75N95023R00004_Att. 3_Statement of Work.pdf

STATEMENT OF WORK

Pharmacology Studies and Animal Model Development and Related Services for Drug Development

June 13, 2023

I. Introduction/Background

The Therapeutic Development Branch (TDB) within the Division of Preclinical Innovation (DPI) at the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), conducts translational research on human therapeutics development by moving small molecule and biologic drug candidates forward in the drug development pipeline. Upon reaching predetermined milestones, TDB hands off clinical candidates to external partners to bring these novel therapies to patients. In addition to developing new candidate drugs, TDB seeks to advance the entire field of drug discovery and development by encouraging scientific and technological innovations aimed at improving success rates in the crucial preclinical stage of drug development. The TDB model is to operate as a comprehensive small molecule and biologics drug development organization, moving therapeutic candidates through each phase of the preclinical development process until an Investigational New Drug (IND) application is filed with the US Food and Drug Administration (FDA). For certain drug development campaigns, TDB will support studies up to human Phase IIb. TDB conducts drug development through collaborations, with therapeutic candidates originating from academia, industry, non-profit foundations, or internally from NCATS and other NIH institutes. TDB’s operational strategy is to combine the capabilities of in-house staff and collaborative partners with complementary support from contract research organizations (CROs). Each development program operates in a multi-disciplinary matrix team environment, with NCATS responsible for overall planning and execution.

II. Scope and Objectives

The scope of this contract is to provide pharmacology services related to the execution of in vivo and in vitro/ex vivo and related studies, including the optimization and/or development of animal models.

The objectives are to obtain information about the biological effects of test articles on cellular and organismal function during the drug discovery and development process; to provide expertise in designing, executing, interpreting, and reporting on such studies, including in support of regulatory filings; and to optimize or develop relevant in vivo animal models and/or in vitro / ex vivo animal model replacement systems that support preclinical drug development efforts.

The test article/product formats may include small molecules, short oligomeric compounds, biological (large) molecules, quaternary molecular assemblies (homogenous or heterogenous), vectors for gene therapy, nanoparticles, and any of the above modified genetically, biologically, or chemically. Novel formats identified after this draft might also be needed. Formats could also include Devices or Combination Products.

The breadth of this Statement of Work (SOW) includes capabilities to support a range of activities differing in size, complexity, and duration.

RFP No. 75N95023R00004 Attachment 3

III. General Requirements

The below General Requirements apply to each task order issued under this indefinite-delivery, indefinite-quantity (IDIQ) contract and will be supplemented by additional details as needed for each task order.

Research Involving Animals

This Statement of Work involves live vertebrate animals. All work involving live vertebrate animals shall be conducted in accordance with the terms and conditions of the IDIQ contract.

Contract Administration

The Contractor shall perform activities related to the overall administration of the contract. This includes fulfilling administrative reporting and deliverable requirements, ensuring contract terms and conditions are adhered to, and communicating with the Contracting Officer’s Representative (COR) and Contracting Officer (CO) as needed.

Project Management

The Contractor shall provide project management for their own core team to ensure effective project planning, execution, delivery of reports, and accurate and timely communication with the COR, CO, and other stakeholders. The Contractor shall provide and implement overall project management to coordinate and integrate activities for each task order. The Contractor shall provide sufficient project management staff to ensure management and monitoring of all task order activities and shall identify for each task order a lead individual who will serve as a primary point of contact for the Government.

The Contractor shall provide qualified multidisciplinary staff to fulfill the requirements of each task order award. For each discipline, the staff shall have all the required and customary training, experience, and licensure or certification needed to fulfill their assigned role.

Collaboration and Communications

The Contractor shall provide effective collaboration and communication with the COR, CO, and other stakeholders as needed to support successful task order performance and project outcomes. This includes providing status updates and technical information when requested and providing information as needed to ensure the Government is sufficiently informed in accordance with the needs of the project. This also includes collaboration on deliverables, technical approaches, or other areas.

The Contractor shall participate in regularly-scheduled and ad hoc meetings with the Government and other stakeholders as needed. The Contractor will generally be required to provide meeting support such as logistics and arrangements, facilitation, graphics and video support, materials preparation and distribution, and translation, as well as meeting notes, minutes, summaries and/or summary reports.

Such meetings may include:

• Task Order Initiation / Kick-Off Meetings. These meetings are to review the applicable requirements and timelines, discuss technical plans/Project Management Plan and approaches, and identify any anticipated problems/obstacles to completing the requirements.

• Progress Review Meetings. These meetings are to review and discuss ongoing and planned activities, protocols and associated data; timelines for task initiation and completion, submission of data and other information; any problems or deficiencies identified with respect to the accuracy, timeliness, and completeness of research, trials and studies, including outcomes such as data submission; and any other matters relevant to the task order performance or administration.

• Ad Hoc Meetings. These meetings may be required to address issues or questions that arise related to performance or administration. They may also include investigator, protocol, working group, strategic planning, and network meetings.

Quality Management

The Contractor shall ensure that all work performed under this contract, including by any subcontractors, meets the highest levels of quality, as appropriate for the task. All management and operational systems used must be sufficient to monitor, maintain, and document quality.

One or more domestic or international regulations may apply to task orders issued under this IDIQ.

These include, but are not limited to, US FDA current Good Manufacturing Practice (cGMP), Good Laboratory Practice (GLP) and Good Clinical Practice (GCP) regulations, and/or International Council for Harmonisation (ICH) and International Organization for Standardization (ISO) regulations. When one or more regulations apply, the Contractor shall:

• Provide a Quality Assurance Unit (QAU) that is independent of other operations of the Contractor to assure that all products and services meet quality requirements and comply with international, federal, state and local government regulations, as applicable.

• Provide a Quality Assurance/Quality Control (QA/QC) infrastructure for the awarded Contract including SOPs for establishing and maintaining the QA/QC processes and approaches/methods to document, identify the source(s) of and address any problems and deviations as they occur, as well as provide recommendations for the resolution of problems and correction of deviations.

The Contractor shall have a Quality Management Plan (QMP) that shall include management responsibilities, resources, assessment and training, oversight of outsourced operations, defined metrics, and accountability for identification and remediation of errors as well as communication processes and timelines.

• Arrange and/or accommodate independent audits of any Contractor or subcontractor sites. The Government may require an independent audit of any Contractor and/or subcontractor sites to ensure that all facilities satisfy the quality requirements set forth for successful performance of the work. During such an audit, the Contractor shall ensure that staff, facilities, and relevant documentation are available. The Contractor shall prepare updates to the QMP and provide updated plans including corrective actions and preventative actions (CAPA) as needed.

Facilities, Resources, and Operations

The Contractor shall provide and maintain facilities, equipment, space, and other resources as needed that comply with all local, domestic, in-country, state, federal and NIH regulations. The Contractor shall maintain QA documentation to support adherence to these areas. This includes providing safe and secure operation/access to facilities; establishing processes and procedures limiting access to only approved and qualified staff to physical sites, systems, equipment, technology, internet, and/or data;

and providing biohazard, environmental and occupational health safety, emergency management/preparedness, security, transportation and logistics services. All work with hazardous biological materials shall comply with all local, domestic, in-country, state, federal and NIH regulations.

Supply Chain and Logistics Management

The Contractor shall provide for overall management and conduct of the receipt, storage, retrieval, custom clearance, packaging and shipping of materials, including obtaining appropriate licenses and permits and developing SOPs for processes and procedures. All storage, packaging, and shipping shall comply with all local laws and all applicable regulations. As appropriate, material shall be inventoried and tracked to ensure chain of custody.

Data Access and Technology Transfer

The Contractor shall fully support submission of technology transfer packages to the Government or a designated third party when directed by the COR and/or at the completion of the Task Order.

Technology transfer packages will include information, technology, and documentation created with sufficient detail, clarity, and completeness to enable the receiving party to fully understand, and if needed, repeat activities of the Task Order. In certain cases, the Contractor may be required to provide training to the Government or designated third parties to utilize or operate a subject technology. The Contractor will support NCATS regulatory affairs processes by providing authorization to the Government and/or any relevant third parties identified by the Government to access and cross reference relevant prior data generated by the Contractor, including but not limited to, DMFs or other previous regulatory filings, as needed.

Site Visits

The Contractor shall arrange and/or accommodate site visits and independent audits as needed. Site visits may be necessary to ensure that all required equipment is available and in good working order and to review the training records of all key technical staff, as available. Audits may be needed to assure Contractor and subcontractor facilities and all planned procedures meet regulatory (e.g., GMP, GLP) standards. The Contractor 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 COR. All data generated by the Contractor to support manufacture of cGMP material shall have a strict quality system review of raw data and transcription, technical supervisor approval, and quality assurance (QA) release.

Transition

The Contractor shall ensure an orderly, secure, and efficient transition at the conclusion of each task order. This may include preparing and submitting a Transition Plan; transferring and/or disposing of contract-related materials, supplies, and information; and retaining documents in secure storage.

IV. Technical Requirements

Independently and not as an agent of the Government, the Contractor shall be required to furnish all the necessary services, qualified personnel, materials, equipment, and facilities not otherwise provided by the Government to provide the services described in this Statement of Work and subsequent task orders. Task orders will include tasks and activities that fall under one or more of the below technical areas.

Technical Area 1: In Vivo Pharmacology Services and Model Development in Small Animals

The Contractor shall provide services related to the conduct of in vivo studies with therapeutics under development. The studies under this technical area will be conducted using small animal models to support demonstration / verification of efficacy and further drug development activities. The Contractor also shall provide services related to the optimization / refinement of existing animal models or the development of novel models, including characterizing and validating such models to support drug development activities.

Anticipated in vivo pharmacology services under this technical area include, but are not limited to:

1. Defining pharmacokinetic / pharmacodynamic (PK/PD) relationships from existing data or by independently establishing the PK parameters for therapeutic candidates.

2. Optimizing / refining or developing biomarkers and efficacy endpoints.

3. Determining correct route of administration (e.g., SC, IV, PO, IT, or ICV).

4. Determining appropriate dosing parameters.

5. Determining appropriate formulation(s) for administration.

6. Evaluating efficacy and biomarkers in response to treatment with test article.

7. Examination of preliminary toxicity and safety parameters.

Anticipated model refinement / development services under this technical area may include, but are not limited to:

1. Developing novel or similarly existing genetically modified animals that are organ system-specific or whole-body targeted for stable or conditional knock-ins, knock-outs, knock-downs, overexpression, etc. using appropriate genomic techniques such as, but not limited to:

a. Generating targeting constructs per model requirement, including, plasmid DNA vector, single-stranded oligodeoxynucleotides (ssODNs), and ribonucleic acid interference (RNAi) (e.g., silencing ribonucleic acid (siRNA) or short hairpin RNA (shRNA)).

b. Use of cre-lox or tetracycline-induced technology.

c. Use of random DNA transgenesis or optimization of other delivery / gene editing system

(e.g., CRISPR/Cas9 or recombinant adeno-associated viruses (rAAVs)-mediated or other applicable technology).

d. Transfection or electroporation of appropriate cells (e.g., skin fibroblasts (somatic) or embryonic stem (ES) cells) with targeting construct with appropriate gene/editing delivery system(s).

e. Conducting somatic cell nuclear transfer (SCNT) into oocytes, transgene pronuclear microinjection or ES cell microinjection into fertilized eggs for uterine implantation to generate required fetuses / harvest appropriate cells for downstream procedures as necessary including genetic characterization.

f. Cryopreservation of embryos or sperm or harvested fibroblast for SCNT to resuscitate model as needed for future studies.

2. Chemically- or diet-induced models (e.g., CNS, respiratory or metabolic).

3. Physiologically- or procedure-induced models (e.g., anemic).

4. Mechanically-induced models.

5. Single or multiple genetic crossings / breeding.

6. Re-derivation, back-crossing, etc. as necessary to optimize or refine existing models, if feasible and cost-effective.

7. Production of live animals of the model.

8. Basic phenotypic characterization / validation of the model and/or defining comprehensively the natural history of disease progression.

Technical Area 2: In Vivo Pharmacology Services and Model Development in Large Animals

The Contractor shall provide services related to the conduct of in vivo studies with therapeutics under development. The studies under this technical area will be conducted using large animal models, inclusive of non-human primates, to support demonstration / verification of efficacy and further drug development activities. The Contractor also shall provide services related to the optimization / refinement of existing animal models or the development of novel models, including characterizing and validating such models to support drug development activities.

Anticipated in vivo pharmacology services under this technical area include, but are not limited to:

1. Defining pharmacokinetic / pharmacodynamic (PK/PD) relationships from existing data or by independently establishing the PK parameters for therapeutic candidates.

2. Optimizing / refining or developing biomarkers and efficacy endpoints.

3. Determining correct route of administration (e.g., SC, IV, PO, IT, or ICV).

4. Determining appropriate dosing parameters.

5. Determining appropriate formulation(s) for administration.

6. Evaluating efficacy and biomarkers in response to treatment with test article.

7. Examination of preliminary toxicity and safety parameters.

Anticipated model refinement / development services under this technical area may include, but are not limited to:

1. Developing novel or similarly existing genetically modified animals that are organ system specific or whole-body targeted for stable or conditional knock-ins, knockouts, knock-downs, overexpression, etc. using appropriate genomic techniques such as, but not limited to:

a. Generating targeting constructs per model requirement (e.g., plasmid DNA vector, single-stranded oligodeoxynucleotides (ssODNs), and ribonucleic acid interference (RNAi) (e.g., silencing ribonucleic acid (siRNA) or short hairpin RNA (shRNA)).

b. Use of cre-lox or tetracycline-induced technology.

c. Use of random DNA transgenesis or optimization of other delivery / gene editing system

(e.g., CRISPR/Cas9 or recombinant adeno-associated viruses (rAAVs)-mediated or other applicable technology).

d. Transfection or electroporation of appropriate cells (e.g., skin fibroblasts (somatic) or embryonic stem (ES) cells) with targeting construct with appropriate gene/editing delivery system(s).

e. Conducting somatic cell nuclear transfer (SCNT) into oocytes, transgene pronuclear microinjection or ES cell microinjection into fertilized eggs for uterine implantation to generate required fetuses / harvest appropriate cells for downstream procedures as necessary including genetic characterization.

f. Cryopreservation of embryos or sperm or harvested fibroblast for SCNT to resuscitate model as needed for future studies.

2. Chemically- or diet-induced models (e.g., CNS, respiratory or metabolic).

3. Physiologically- or procedure-induced models (e.g., anemic).

4. Mechanically-induced models.

5. Single or multiple genetic crossings / breeding.

6. Re-derivation, back-crossing etc. as necessary to optimize or refine existing models, if feasible and cost-effective.

7. Production of live animals of the model.

8. Basic phenotypic characterization / validation of the model and/or defining comprehensively the natural history of disease progression.

Technical Area 3: In Vitro Pharmacology Studies in Ex Vivo Tissue-, Cell-Based, or Other Relevant Animal Replacement Models

The Contractor shall conduct in vitro pharmacology studies to establish biomarkers and efficacy endpoints, and to test the efficacy and toxicity of therapeutics in existing, optimized / refined, or newly developed in vitro / ex vivo cell- or tissue-based models of disease or other relevant animal replacement models, including those derived from human samples.

The Contractor shall provide services related to the optimization / refinement of existing alternative animal replacement models or the development of such novel alternative animal replacement models. The Contractor shall characterize and validate such models to support drug development activities.

Anticipated in vitro / ex vivo models under this technical area include, but are not limited to:

1. Stably (immortalized) or transiently transfected genetically modified cell lines (e.g., knock-in, knock-down, knock-out, overexpressing transgene).

2. Unaffected or affected donor-derived cells (e.g., induced pluripotent stem cells (iPSCs) or progenitor or primary cells from human patients or animal models).

3. Tissue-chip technology (e.g., single or interconnected organ systems).

4. 3D cell- or tissue-based models (e.g., skin, liver, neuronal architecture).

5. Freshly harvested cells / tissues.

Anticipated in vitro / ex vivo study activities under this technical area include, but are not limited to:

1. Optimizing conditions / performing cell or tissue culture maintenance.

2. Optimizing / refining or developing biomarkers and efficacy endpoints.

3. Treatment with test articles, collection of samples (e.g., cells, tissues, fluids) and performance of relevant assays (e.g., protein concentration, imaging).

4. Performing relevant biomarker and/or efficacy assays.

5. Assessment of cell viability / toxicity.

IV. Technical Requirements