Attachment_3thru9.pdf

RFP

75N91023R00024

Attachments 3 - 9

PREVENT Efficacy Pool Statement of Work Attachment 3

STATEMENT OF WORK dated 11/07/2022

ATTACHMENT 3

PREVENT Cancer Preclinical Drug Development Program: Preclinical Efficacy and Intermediate Endpoint Biomarkers

Independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, materials, equipment, and facilities, not otherwise provided by the Government, as needed to perform the Statement of Work.

1) SCOPE

This IDIQ will be administered and used primarily to support the PREVENT Program initiatives as necessary to help the Program achieve its mission. More specifically, the contract shall support the development of potential cancer preventive agents, vaccines, or other immunopreventive agents, by conducting preclinical animal studies for cancer preventive efficacy evaluation, employing detailed pharmacological and/or immunological studies, determining pharmacodynamic (PD) and/or immunodynamic (ID) effects of test agents, and correlating pharmacokinetic and/or immunologic biomarker profile(s) with the effectiveness of test agents. The primary endpoint of the efficacy studies shall be to prevent the development of invasive cancers whereas the biomarker studies will identify and validate endpoints, which correlate with or represent the effectiveness of given chemopreventive agents, vaccines, or other immunopreventive agent. These endpoints might be measured in body fluids, normal or at-risk tissue from the target, or in histopathologically altered tissue from the target organ(s).

2) GENERAL TASK ORDER REQUIREMENTS

Specific Task Orders will depend on the status of the candidate agent(s) or biomarkers in relation to an overall development plan and/or regulatory submission plan to the FDA. Tasks shall be conducted in accordance with quality oversight that is appropriate to the phase of the specific task and within all applicable and current federal, state, and local laws, codes, ordinances and regulations, as well as all applicable Public Health Service (PHS) Safety and Health provisions.

The following requirements shall apply to each Task Order:

2.1 PROJECT MANAGEMENT

1. Task Order Initiation Meeting and/or Teleconference: Within 10 calendar days after the effective date of the Task Order or before the start of any tasks, plan for and participate in an Initiation Meeting or Teleconference to review the Task Order requirements and timelines, discuss Task Order technical plans and approaches, and identify any anticipated problems/obstacles to completing the Task Order requirements. The Task Initiation Meeting will be attended by Contractor key personnel (including subcontractor personnel as

Work Attachment 3 appropriate), the Contracting Officer’s Representative (COR), and any other key personnel at the discretion of the COR and Contractor.

2. Develop, monitor, and modify the timelines, tasks, budgets, objectives and milestones as discussed with and/or prioritized by the COR before and during the performance of activities under the Task Order. If changes need to be made to the technical protocol at any time, updates shall be provided to the CO and COR immediately by teleconference or email and also documented as part of the quarterly progress reports for each Task Order. The CO and COR must provide concurrence and approval prior to the Contractor implementing any proposed change(s). Updates will include changes made and current project rationale.

3. The Principal Investigator (or equivalent) shall be responsible for overall compliance with quality requirements, project management and communication, tracking performance, monitoring and reporting on project status and progress, and recommending modifications to project requirements and timelines, including projects undertaken by subcontractors.

4. Key personnel or other senior staff coordinator(s) shall be available for ad hoc meetings/teleconferences with the COR immediately upon a meeting request.

5. Progress Review Meetings and Teleconferences

a. Plan and participate in Progress Review Meetings or Teleconferences, to be attended by Contractor key personnel (including subcontractor personnel as appropriate), the COR, the designated Subject Matter Experts, the Contracting Officer, any other key personnel at the discretion of the COR and Contractor, as necessary, at monthly intervals or as issues arise. The purpose of these meetings/teleconferences shall be to review and discuss:

1) ongoing and planned activities, protocols and associated data,

2) timelines for task initiation and completion, submission of data and other information,

3) any problems or deficiencies identified with respect to the accuracy, timeliness and completeness of data submitted, and

4) any other matters relevant to the technical and financial administration of the task.

b. The Contractor shall be responsible for:

1) preparing and distributing meeting/teleconference agendas and background materials at least one business day prior to each meeting/teleconference, and

2) preparing and submitting to the COR written summaries of all major decisions and action items resulting from such meetings and teleconferences within seven calendar days after each meeting/teleconference.

Work Attachment 3

The following Quality Management requirement outlined in 2.2 shall apply to the base IDIQ and all subsequent task orders:

2.2 QUALITY MANAGEMENT

1. The Contractor shall demonstrate responsibility for the quality and applicable regulatory compliance of the materials and documentation generated per this Statement of Work (SOW). The Contractor shall provide a Quality Management (QM) Plan (QMP) outlined in the proposal at the Base IDIQ level (Master QMP) which applies to all subsequent task orders which describes how Quality Assurance (QA) is addressed within the organization, including quality management responsibilities, resources, training program, oversight of all subcontractors if applicable, and communication processes including timelines. The contractor shall provide a QMP as part of the initial task order which will apply to the IDIQ and subsequent task orders. The QMP will provide a contractor point of contact and be a brief document which supports how the contractor will ensure compliance with industry/ academic standards in the processes supporting Efficacy studies and research.

2.3 FACILITIES, ANIMALS, EQUIPMENT, AND OTHER RESOURCES

As outlined in the Task Order:

1. The Contractor shall provide facilities, equipment, space, training, and other resources to conduct work with potentially hazardous chemical or biological materials in compliance with all federal and NIH regulations in accordance with the guidelines including, but not limited to, those listed in the Addendum titled “References” as applicable.

2. The Contractor shall provide facilities, equipment, space, and other resources to conduct work in a manner to prevent cross-contamination with other materials.

3. All personnel, equipment, and facilities shall be compliant with applicable regulatory agency requirements in effect throughout the entire period of performance. The Contractor shall maintain quality assurance documentation to support adherence to these areas.

4. Animal Facility: The Contractor and any proposed subcontractor laboratories shall be accredited by or registered as follows:

a. The Contractor shall have 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 PHS 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.

http://grants.nih.gov/grants/olaw/olaw.htm

Work Attachment 3

b. The Contractor and any subcontractors performing work under this contract shall be fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International or equivalent and maintain that accreditation for the life of the contract. Information about AAALAC accreditation is available at https://www.aaalac.org/.

c. The Contractor and any subcontractors performing work under this contract shall comply with the 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 (https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf).

d. The Contractor and any subcontractors performing work under this contract shall comply with the Animal Welfare Act and Animal Welfare Regulations established by the United States Department of Agriculture (USDA), available at http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/animalwelfare.

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

5. Animals: All animals for studies shall be furnished by the Contractor from established, reputable, known commercial breeders or shall be bred by the Contractor. The Contractor shall quarantine the animals for an appropriate period prior to placing them on test for studies and their release shall be documented by the attending American College of Laboratory Animal Medicine (ACLAM) veterinarian.

2.4 STORAGE AND SHIPPING

As outlined in the Task Order:

1. The Contractor shall be responsible for the overall management and conduct of the receipt, storage, retrieval, packaging and shipping of products, materials, and specimens, including obtaining appropriate licenses and permits, where applicable.

2. Receive and record products, materials, reagents, and specimens.

3. Store products, materials, and test samples at the specified temperature range and conditions in a secure area. Specific temperature ranges include, but are not limited to, liquid nitrogen, -80°C ± -10°C, -20°C ± -5°C, 4°C (2-8°C), and room temperature.

4. The conditions in all controlled temperature chambers shall be monitored and documented as appropriate for the level of regulatory compliance, as necessary.

5. Temperature chambers shall be qualified or validated as proposed by the Contractor and https://www.aaalac.org/ https://www.aaalac.org/ http://grants.nih.gov/grants/olaw/references/phspol.htm https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/animalwelfare

Work Attachment 3 reviewed and approved by the COR.

6. The Contractor shall be responsible for retrieval, packaging, and shipping of materials to various domestic and international locations. Detailed shipping instructions will be supplied by the Government or the Contractor at the time of shipment as appropriate. When necessary, a documented shipping procedure compatible with all applicable regulations is to be established and followed. Temperatures maintained during shipping and storage shall be captured and documented. Packaging shall adhere to U.S. and international standards as applicable.

2.5 TRANSITION

At the completion of each Task Order or at any point as determined by the COR, the Contractor shall deliver the following items:

1. all data obtained from all work carried out under each Task Order by the Contractor, all subcontractors, and all third parties as designated by the COR,

2. all materials, critical reagents and/or reference materials remaining from the work carried out under each Task Order by the Contractor, all subcontractors, and all third parties as designated by the COR, unless otherwise instructed by the COR,

3. any critical reagents, references and/or materials developed under each Task Order by the Contractor, all subcontractors, and all third parties as designated by the COR, unless otherwise instructed by the COR, and

4. all files pertaining to each Task Order generated by the Contractor, all subcontractors, and all third parties as designated by the COR.

3) TASK AREAS

In performance of work under any Task Area, the Contractor shall comply with all applicable guidelines including, but not limited to, those listed in the Addendum to this SOW titled “References”. Services to be performed under this contract could include the following:

A. Preclinical Evaluation of Cancer Preventive Efficacy B. Evaluation and Validation of Intermediate Endpoints for Chemopreventive Agents C. Evaluation and Validation of Intermediate Endpoints for Immunopreventive Agents

For the purposes of this contract:

Chemopreventive agents – Chemical, pharmaceutical, and nutraceutical entities used to prevent cancer including, but not limited to, licensed pharmaceutical products; novel molecularly targeted small molecule compounds; natural products and derivatives; peptides;

Work Attachment 3 and nucleic acid-based materials.

Immunopreventive agents – Materials and products used to modulate the host immune system to prevent cancer including, but not limited to, monoclonal antibodies and derivatives of monoclonal antibodies; vaccines based on recombinant proteins, peptides, or nucleic acids (such as RNAs and DNAs) formulated with/without vaccine adjuvants and delivery systems;

and live, modified-live, and/or attenuated entities.

Note to Offerors: Contractors may need to be supported to a certain extent by the expertise and resources of other organizations or persons through consortia agreements, partnerships, subcontracts, and/or consultants. However, Contractors shall be responsible for ALL work performed and shall be responsible for project planning, initiation, implementation, management, and communication; evaluation, selection, and management of subcontractors; and for all deliverables specified in this contract and each awarded Task Order.

3.1 TASK AREA A: PRECLINICAL EVALUATION OF CANCER PREVENTIVE

EFFICACY

The Contractor shall determine cancer preventive efficacy of a given test agent (chemopreventive or immunopreventive) using animal models that include, but are not limited to, syngeneic tumor-graft, carcinogen-induced, and/or genetically engineered (transgenic) models of cancers of the mammary gland, lung and bronchus, esophagus, colon and intestinal tract, prostate, bladder, skin, ovary and other gynecologic tissues, mouth, head and neck, pancreas, liver, and hematopoietic system. The Contractor shall select the animal model(s) most suited for each Task Order’s specific study objectives defined in the Task Order SOW and obtain approval from the COR before commencing all proposed tasks under each awarded Task Order.

Technical Requirements for Task Area A include one or more of the following:

1. The Contractor shall develop and/or update preclinical agent evaluation and development plans in collaboration with the product investigator and COR, as necessary. Plans shall include preclinical study activities to be undertaken for a product efficacy evaluation.

Anticipated timelines for completion of tasks related to the activity shall be provided to the COR.

2. The Contractor shall procure/obtain the test agent(s), unless provided by the NCI. The Contractor shall determine the purity, homogeneity, concentration, and stability of the test agents in administering vehicles and conditions of use as defined in each awarded Task Order SOW. If necessary, the Contractor shall perform chemical analysis of feed or diet concerning preventive agents to be administered.

3. The Contractor shall breed and maintain animal colonies of wild type rodents and specified transgenic rodents in sufficient numbers for preventive efficacy testing purposes. The Contractor shall use animal facilities that meet all requirements specified in each awarded

Work Attachment 3

Task Order (e.g., special barrier facilities), where applicable.

4. The Contractor shall administer chemopreventive agents by different routes specified in the Task Order SOW, including but not limited to diet, gavages, topical, inhalation, injection, or pellet implantation. If more than one route of administration must be studied, the Contractor shall propose appropriate routes of administration tailored for the Task Order-specified study objectives and obtain approval from the COR before commencing all proposed tasks under each awarded Task Order.

5. The Contractor shall administer immunopreventive agents (e.g., vaccines and adjuvants) using appropriate routes of administration as specified in the Task Order SOW. If more than one route of administration must be studied, the Contractor shall propose appropriate routes of administration tailored for the Task Order-specified study objectives and obtain approval from the COR before commencing all proposed tasks under each awarded Task Order.

6. The Contractor shall design research studies, outlining key determinants including but not limited to the order and timing of administration of carcinogen(s), oncogene- or tumor promoting-gene inducing/activating agents, hormones, and/or a given test agent (chemopreventive or immunopreventive) to laboratory animals, as well as different dosing intervals and different doses of test agents, if required. The Contractor shall clearly indicate the number of animals to be used in each proposed technical task supported by appropriate statistical considerations including, but not limited to, power calculations and appropriate corrections for multiple comparisons. The Contractor shall obtain approval from the COR on the research outline before commencing all proposed tasks under each awarded Task Order.

7. The Contractor shall conduct the approved studies to evaluate and determine cancer preventive efficacies of test agents (chemopreventive and/or immunopreventive) using clinical parameters including, but not limited to, appearance, body weight, food and water intake, tumor growth rates/incidence, and survival. If warranted, the Contractor shall employ appropriate tumor imaging technologies (e.g., CT, PET, MRI, ultrasound, bioluminescence, fluorescence) for monitoring tumor growth and progression in live animals.

8. The Contractor shall perform pharmacokinetic studies in appropriate laboratory animals if specified in awarded Task Orders and shall correlate with pharmacodynamic (PD) effects (see 3.2).

9. The Contractor shall collect and preserve blood and other body fluid specimens over the course of in-life animal studies, if specified in each awarded Task Order SOW, for intermediate biomarker studies. The Contractor shall maintain all collected study biospecimens under appropriate storage condition(s) until use.

10. The Contractor shall carry out gross necropsies, and collect and preserve study biospecimens including, but not limited to, whole blood, peripheral blood mononuclear cells (PBMC), plasma, serum, urine, other body fluids (e.g., ascites), lymphoid and other organ tissues, and

Work Attachment 3 tumor samples, as specified in each awarded Task Order SOW. The Contractor shall maintain all collected study biospecimens under appropriate storage condition(s) until use.

Specifically, the Contractor shall store collected tissues at either 4°C (2-8°C), -20°C ± -5°C, -80°C ± -10°C, or liquid nitrogen, according to the instructions and/or requirements of the experimental protocol on the specific Task Order issued. The Contractor shall keep plasma, sera, or other body fluids at appropriate storage temperature (4°C [2-8°C], -20°C ± -5°C, -80°C ± -10°C) until use, pursuant to the instructions or specifications for specified assays under each awarded Task Order.

11. The Contractor shall carry out histopathological examination of selected organ and tumor tissues from control and treated animals as specified in each awarded Task Order SOW. The Contractor shall also carry out immunohistochemistry (IHC) and other appropriate assay methods to evaluate tumor grades and disease stage, if specified in each awarded Task Order.

12. The Contractor shall report all collected tumor growth data including, but not limited to, tumor growth rates, tumor incidence, tumor multiplicity, and tumor latency as specified in each awarded Task Order SOW. The Contractor shall perform statistical analyses of the data and include in the report, as required, means and standard deviations as well as identifying statistically significant and insignificant findings.

13. The Contractor shall ship some or all biospecimens with technical documentation to other investigators at the direction of the Task Order COR (also see 2.4.6).

3.2 TASK AREA B: EVALUATION AND VALIDATION OF INTERMEDIATE

ENDPOINTS FOR CHEMOPREVENTIVE AGENTS

The Contractor shall conduct intermediate endpoint assays using biospecimens that include, but are not limited to, blood, PBMC, plasma, sera, other body fluids, isolated splenocytes, lymphocytes, tumor cells, other specific cell populations, and tissues, collected from preclinical cancer prevention efficacy studies for given test agents. The relevant tissues shall be supplied to the Contractor unless otherwise specified in the Task Order. The Contractor shall select the intermediate endpoint assays most suited for each Task Order’s specific study objectives defined in the Task Order SOW, and obtain approval from the COR before commencing all proposed tasks under each awarded Task Order.

Technical Requirements for Task Area B include one or more of the following:

1. The Contractor shall develop and validate intermediate endpoint assays that shall examine changes in cellular, genomic, epigenomic, proteomic, and/or metabolomic profiles in relevant biospecimens, as specified in each awarded Task Order SOW. Endpoints to be examined shall include, but are not limited to, quantitative and/or qualitative profiles of specific cell population(s) in circulation (e.g., circulating tumor cells) and/or organs, specific gene transcripts, microRNA (miRNA) and other small non-coding regulatory RNA species, DNA adducts, DNA methylation, histone modifications (e.g., acetylation, deacetylation, Work Attachment 3 ubiquitination, phosphorylation, etc.), exosomes, proteins with/without post-translational modifications (e.g., phosphorylation, ubiquitination, glycosylation, etc.), peptides, and other macromolecular complexes.

2. The Contractor shall select and examine quantitative levels of appropriate intermediate endpoints that are proposed or understood to be involved in the molecular mechanism of action (MOA) of a given test agent, using the validated assays in relevant biospecimens, as specified in each awarded Task Order SOW.

3. The Contractor shall select and examine quantitative levels of appropriate intermediate endpoints that are not directly involved in the MOA, but proposed or understood to be correlated with the test agent’s cancer preventive effects, using the validated assays in relevant biospecimens as specified in each awarded Task Order SOW.

4. The Contractor shall determine pharmacokinetic endpoints directly related to the test agent (e.g., the parent compound and/or metabolites) if specified in the Task Order SOW (also see 3.1.8).

5. The Contractor shall present/report all collected intermediate endpoint data in tabular and/or graphic forms, perform statistical analyses of the data, and shall provide a written commentary regarding the results as specified in each awarded Task Order. Further, the Contractor shall correlate intermediate biomarker results with pharmacokinetic data, if applicable, and demonstrate pharmacodynamic (PD) effects. Furthermore, the Contractor shall correlate the PD effects with the effectiveness of a given agent and shall determine the PD correlates of protective efficacy.

3.3 TASK AREA C: EVALUATION AND VALIDATION OF INTERMEDIATE

ENDPOINTS FOR IMMUNOPREVENTIVE AGENTS

The Contractor shall conduct intermediate endpoint assays using biospecimens that include, but are not limited to, blood, PBMC, plasma, sera, other body fluids, isolated splenocytes, lymphocytes, and tissues, collected from preclinical cancer prevention efficacy studies for given test agents. The relevant tissues shall be supplied to the Contractor unless otherwise specified in the Task Order. The Contractor shall select the intermediate endpoint assays most suited for each Task Order’s specific study objectives defined in the Task Order SOW and obtain approval from the COR before commencing all proposed tasks under each awarded Task Order.

Technical Requirements for Task Area C include one or more of the following:

1. The Contractor shall develop and validate intermediate endpoint assays that shall examine changes in humoral and/or cellular immune responses to vaccine, non-vaccine immunomodulatory agents, and/or select tumor antigens (Ags), using relevant biospecimens as specified in each awarded Task Order SOW. Endpoints to be examined shall include, but are not limited to, quantitative levels of Ag-specific antibodies, specific immune cell populations (e.g., Ag-presenting cells, T lymphocytes, B lymphocytes, natural killer cells, Work Attachment 3 effector, suppressor, and memory T/B cell subsets, regulatory T/B cells, myeloid derived suppressor cells, etc.) in circulation and/or in organs and tumors, Ag-specific T helper cell population-related cytokine production profiles (e.g., Th1/Th2/Th17), cytotoxic T lymphocyte activity (CTL), and/or antibody dependent cellular cytotoxicity (ADCC), as specified in the Task Order SOW.

2. The Contractor shall determine immunogenic epitopes of vaccine antigens and/or select tumor antigens as specified in the Task Order SOW using appropriate application technologies including, but not limited to, synthetic peptide library-based methods with different assay readouts such as lymphoproliferation, cytokine production (e.g., interferon gamma ELISpot, ELISA), cytokine staining by flow cytometry, MHC binding, and antibody binding; peptide recovery from MHC complexes by mass spectrometry; and other molecular/biochemical/biophysical methods as specified in the Task Order.

3. The Contractor shall develop and validate intermediate endpoint assays that shall examine changes in cellular, genomic, epigenomic, proteomic, and/or metabolomic profiles of immune system-cells (e.g., splenocytes, circulating lymphocytes, and tumor infiltrating lymphocytes) and other organ systems using relevant biospecimens, as specified in each awarded Task Order SOW. Endpoints to be examined shall include, but are not limited to, quantitative and/or qualitative profiles of specific cell population(s) in circulation (e.g., circulating tumor cells) and/or organs, specific gene transcripts, miRNA and other small non-coding regulatory RNA species, DNA adducts, DNA methylation, histone modifications (e.g., acetylation, deacetylation, ubiquitination, phosphorylation, etc.), exosomes, proteins with/without post-translational modifications (e.g., phosphorylation, ubiquitination, glycosylation, etc.), peptides, and other macromolecular complexes in laboratory animals treated or untreated with test agents as specified in the Task Order SOW.

4. The Contractor shall select and examine quantitative levels of appropriate intermediate endpoints that are proposed or understood to be involved in the immunomodulatory mechanism(s) of action of a given test agent, using the validated assays in relevant biospecimens as specified in each awarded Task Order SOW. The Contractor shall select and examine quantitative levels of appropriate intermediate endpoints that are not directly involved in the MOA, but proposed or understood to be correlated with the test agent’s cancer preventive effects, using the validated assays in relevant biospecimens as specified in each awarded Task Order SOW.

5. The Contractor shall determine immune response kinetic endpoints directly related to test agents (e.g., vaccine or non-vaccine immunomodulatory agents) if specified in the Task Order SOW.

6. The Contractor shall present/report all collected intermediate endpoint data in tabular and/or graphic forms, perform statistical analyses of the data, and shall provide a written commentary in the report regarding the results, as specified in each awarded Task Order.

Further, the Contractor shall correlate intermediate biomarker results with immunokinetic data, if applicable, and demonstrate immunodynamic (ID) effects. Furthermore, the

Work Attachment 3

Contractor shall correlate the ID effects with the effectiveness of a given agent and shall determine the immune correlates of protection, as specified in the Task Order SOW.

Base Contract Management Support Activities

These activities support parent contract requirements as stated in the contract. The scope includes management functions performed by the Contractor in support of NCI’s contract entitled

“PREVENT CANCER PRECLINICAL DRUG DEVELOPMENT PROGRAM: PRECLINICAL

EFFICACY AND INTERMEDIATE ENDPOINT BIOMARKERS,” which occurs independent of other specific Task Orders to be awarded under the contract.

Requirements include:

1. Kick off Meeting: Participate in the initial parent contract kick-off meeting after award of initial task order to be held in Rockville, Maryland or virtually or virtual-hybrid as agreeable by all parties. The kick-off meeting shall be attended by the Principal Investigator, key Contractor technical and business staff, the COR and his/her designees, and the Contracting Officer and/or his/her designees.

Work Attachment 3

Addendum to the Statement of Work: References

1) Office of Laboratory Animal Welfare, Office of the Director, NIH:

http://grants.nih.gov/grants/olaw/olaw.htm

2) Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International: https://www.aaalac.org/

3) The Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals: http://grants.nih.gov/grants/olaw/references/phspol.htm

4) Guide for the Care and Use of Laboratory Animals:

https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf

5) Animal Welfare Act and Animal Welfare Regulations established by the United States Department of Agriculture (USDA):

http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/animalwelfare

6) “Biosafety in Microbiological and Biomedical Laboratories”, Centers for Disease Control and Prevention, and the National Institutes of Health, Fifth Edition 2009 http://www.cdc.gov/biosafety/publications/bmbl5/index.htm

7) NIH Guidelines for Research involving Recombinant or Synthetic Nucleic Acid Molecules: https://osp.od.nih.gov/biotechnology/nih-guidelines/

8) FDA Guidance for Industry: Integrated Summary of Effectiveness:

http://www.fda.gov/downloads/drugs/guidances/ucm079803.pdf

9) FDA Guidances on Biologics including Vaccines:

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformatio n/Guidances/default.htm

10) FDA Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines:

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator yInformation/Guidances/Vaccines/UCM278673.pdf

11) FDA Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products:

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator yInformation/Guidances/CellularandGeneTherapy/UCM376521.pdf

12) FDA Guidance for Industry: Considerations for Plasmid DNA Vaccines for Infectious Disease Indications: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-plasmid-dna-vaccines-infectious-disease-indications http://grants.nih.gov/grants/olaw/olaw.htm https://www.aaalac.org/ http://grants.nih.gov/grants/olaw/references/phspol.htm https://grants.nih.gov/grants/olaw/guide-for-the-care-and-use-of-laboratory-animals.pdf http://www.aphis.usda.gov/wps/portal/aphis/ourfocus/animalwelfare http://www.cdc.gov/biosafety/publications/bmbl5/index.htm https://osp.od.nih.gov/biotechnology/nih-guidelines/ http://www.fda.gov/downloads/drugs/guidances/ucm079803.pdf http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM278673.pdf http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM278673.pdf http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM376521.pdf http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM376521.pdf https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-plasmid-dna-vaccines-infectious-disease-indications https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-plasmid-dna-vaccines-infectious-disease-indications

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FDA Guidance for Industry: Content and Format of Chemistry, Manufacturing, and Controls Information and Establishment Description Information for Vaccine or Related Product:

http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulator yInformation/Guidances/Vaccines/ucm092272.pdf http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm092272.pdf http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm092272.pdf

1 | P a g e PREVENT GMP Pool IDIQ Statement of Work Attachment #4

STATEMENT OF WORK dated 11/07/2022

ATTACHMENT 4

PREVENT Cancer Preclinical Drug Development Program: CGMP Preclinical Services for Biopharmaceutical Product Development and Manufacturing

Independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, materials, equipment, and facilities, not otherwise provided by the Government, as needed to perform the Statement of Work.

1) SCOPE

This Statement of Work directly supports the PREVENT initiatives, as necessary, to help the Program achieve its mission. The Preclinical Services for Biopharmaceutical Product Development and Manufacturing Program will provide the PREVENT initiatives with a broad and flexible range of timely, proactive and development-oriented capabilities to provide preclinical product development and manufacturing support for promising biopharmaceutical products and diagnostic reagents.

2) GENERAL TASK ORDER REQUIREMENTS

The Technical Task Area(s) identified under each specific Task Order will depend on the status of the candidate agent(s) as part of an overall product development plan and/or regulatory submission plan to the U.S. Food and Drug Administration (FDA). Tasks shall be conducted in accordance with quality oversight that is appropriate to the phase of the specific task and within all applicable and current federal, state, and local laws, codes, ordinances and regulations, as well as all applicable Public Health Service (PHS) Safety and Health provisions.

The following requirements shall apply to each Task Order:

2.1 PROJECT MANAGEMENT

1. Task Order Initiation Meeting and/or Teleconference: Within 10 calendar days after the effective date of the Task Order or before the start of any tasks, the Contractor shall plan for and participate in a Task Order Initiation Meeting or Teleconference to review the Task Order requirements and timelines, discuss Task Order technical plans and approaches, and identify any anticipated problems/obstacles to completing the Task Order requirements. The Task Initiation Meeting shall be attended by Contractor key personnel (including subcontractor personnel as appropriate), the Contracting Officer’s Representative (COR), and other representatives at the discretion of the COR (e.g., CO, Subject Matter Experts, investigator representatives).

2. The Contractor shall provide and maintain an acceptable Project Management Plan (PMP) depicting overall project management and implementation plans including coordination and integration of task activities to be conducted under the Task Order to meet all Technical

2 | P a g e PREVENT GMP Pool IDIQ Statement of

Requirements. The PMP shall clearly delineate all the roles and responsibilities of key personnel and site(s) involved on the Task Order and any preparation and/or planning to be done prior to performance of the tasks. The PMP shall be provided to the Contracting Officer’s Representative (COR) describing proposed project management of all proposed tasks for each Task Order including:

a. Project Management

1) Project Organization

2) Roles and Responsibilities of Personnel and Staffing Plan

3) Project Deliverable Tracking including Acceptance Criteria

4) Subcontract Management (if applicable)

5) Communication Approach

6) Risk Management Approach

7) Quality Management Approach

b. Technical Approach

c. Project Monitoring and Control

1) Schedule including Gantt chart(s).

2) Budget: task-linked budgets will be required under any cost-reimbursement task orders that separate costs for each milestone, while for any fixed-priced task orders, payments will be tied to receipt and approval of task order deliverables to facilitate tracking and reporting costs with regards to progress made and activities accomplished.

3) On-time submission of Project Reports as outlined in the Task Order.

4) Tracking of action items.

4. The Contractor shall develop, monitor, and modify the timelines, tasks, budgets, objectives and milestones as discussed with and/or prioritized by the COR before and during the performance of activities under the Task Order. If changes need to be made to the technical protocol at any time, the Contractor shall provide updates to the CO and COR immediately by teleconference or email and also document the change in the monthly progress reports for each Task Order. The CO and COR must provide written concurrence and approval prior to Contractor implementing any proposed change(s). These updates shall include changes made and current project rationale.

5. The Principal Investigator (or equivalent) shall be responsible for overall compliance with quality requirements, project management and communication, tracking performance, monitoring and reporting on project status and progress, and recommending modifications to project requirements and timelines, including projects undertaken by subcontractors.

6. Key personnel or other senior staff coordinator(s) shall be available for ad hoc meetings/teleconferences with the COR immediately upon a meeting request.

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7. Progress Review Meetings and Teleconferences

a. The Contractor shall plan and participate in Progress Review Meetings or Teleconferences, which shall be attended by Contractor key personnel (including subcontractor personnel as appropriate), the COR, the Contracting Officer, and other individuals designated by the COR (e.g., Subject Matter Experts, investigator representatives), as necessary, at monthly intervals or as issues arise. The purpose of these meetings/teleconferences shall be to review and discuss:

1) ongoing and planned activities, protocols and associated data,

2) timelines for task initiation and completion, submission of data and other information,

3) any problems or deficiencies identified with respect to the accuracy, timeliness and completeness of data submitted, and

4) any other matters relevant to the technical and financial administration of the task.

8. The Contractor shall be responsible for the following:

a. preparing and distributing meeting/teleconference agendas and background materials at least one business day prior to each meeting/teleconference; and

b. preparing and submitting to the COR written summaries of all major decisions and action items resulting from such meetings and teleconferences within seven calendar days after each meeting/teleconference.

The following Quality Management requirement outlined in 2.2 shall apply to the base IDIQ and all subsequent task orders:

2.2 QUALITY MANAGEMENT

1. The Contractor shall demonstrate responsibility for the quality and applicable regulatory compliance of the materials and documentation generated per this Statement of Work (SOW). The Contractor shall provide a Quality Management (QM) Plan (QMP) outlined in the proposal at the Base IDIQ level (Master QMP) which applies to all subsequent task orders which describes how Quality Assurance (QA) is addressed within the organization, including quality management responsibilities, resources, training program, oversight of all subcontractors if applicable, and communication processes including timelines. The contractor shall provide a QMP as part of the initial task order which will apply to the IDIQ and subsequent task orders. The QMP will provide a contractor point of contact and be a brief document which supports how the contractor will ensure compliance with industry and government Good Laboratory Practices (GLP) and the processes supporting Current Good Manufacturing Practice (CGMP) standards, protocols, and procedures. The Contractor shall ensure the products meet any additional GLP/ CGMP quality standards specified in each Task Order.

2. The Contractor shall maintain an acceptable Quality Management Plan (QMP), outlined in the Final Proposal Revision, that describes how quality assurance is addressed within the

4 | P a g e PREVENT GMP Pool IDIQ Statement of organization, including quality management responsibilities, resources, training program, oversight of all subcontractors if applicable, and communication processes including timelines. The Quality Management Plan shall include any Quality Agreements (QA) between the Prime Contractor and any subcontractors which clearly delineates:

responsibilities, communication processes including timelines, personnel, production and process controls, facilities, equipment, laboratory controls, training, materials management, packaging and labeling, records and documentation, plans for routine and “for cause” audits of the subcontractor facility(s), participation in and/or communication of audit findings with Government personnel, and deviations, corrective and preventive action (CAPA), and out of specification (OOS) documentation. The Contractor shall also ensure adequate environmental controls are in place to prevent cross-contamination in any multiproduct manufacturing environment. If changes need to be made to the QMP or QA, the Contractor shall provide updates to the CO and COR immediately by teleconference or email. The CO and COR must provide written concurrence and approval prior to Contractor implementing any proposed changes.

2.3 FACILITIES, EQUIPMENT AND OTHER RESOURCES

As outlined in the Task Order:

1. The Contractor shall provide facilities, equipment, space, training and other resources to conduct work with potentially hazardous chemical and biological materials in compliance with all federal and NIH regulations in accordance with the following guidelines where applicable:

a. “Biosafety in Microbiological and Biomedical Laboratories”, Centers for Disease Control and Prevention, and the National Institutes of Health, 6th Edition 2020 June. Available at: https://www.cdc.gov/labs/BMBL.html

b. NIH Guidelines for Research involving Recombinant or Synthetic Nucleic Acid Molecules. 2019 April. Available at: https://osp.od.nih.gov/biotechnology/nih-guidelines/

2. The Contractor shall provide facilities, equipment, space and other resources to conduct work in a manner to prevent cross-contamination with other materials.

3. All personnel, equipment and facilities shall be compliant with applicable regulatory agency requirements in effect throughout the entire period of performance. The Contractor shall maintain quality assurance (QA) documentation to support adherence to these areas.

2.4 STORAGE AND SHIPPING

As outlined in the Task Order:

1. The Contractor shall be responsible for the overall management and conduct of the receipt, storage, retrieval, packaging and shipping of products, materials, and specimens, including obtaining appropriate licenses and permits, where applicable.

https://www.cdc.gov/labs/BMBL.html https://osp.od.nih.gov/biotechnology/nih-guidelines/ https://osp.od.nih.gov/biotechnology/nih-guidelines/

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2. The Contractor shall receive and record products, materials, reagents, and specimens.

3. The Contractor shall store products, materials, and test samples at the specified temperature range and conditions in a secure area. Specific temperature ranges include but are not limited to liquid nitrogen, -70°C +/- 10°C, -20°C +/-5°C, 2-8°C, room temperature.

4. The Contractor shall monitor and document the conditions in all controlled temperature chambers as appropriate for the level of regulatory compliance, under which each product is produced: specific procedures should be proposed by the Contractor and will be reviewed and approved by the COR.

5. The Contractor shall qualify or validate temperature chambers as proposed by the Contractor and reviewed and approved by the COR.

6. The Contractor shall be responsible for retrieving, packaging, and shipping of materials to various domestic and international locations. If not provided by the Government, detailed shipping instructions shall be supplied by the Contractor as appropriate, at the time of shipment. The Contractor shall also be responsible for establishing and following a documented shipping procedure compatible with CGMP regulations when appropriate;

capturing and documenting temperatures maintained during shipping and storage; and adhering to U.S. and international standards for packaging.

2.5 TRANSITION

At the completion of each Task Order or at any point as determined by the COR, the Contractor shall deliver to the Government the following items:

1. all data obtained from all work carried out under each Task Order by the Contractor, all subcontractors, and all third parties as designated by the COR,

2. all products remaining from the work carried out under each Task Order by the Contractor, all subcontractors, and all third parties as designated by the COR,

3. any critical reagents (such as proteins, peptides, molecular constructs, vectors, viruses, cell banks; also see 3.3.3), test results, reference standards or materials developed under each Task Order by the Contractor, all subcontractors, and all third parties as designated by the COR, and

4. all files pertaining to each Task Order generated by the Contractor, all subcontractors, and all third parties as designated by the COR.

3) TECHNICAL TASK AREAS

Services to be performed under this contract have been assembled into the following Task Areas:

Task Area A – Product Development Planning and Evaluation Task Area B – Analytical Assay Development and Product Characterization

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Task Area C – Process Development and Related Activities Task Area D – CGMP Manufacture, Related Activities and Documentation

For the purposes of this contract:

Biopharmaceutical Products are defined as materials that are derived from biotechnology processes including, but not limited to, recombinant proteins derived from traditional and non-traditional expression systems; peptides; nucleic acid-based materials (such as RNAs and plasmids); vaccine adjuvants and delivery systems; and other biotechnology or cell-derived products.

Contractors may need to be supported to a certain extent by the expertise and resources of other organizations or persons through consortia agreements, partnerships, subcontracts, and/or consultants. However, the Prime Contractor shall be responsible for ALL work to be performed, including project planning, initiation, implementation, management and communication;

evaluation, selection, and management of subcontractors; and for all deliverables specified in this contract and each awarded Task Order.

Scope and Requirements for each Technical Task Area

The Technical Requirements for each Technical Task Area are considered applicable to all Task Orders, unless otherwise indicated in the specific Task Order. Similarly, all Technical Task Areas are considered applicable to all Task Orders, unless otherwise indicated in the specific Task Order.

3.1 Task Area A: Product Development Planning and Evaluation

Scope of Task Area A:

Task Area A will support the assessment of products with respect to feasibility of design, development, manufacture, assay development and stability testing for the preparation of Preclinical, Phase I - III clinical trial materials, and materials for diagnostic purposes; developing and writing Preclinical and/or Product Development Plans for specified products; and conducting, reviewing and evaluating technical and/or facility audits of potential subcontractors.

Technical Requirements for Task Area A:

1. The Contractor shall conduct an evaluation of the current status and overall scientific feasibility of the project as determined by: 1) product development history, if applicable, including all current scientific documents related to the project, laboratory notebooks, publications, and any ancillary documentation, plus all regulatory documentation; 2) the manufacturing feasibility and traceability of all project reagents; and 3) the financial feasibility of the project.

2. The Contractor shall develop and/or update Pre-clinical and/or Product Development Plans for candidate products in collaboration with the product investigator/sponsor and COR. The investigator(s)/sponsor(s) will be named in the task order request for proposals (TORFPs).

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The plans shall include regulatory, pre- clinical, clinical, non-clinical, and manufacturing…