PreSolicitation Notice 75N93021R00020.pdf

PRESOLICITATION NOTICE

RESOURCES TO ADVANCE PEDIATRICS AND HIV PREVENTION SCIENCE (RAPPS)

RFP Number 75N93021R00020

Background As a resource to the fields of HIV treatment and prevention, NIAID maintains contracts to support the development of emerging HIV therapeutics, vaccines, and nBP candidates. The services under these contracts are provided on a case-by-case basis and are designed to assist in filling key gaps in their product development pathway. These services have enabled the acquisition of critical data, development of essential methods, manufacture and characterization of products, fulfillment of regulatory requirements, and/or completion of studies necessary for entering clinical trials. Over the past years, these contract activities have helped investigators to obtain critical data and materials to attract additional funding, gain prospective partnership, fulfill regulatory requirements, and complete studies before entering clinical trials. Information about these contract resources or activities can be found at the following website: https://www.niaid.nih.gov/research/resources.

Some of these activities are currently being provided under the following NIAID contracts:

• Comprehensive Resources for HIV Microbicides and Biomedical Prevention:

o HHSN272201600008I with Advanced Bioscience Laboratories, Inc., 9800

Medical Center Drive, Rockville, Maryland 20850-3770 o 75N93022D00001, formally HHSN272201600009I, with Lovelace Biomedical and Environmental Research Institute, 2525 Ridgecrest Drive, SE, Albuquerque, NM 87108-5127 o HHSN2722016000010I with SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493

Purpose and Objectives The purpose of the proposed Indefinite Delivery/Indefinite Quantity contracts is to provide the extramural scientific community with research materials and preclinical product development support for candidate products that emerge from investigator-initiated research studies or from collaborations with private sector or academic partners. These services may also be used to support product discovery and development leading to IND, Investigational Device Exemption (IDE), and/or New Drug Application (NDA) filings with the Food and Drug Administration (FDA).

NIAID will primarily use these contracts to fill critical development and resource gaps more rapidly and efficiently and advance promising products into clinical testing. The focus of these contracts will be development of therapeutics and prevention products for HIV, including single or combination products with activity against associated co-infections such as Mycobacterium tuberculosis or MPTs that incorporate contraceptives. At the discretion of NIAID, these contracts may also be used to advance therapeutic and preventive strategies for other infectious diseases.

Throughout this Statement of Work (SOW), these candidate products and/or strategies will collectively be referenced as “products.”

https://www.niaid.nih.gov/research/resources

Throughout this contract, preclinical (i.e., undertaken before testing in humans) and nonclinical (i.e., undertaken to address specific regulatory requirements during clinical testing) studies will collectively be referenced as “preclinical”.

The Government intends to solicit these services as Indefinite Delivery/Indefinite Quantity multiple contract awards. Task Orders will be issued in the following Task Areas:

• Task Area A: Preclinical Gap-Filling Services

• Task Area B: Animal Models Supporting Product Development

• Task Area C: Bioanalytical Support Services

• Task Area D: Product Manufacturing

• Task Area E: Scientific and Quality/Regulatory Support Services

Offerors may respond to one Task Area only, to several Task Areas, or to all Task Areas. It is anticipated that NIAID will award Base contract awards to one or multiple contractors for each of the Task Areas A, B, C, D, and E. In order to ensure the independence and objectivity required for the functions carried out under Task Area E, if an offeror submits a proposal under Task Area E, in addition to submitting a proposal under any of Task Areas A, B, C, and/or D, then the offeror shall provide a Conflict of Interest Mitigation Plan. This includes both the Prime Contractor as well as any potential Subcontractor(s).

Scope The Contractor shall provide preclinical development support for candidate products and drug development activities. The scope of work encompasses activities that range from initial product discovery to those required to support clinical trials and/or product licensure.

This contract will be used primarily to support pre-clinical research, development of pediatric formulations, and advancement of next generation nBPs and MPTs. However, other NIAID programs may initiate Task Orders under this contract as necessary to help accomplish their mission.

General Technical Requirements:

The following requirements shall apply to all Task Orders, as applicable:

1. Meetings and Teleconferences

a. Task Order Initiation Meetings/Teleconferences A Task Order Initiation Meeting shall be scheduled within 10 business days of the award of the first Task Order to each Contractor. The Task Order Initiation Meeting will be held either in person or via teleconference, with the Contracting Officer’s Representative (COR), the Contracting Officer and other NIAID personnel designated by the COR, at a location determined by the COR. The purpose of the Task Order Initiation Meeting will be to orient the Contractor to NIAID Task Order procedures, to review contract requirements, and to plan implementation of initial

Task Order activities.

b. Progress Meetings/Teleconferences The Contractor shall plan and conduct meetings between key Task Order personnel, including the COR, and other project staff (e.g., subcontractors, consultants, product sponsors, and/or other personnel designated by the COR) at regular intervals, to review protocols, data, the status of approved projects, and to discuss any matters relevant to the scientific and/or financial administration of the contract and future activities. The schedule for these meetings will be established by the COR after Task Order award (i.e., weekly, biweekly, monthly, or as needed to address emerging issues).

c. For each type of meeting/teleconference, the Contractor shall prepare and electronically submit the agenda and meeting materials to the COR and/or COR-designated NIAID staff for review and approval prior to the meeting, distribute the agenda and background materials to meeting participants in advance of the meeting, and provide a written summary of all meetings and teleconferences to the COR after the conclusion of the meeting/teleconference. In addition, as directed by the COR or in the Task Order SOW, the Contractor shall develop written or oral presentation materials and/or arrange for the logistics (e.g., meeting location, travel itineraries, etc.). For each Task Order, specific due dates and time frames for receipt and review of meeting agendas, materials, and summaries shall be determined prior to the issuance of the Request for Task Order Proposals and included in the SOW for the Task Order.

2. Intellectual Property

The Contractor shall ensure the protection of third-party intellectual property, information provided by third parties or by the Government, as well as data generated through this contract. Information shall be deemed as proprietary and shall not be used or distributed without the expressed consent of the third party or as authorized in Agreements between NIAID and the third party provider.

As applicable and upon direction of the COR, the Contractor shall develop an Intellectual Property Plan outlining for how intellectual property will be handled, as well as the disposition of data/materials developed under Task Orders. This includes any intellectual property that may pre-exist or be developed during performance of work. Included in the Plan will be the assignment of such rights and obtaining concurrence from any interested parties, including maintenance of security for confidential and/or proprietary data. A copy of the Plan shall be provided to the COR within 30 days of initiation of the Task Order.

The Contractor shall also consult and coordinate with the third-party providers of proprietary materials or data throughout the development process and complete a material transfer agreement with the third-party provider, if needed.

3. Technology Transfer

As required by the Task Order and as specified by the COR, the Contractor shall prepare and submit to the COR for review and approval, technology transfer packages for the transfer of assays, processes, methods, Standard Operating Procedures (SOPs), reagents, animal models, and/or any other material or documentation generated under the contract, to any third party designated by the COR, or directly to the COR. The technology transfer packages may include material, reagents, and training of others at the Contractor’s or Subcontractors’ site. All technology transfer packages must be sufficient to completely and effectively transfer the technology.

4. Document and Data Management

The Contractor shall provide the following:

a. Ensure that studies are conducted and related records (e.g., raw data, analyzed data, protocols, final reports, etc.) are stored in compliance with the Contractor’s Quality Assurance Plan, Task Order Quality Management Plans, and specified regulatory requirements, such as Good Laboratory Practice (GLP; 21 CFR 58), current Good Manufacturing Practice (cGMP; 21 CFR 210-211), International Conference on Harmonization (ICH) guidelines, or other local, state, Federal (e.g., FDA), or non- U.S. (e.g., European Medicines Agency [EMA], South African Health Products Regulatory Authority [SAHPRA]) product quality and development regulations, when required by the Task Order SOW

b. Provide and maintain a document and data management process that supports all data types generated by, or related to, the requirements of the contract and ensures data integrity throughout the product development lifecycle using data management best practices to ensure that all records shall be held in a format that is not readily corruptible and protected from deliberate or accidental alteration for both non-GxP and GxP studies (e.g., CFR 21 part 11, GLP: see OECD GLP Guidance Document 17).

c. Documents and data shall be submitted to NIAID in an electronic format to a government owned, secure database (e.g., Electronic Report Deliverable Submission [eRDS]). When required by the Task Order SOW documents and data shall be provided in a format suitable to meet requirements for regulatory submissions and applications such as Investigational New Drug (IND) Applications, New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), and Biologics License Applications (BLAs). Some or all of the data may be transferred into the NIAID data management system.

d. All electronic reports submitted shall be compliant with Section 508 of the

Rehabilitation Act of 1973. Additional information about testing documents for Section 508 compliance, including guidance and specific checklists, by application, can be found at: http://www.hhs.gov/web/508/index.html under "Accessibility @

HHS."

e. All written communications shall be electronic. The Contractor shall minimize the use of paper documents and paper information distribution to the greatest extent http://www.hhs.gov/web/508/index.html possible. Paper documentation shall be used only when required by federal, state, local or international law or where validated electronic systems are not available. The duration of electronic documentation storage will be as required by regulation.

5. Material Receipt, Storage, Shipping, and Inventory

The contractor shall:

a. Develop and maintain effective procedures to support contract activities for receiving, storing, shipping and inventory of products (i.e., Active Pharmaceutical Ingredients (APIs), formulations, or investigative drug products), pathogens (e.g., HIV, Simian immunodeficiency virus [SIV], Hepatitis B virus [HBV], Hepatitis C virus [HCV], Mycobacterium tuberculosis [MTB], etc.), human and animal specimens (e.g., biological cells, fluids, tissues, etc.), and reagents (e.g., common assay controls, kit components, etc.); including the secure, safe, and stable storage of these contract materials under the required conditions (e.g., Biosafety Level, aseptic, Good Manufacturing Practices (GMP), etc.) and according to specifications provided by the provider, as applicable.

b. Obtain and maintain the appropriate licenses and permits required by international, federal, state, and local authorities for the safe import or export, storage and shipping, handling, transportation and distribution of products, drugs, biologics, pathogens, specimens and reagents (may include biohazardous or radiological agents).

c. Provide for safe packing, labeling, and shipment of products, pathogens, specimens and reagents, so that shipments are coordinated for timely receipt.

d. Provide shipping containers and associated documentation that comply with domestic and international postal requirements; pertinent International Air Transport Association (www.iata.org) and the International Civil Aviation Organization (www.icao.int) requirements. The shipping containers shall ensure environmental safety, as well as the maintenance of appropriate environmental safeguards and desired temperatures for specific products in transit, depending on the mode of transportation employed.

e. Establish and maintain an inventory of specific contract materials as designated by the COR or in the Task Order SOW, such as in an Excel spreadsheet or database, that includes searchable information, such as compound identifiers, amounts available, storage locations, shipping data and other biological and chemical characteristics of the compound, source and relevant material transfer agreements, or animal inventories and animal data.

6. Regulatory Compliance

When required, all activities supporting specific regulatory requirements shall be conducted in compliance with Good Laboratory Practice (GLP; 21 CFR 58), current file://niaid-fas2/cmbsh/AIDS%20RCB/Solicitations/FY-23%20RFPs/RAPPS%20(Bobby)/Tab%20B%20-%20Presolicitation/Reviews/OID%20Review/www.iata.org file://niaid-fas2/cmbsh/AIDS%20RCB/Solicitations/FY-23%20RFPs/RAPPS%20(Bobby)/Tab%20B%20-%20Presolicitation/Reviews/OID%20Review/www.icao.int

Good Manufacturing Practice (cGMP; 21 CFR 210-211), International Conference on Harmonization (ICH) guidelines, or other local, state, Federal, or non-U.S. (e.g., European Medicines Agency (EMA), South African Health Products Regulatory Agency (SAHPRA)) product quality and development regulations. For FDA submissions, this shall require performance of studies at a level of quality that is suitable for incorporation into pre-IND, IND, IDE, and NDA documents. Although studies that support product development outside of regulatory requirements (i.e., non-GLP or non-cGMP) may also be performed, the resulting data, processes and data/record keeping shall be well-documented and of suitable quality to be acceptable for inclusion in an IND/IDE/NDA filing.

When applicable, the preclinical development services should meet the FDA recommended preclinical requirements for the product (e.g., for antiviral products):

(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/antiviral-product-development-conducting-and-submitting-virology-studies-agency ), and/or the guidance for vaginal microbicides (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vaginal-microbicidesdevelopment-prevention-hiv-infection-pdf )

When applicable for non-GLP/non-cGMP activities, the Contractor shall ensure that services meet the NIH requirements for rigor and reproducibility, guideline available at:

https://www.nih.gov/research-training/rigor-reproducibility.

7. Site Visits

If required in the Task Order SOW, arrange for and conduct site visits (e.g., study initiation, interim, or termination visits) for Contractor/subcontractor staff, NIAID staff, contract consultants, and/or other third-party individuals designated by the COR to review and discuss activities related to the Task Order SOW.

The following types of discussions may occur in these meetings, but other topics may be included as specified by the COR or in the Task Order SOW: project progress;

approaches to overcoming identified problems and obstacles; recommendations for modifications to project timelines, objectives, and research approaches/methodologies based on outcomes to date; future plans; and financial issues.

8. Quality Assurance/Quality Control (QA/QC)

a. The Contractor shall implement a written Quality Plan and program to monitor all operations and processes, develop, implement and evaluate SOPs; define metrics to assess performance; methods to identify and address deficiencies and resolution of issues; and QA training of staff. Project-specific QA/QC requirements will be specified in each Task Order.

b. The Contractor shall ensure compliance of all Task Order specific activities with the https://www.fda.gov/regulatory-information/search-fda-guidance-documents/antiviral-product-development-conducting-and-submitting-virology-studies-agency https://www.fda.gov/regulatory-information/search-fda-guidance-documents/antiviral-product-development-conducting-and-submitting-virology-studies-agency https://www.fda.gov/regulatory-information/search-fda-guidance-documents/antiviral-product-development-conducting-and-submitting-virology-studies-agency https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vaginal-microbicidesdevelopment-prevention-hiv-infection-pdf https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vaginal-microbicidesdevelopment-prevention-hiv-infection-pdf https://www.nih.gov/research-training/rigor-reproducibility

Contract’s QA/QC Plan and the Task Order specific Quality Management Plan.

Oversight activities performed in the application of the quality management process shall include the following:

i. Review of all protocols to assure there is detail to ensure proper evaluation and analysis of the results.

ii. The process and product quality standards that shall cover product content, design, development, deployment, environment, technology, security, maintainability, and others within the constraints of a project’s schedule, available resources, and internal policies and procedures.

iii. Quality reviewer(s) having the expertise, competence, and objectivity to perform an engaging review of the activities and associated data/results in this Task Order.

iv. Detailed review of all results to assure that the data and final report are in compliance with the standards established in the quality management process.

c. When applicable and as required by the Task Order, the Contractor shall implement a formal documentation method to manage quality throughout all stages of the activities that are described above. This quality management process shall include the following:

i. Include the oversight processes for the activities in this Task Order, which shall include:

(a) Planning

(b) Training

(c) Performance

(d) Monitoring

(e) Documentation

(f) Archiving

d. Designing efficient study protocols and tools and procedures for data collection and processing, including information that is essential for decision-making

e. Establishing methods to assure and control the quality of the studies

f. Ensuring that all study protocols, study reports, and other operational documents are clear, concise, and consistent, and available (if requested by the COR)

g. Establishing a quality risk management process for the assessment, control, communication, and review of risks to the quality of the activities in this Task Order assuring that project risks are well understood and appropriately mitigated or managed.

h. This quality risk management process shall include the following:

i. Pertinent assumptions identifying the potential of risk and their likelihood of occurring, and provide an evaluation of the planned schedule, resources (budget and staffing) and processes.

ii. Activities of Quality Management that determine the quality policy, objectives, and responsibilities, and implements them by means such as quality planning quality control, and quality assurance.

iii. Identifying a Point of Contact (POC) and critical resources.

iv. Specifying a timeline, deliverables, and appropriate level of decision-making for the risk management process that indicates what is being reviewed, who is reviewing (i.e., department), and the information or reasoning that non-adherence to a specific quality standard causes risk.

v. Perform a risk assessment as to where assay development is needed and what may influence robustness and stability.

i. The Contractor shall establish a risk-based approach to determine the totality of evidence needed to demonstrate a successful method transfer that reduces risk to an acceptable level by incorporating risk-reduction activities into:

i. Protocol design and implementation.

ii. Agreements between parties establishing roles and responsibilities.

iii. Systemic safeguards to ensure adherence to standard operating procedures.

iv. Training in processes and procedures.

j. When applicable and as required by the Task Order, the Contractor shall ensure

Contractor Quality staff are integrated members of the Task Order teams that are responsible for execution and revision of the Quality Management and Risk Managements Plans, as well as technical execution of the studies, data review and management, and final reporting.

k. The COR may require an external audit of the QA/QC infrastructure before awarding a Task Order. The COR may authorize, at any time during the contract period of performance, independent audits of the Contractor with one (1) week advance notice of the scheduled audit. For-cause audits or IND file audits may be performed at any time and without advance notice to the Contractor. The Contractor shall comply with audits authorized by the COR.

l. When applicable and as required by the Task Order, the Contractor shall have and implement the appropriate QA/QC infrastructure (facilities, processes and training) in place to ensure compliance with GLP, cGMP, and GCP regulations. When performance under strict GLP/cGMP is not possible, suitable QA/QC shall be performed and documented to ensure that all data is acceptable for inclusion in an IND/IDE/NDA filing.

m. When applicable for non-GLP/non-cGMP activities, the Contractor shall ensure that services meet the NIH requirements for rigor and reproducibility, guideline available at: https://www.nih.gov/research-training/rigor-reproducibility.

n. QA/QC infrastructure must include SOPs for establishing and maintaining the

QA/QC processes and approaches/methods to document, identify the source(s) for, and address problems and deviations as they occur, as well as recommendations for the resolution of problems and correction of deviations.

o. Maintain a process for quality control of data.

9. Biocontainment Facilities and Safety

As required for all studies conducted under these Task Areas, the Contractor shall:

a. Provide safe facilities and resources and conduct work with hazardous biological materials in compliance with the Biosafety in Microbiological and Biomedical Laboratories (BMBL), 6th Edition, guideline available at:

https://www.cdc.gov/labs/pdf/SF__19_308133-A_BMBL6_00-BOOK-WEB-final-3.pdf

b. Conduct work in accordance with all Federal, state, and local laws, codes, ordinances, and regulations

c. Where applicable, address conflicts between biosafety and clean facility requirements.

10. Acquisition, Care, and Housing of Animals As required for all animal studies conducted under these Task Areas, the Contractor shall:

a. Acquire, as necessary, suitable numbers of animals to carry out the specific task. The decision of which animal species, ages, and sexes to be used and any requirements for specific-pathogen free (SPF) animals shall be made jointly by the COR and the https://www.nih.gov/research-training/rigor-reproducibility https://www.cdc.gov/labs/pdf/SF__19_308133-A_BMBL6_00-BOOK-WEB-final-3.pdf

Contractor, with the COR having final approval authority.

b. House and maintain the animals in well-equipped facilities with Association for the

Assessment and Accreditation of Laboratory Animal Care (AAALAC) International Accreditation or the equivalent.

c. Comply with all applicable laws, policies, and guidelines regarding the care and use of laboratory animals, including the PHS Policy on the Human Care and Use of Laboratory Animals: http://grants1.nih.gov/grants/olaw/references/phspol.htm

d. Provide routine care and health surveillance or laboratory animals including on-call veterinary coverage 24 hours per day, seven days per week. Provide at least daily observations of the health status of each animal, including weekends and holidays.

e. Document and maintain detailed records on the health status of each animal, including clinical observations and testing, any treatments received, the results of periodic weighing and any other care or procedures required during the contract.

Project Requirements:

Contractors will carry out Task Orders in one or more of the following Task Areas:

Task Area A: Preclinical Gap-Filling Services

Scope for Task Area A: Under this Task Area, the Contractor shall conduct the following types of activities to support product development and fulfill regulatory requirements: 1) In vitro/ex vivo assays or methods; 2) Small and large animal safety models; and 3) Other specific activities in support of this task area as required by the FDA to advance products into clinical testing.

Requirements for Task Area A: Under this Task Area, The Contractor shall conduct activities suitable to facilitate regulatory submissions and intellectual property applications of third parties and to support decision-making by the investigator/sponsor and the FDA or non-U.S. regulatory authorities (e.g., EMA, SAHPRA). The Contractor shall conduct GLP and non-GLP studies, as appropriate. These services shall be performed with suitable quality and oversight to meet all applicable regulatory requirements. Products may include small organic molecules, polymers, or biologics (e.g., peptides, oligonucleotides, antibodies), cellular and genetic drug products (e.g., CAR-T cells), products with nanomaterials in their finished dosage form, or combination products for more than one indication (e.g., multipurpose prevention technologies (MPTs) and will have been selected for further development based on their potential to advance to clinical testing.

Specifically, the Contractor shall:

1. Validate assays and processes, and implement appropriate Quality Assurance (QA) and Quality Control (QC) standards for all services provided.

2. Evaluate the data resulting from the preclinical services and provide technical project updates at intervals and in formats designated by the COR or in the Task Order SOW.

http://grants1.nih.gov/grants/olaw/references/phspol.htm

3. Retain all records, samples and histology/microscopy slides, as required under relevant regulatory guidelines.

4. Provide and implement services that are customized to the needs of an individual third-party product sponsor and/or the evolving requirements for emerging products as designated by the COR or in the Task Order SOW.

5. Evaluate stability of active pharmaceutical ingredients (APIs) in formulation, biological fluids, and/or tissues.

6. Perform characterization studies of formulated products to determine particle size, dispersion, and morphology.

7. Provide preclinical testing in vitro (e.g., drug-drug interaction and transporter assays, ISO 10993 assays for extractables, leachables and biocompatibility), ex vivo (e.g., explant tissue assays), or using relevant animal models (which may include rodents and non-rodents, such as dogs, sheep, pigs, and cattle) for conducting relevant safety, toxicity, biokinetic, biodistribution, and/or pharmacological studies of drug products, biologics, placebos, APIs, formulated products, and medical devices (placebo and drug product containing). As directed by NIH policies, the Contractor may be required to balance use of specific ages and sexes in preclinical animal studies. This service includes all activities that are required to support clinical use in humans, must be suitable to meet requirements for IND/IDE/NDA filing, and shall be performed under GLP requirements and ICH guidelines, when requested in the Task Order

SOW.

Dosing routes for preclinical studies may include, direct dosing of the female reproductive tract, male genital tract, GI tract, and or a dosing system/strategy designed to deliver the product systemically to prevent or treat HIV infection, and other pathogens. This may involve the testing of drug products, biologics, placebos, APIs, formulations (research-based, interim, and final), and devices, as well as comparator studies of multiple products. Preclinical studies under this Task Area may include:

a. Pharmacology studies of potential preventative/therapeutic agents including in vitro studies to assess absorption, distribution, metabolism and excretion (ADME); and/or plasma protein binding; in vivo studies in relevant animal species (examples include mice, rats, dogs, nonhuman primates and/or other) to assess pharmacokinetic parameters of ADME, bioavailability and bioequivalence; and potential drug interactions.

b. Toxicology studies of potential preventative/therapeutic agents including in vitro studies to assess: genotoxicity; off-target toxicity profiling (e.g. mitochondrial toxicity, cardiovascular toxicity, hepatic toxicity, renal toxicity, or vasculitis); in vivo studies in relevant animal species (examples include mice, rats, dogs, nonhuman primates, and/or other) to assess genotoxicity; determination of No Observed Adverse Effect Level (NOAEL); toxicity associated with single dose and repeated dose administration; local tolerance and/or irritability; reproductive toxicity, carcinogenicity, and/or immunotoxicity.

c. Safety pharmacology studies of potential preventative/therapeutic agents (e.g., pharmacodynamic effects on cardiovascular, immunologic, respiratory, gastrointestinal, genitourinary, and central nervous systems).

d. Toxicogenomic, proteomic, and/or metabolomic studies of potential preventative/therapeutic agents.

8. Develop new toxicology models and test systems, (examples include 3-dimensional culture, hollow-fiber cell culture, or organ-on-a-chip technology).

9. All analytical services required for performance of in vitro, ex vivo, and in vivo safety and efficacy studies. Analytical services may include biophysical characterization, homogeneity testing and polymorphism of APIs and formulations, activity in relevant matrices derived from in vitro and ex vivo culture conditions, and/or in vivo-derived body fluids.

10. Produce and characterize HIV strains, sexually transmitted infection (STI) and other pathogens, bacterial stocks, cell lines, or other assay or animal model components

a. Provide as required microbiological support for the relevant assay or model components specified in the task order including quality-controlled master and working banks; SOPs for producing and characterizing material under standardized media and growth conditions; and master and working banks for cell lines where applicable. Use specific viral or bacterial strains as required.

b. Characterize HIV or other pathogens to include the following types of parameters:

identity, purity, titer, virulence, microscopic characteristics, growth characteristics, special plating and/or stains, sequencing, etc.

11. Develop protocols

The Contractor shall develop and provide to the COR protocols for all in vitro, ex vivo, or in vivo studies to be performed with cells, fluids, tissues, or whole animals. In the case of GLP and cGMP activities, the protocols must conform to the appropriate regulations and, for non- GLP studies, must describe the studies in detail suitable for submission to regulatory authorities. This includes protocols developed for GLP and non-GLP animal studies, in vitro and ex vivo assays, and/or activities where the protocol is to be developed, qualified, or validated. The final protocol must be in a format compatible with the contractor QA/QC protocols and Standard Operating Procedures (SOPs).

Task Area B: Animal Models Supporting Product Development

Scope for Task Area B: Under this Task Area, the Contractor shall conduct pharmacokinetic (PK), safety, and efficacy studies in animal models of transmission of HIV/SIV/SHIV, other pathogens, and contraception to characterize promising products, inform dose selection, optimize formulations, and/or obtain other information necessary to advance or support product testing in subsequent animal or human studies. These models may include nonhuman primates (NHP), humanized mice, or other animal models of infection or pathogenesis as they become available.

When applicable, other activities (e.g., immunology, histopathology, etc.) shall be performed as specified in the Task Order SOW.

Requirements for Task Area B: Although NIAID anticipates that these animal studies may not necessarily be conducted under GLP, the resulting data must be of quality suitable to be included in regulatory filings.

The Contractor shall provide one or more animal model(s) for evaluation of products. These models may include single or co-infections with relevant strains of HIV, SIV, SHIV, or other pathogens as specified in the Task Order SOW.

Studies conducted with these models may be conducted under GLP; however, when conducted non-GLP the processes and resulting data shall be well-documented and of quality suitable for inclusion in an IND/IDE/NDA filing.

Examples of HIV animal models include, the following:

• Single high-dose or repeat, low-dose SIV/SHIV vaginal, penile, rectal, or i.v. transmission studies in relevant macaque species, which may include but are not limited to Chinese and Indian rhesus macaques (Macaca mulatta), cynomyologous macaques (Macaca fascicularis), or pig-tailed macaques (Macaca nemestrina)

• HIV vaginal, penile, rectal, or i.v. transmission studies in relevant strains of humanized mice, including (bone marrow, liver, thymus [BMT]) or CD34+ cell transplanted (double knockout [DKO]) mice.

Specifically, the Contractor shall provide the following:

1. Humanization of Animals (if required)

Humanized animal models may utilize human tissue of any origin. Tissue acquisition must be in compliance with federal, state, and local laws and regulations as well as current Department of Health and Human Services requirements and NIH policies. The Contractor shall assure that humanized animals meet accepted model standards and/or study-specific or Task Order-specific standards for creating the humanized model (e.g., degree of engraftment of human cells and susceptibility to infection). The Contractor shall also be responsible for specific housing and handling procedures required to support the model.

2. Production and Characterization of HIV/SIV/SHIV Strains, other pathogens, and Other

Assay or Model Components

a. Provide as required microbiological support for the relevant assay or model components specified in the contract including quality-controlled master and working banks; SOPs for producing and characterizing material under standardized media and growth conditions; and master and working banks for cell lines where applicable. Use specific viral or bacterial strains as required in the Task Order SOW.

b. Provide as required cell culture support and/or acquisition and banking of appropriate human cells to assure consistent humanization.

c. Characterize HIV/SIV/SHIV or other pathogens to include the following types of parameters: identity, purity, titer, virulence, microscopic characteristics, growth characteristics, special plating and/or stains, sequencing, etc.

d. Develop and/or provide acceptance criteria for the use of challenge material in animal model studies.

e. Confirm the challenge dose for each experiment or animal as required in the Task

Order SOW. Provide confirmation of infection in animals and, in some instances, isolation of pathogens for further characterization of phenotypes (e.g., resistance mutations).

3. Product Safety and Efficacy Evaluations

Perform safety and efficacy evaluations of products. Products will be provided to the Contractor by the COR or a third party after COR approval. As specified in the Task Order SOW, these studies may include pharmacokinetic/ pharmacodynamic (PK/PD) evaluations and/or other COR-identified safety evaluations.

a. These studies shall include appropriate uninfected, sham, and/or untreated controls.

b. Evaluation activities shall include, the following quantitative and/or qualitative assessments which detect differences with a level of statistical confidence between treatment groups of animals:

i. General indicators of morbidity and mortality (e.g., plasma viral load, CD4+ T cell counts, endogenous hormone levels, and metabolic indicators, etc.)

ii. Standard or unique markers of infection (e.g, plasma viral load, pathogen-specific antibodies, etc.)

iii. Tissue, organ, and whole body microbiological and histological analyses to document the identity, severity, pathology, and location of the animal infection.

iv. Necropsy/pathology.

v. Appropriate observations and measures of general toxicity, to include body weight, blood chemistries, hematologic measures, body temperature, behavior, effects on indigenous microflora, and other indicators of general health.

vi. Determination of serum and tissue levels of APIs or other analytes to support

PK/PD studies.

vii. Assess immunogenicity and/or innate and adaptive immune responses when appropriate for the product.

4. Pharmacokinetic/Pharmacodynamic (PK/PD) Studies

Perform PK/PD evaluations that are specific and/or relevant to the product, which may require the transfer of product-specific instructions, including dosing, handling, and/or analytical methods to the Contractor by the COR or a third-party provider. This may include transfer of samples (i.e., tissues, fluids, and secretions) by the Contractor to another laboratory designated by the COR for analysis.

5. Assay Development and Reagents

a. Develop and/or provide assays for current or emerging strains of HIV/SIV/SHIV and other pathogens with cells and/or tissues from relevant models/species, as well as update existing assays to allow for state-of the art evaluation of products.

b. Develop relevant diagnostic or immunological assays that may include the following:

i. Quality testing of reagents and animal model parameters, as appropriate

ii. Development of positive, negative, and sham control samples

iii. Optimization of assays used in support of animal model studies

iv. Qualify and/or validate, as requested by the COR, assays and reagents that become integral features of the animal model

v. Other studies to explore whether new assays or procedures are meaningful for the intended purpose

c. Produce reagents as needed to support animal model performance after receiving approval by the COR. Production of reagents may be new reagents or may include the generation and/or expansion of renewable reagents.

6. Protocol Development

The Contractor shall develop and provide to the COR protocols for all in vitro, ex vivo, or in vivo studies to be performed with cells, fluids, tissues, or whole animals. In the case of GLP and cGMP activities, the protocols must conform to the appropriate regulations and, for non- GLP studies, must describe the studies in detail suitable for submission to regulatory authorities. This includes protocols developed for GLP and non-GLP animal studies, in vitro and ex vivo assays, and/or activities where the protocol is to be developed, qualified, or validated. The final protocol must be in a format compatible with the contractor QA/QC protocols and Standard Operating Procedures (SOPs).

Task Area C: Bioanalytical Support Services:

Scope for Task Area C: Under this Task Area, the Contractor shall conduct the following types of activities to support product development and fulfill regulatory requirements: 1) Analytical method development, method transfer and validation, and/or performance of the method; and 2) Other specific activities in support of this task area as required by FDA to advance products into clinical testing.

Requirements for Task Area C: The Contractor shall conduct activities suitable to facilitate regulatory submissions and intellectual property applications of third parties and to support decision-making by the investigator/sponsor and the FDA. The Contractor shall conduct GLP and non-GLP studies, as appropriate. Products supported may include small organic molecules, polymers, or biologics (e.g., peptides, oligonucleotides, antibodies), cellular and genetic drug products (e.g., CAR-T cells), products with nanomaterials in their finished dosage form, or combination products for more than one indication (e.g., multipurpose prevention technologies (MPTs) and will have been selected for further development based on their potential to advance to clinical testing. These services shall be performed with suitable quality and oversight commensurate with all applicable regulatory requirements and guidelines.

Specifically, the Contractor shall provide analytical services that may include:

1. Development, validation, and performance of analytical methods for characterization of active pharmaceutical ingredients (APIs), degradation products, or metabolites in biological samples (e.g., plasma, blood, urine, feces, tissues) to support in vitro and in vivo safety, pharmacokinetic and pharmacodynamic studies, and other preclinical and clinical evaluations. Analytical methods for combination products shall ensure minimal interference from combined molecules, their metabolites or degradation products.

2. Synthesis of labeled API and formulations for preclinical and clinical pharmacology and pharmacodistribution studies. Labeling may include attachment or inclusion of any entity or modification that facilitates detection of the product in vitro or in vivo, such as radiolabeling or fluorescent-tagging. The Contractor may be requested to supply labeled material with the appropriate quality standard for preclinical, nonclinical, and clinical assessments and perform directed analysis of samples. The Contractor will only analyze human samples without personal identifiers and will not be involved in the conduct of any clinical trial.

3. Synthesize or purchase reference standards.

4. All analytical services required for performance of in vitro, ex vivo, and in vivo safety and efficacy studies. Analytical services may include biophysical characterization, homogeneity testing and polymorphism of APIs and formulations, activity in relevant matrices derived from in vitro and ex vivo culture conditions, and/or in vivo-derived body fluids.

Task Area D: Product Manufacturing:

Scope for Task Area D: Under this Task Area, the Contractor shall provide services and conduct studies to support the development and manufacture of formulations of promising compounds for the treatment and prevention of HIV and other pathogens of relevance to the research agenda of NIAID. Potential targeted formulations shall include tablets (including water-dispersible tablets, minitablets), capsules, lyophilized powders, solutions, suspensions, aerosols, nanomaterials, implants, intravaginal rings, etc., for oral, intravenous, subcutaneous, intramuscular, intranasal, topical vaginal or rectal delivery to support short (daily, weekly) or extended (monthly or longer) dosing intervals. Other innovative or newly developed drug formulations or biologics or delivery platforms shall also be considered.

The Contractor shall perform small scale synthesis of compounds in quantities required for testing in either in vitro or in animals, and large-scale manufacturing of formulations for early Phase I clinical studies. Some compounds and/or formulations will require synthesis in compliance with Current Good Manufacturing Practices (cGMP) regulations.

The Contractor shall also manufacture, package, label, release, and ship final versions of formulations intended for evaluation in clinical trials. Activities shall be performed in compliance with current Good Manufacturing Practice (cGMP) guidelines (21 CFAR 210-211) and other applicable regulatory guidelines when requested. Formulations shall be manufactured as sterile products when requested.

Requirements for Task Area D: The Contractor shall provide services with suitable quality and oversight commensurate with all applicable regulatory requirements and guidelines.

Specifically, the Contractor shall:

1. Provide and implement services that are customized to the needs of an individual product sponsor and/or the evolving requirements for emerging products as designated by the COR or in the Task Order SOW.

2. Acquire or conduct synthesis of small scale (10mg - 10g) and large (10-1000 g) batches of compounds of purity greater than 95 percent for subsequent biological and biochemical analyses, in vitro and in vivo testing. Compounds will be candidates for treatment of infectious disease and may include but are not limited to antiviral or antimicrobial agents and immune regulatory molecules. The focus of this Task Area will be for the synthesis of small molecules. When requested, the Contractor shall develop experimental design(s) and methodology for synthesis and/or analytics and identify or develop specific route(s) or procedure(s) for synthesis of compounds.

3. When requested, conduct synthesis of compounds for use in human subjects or laboratory animals requiring full cGMP compliance. Upon completion of the studies, the Contractor shall provide the reports and documentation to support regulatory submissions and shall be fully compliant with cGMP manufacturing regulations and standards (refer to Guidance Documents Q7A, Q8, Q9, Q10, and Q11 of ICH) and must maintain all the facilities, procedures, and documentation in compliance with cGMP.

4. Purify and/or characterize compounds or therapeutic agents for purity, perform chemical screens for physiochemical properties, confirm chemical identity and purity of compounds by established methods such as 1H-nuclear magnetic resonance (NMR), infrared (IR) and ultraviolet- visible (UV-VIS) spectroscopy, and elemental analysis.

When requested, methods shall include mass spectroscopy (MS), 13C NMR, optical purity, or HPLC-UV or HPLC-MS chromatography.

5. As applicable, develop and/or provide data sheets and preparative methods, provide Material Safety Data Sheets (MSDS) for all compounds and maintain documentation needed for regulatory requirements.

6. Determine the physicochemical and stability properties of drug substances and formulated products.

7. Develop, validate, and/or perform analytical assays for characterization of active pharmaceutical ingredients (APIs) and degradation products, and implement appropriate Quality Assurance (QA) and Quality Control (QC) standards for all services provided.

8. Procure and/or produce reference standards.

9. Develop and characterize formulations to meet one or more of the following: increased drug solubility, drug stability; bioavailability; enhancement of recipient's immune response to a supplied antigen; targeted drug delivery; sustained drug release; taste masking; alternate routes of administration; and/or alternate dosage strengths or physical dosage forms.

10. Evaluate the compatibility of APIs with potential formulation excipients.

11. Conduct in vitro drug absorption/permeability studies.

12. Provide manufacturing services that may include:

a. Performance of cGMP manufacturing and support activities, such as assessment of the availability of raw materials, scale-up of manufacturing, packaging and repackaging of API and/or formulated products (e.g., filling and labeling applicators and/or devices), and all studies required to ensure the stability and sterility of a research or investigational product prior to use in animals or humans (e.g., early pre- Phase 0/I, I, II and III clinical trials).

b. Analytical chemistry services in support of product manufacture that may include:

Development and performance of analytical methods to characterize API, formulatory components and proposed formulations in support of product characterization, release, stability, identity, homogeneity, and other preclinical evaluations.

c. Conduct product stability studies in compliance with cGMP guidelines.

d. Retain all records as required under cGMP guidelines.

e. Provision of all the necessary documentation and guidance required to assemble a

Chemistry Manufacturing and Control (CMC) section for an IND submission.

f. Provision of master stocks and cGMP-compliant documentation for master stocks of plants, cell lines, bacterial, genetic clones or other systems used to create recombinant/protein products.

13. Other specific activities in support of this Task Area as required by FDA (21 CFR

312.23(a)(7)) to advance products into clinical testing.

Task Area E: Scientific and Quality/Regulatory Support Services:

Scope for Task Area E: Under this Task Area, the Contractor shall perform the following types of activities to advise and support the COR, other NIAID staff, and/or product sponsors, or support the general development of products through provision of resources: 1) provide additional expertise in support of all task areas; 2) develop and support programmatic meetings in specific regulatory requirements or other topics; 3) provide assurance/quality control (QA/QC) support; 4) conduct audits; 5) prepare regulatory documentation; 6) convene scientific groups related to products in support of this contract; and 7) provide centralized storage for contract materials.

Requirements for Task Area E:

Specifically, the Contractor shall

1. As…