HHS-NIH-NIAID-BAA2022-1.pdf

NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES (NIAID)

2022 DMID Omnibus Broad Agency Announcement (BAA):

No. HHS-NIH-NIAID-BAA2022-1

Solicitation Issue Date: January 18, 2022

Participating NIAID Divisions: Division of Microbiology & Infectious Diseases (DMID)

Issuing Office: Office of Acquisitions, DEA, NIAID, NIH

5601 Fishers Lane, Room 3D37, MSC 9821, Bethesda, MD 20892-9821

Issuing Contracting Officer: Julie Rodriguez Email: Julie.Rodriguez@nih.gov Phone: (301)761-7735

This solicitation contains opportunities to submit a proposal under the following distinct Research Areas, which are identified below:

RESEARCH

AREA

NIAID

DIVISION

TITLE PAGE

NO.

PROPOSALS

DUE*

DMID

Development of Vaccine Candidates for Biodefense, Antimicrobial Resistant

(AMR) Infections and Emerging Infectious Diseases

April 18, 2022

Development of Therapeutic Candidates for Biodefense, Antimicrobial Resistant

(AMR) Infections and Emerging

The Antiviral Program for Pandemics (APP): Development of Antivirals for

Specific RNA Viral Families of Pandemic Potential

March 18, 2022

Development of In Vitro Diagnostics for Biodefense, Antimicrobial Resistant

Infections (AMR), and Emerging

* Proposals must be received before 3:00 PM Eastern Time on the date specified herein. Please see the Proposal Submission Instructions (Section 4.3.2.1) for more information. For planning purposes, the Government requests potential Offerors to submit a Notice of Intent. Please see Notice of Intent (Section 4.3.2.1.4) for more information.

Offers will be valid for 240 days unless a different period is specified by the Offeror on the Attachment entitled, "Proposal Summary and Data Record, NIH 2043.

mailto:Julie.Rodriguez@nih.gov

NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES (NIAID)

2022 DMID Omnibus Broad Agency Announcement

No. HHS-NIH-NIAID-BAA2022-1

TABLE OF CONTENTS

SECTION 1 – Broad Agency Announcement Information…………………….…………………………… p. 3

SECTION 2 – Contracting Officer Points of Contact……………………………….………..……………... p. 4

SECTION 3 – Research Areas and Technical Objectives……………………………….………..…………. p. 5

3.1 – Division of Microbiology and Infectious Diseases (DMID) Background………………..…… p. 5

3.2 – Funding and Award Information………………………………………...………………..…… p. 5

3.3 – Research Areas

3.3.1 – Research Area 001: Development of Vaccine Candidates for Biodefense, Antimicrobial Resistant Infections and Emerging Infectious Diseases………………...…… p. 6

3.3.2 – Research Area 002: Development of Therapeutic Candidates for Biodefense, Antimicrobial Resistant (AMR) Infections and Emerging Infectious Diseases ……...…..... p. 9

3.3.3 – Research Area 003: The Antiviral Program for Pandemics (APP): Development of Antivirals for Specific RNA Viral Families of Pandemic Potential ……..……….…….. p. 13

3.3.4 – Research Area 004: Development of In Vitro Diagnostics for Biodefense, Antimicrobial Resistant Infections, and Emerging Infectious Diseases ….…………..…… p. 16

3.4 – Research Areas 001, 002 and 003: Additional Technical Proposal Instructions ……………... p. 19

3.5 – Research Areas 001, 002 and 003: Reporting Requirements and Deliverables ……...….……. p. 24

3.6 – Research Area 004: Additional Technical Proposal Instructions …………...………………… p. 29

3.7 – Research Area 004: Reporting Requirements and Deliverables …………….……..…………. p. 33

SECTION 4 – Instructions, Conditions, and Notices to Offerors……………………………..…………...… p. 36

4.1 – General Instructions to Offerors………………………………………..……… ………........... p. 36

4.2 – General Information……………………………………………………………………….….. p. 39

4.3 – Instructions to Offerors ……………………………………………………………………... p. 41

4.3.1 – General Information…………………………...……………………...……............ p. 41

4.3.2 – Technical Proposal Instructions …………………………………………….…...... p. 48

4.3.3 – Business Proposal Instructions ………………………………….………………… p. 77

SECTION 5 – Special Contract Requirements ……………………………………………………..……. p. 93

SECTION 6 – Evaluation Factors for Award ………………………………………………………… p. 116

SECTION 7 – Definitions ………………………………………………………………..………… p. 125

SECTION 8 – Attachments ………………………………………………………………..………… p. 126

SECTION 1. - BROAD AGENCY ANNOUNCEMENT INFORMATION

You are invited to submit a proposal in accordance with the requirements of this BROAD AGENCY ANNOUNCEMENT (BAA). The BAA is governed by Federal Acquisition Regulation (FAR) 6.102 and further described in FAR 35.016 as well as the National Institutes of Health (NIH) Policy Manual, Manual Chapter 6035, Broad Agency Announcements. A BAA may be used as a solicitation mechanism for basic and applied research directed toward advancing the state-of-the-art or increasing knowledge or understanding and that part of development not related to the development of a specific system or hardware procurement. BAAs are general in nature, identifying areas of research interest, and shall only be used when meaningful proposals with varying technical/scientific approaches can be reasonably anticipated.

This BAA contains multiple distinct Research Areas. Offerors may submit a proposal in response to one, or more, of the Research Areas contained herein. Offers submitted in response to this BAA must present separate detailed technical and business proposals designed to meet the Technical Objectives described for each Research Area proposed. The Statement of Work (SOW), including the specific technical requirements and performance specifications, is developed and proposed by the Offeror, not the Government.

Proposals are NOT evaluated against each other since they are not submitted in accordance with a common SOW issued by the Government. Instead, Research and Technical Objectives are provided in the BAA that describe individual Research Areas in which the Government is interested. Proposals received in response to the BAA are evaluated in accordance with the Evaluation Factors for Award specified in Section 6. The Government reserves the right to conduct discussions with all, some, one, or none of the proposals received in response to this BAA. If discussions are conducted, NIAID reserves the right to suggest modifying, adding or deleting milestones, decision points, research plans, processes, schedules, budget or product. The Government also reserves the right to make awards without discussions. Additionally, the Government reserves the right to accept proposals in their entirety or to select only portions of proposals for award. Multiple awards are anticipated. The selection for award under this BAA will be based upon the evaluation factors, importance to the agency programs, and the availability of funds.

SECTION 2. - CONTRACTING OFFICER POINTS OF CONTACT

This BAA contains Research Areas issued by the Division of Microbiology and Infectious Diseases (DMID) within the NIAID. The Contracting Officer (CO) point of contact for questions related to the specific DMID Research Areas is identified below:

Research Area 001: Development of Vaccine Candidates for Biodefense, Antimicrobial Resistant Infections and Emerging Infectious Diseases

Research Area 002: Development of Therapeutic Candidates for Biodefense, Antimicrobial Resistant Infections and Emerging Infectious Diseases

Research Area 003: Antiviral Program for Pandemics (APP): Development of Antivirals for Specific RNA Viral Families of Pandemic Potential

Research Area 004: Development of In Vitro Diagnostics for Biodefense, Antimicrobial Resistant Infections, and Emerging Infectious Diseases.

Julie Rodriguez, CO Email: Julie.Rodriguez@nih.gov Phone: (301) 761-7735 mailto:Julie.Rodriguez@nih.gov

SECTION 3. - RESEARCH AREAS AND TECHNICAL OBJECTIVES

3.1 - DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) BACKGROUND

Research supported by the National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), and the Department of Health and Human Services (DHHS), strives to understand, treat, and ultimately prevent the myriad infectious, immunologic, and allergic diseases that threaten millions of human lives. NIAID also has a key role in the development of new medical countermeasures (MCMs) against potential agents of bioterrorism, drug-resistant pathogens, and emerging and re-emerging infectious diseases. Through a variety of research grants and contracts, NIAID’s Division of Microbiology and Infectious Diseases (DMID) supports basic and applied research to develop and evaluate therapeutics, vaccines, and diagnostics targeting multiple pathogens, including NIAID Emerging Infectious Diseases/Pathogens which encompass Category A, B, and C priority pathogens (https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens).

NIAID/DMID intends to use this BAA to help address goals articulated in a number of strategic plans as well as new pandemic preparedness programs. The National Biodefense Strategy released in 09/2018 (https://www.hsdl.org/?view&did=815921) articulates the need to enhance preparedness through MCMs, including vaccines, therapeutics and diagnostics. The World Health Organization (WHO) has prioritized diseases with epidemic potential and for which there are no or insufficient MCMs (https://www.who.int/blueprint/priority-diseases/en/), as well as pathogenic bacteria for which new antibiotics are urgently needed (https://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed). Similarly, the Centers for Disease Control and Prevention (CDC) has highlighted antibiotic resistant infections caused by urgent, serious and concerning pathogens (https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf).

The coronavirus disease 2019 (COVID-19) pandemic has emphasized the need for a robust medical countermeasure development program, to include research resources and flexible platform technologies, aimed at preparedness against ribonucleic (RNA) viruses of pandemic potential. To this end, NIAID published a pandemic preparedness plan (https://www.niaid.nih.gov/research/pandemic-preparedness) that aims to develop countermeasures for prototype pathogens identified for each key RNA virus family that causes human disease and has high, pandemic potential. The NIAID pandemic preparedness plan contributes to the American Pandemic Preparedness Plan (APPP or AP3) (https://www.whitehouse.gov/wp-content/uploads/2021/09/American-Pandemic-Preparedness-Transforming-Our-Capabilities-Final-For- Web.pdf). The COVID-19 pandemic also highlighted the urgent need to develop safe and effective antivirals to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes COVID-19, and the necessity to identify and develop sustainable platforms for targeted drug discovery and generate a robust pipeline of antivirals against viruses of pandemic potential. To address this gap, the Antiviral Program for Pandemics (APP) (https://www.niaid.nih.gov/research/antivirals) was created to address the RNA virus families of pandemic potential.

Through this BAA, NIAID aims to advance the research and development of promising candidate vaccines, therapeutics and diagnostics for Biodefense, Emerging Infectious Diseases, and Pandemic Preparedness in each of four (4) Research Areas described in Section 3.3 below.

3.2 – FUNDING AND AWARD INFORMATION

Contract funding will support vaccine and therapeutic development through candidate testing, manufacture, preclinical or nonclinical toxicology testing, and early clinical studies which may include Phase 1 and Phase 2 clinical trials (See specifics within each Research Area). Diagnostics can be most critically supported in the planning, design, development, and verification phases of product development.

https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens https://www.hsdl.org/?view&did=815921 https://www.who.int/blueprint/priority-diseases/en/ https://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed https://www.who.int/news-room/detail/27-02-2017-who-publishes-list-of-bacteria-for-which-new-antibiotics-are-urgently-needed https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf https://www.niaid.nih.gov/research/pandemic-preparedness https://www.whitehouse.gov/wp-content/uploads/2021/09/American-Pandemic-Preparedness-Transforming-Our-Capabilities-Final-For-Web.pdf https://www.whitehouse.gov/wp-content/uploads/2021/09/American-Pandemic-Preparedness-Transforming-Our-Capabilities-Final-For-Web.pdf https://www.whitehouse.gov/wp-content/uploads/2021/09/American-Pandemic-Preparedness-Transforming-Our-Capabilities-Final-For-Web.pdf https://www.niaid.nih.gov/research/antivirals

3.3.1- Research Area 001 - Development of Vaccine Candidates for Biodefense, Antimicrobial Resistant Infections and Emerging

The Government thereby reduces risk and enables projects to transition to other funding to support advanced clinical development (Phase 2 and beyond) and large-scale manufacturing.

For all Research Areas, the total duration of a proposed contract should be consistent with the nature and complexity of the Offeror’s proposed research and may vary depending upon the scope of the project and the technical objectives. The total performance period comprised of combined Base Period and all Options proposed by an Offeror shall not exceed 5 years. If applicable, clinical trial activities are encouraged to start as soon as possible and be completed within the 5-year period.

The total budget estimated in the Fiscal Year 2023 (FY 23) is described below:

Research Areas 001, 002, and 004: For FY 23 the NIAID estimates up to $12.8 million for the award of 5-6 cost reimbursement type contracts across all three Research Areas (001, 002 & 004). The estimated FY 23 funding is for the non-severable Base period (direct and indirect costs combined) only. If options are proposed by an Offeror, they will be evaluated in accordance with Section 6 of the BAA. The number of awarded contracts will depend on the number of technically meritorious proposals, importance to agency programs, and availability of funds.

For Research Areas 001, 002, and 004 awards are anticipated to be made in or around May 2023. At the discretion of the Government, awards may be streamlined to meet agency needs.

Research Area 003: For FY 23 the NIAID estimates up to $34 million for the award of 2 or more cost reimbursement type contracts in Research Area 003 only. The estimated FY 23 funding is for the non-severable Base period (direct and indirect costs combined) only. If options are proposed by an Offeror, they will be evaluated in accordance with Section 6 of the BAA. The number of awarded contracts will depend on the number of technically meritorious proposals, importance to agency programs, and availability of funds.

For Research Area 003 awards are anticipated to be made in or around November 2022. At the discretion of the Government, dates are subject to change.

3.3 - RESEARCH AREAS

3.3.1.1 - Technical Objectives

The goal of Research Area 001 is to protect human health and well-being by advancing vaccine candidates, technologies and platforms that could be deployed against agents that include:

• Vaccines for the NIAID Emerging Infectious Diseases/Pathogens including NIAID Category A, B and C priority pathogens (https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens), such as but not limited to:

o RNA viruses of pandemic potential Coronaviridae [e.g. Middle East Respiratory Syndrome (MERS), SARS-

CoV-2] https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens

Bunyavirales (e.g. Lassa, Junin, Rift Valley Fever Virus, Andes, Sin Nombre, LaCrosse, California Encephalitis, Crimean Congo Hemorrhagic Fever)

Filoviruses (e.g. Ebola, Marburg; excluding Ebola Zaire) Flaviviruses (e.g. Dengue, Zika, West Nile) Paramyxoviridae (e.g. Nipah, Hendra) Picornaviridae [e.g. Enterovirus (EV)-D68, EV-A71] Togaviridae [e.g. Chikungunya, Eastern equine encephalitis (EEE), Venezuelan equine encephalitis (VEE), and Western equine encephalitis

(WEE)]

o Burkholderia spp o Group A & B Streptococci o Hepatitis C o Mycobacterium tuberculosis o New or improved vaccines against Streptococcus pneumoniae, Bordetella pertussis o Tick-borne viruses o Bacillus anthracis is excluded

• Vaccines for Antimicrobial Resistant (AMR) Organisms including biodefense, Gram-negative and Gram-positive bacterial and fungal pathogens. Pathogens of particular interest are described below:

o Vaccines focused on antimicrobial resistant Gram-negative bacteria, such as but not limited to, Pseudomonas aeruginosa, Escherichia coli, Salmonella, and Shigella spp.

o Vaccines focused on multi drug resistant Gram-positive bacteria, such as but not limited to, Staphylococcus aureus and Mycobacterium tuberculosis o Vaccines focused on fungal pathogens, such as but not limited to, Candida auris, other AMR Candida species, Aspergillus fumigatus, Mucorales and Coccidioides.

3.3.1.2 - Technical Approach

Research Area 001 focuses on the advancement of a promising lead vaccine candidate from pre-clinical testing through evaluation in a clinical trial. A lead vaccine candidate is defined by the following criteria:

1. Antigen/immunogen design and technology platform selection completed (both well characterized)

2. Preliminary data that demonstrates proof-of-concept immunogenicity in relevant animal model(s)

3. Prefer, but do not require, evidence of proof-of-concept efficacy data in a relevant animal model

4. Prefer, but do not require, a defined manufacturing process sufficient to produce research grade material that could be scalable/amenable to Good Manufacturing Practice (GMP) production with targeted process development

5. Prefer, but do not require, characterization of the lead candidate using well-characterized, quality-controlled assays including potency assay(s).

Proposals shall provide data on the lead vaccine candidate and/or experimental plans for the following:

1. Background on disease indication, gaps in corresponding medical countermeasure pipeline (if applicable)

2. Justification/rationale for antigen selection, immunogen design and/or platform selection

3. Characterization and optimization of the lead vaccine candidate

4. Non-clinical immunogenicity and efficacy studies (to include 2. and 3. from the paragraph above) and Investigational New Drug (IND)-enabling toxicology studies

5. Any clinical data available for the lead candidate and/or platform

6. A Target Product Profile (TPP) and Product Development Plan (PDP) for the candidate product, including nonclinical, manufacturing, regulatory, and clinical activities to be undertaken

7. Description of current manufacturing processes including product characterization, assay development, formulation, and stability.

8. Process development and manufacture of non-GMP and GMP lots of product.

9. Regulatory activities required to support proposed clinical trials.

10. Development of all assays and reagents needed to support clinical trials

11. Clinical trial plan (even if funding is not requested for clinical trial testing, a synopsis of the clinical plan must be provided with application)

• Note: Upon completion of protocol development, DMID will determine if the offeror will hold the IND and conduct the clinical trial.

12. A provision of human samples from all studies to be delivered to NIAID and, for subjects in clinical trials, obtaining future use consent form from volunteers for evaluation of their samples

Offerors may propose a vaccine against a single pathogen or multiple pathogens; NIAID reserves the right to negotiate vaccines for a single indication, multiple indications and/or combined indications, balancing the faster, straightforward development and regulatory path of a single indication with flexibility and preparedness against multiple pathogens.

Competitive applications will propose vaccine candidates that can be rapidly developed and tested in Phase 1 clinical trials to identify promising candidates and/or vaccine platforms for subsequent development. If Phase 1 clinical testing funding is not requested via this BAA due to the maturity of the candidate or an alternative funding source, a general outline of the clinical plan with clinical output parameters and sufficient detail of manufacturing processes and needs must still be included.

Adjuvant formulations and/or delivery platforms that reduce dosing requirements, lessen logistical requirements, bypass supply chain limitations, are readily scalable, and/or provide other benefits such as generation of potent mucosal immunity, are of specific interest. Cross-cutting technologies applicable to more than one vaccine component are also encouraged.

Organizations responding to this Research Area, collectively with the proposed subcontractors and consultants where applicable, must have documented expertise in vaccine development, including demonstrated knowledge of regulatory guidelines and submission processes for candidate products directed against emerging infectious diseases and/or biological threats identified in the Technical Objectives.

3.3.1.3 – Contracts awarded under this Research Area will NOT support:

• Basic research; selection of antigen or platform, and discovery of new candidates/products

• Development of devices, diagnostics, or adjuvants in the absence of a companion product

• Development of therapeutics

• Vaccine candidates directed against Bacillus anthracis and Ebola Zaire

• Research involving the use of Human Fetal Tissue

3.3.2 - Research Area 002 - Development of Therapeutic Products for Biodefense, Antimicrobial Resistant Infections and Emerging

3.3.2.1 - Technical Objectives

The objective of Research Area 002 is the development of promising new therapeutics to address infections and diseases caused by the NIAID Emerging Infectious Diseases/Pathogens including Category A, B and C priority pathogens (https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens) and selected bacterial and fungal pathogens identified in the 2019 CDC Antibiotic Resistance Threats Report https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf.

For the purposes of this solicitation, therapeutic activity is defined as the cure or mitigation of disease, preferably once signs and symptoms of infection are evident. A therapeutic candidate may be an advanced lead series, a small number of advanced leads from which a preclinical candidate will be selected, a preclinical candidate, or a clinical candidate. It may be a small molecule (e.g.

synthetic or natural products), a drug conjugate or a biological product (e.g. monoclonal antibodies, recombinant proteins, or nucleic acid-based products).

Proposals are encouraged for the development of broad-spectrum therapeutics with extended therapeutic activity over more than one pathogen. Therapeutic candidates with a limited spectrum that target high-priority pathogens for which inadequate standard clinical treatment exists or for which drug resistance poses a significant public health concern are eligible. If needed, for narrow-spectrum candidates at later stages of development (IND enabling/Phase 1/Phase 2), efforts to incorporate investigation of novel diagnostics (useful for clinical development or clinical use) and/or collaborations with diagnostics developers are encouraged.

Proposals on non-traditional therapeutics and antitoxins are encouraged, provided they have demonstrated therapeutic activity in in vitro and in vivo models when used alone or in combination with an existing licensed product.

Research Area 002 will support lead optimization, pre-clinical (IND enabling) studies and clinical trials that include Phase 1 or Phase 2 studies or confirmatory trials of no greater than 120 subjects.

For some pathogens or toxins, product efficacy determination under the Animal Rule is supported.

The scope of support differs depending on the stage of the project being proposed, as outlined below:

Details of development phases in-scope for Research Area 002:

Lead Optimization

• Optimization of a lead scaffold by generation of new analogs with improved potency, reduced off-target activities, and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics, leading to preclinical candidate selection.

• Conduct non-Good Laboratory Practices (GLP) in vivo toxicity in accordance with the product's intended use.

https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf

• Demonstrate in vivo activity and potential for efficacy consistent with the product's intended use (i.e., dose, schedule, duration, route of administration).

• Initiate experiments to identify pharmacokinetic/pharmacodynamic (PK/PD) relationships and define efficacious exposure targets for further pre-clinical and clinical studies.

• Select a preclinical candidate and initiate IND-enabling studies.

Pre-Clinical (IND Enabling) Studies

• Demonstrate acceptable absorption, distribution, metabolism, and excretion (ADME) characteristics and/or immune responses in non-GLP animal studies as necessary for IND filing.

• Conduct GLP non-clinical studies for toxicology, pharmacology, and immunogenicity (as appropriate).

• Continue development of animal models for determining efficacy and defining PK/PD relationships for further preclinical and clinical studies.

• Develop a scalable and reproducible manufacturing process amenable to GMP.

Manufacture GMP-compliant pilot lots.

• Initiate development of in-process assays and analytical methods for product characterization and release, including assessments of potency, purity, identity, strength, sterility, and quality as appropriate.

• Prepare and submit IND package to the U.S. Food and Drug Administration (FDA).

Phase 1 Studies

Phase 1 clinical trial(s) to determine the safety and pharmacokinetics of the clinical test article in healthy volunteers.

Phase 2 Studies

Phase 2 clinical trials(s) to determine safety, pharmacokinetics, immunogenicity and efficacy of the clinical test article in patients. Phase 2 trial designs shall be no greater than 120 subjects.

Proposals that initiate with a single therapeutic candidate for evaluation in clinical trials are expected to complete evaluation in a Phase 1 and/or Phase 2 clinical trial within the 5-year proposed period of performance. Phase 1 and Phase 2 clinical trial completion is defined as completion of a Final Clinical Study Report following International Conference on Harmonization (ICH) Guidelines on Structure and Content of Clinical Study Reports E3 (https://www.fda.gov/media/71271/download).

Proposals that initiate with a single therapeutic candidate for support of IND-enabling studies are expected to complete evaluation in a Phase 1 clinical trial within the 5-year proposed period of performance. Phase 1 clinical trial completion is defined as completion of a Final Clinical Study Report following ICH Guidelines on Structure and Content of Clinical Study Reports E3.

Proposals that initiate with more than one lead compound (or lead series) for support of lead optimization are expected to provide clear plans and criteria for selecting a single clinical candidate therapeutic by the end of the second year of funding to enable completion of IND-enabling activities and submission of the IND within a 5-year period of performance.

https://www.fda.gov/media/71271/download

3.3.2.2 - Technical Approach

Proposals are encouraged for the development of broad-spectrum therapeutics with extended therapeutic activity over more than one pathogen in the list of NIAID Emerging Infectious Diseases/Pathogens including Category A, B, and C priority pathogens (https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens), and infectious pathogens listed in the 2019 CDC Antibiotic Resistance Threats in the United States Report (https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf). Priorities are listed below but broad-spectrum therapeutics do not require activity against pathogens in the listed priorities; Limited spectrum therapeutic candidates that target high-priority pathogens for which no standard clinical treatment exists or for which drug resistance poses a significant public health concern are eligible if they target one of the specific pathogens listed below:

1. Antimicrobial Therapeutics

a. Active against the effects of one or more of the urgent or serious, and concerning drug-resistant bacterial threats or urgent fungal threats (Candida auris) listed in the 2019 CDC Antibiotic Resistance Threats Report (https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report- 508.pdf); OR

b. Display activity against the effects of one of the following bacterial pathogens:

Bacillus anthracis, Francisella tularensis, Yersinia pestis, Burkholderia pseudomallei, and especially Burkholderia mallei.

c. Development of new therapies against severe infections and/or drug resistant strains of Pseudomonas aeruginosa, Streptococcus pneumoniae, and Group A and B Streptococci.

2. Antiviral Therapeutics

a. Active against viruses that are classified as NIAID Emerging Infectious Diseases/Pathogens including Category A, B, or C viral threat agents (https://www.niaid.nih.gov/research/emerging-infectious-diseases-pathogens).

b. Drug candidates that indirectly block viruses via modulation of the host responses are included in this Research Area 002.

c. Excluded are drug candidates eligible under Research Area 003 criteria (non-monoclonal antibody therapeutics that directly block viral targets or functions and can be used for outpatient treatment via oral or intranasal administration routes against viruses belonging to 7 RNA viral families of pandemic potential).

3. Antitoxin Therapeutics

Antitoxin lead series/lead/product candidate must meet at least one of the following criteria:

a. Displayed activity against Ricin intoxication.

b. Displayed activity against the effects of Staphylococcus enterotoxin B.

c. Biological product: displayed broad-spectrum activity against the effects of most/all the known serotypes of Clostridium botulinum neurotoxin (serotypes A, B, C, D, E, F, G).

d. Small molecule product: displayed activity against the effects of at least two of the known serotypes of Clostridium botulinum neurotoxin.

https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf

For this Research Area 002, an antitoxin therapeutic lead series/lead/product candidate is a single product meeting the following criteria/definitions:

a. An agent intended for use in the cure, mitigation or treatment of intoxication.

b. An agent that has demonstrated activity against a specific toxin in an appropriate in vivo model of disease.

3.3.2.3 – Additional Requirements

1. Regardless of the proposed entry point, the therapeutic lead series/lead/product candidate must demonstrate phase-appropriate evidence of all the following characteristics:

• Chemical structure and if appropriate, relevant Structure Activity Relationships to support lead optimization strategy

• Synthesis/manufacturing feasibility

• Drug development stage appropriate in vitro AND in vivo efficacy; and

• Drug development stage appropriate in vitro AND in vivo pharmacokinetic and toxicology.

These characteristics must be reflected in the draft Target Product Profile (TPP) and supporting data provided in the technical proposal

2. Offerors responding to this Research Area, collectively with the proposed subcontractors and consultants where applicable, must have documented expertise in drug discovery and development, including demonstrated knowledge of regulatory guidelines, and submission processes for candidate products directed against emerging infectious diseases

3.3.2.4 – Contracts awarded under this Research Area will NOT support:

• Basic research and discovery of new series

• Hit-to-Lead optimization and studies

• Development of candidates/products or lead series that have not demonstrated therapeutic activity in a relevant animal model of disease OR have not demonstrated drug development stage appropriate pharmacokinetics

• Development of candidates/products or lead series from a known class that don’t demonstrate a unique advantage over other members of the class

• Development of products licensed/approved by the United States (US) and non-US regulatory agencies (e.g. FDA, European Medicines Agency (EMA)) as new formulations or prodrugs without added innovation and significant advantages compared to the original products.

• Development of products licensed/approved by the US and non-US regulatory agencies (e.g. FDA, EMA) to pursue additional clinical indications

• Development of products licensed/approved by the US and non-US regulatory agencies (e.g. FDA, EMA) to pursue combination with other products licensed/approved by the FDA

• Development of topical sanitation products

• Development of serum-derived products

• Development of devices

• Development of probiotics and other microbiome related products

• Research involving the use of Human Fetal Tissue

• Drug candidates eligible under RA 003 criteria (e.g. viral direct-acting, home-administered antivirals against viruses of viral families of pandemic potential).

3.3.3 - Research Area 003 – Antiviral Program for Pandemics (APP): Development of Antivirals for RNA Viral Families of Pandemic Potential

3.3.3.1 - Technical Objectives

The focus of Research Area 003 as described in https://www.niaid.nih.gov/research/antivirals is the development of antivirals that:

• Directly block viral targets and function, AND

• Active against RNA viruses of pandemic potential (Coronaviridae, Bunyavirales, Filoviridae, Flaviviridae, Paramyxoviridae, Picornaviridae, and Togaviridae), AND

• Are new chemical entities which include small molecules and small biotherapeutics (e.g.

nucleic acids or peptides) that are directly acting against viral targets and functions (not through the modulation of the host responses) AND

• Have suitable routes of administration (e.g. oral or intranasal) and safety profiles for broad use in the outpatient setting to treat early stages of infection by reducing viral burden

For the purposes of this solicitation, therapeutic activity is defined as the cure or mitigation of disease, preferably, once signs and symptoms of infection are evident. A therapeutic candidate refers to an advanced lead series, optimized leads, or product candidate, that is a new chemical entity and either a small molecule or biotherapeutic (Note: monoclonal antibodies are not in the scope of this Research Area).

Proposals are encouraged for the development of broad-spectrum therapeutics with extended therapeutic activity over more than one pathogen. Therapeutic candidates with a narrower spectrum of activity against priority viruses also are eligible.

Research Area 003 will support lead optimization, pre-clinical (IND enabling) studies and Phase 1 clinical trial only. Phase 2 trial studies in human are not supported.

The scope of support differs depending on the stage of the project being proposed, as outlined below.

Details of development phases in-scope of Research Area 003:

Lead Optimization

• Synthesize late-lead compounds from selected lead scaffolds or biotherapeutics to generate new candidates with improved potency in directly targeting viral targets or functions, reduced off-target activities and toxicity, and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics.

• Conduct non-GLP in vivo toxicity in accordance with the product's intended use.

• Demonstrate in vivo activity and potential for efficacy consistent with the product's intended use (i.e. dose, schedule, duration, route of administration that is suitable for at outpatient setting such as oral or intranasal).

• Initiate experiments to identify PK/PD relationships and define efficacious exposure targets for further pre-clinical and clinical studies.

• Select lead candidate and initiate IND-enabling studies https://www.niaid.nih.gov/research/antivirals

Pre-Clinical (IND Enabling) Studies

• Demonstrate acceptable ADME characteristics and/or immune responses in non-GLP animal studies as necessary for IND filing.

• Conduct GLP non-clinical studies for toxicology, pharmacology, and immunogenicity (as appropriate).

• Continue development of animal models for determining efficacy and defining PK/PD relationships for further pre-clinical and clinical studies.

• Develop a scalable and reproducible manufacturing process amenable to GMP.

Manufacture GMP-compliant pilot lots.

• Initiate development of in-process assays and analytical methods for product characterization and release, including assessments of potency, purity, identity, strength, sterility, and quality as appropriate.

• Prepare and submit IND package to FDA.

Phase 1 Studies

Phase 1 clinical trial(s) to determine the safety and pharmacokinetics of the clinical test article in healthy volunteers.

Proposals that initiate with a single therapeutic candidate for support of IND-enabling studies or evaluation in clinical trials are expected to complete evaluation in a Phase 1 clinical trial within the 5-year proposed period of performance. Phase 1 clinical trial completion is defined as completion of a Final Clinical Study Report following International Conference on Harmonization (ICH) Guidelines on Structure and Content of Clinical Study Reports E3.

Proposals that initiate with more than one lead compound (or lead series) for support of lead optimization are expected to provide clear plans and criteria for selecting a single clinical candidate therapeutic by the end of the second year of funding to enable completion of IND-enabling activities and submission of the IND within a 5-year period of performance.

3.3.3.2 - Technical Approach

Proposals are encouraged for the development of broad-spectrum small molecule or non-monoclonal antibody biotherapeutics, preferably for oral or intranasal dosing, with activity against one or more viruses of pandemic potential listed below. Limited spectrum therapeutic candidates that target pandemic pathogens for which limited standard clinical treatment exists or for which drug resistance poses a significant public health concern are eligible.

Therapeutics for viruses of pandemic potential: Display activity against infection caused by at least one of seven viral families with some examples below:

1. Coronaviridae (e.g. MERS, SARS-CoV-2)

2. Bunyavirales (e.g. Lassa, Junin, Rift Valley Fever Virus, Andes, Sin Nombre, LaCrosse, California Encephalitis, Crimean Congo Hemorrhagic Fever)

3. Filoviruses (e.g. Ebola, Marburg)

4. Flaviviruses (e.g. Dengue, Zika, West Nile)

5. Paramyxoviridae (e.g. Nipah, Hendra)

6. Picornaviridae (e.g. EV-D68, EV-A71)

7. Togaviridae (e.g. Chikungunya, EEE, VEE, WEE)

3.3.3.3 – Additional Requirements

1. Regardless of the proposed entry point, therapeutic late-lead series/product candidate must show demonstrated, drug development stage-appropriate evidence of all the following characteristics:

• Chemical structure and, if appropriate, relevant Structure Activity Relationships to support the proposed lead optimization strategy

• Synthesis or manufacturing feasibility

• Drug development stage appropriate in vitro AND in vivo efficacy; and

• Drug development stage appropriate in vitro AND in vivo pharmacokinetics and toxicology.

These characteristics must be reflected in the proposed Target Product Profile (TPP).

2. Organizations responding to this Research Area, collectively with the proposed subcontractors and consultants where applicable, must have documented expertise in drug discovery and development, including demonstrated knowledge of regulatory guidelines, and submission processes for candidate products directed against emerging infectious diseases and/or biological threats.

3.3.3.4 – Contracts awarded under this Research Area will NOT support:

• Monoclonal antibody development

• Basic research and discovery of new series

• Hit-to-Lead optimization and studies

• Development of candidates/products or lead series that have not demonstrated therapeutic activity in a relevant animal model of disease OR have not demonstrated stage appropriate pharmacokinetics

• Development of candidates/products or lead series from a known class that don’t demonstrate a unique advantage over other members of the class

• Development of products licensed/approved by the United States (US) and non-US regulatory agencies (e.g. FDA, European Medicines Agency (EMA)) as new formulations or prodrugs.

• Development of products licensed/approved by the US and non-US regulatory agencies (e.g.

FDA, EMA) for additional clinical indications

• Development of products licensed/approved by the US and non-US regulatory agencies (e.g.

FDA, EMA) in combination with other products licensed/approved by the FDA

• Development of topical sanitation products

• Development of serum-derived products

• Development of devices

• Development of probiotics and other microbiome related products

• Research involving the use of Human Fetal Tissue.

3.3.4 - Research Area 004 – Development of In Vitro Diagnostics for Biodefense, Antimicrobial Resistant Infections, and Emerging

3.3.4.1 - Technical Objective

NIAID is interested in supporting the development of promising diagnostics technologies in three areas for detection of signatures from biothreat pathogens as well as pathogens causing emerging, reemerging, antimicrobial resistant infectious diseases, and for pandemic preparedness.

1. Next-Generation Nucleic Acid Sequencing on Portable Systems

The first objective of Research Area 004 is to improve the overall performance of nucleic acid sequencing solutions on portable commercial sequencing platforms for the targeted and agnostic detection and identification of microbial pathogens for biodefense, antimicrobial resistance, emerging infectious diseases, and pandemic preparedness.

Development activities that are IN SCOPE for this objective:

• Automated nucleic acid extraction and preparation method development;

• Sequencing assay development to detect signatures from one or more required pathogens;

• Metagenomic sequencing assay development for untargeted detection of required pathogens;

• Internal and external controls standardization;

• Integration of chemistry improvements on automated portable platforms;

• Software development, including database improvement for faster and/or more comprehensive analysis of patient sample data;

• Reagent scale-up methods for process validation and pilot manufacturing;

• Initial clinical testing to establish validation of performance.

Areas of focus to improve performance could include but are not limited to:

• Reduced turnaround time: Pathogen ID in 2-4 hours beginning with specimen processing;

• Increased throughput on portable sequencing devices: > 10 patient samples processed per sequencing run;

• Sensitivity: False negative rate of < 5% for infectious pathogen detection;

• Specificity: False positive rate of < 5%;

• Improved ease of use: Automated nucleic acid or protein extraction and sample preparation; simplified transfer to portable sequencing system; data analyses operated and interpreted with minimal training;

Development activities should be consistent and compliant with presumed eventual submission to FDA for pre-Emergency Use Authorization (EUA) and/or 510(k) clearance.

2. Rapid Protein Detection

The second objective of Research Area 004 is to develop methods that improve near-patient, rapid and sensitive detection of proteins or other biomolecules, including methods that simplify sample preparation, enhance target capture and detection, and increase signal output. Rapid diagnostic testing devices, so-called RDTs, are fast, simple, and cost-effective, but suffer from lower clinical sensitivity than other methods of pathogen analyte detection.

Development areas that are IN SCOPE for this objective include:

• Improved binding surfaces for capture and detection, e.g., graphene or other carbon-electrode surfaces

• Adoption of improved portable signal detection devices for better analytical sensitivity

• Platforms for faster, easier development of capture moieties for target analytes; e.g., aptamers or nanobodies

• Improved chemistries, including electro-chemistries (e.g., voltammetry), for faster, more-sensitive signal output

• Expanded types of clinical matrices, including oropharyngeal swabs, expired breath, and saliva

• Target antigens other than proteins will be considered IN SCOPE

Areas of focus in this objective to improve performance could include but are not limited to:

• Shorter sample-to-result turnaround time, 2-5 min

• Greater analytical sensitivity, with analyte detection at < 50 pg/mL of clinical specimen

• Development of capture moieties in days or weeks instead of months

• Simpler or no sample preparation

• Fewer or no external consumable for reagent or specimen manipulation

• Multiplex pathogen analyte detection in one run

3. Bacterial Identification and Phenotypic Antimicrobial Resistance Characterization

The third objective of Research Area 004 is to improve direct-from-blood or other biofluid detection and identification of microbial infection coupled with phenotypic antimicrobial resistance characterization which can play a central role in limiting the onset of sepsis.

Development areas that are IN SCOPE for this objective include:

• Sample preparation methods to improve ratio of pathogen-to-human nucleic acid ahead of molecular testing

• Target amplification methods to improve analytical sensitivity

• Sequencing methods to improve accuracy of bacterial identification

• Antibacterial susceptibility testing (AST) methods

• Phenotypic antimicrobial resistance characterization

Areas of focus to improve performance in this objective could include but are not limited to:

• Smaller volume of whole blood to detect bloodstream infection

• Greater clinical sensitivity to detect pathogen analyte from whole blood

• Shorter detection time to identify pathogen of infection without blood culture, < 4 hr

• Shorter reaction time for detection of phenotypic resistance, < 2 hr

3.3.4.2 - Technical Approach

The proposed program must have sufficient feasibility research completed and working in early (planning and design) through late-stage (design verification) development for diagnostic test system that supports biodefense and naturally emerging and re-emerging infectious pathogen preparedness. Diagnostic test system must detect one of the following agents:

• Bacillus anthracis, including genotypic resistance markers

• Yersinia pestis, including genotypic resistance markers

• Francisella tularensis, including genotypic resistance markers

• Burkholderia spp, including genotypic resistance markers

• Botulinum toxin, including identifying and distinguishing relevant serotypes

• ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp), including genotypic resistance markers

• Lassa virus

• Nipah virus

• Rift Valley Fever virus

• Enterovirus D68 virus

• Candida auris

• Coccidioides sp.

• Novel coronaviruses

At the end of the performance period, it is expected that the diagnostic or diagnostic prototype shall:

• Detect proposed pathogen analyte reproducibly and with clinical accuracy directly from a relevant clinical matrix (blood, urine, respiratory swab, cerebrospinal fluid, stool, or bronchoalveolar lavage) without a culture step;

• Be designed either for low-throughput use in near-patient settings such as physician’s office, community pharmacy, and hospital emergency room, or for moderate throughput in hospital laboratories or clinical microbiology labs;

• Require at most a minimum of manual preparation prior to loading the clinical sample for automated processing; and

• Generate actionable diagnostic results within expected time frame without additional manual intervention.

The capability to detect and distinguish a required agent from among multiple other agents common to a geographic region or population is strongly encouraged.

3.3.4.3 – Additional Requirements

1. Developers must present proof-of-concept data that the proposed diagnostic method can detect the targeted pathogen analyte (see pathogen list above) preferably from a relevant clinical matrix (e.g., blood, urine, respiratory swab, cerebrospinal fluid, stool, or bronchoalveolar lavage).

2. Organizations responding to this Research Area, collectively with their proposed subcontractors and consultants where applicable, should have documented or proposed access to all reagents, facilities, and capabilities required to perform the proposed research, such as antibodies or other capture reagents, virulent pathogens, clinical samples, and biocontainment facilities. They should also have documented or planned expertise in product development in order to have the capability to advance the development and validation of a candidate diagnostic through FDA clearance and commercial launch.

3.3.4.4 – Contracts awarded under this Research Area will NOT support:

• Development of a diagnostic that does not include one (1) of the above-listed agents.

• Development of diagnostic tests to identify pathogens from culture or isolate (bacterial plate).

• Development of diagnostics that rely solely on the detection of host-response antibodies.

• Basic research and discovery of new host-based diagnostic targets.

• Development of platforms that will require more than 5 minutes of manual steps to process the sample prior to loading it into the diagnostic.

• Development of diagnostics that will require additional manual steps after the clinical sample has been loaded to start the test.

• Development of diagnostics that will only be validated using non-pathogenic or surrogate organisms.

3.4 - RESEARCH AREAS 001, 002 AND 003 - ADDITIONAL TECHNICAL PROPOSAL

INSTRUCTIONS

The following information supplements Section 4 – Instructions, Conditions, and Notices to Offerors of this solicitation, and should be used for preparing…