report/ Summary of Salient Results - Upon final completion of the contract/TO, the Contractor shall deliver a comprehensive final report to the CO and COR that briefly summarizes all the projects initiated over the course of…