Attachment_-_HHS-NIH-NIAID-BAA2019-1_-_Amendment_3.pdf

NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES (NIAID)

2019 Omnibus Broad Agency Announcement:

No. HHS-NIH-NIAID-BAA2019-1 – Amendment 3

Solicitation Issue Date: February 22, 2019 Amendment 3 Issue Date: May 23, 2019

Participating NIAID Divisions: Division of Allergy, Immunology, and Transplantation (DAIT);

Division of Microbiology & Infectious Diseases (DMID)

Issuing Office: Office of Acquisitions, DEA, NIAID, NIH, 5601 Fishers Lane, Room 3D32, MSC 9821, Bethesda, MD 20892-9821

Issuing Contracting Officer: George Kennedy kennedyg@mail.nih.gov

(240) 669-5170

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

* Proposals must be received before 3:00 PM Eastern Time on the date specified herein. Please see the Proposal Submission Instructions 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.

RESEARCH

AREA

NIAID

DIVISION

TITLE PAGE

NO.

PROPOSALS

DUE:

001 DAIT

Development of Radiation/Nuclear Medical Countermeasures (MCMs)

05/20/2019 *

002 DMID Development of Therapeutic Products for Antibiotic Resistant Bacteria

15 06/10/2019 *

003 DMID Advanced Development of Vaccine Candidates for Antibiotic Resistant Bacteria

32 06/10/2019 *

004 DAIT Characterizing and Improving Humanized Immune System Mouse Models (IMM-HIS)

48 09/16/2019 * mailto:kennedyg@mail.nih.gov

NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES (NIAID)

2019 Omnibus Broad Agency Announcement

No. HHS-NIH-NIAID-BAA2019-1

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 Allergy, Immunology, and Transplantation (DAIT)

3.1.1 - Background……………………………………………………………..……………….. p. 5

3.1.2 - Research Area

3.1.2.1 - Research Area 001: Development of Radiation/Nuclear Medical Countermeasures (MCMs) …………………………….……………………………….. p. 6

3.1.3 - Additional Technical Proposal Instructions …………………………………………… p. 9

3.1.4 - Reporting Requirements and Deliverables …………………………………..………... p. 13

3.2 – Division of Microbiology and Infectious Diseases (DMID)

3.2.1 - Background……………………………………………………………………………. p. 15

3.2.2 - Research Areas

3.2.2.1 - Research Area 002: Development of Therapeutic Products for Antibiotic Resistant

Bacteria………………………………………………………………………………………..… p. 15

3.2.2.1.6 – Additional Technical Proposal Instructions (Research Area 002)…… p. 18

3.2.2.1.7 – Reporting Requirements and Deliverables (Research Area 002)…….. p. 26

3.2.2.2 - Research Area 003: Advanced Development of Vaccine Candidates for Antibiotic Resistant Bacteria………………………………………………………………..……….. p.32

3.2.2.2.6 – Additional Technical Proposal Instructions (Research Area 003)……. p. 34

3.2.2.2.7 – Reporting Requirements and Deliverables (Research Area 003)……… p. 41

3.3 - Division of Allergy, Immunology, and Transplantation (DAIT):

Research Area 004: Characterizing and Improving Humanized Immune System Mouse Models (IMM-HIS)

3.3.1 - Background…………………………………………………………………………... p. 48

3.3.2 - Research Area 004: : Characterizing and Improving Humanized Immune System Mouse Models Mouse Models (IMM-HIS) …………………………………..……… p. 49

3.3.3 – Additional Technical Proposal Instructions (Research Area 004)………………...… p. 50

3.3.4 – Additional Business Proposal Instructions and Uniform Cost Assumptions (Research Area 004)………………………………………………………………….. p. 58

3.3.5 – Reporting Requirements and Deliverables (Research Area 004)………………….…… p. 59

3.3.6 – Advance Understandings (Research Area 004)……………………..…………….…… p. 61

SECTION 4 - Instructions, Conditions, and Notices to Offerors…………………………………………… p. 62

4.1 - General Instructions……………………………………………………………… ………....... p. 62

4.2 – General Information…………………………………………………………………………. p. 65

4.3 – Instructions to Offerors …………………………………………………………………….. p. 67

4.3.1 - General Information………………………………………………………………... p. 67

4.3.2 - Technical Proposal Instructions …………………………………………………… p. 74

4.3.3 - Business Proposal Instructions …………………………………………………….. p.104

SECTION 5 – Special Contract Requirements ……………………………………………………. p.121

SECTION 6 - Evaluation Factors for Award ……………………………………………………….. p. 146

SECTION 7 - Attachments……………………………………………………………………………… p. 155

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 FAR 35.016, as well as the 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 solicitation 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, shall be 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 Statement of Work 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 this announcement. 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 multiple Divisions within the National Institute of Allergy and Infectious Diseases. The Contracting Officer points of contact for questions related to specific Research Areas issued by the Division of Allergy, Immunology, and Transplantation (DAIT) and Division of Microbiology and Infectious Diseases (DMID) are identified below:

Division of Allergy, Immunology, and Transplantation (DAIT)

Research Area 001: Development of Radiation/Nuclear Medical Countermeasures (MCMs)

Research Area 004: Characterizing and Improving Humanized Immune System Mouse Models

(IMM-HIS)

Liem Nguyen Contracting Officer Phone: (240) 669-5144 E-mail: Liem.Nguyen@nih.gov

Division of Microbiology and Infectious Diseases (DMID)

Research Area 002: Development of Therapeutic Products for Antibiotic Resistant Bacteria

Research Area 003: Advanced Development of Vaccine Candidates for Antibiotic Resistant Bacteria

George Kennedy, J.D.

Contracting Officer Phone: (240) 669-5170 Email: kennedyg@mail.nih.gov mailto:Liem.Nguyen@nih.gov mailto:kennedyg@mail.nih.gov

SECTION 3. - RESEARCH AREAS AND TECHNICAL OBJECTIVES

3.1 - DIVISION OF ALLERGY, IMMUNOLOGY, AND TRANSPLANTATION (DAIT), NIAID

3.1.1 - BACKGROUND

World events have highlighted the growing threat of terrorism and its many forms, including the 1995 Tokyo sarin gas attack; radiological dispersal devices (dirty bombs) planted, but never detonated in Chechnya in 1995 and 1998; and the deliberate spread of anthrax spores and ricin through the United States postal service in 2001 and 2003, respectively. These incidents provide insight into the range of approaches used by terrorists, which include the potential to use chemical, biological, and/or radiological/nuclear weapons. Acts of radiological or nuclear terrorism could involve the use of stolen or improvised nuclear devices, attacks on nuclear power plants or reactors, the detonation of a dirty bomb, or the placement of radiation sources in public locations or in food or water supplies. Moreover, natural disasters like the 2011 earthquake and tsunami in Japan, which resulted in damage to the Fukushima Daiichi Nuclear Power Plant, and release of radiation into the environment, further emphasize the need for the United States Government to be prepared with stockpiled medical countermeasures (MCMs, e.g. drugs, biologics, and/or biodosimetry devices) to be used in the event of a radiation incident.

Radiation/nuclear incidents and disasters can potentially result in the exposure of large civilian populations to a high dose of radiation in a short period of time. Depending on the dose of whole-body exposure to external radiation, biological effects can range from acute effects, including nausea and vomiting within hours; hematopoietic and gastrointestinal injury leading to immunosuppression, infection, hemorrhage and death within days to weeks (acute radiation syndrome, ARS); to pulmonary, cardiovascular, and renal complications months after irradiation (delayed effects of acute radiation exposure or DEARE).

The United States Government recognizes the need to develop MCMs to address the systemic damage from radiation exposure following a radiological/nuclear incident. To this end, the Project BioShield Act of 2004, “Project BioShield”, Public Law 108-276, was enacted on July 21, 2004. It provides the Department of Health and Human Services (HHS) with authorities to procure MCMs for the Strategic National Stockpile (SNS) and to perform advanced research and development on priority MCMs against chemical, biological, radiological, and nuclear threats. Under this act, the National Institute of Allergy and Infectious Diseases (NIAID) Radiation and Nuclear Countermeasures Program (RNCP) was charged by HHS, on behalf of the National Institutes of Health (NIH), to address radiation-induced injuries resulting from a radiological/nuclear incident, with funds provided from a special congressional appropriation.

The coordinated efforts to support radiation research and development by the NIH, as well as other HHS sister agencies, are outlined in the HHS Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy and Implementation Plan. The NIH is committed to accelerating the development of drugs and biologics to treat injuries, for triage use in mass casualty situations. NIAID/RNCP supports advanced development and deployment efforts to make these medical countermeasures available for possible procurement by the Biomedical Advanced Research and Development Authority (BARDA) and subsequent storage in the SNS.

https://www.phe.gov/Preparedness/mcm/phemce/Pages/strategy.aspx https://www.phe.gov/Preparedness/mcm/phemce/Pages/strategy.aspx

3.1.2.1 - Research Area 001 – Development of Radiation/Nuclear Medical Countermeasures (MCMs)

In 2005, based on the recommendations of a Blue Ribbon Panel, NIAID published its Strategic Plan and Research Agenda for Medical Countermeasures against Radiological and Nuclear Threats. These plans describe a multifaceted program to expand research infrastructure and radiobiology expertise; promote the development of biodosimetry methods to assess radiation injury; and research, identify, develop, and obtain licensure for MCMs to mitigate/treat radiation-induced injuries, in order to save lives during a radiation emergency.

The goal of Research Area 001 is to support the development of safe and effective MCMs to mitigate and/or treat tissue injuries exposure to ionizing radiation from a radiological or nuclear incident, thereby leading to a reduction in radiation-associated morbidities and mortalities.

Given the extent of damage sustained after a mass casualty incident, drugs are not expected to be mobilized from the SNS before 24 hours, hence the need for MCMs that are efficacious 24 hours or later post-exposure.

Since the program’s inception, NIAID/RNCP has sponsored early-stage/applied research, product development programs and targeted initiatives focused on development of drugs to mitigate and/or treat complications of ARS and DEARE. Investment in this portfolio has led to the establishment of several rodent and non-human primate animal models, which are critical for licensure of radiation mitigators under the U.S. Food and Drug Administration (FDA) Animal Rule. In fact, studies funded by the RNCP led to FDA approval of both Neupogen®

(filgrastim) and Neulasta® (pegfilgrastim) for the hematopoietic-ARS indication in March 2015 and November 2015, respectively. Although progress has been made in licensing products to treat some forms of radiation injury, drugs are still needed to address other forms of hematopoietic injury, as well as for the treatment of other organ systems affected by radiation exposure.

3.1.2 - RESEARCH AREA

3.1.2.1.1 - Budget and Award Information

NIAID estimates that one or two awards may be issued for a total cost of up to $2 million per contract for the non-severable base period (direct and indirect costs combined), depending on the number of technically meritorious proposals, importance to agency programs, and availability of funds. The total cost for each award(s) may vary depending upon the scope of the project and the technical objectives of the award(s).

The total duration of a proposed contract should be consistent with the nature and complexity of the offeror’s proposed research. The total performance period comprised of the base and any options proposed by an Offeror should not exceed three (3) years.

Awards are anticipated to be made in or around May 2020.

3.1.2.1.2 - Technical Objectives https://www.niaid.nih.gov/sites/default/files/radnucstrategicplan.pdf

Offerors are invited to submit proposals to advance the development of one lead candidate MCM that has already demonstrated concept feasibility. MCM drug candidates should increase survival by mitigating and/or treating acute or delayed radiation injury.

Proposals should include a plan to conduct translational research and development and, if applicable, provide additional information and data to support U.S. Food and Drug Administration (FDA) approval or licensure and submission of an Investigational New Drug (IND) application. Offerors should provide a well-defined product development path that includes IND-enabling studies that will be performed under the contract.

Specifically, Research Area 001 is intended to support the research and development of promising new approaches to mitigate and/or treat tissue injuries arising from exposure to ionizing radiation, which may include, but are not limited to: biologics, including cytokines and free radical scavengers; cellular therapies; and drugs, such as, anti-inflammatory agents, antibiotics, and anti-fibrotics. This solicitation is not intended to support the development of biodosimetry biomarkers and/or devices to detect ionizing radiation exposure, unless the biomarkers are being developed to assess the biological effects and efficacy of the lead MCM.

3.1.2.1.3 - Technical Approach

The lead MCM to be supported by this initiative should be easy to distribute and use in a mass casualty incident (e.g., the preferred routes of administration are oral, subcutaneous, inhalation, transdermanl or intramuscular), with the exception of cellular therapies, which may require intraveneous administration. In addition, the lead MCM must meet all of the following scientific and technical requirements prior to submission of the proposal:

1. The lead MCM must already have demonstrated efficacy (i.e., demonstrating clinically-relevant and statistically-significant reduction in mortality and/or major morbidity in animal models of acute or delayed radiation injury predictive of the human response) when administered at least 24 hours after radiation exposure.

2. The lead MCM must be previously identified as having a favorable safety profile using animal model safety studies and/or in human clinical studies for another indication, in case appropriate biodosimetry is not available to confirm the radiation dose received prior to initiating treatment.

3. Radiation exposure type, dose level, and dose rates proposed for the study must be relevant to a terrorist incident or accidental exposure. Studies using fractionated radiation exposures, commonly used for clinical radiotherapy treatments are not appropriate, unless information gained would be directly applicable to an unintentional exposure scenario; and

4. The lead MCM must have a target product profile, including:

a. Preliminary data to support the selection of the MCM, specifically: animal studies that demonstrate efficacy when delivered 24 hours or later after radiation exposure using appropriate animal models and assays.

b. Safety studies.

c. The intended use/indication of the lead MCM and the biodefense/public health gap that the product is intended to fill.

d. The performance specifications and features that the MCM will meet in order to provide therapeutic benefit.

e. In addition, include the following, if available:

i. Pharmacokinetics/pharmacodynamics (PK/PD) studies.

ii. Physicochemical characteristics, current formulation, and a mechanism of action.

iii. Documentation of communications with the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) that are relevant to development activities for the proposed therapeutic product.

This contract will provide funds to support the following activities:

1. Non-clinical Research and Development, including:

a. Animal model(s) development.

b. Reagent and assay development, including biomarkers to assess the biological effects and efficacy of the lead MCM.

c. Efficacy studies in animals to optimize the route of administration, formulation, dose, and dosing schedule when administered at least 24 hours or later after radiation exposure. Studies should be designed to be suitable (species, endpoints, measurements) for predicting future pivotal Good Laboratory Practice (GLP) efficacy studies under the FDA Animal Rule (21 CFR 314.600-314.650, 601.90- 601.95).

d. Mechanism of action studies.

e. Bioavailability; pharmacokinetic; and adsorption, distribution, metabolism, and excretion (ADME) studies.

f. GLP and non-GLP toxicology and pharmacology safety studies.

g. Ex vivo studies using human subject samples.

2. Manufacturing, including:

a. Formulation development, stability, and production scale-up.

b. Physicochemical and bioanalytical methods development.

c. Current Good Manufacturing Practice (cGMP) and non-GMP manufacturing development and scale-up support of lead candidate in amounts sufficient to carry out the proposed non-clinical research.

d. Stability studies.

3. Other IND or New Drug Application (NDA) and Biological License Application (BLA) activities, including:

a. Development and drafting of Phase 1 human safety and pharmacokinetic study protocols.

b. Regulatory efforts to support pre-IND interactions with the FDA, drafting of an IND, and preparation of IND package.

c. Quality control over the implementation, coordination and conduct of the proposed activities.

d. Drug Master File (DMF) submissions under cGMP guidelines. (see 21 CFR 314.420)

e. Discussions with the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) related to development for the proposed therapeutic product.

NOTE: Research and development studies are anticipated to advance MCMs toward submission of an Investigational New Drug (IND) application and eventual approval/clearance from the FDA under the FDA Animal Rule (21 CFR 314.600- 314.6R50, 601.90-601.95). For more information please see the Animal Rule Guidance provided by the FDA.

This contract will NOT provide funds to support the following activities:

• Screening activities to identify new MCMs.

• Performance of clinical trials (All Phases).

• Development of more than one lead candidate MCM per proposal.

• Development of biodosimetry biomarkers and/or devices, unless the biomarkers are being developed to assess the biological effects and efficacy of the lead MCM.

• Studies using fractionated radiation exposures, commonly used for clinical radiotherapy treatments, unless information gained would be directly applicable to an unintentional exposure scenario.

- END OF RESEARCH AREA 001 - TECHNICAL DESCRIPTION -

3.1.3 - Additional Technical Proposal Instructions - DEVELOPMENT OF

RADIATION/NUCLEAR MEDICAL COUNTERMEASURES (MCMs)

The following information supplements Section 4 – Instructions, Conditions, and Notices to Offerors, of this solicitation, and should be used for preparing proposals in response to Research Area 001. Separate and distinct proposals must be submitted for each Research Area to which you http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM399217.pdf http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM399217.pdf are proposing. It is recommended that your proposal be organized in accordance with the order of your Statement of Work and the technical evaluation criteria provided in Section 6.

As appropriate to the Statement of Work:

3.1.3.1 - Experimental Plan (Include the following in SECTION 4: TECHNICAL DISCUSSIONS, of your Technical Proposal)

NIAID recognizes that the regulatory path to licensure for products within the scope of this BAA may not have been previously defined. The regulatory requirements are likely to be defined in an iterative decision-making process with the FDA based on product-specific data as it emerges.

Provide an Experimental Plan that details the specific tasks and stages that the Offeror proposes to perform with contract funding that can reasonably be completed in three years. The Experimental Plan must also include:

a. Details of the critical path to licensure for the proposed product, based on current data and/or discussions with the FDA. Specify the elements of this critical path that would be completed under the proposed Statement of Work.

b. Activities and stages of product development that the Offeror proposes to perform under contract funding, including Go/No Go decisions for advancement to the next stage.

c. Timelines for the initiation, conduct and completion of product development activities for each stage, the analysis of outcomes and findings, and the preparation of detailed reports summarizing the results of work completed and an analysis of the data as it relates to the qualitative and quantitative criteria established for Go/No Go decision making. Provide a Gantt chart of proposed activities.

d. A detailed discussion of the proposed technical approach for each activity to be performed to achieve the project objectives, containing sufficient detail to fully explain and justify the scientific and technical rationale for the proposed approach and methodologies. Also include: (i) detailed information on radiation dosimetry and irradiator set-up (e.g., radiation dose and quality, dose rate, source, geometry of irradiation); (ii) plans to ensure the correct dose is delivered (e.g. frequency of dosimetry confirmation, in-run dosimetry (if appropriate).

e. An analysis of risks that could compromise performance of activities described in the Statement of Work, along with a risk mitigation plan in the event that the specified risks materialize.

f. NIH expects that sex as a biological variable will be factored into research designs, analyses, and reporting in vertebrate animal and human studies. Strong justification from the scientific literature, preliminary data, or other relevant considerations must be provided for applications proposing to study only one sex. Further information regarding NIH expectations for the consideration of sex as a biological variable is provided at the following website:

http://orwh.od.nih.gov/sexinscience/overview/pdf/NOT-OD-15-102_Guidance.pdf

g. Inclusion of vulnerable special populations (e.g., pediatrics and geriatrics) in the research plan, including the development of appropriate animal models to test the efficacy of the lead MCM, if applicable.

http://orwh.od.nih.gov/sexinscience/overview/pdf/NOT-OD-15-102_Guidance.pdf

3.1.3.2 - Data Management, Quality Assurance and Regulatory Compliance (Include the following in SECTION 4: TECHNICAL DISCUSSIONS, of your Technical Proposal)

a. Include a description of: (1) proposed data management that will be used for all studies;

(2) the procedures for the data entry and validation; (3) documentation of data corrections, routine maintenance and backup, transmission of data, data reporting and exporting system, access control and confidentiality, and data retrieval and disaster recovery; and (4) the statistical design and analysis resources that will be used to support contract activities.

b. Describe procedures to be used to maintain documentation adhering to FDA regulatory standards and published guidance documents, for the conduct of assays under GLP and manufacturing under cGMP standards. Include information on data management for GLP and cGMP activities (applicable only to Research Area 001, as appropriate to the statement of work).

c. Describe processes and procedures for regulatory compliance including: timing of audits, timely scheduling of audits, performance of audits, responding to audit reports and supporting documentation, as well as an audit history of the facilities proposed for use in carrying out contract activities (applicable only to Research Area 001, as appropriate to the Statement of Work).

d. List any applicable FDA inspection reports (Form 483), audit reports and/or any other FDA communications about the lead MCM (applicable only to Research Area 001; this information should not exceed more than 1 page).

e. Provide documentation that the offeror has intellectual property protection and/or proprietary freedom to develop the lead MCM.

3.1.3.3 - Scientific and Technical Personnel (Include the following in SECTION 5: Scientific and Technical Personnel, of your Technical Proposal):

a. Principal Investigator (PI): Describe the scientific and technical expertise of the proposed Principal Investigator with regard to radiation biology and product development. Document the experience of the PI with performing studies of comparable size and scope (completed or ongoing) in accordance with FDA regulations and published guidance documents, including GLP and cGMP guidelines as appropriate to the proposed Statement of Work.

b. Other Key Scientific and Technical Personnel: Provide selected references for publications relevant to the scope of the BAA; include experience with projects of similar scope, size and complexity carried out by the Offeror and any proposed subcontractors over the past five years. Document the experience of scientific personnel and/or subcontractors with performing studies in accordance with FDA regulations and published guidance documents, including GLP and cGMP guidelines, as appropriate to the proposed Statement of Work. Include the qualifications of the staff that will oversee radiation dosimetry and irradiator set-up.

3.1.3.4 - Organizational Facilities, Equipment, and other Resources

a. Document: (1) the availability of proposed facilities for the duration of the contract; (2) plans for obtaining, adding or deleting facilities as necessary due to progress or performance issues that arise during the course of product development.

b. Provide procedures to be utilized to insure compliance with all safety guidelines and regulations, including training and monitoring of personnel.

c. Document entry access to facilities of the contractor or the subcontractor, if any, for performing assays and animal studies under GLP standards and production of therapeutic material under cGMP guidelines as required by the Experimental Plan.

d. Describe provisions for complying with Public Health Service and Department of Agriculture guidelines and regulations for the housing and humane care and use of laboratory animals as prescribed by the Office of Laboratory Animal Welfare (OLAW), the USDA Animal Welfare Act and the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC), if appropriate.

e. Describe provisions for ensuring safe facilities for the conduct of work and the controls and provisions to be in place for handling radioactive materials and irradiation equipment (see Publication 3000 as a recommended program).

3.1.3.5 - Uniform Cost Assumptions

Offerors should use the following assumptions for the purposes of estimating costs and preparing the technical proposal:

a. Technical Cost Assumptions

1. Business Proposals must provide a breakdown by line item cost, including: Direct Labor, Direct Materials, Animal costs (including housing), Subcontracts, Consultants, Travel (refer to the instructions in Section 4 - Business Proposal Instructions, of this solicitation).

2. It is anticipated that this contract will be aligned with the deliverables identified in the Research and Technical Objectives. Consequently, Business Proposals must provide a breakdown of costs for each milestone as well as a cost estimate for the entire project period of performance. The Business Proposal must also include a detailed Gantt chart that provides timelines delineating each milestone and associated tasks, subtasks and budgets to the subtask level of detail.

b. Travel

1. Contract Initiation Meeting: Assume one meeting in the Rockville, Maryland area within 60 calendar days of the effective date of the contract to discuss contract initiation. Assume that this meeting will require a two-night stay and attendance of all of the Contractor’s key personnel (up to 5 individuals), including subcontractor’s personnel.

2. Annual Meetings:

i. Annual Site Visits: Assume annual 1-day site visits at the Contractor’s facilities to be attended by the Principal Investigator and key personnel of the Contractor, 4 Government personnel and 4 collaborators and/or key personnel of subcontractors. Travel and per diem costs for the Government personnel shall not be included in the contract proposal.

ii. Annual Programmatic Meetings: Assume annual ½ day programmatic meetings, to be held in the Rockville, MD area. Include travel costs (transportation, meals, hotel, etc.) for Contractor staff members, including the Principal Investigator, key coinvestigators, collaborators and subcontractors (up to 5 individuals).

https://olaw.nih.gov/ https://www.aphis.usda.gov/aphis/ourfocus/animalwelfare/sa_awa/ct_awa_program_information https://www.aphis.usda.gov/aphis/ourfocus/animalwelfare/sa_awa/ct_awa_program_information http://www2.lbl.gov/ehs/pub3000/CH21.html#_Toc407168416

3. Scientific Meetings: Budget travel costs (transportation, meals, hotel, etc.) for one 3-day scientific meeting per year for up to 2 personnel to travel to present scientific findings generated under this contract.

4. Subcontractor Site Visits: Budget travel costs (transportation, meals, hotels, etc.)

for two 2-day trips per year for up to 3 personnel to visit sites of subcontracts, if applicable.

3.1.4 - Reporting Requirements and Deliverables - DEVELOPMENT OF

RADIATION/NUCLEAR MEDICAL COUNTERMEASURES (MCMs)

3.1.4.1 - Reporting Requirements

In addition to reporting requirements and deliverables identified elsewhere in this solicitation, it is expected that awards resulting from Research Area 001 will include the following reports and deliverables:

a. Quarterly Progress Reports

This report shall include a description of the activities during the reporting period and the activities planned for the ensuing reporting period. The first reporting period consists of the first full three months of performance including any fractional part of the initial month. Thereafter, the reporting period shall consist of three full calendar months.

b. Annual Technical Progress Report for Clinical Research Study Populations

The Contractor shall submit information about the inclusion of women and members of minority groups and their subpopulations (when appropriate) for each study being performed under this contract. The Contractor shall submit this information in the format indicated in the attachment entitled, "Cumulative Inclusion Enrollment Report," which is set forth in SECTION VI of this contract. The Contractor also shall use this format, modified to indicate that it is a final report, for reporting purposes in the final report. If the clinical study(s) involves US and non-US sites, the US sites and non-US sites should be reported on separate Cumulative Inclusion Enrollment Reports.

In addition, the NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research, amended October 2001, applies. If this contract is for Phase III clinical trials, see II.B of these guidelines. The Guidelines may be found at the following website: http://grants.nih.gov/grants/funding/women_min/women_min.htm

For NIH-defined Phase III Clinical Trials: Include a description of the plans for valid analysis in the study design and outcomes. This includes designing the study in a manner that potential differences, as appropriate, by sex/gender and/or racial/ethnic groups in the clinical trial protocol could be conducted. Also, provide a description of any analyses by sex/gender, race, and/or ethnicity, as appropriate, in the annual progress report and the final report. If the analysis reveals no subset differences, a brief statement to that effect, indicating the subsets analyzed, will suffice. The Government strongly encourages inclusion of the results of subset analysis in all publication submissions. In the final report, the Contractor shall include all final analyses of the data on sex/gender, race and/or ethnicity.

http://grants.nih.gov/grants/funding/women_min/women_min.htm

e. Final Report

This report shall consist of the work performed and results obtained for the entire contract performance period. This report shall be in sufficient detail to describe comprehensively the results achieved. The Final Report shall be submitted on or before the last day of the contract performance period. A Quarterly Progress Report will not be required for the period when the Final Report is due.

The Contractor shall provide the Contracting Officer’s Representative and Contracting Officer with an electronic copy of the Final Report in draft form 30 calendar days prior to the completion date of this contract. The Contracting Officer’s Representative will review the draft report and provide the Contracting Officer with comments within 15 calendar days after receipt. The Final Report shall be corrected by the Contractor, if necessary and the final version delivered as specified in the above paragraph.

f. Summary of Salient Results

The Contractor shall submit, with the Final Report, a summary (not to exceed 200 words) of salient results achieved during the performance of the contract.

3.1.4.2 - Deliverables

Delivery of other reports and deliverables will be proposed by the Offerors in their technical proposal. They will be developed further after receipt of proposals as a result of finalization of the Statement of Work and other terms and conditions of any resultant contract during negotiations.

All electronic reports and deliverables shall be submitted through the NIAID Electronic Reports and Deliverables System, available here: https://erds.niaid.nih.gov/

-- END OF SECTION 3.1 - DIVISION OF ALLERGY, IMMUNOLOGY, AND TRANSPLANTATION

(DAIT) --

https://erds.niaid.nih.gov/

3.2 - DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID), NIAID

3.2.1 - BACKGROUND

Research supported by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), 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 Category A, B, and C priority pathogens.

This current announcement is focused on efforts to address Antimicrobial Resistance (AR), a pressing public health problem as described in the National Action Plan for Combatting Antibiotic-Resistant Bacteria, and one of the most urgent public health threats facing the world today.

CDC has identified a list of antibiotic resistant pathogens in the United States due to their significant public health threat to the nation.

Through this solicitation, NIAID aims to advance research and development of promising new therapeutics and vaccines addressing infections caused by these pathogens, as specified in the research topics described under the two Research Areas below:

• Research Area 002 - Development of Therapeutic Products for Antibiotic Resistant Bacteria (See section 3.2.2.1)

• Research Area 003 - Advanced Development of Vaccine Candidates for Antibiotic Resistant Bacteria (see section 3.2.2.2)

3.2.2 - RESEARCH AREAS

3.2.2.1 - Research Area 002 - Development of Therapeutic Products for Antibiotic Resistant Bacteria

3.2.2.1.1 - Budget and Award Information

NIAID estimates that two or more awards may be issued across Research Areas 002 and 003 for a total cost of up to $10 million for the non-severable base work across all contracts (direct and indirect costs combined), depending on the number of technically meritorious proposals, importance to agency programs, and availability of funds. The total cost for each award(s) may vary depending upon the scope of the project and the technical objectives of the award(s).

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/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf https://www.cdc.gov/drugresistance/pdf/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf https://www.cdc.gov/drugresistance/biggest_threats.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fdrugresistance%2Fthreat-report-2013%2Findex.html

The total duration of a proposed contract should be consistent with the nature and complexity of the offeror’s proposed research. The total performance period comprised of the base and any options proposed by an Offeror should not exceed five (5) years.

3.2.2.1.2 - Technical Objectives

The objective of Research Area 002 is the development of therapeutics to address antibiotic resistant bacteria. While proposals for the development of broad-spectrum therapeutics are encouraged, candidate therapeutics or lead series with a limited spectrum 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 as proposed lead series/lead/candidate therapeutic products.

There are a number of threats for which effective treatments are either non-existent, of limited usefulness, or vulnerable to both naturally emerging and intentionally engineered antibacterial resistance. Lead series/lead/candidate products that specifically address drug-resistant bacteria or those for which no treatments exist are encouraged, even if these products have a narrow spectrum of activity. For narrow-spectrum agents at later stage of development (IND enabling/Phase 1) and for which a diagnostic might be beneficial for clinical development or clinical use, efforts to incorporate investigation of novel diagnostics approaches and/or collaborations with diagnostics developers are encouraged.

Strategies to overcome drug resistance could extend the clinical utility of existing antibacterials and have immediate benefits. Moreover, treatments directed towards host targets have the potential to be effective against one or more diseases. For these reasons, proposals on non-traditional therapeutics are encouraged, provided they have demonstrated therapeutic activity when used alone or in combination with an existing licensed product.

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. For the purposes of this solicitation, a lead series/lead/candidate product is defined as either a drug (synthetic or natural product) or a biological product (e.g. monoclonal antibodies, recombinant proteins), and therapeutic activity is defined as the cure or mitigation of disease, preferably once signs and symptoms of infection are evident.

Research Area 002 will support lead optimization, pre-clinical (IND enabling) and Phase 1 studies. The scope of support differs depending on the stage of the project being proposed, as outlined below.

Details below describe development phases in-scope of Research Area 002:

Lead Optimization

• Synthesize lead compounds from selected lead scaffolds - new analogs with improved potency, reduced off-target activities, and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics

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

• Initiate studies to identify correlates of protection (e.g., PK-PD), assays, and endpoints for further pre-clinical and clinical studies.

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

• Select lead candidate

Pre-Clinical (IND Enabling)

• Demonstrate acceptable Absorption, Distribution, Metabolism, and Elimination (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 efficacy and dose-ranging 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 Investigational New Drug (IND) package to FDA

Phase 1

Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial(s) to determine the safety and pharmacokinetics of the clinical test article in healthy volunteers (in certain circumstances, patients).

Proposals that initiate with a single therapeutic candidate product 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 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.

Preliminary Data Requirements: Regardless of the proposed entry point, lead series/lead/candidate products must show all of the following characteristics:

• Demonstrated phase appropriate synthesis/manufacturing feasibility

• In vitro AND in vivo evidence of efficacy; and

• In vitro AND in vivo evidence of acceptable pharmacokinetic and toxicology These characteristics must be reflected in the draft Target Product Profile (TPP)

3.2.2.1.3 - Technical Approach

Solicited Products:

Therapeutics for Antibiotic Resistant Bacteria

Lead series/lead/candidates must address infections caused by one or more bacterial pathogens listed in the 2013 CDC Antibiotic Resistance Threats in the United States report.

3.2.2.1.4 - Additional Requirements

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.

3.2.2.1.5 - Contracts awarded under this Research Area will NOT support:

• Basic research and discovery of new series

• Hit-to-Lead optimization and studies

• Development of lead series/lead/candidate products that have not demonstrated therapeutic activity in a relevant animal model of disease

• Development of licensed products as new formulations, or for additional clinical indications, or in combination with other licensed products

• Development of topical sanitation products

• Development of serum-derived products

• Development of devices

• Development of vaccines

3.2.2.1.6 - Additional Technical Proposal Instructions (Research Area 002)

The following information supplements Section 4 – Instructions, Conditions, and Notices to Offerors of this solicitation, and should be used for preparing proposals in response to Research Area 002.

3.2.2.1.6.1 – LEAD SERIES/LEAD/CANDIDATE PRODUCT PROFILE

Provide a synopsis (suggested 10-page maximum – included in total page limitation) of the intended use of the lead series/lead/candidate product and https://www.cdc.gov/drugresistance/threat-report-2013/index.html background information to support the further development as formulated/designed.

Include the following information:

a. The intended use/indication of the lead/candidate product/formulation/design and the public health gap the product is intended to fill.

b. For candidate product, the performance specifications and features the product would meet in order to provide benefit that would meet the Technical Objectives, including potential stability, dosing and safety.

c. A description of the lead series/lead/ candidate product and its current formulation and/or device description.

d. Data to support the characterization and selection of the lead series/lead/candidate product for further development, including (as relevant): a summary of manufacturing status, processes, scalability product stability and overall potential for commercialization, a summary of data that demonstrates efficacy using appropriate assays and animal models predictive of the human response; a description of the assays and animal models; and, the rationale for the choice of assays and animal models for the outcome/endpoints selected.

e. If any, meeting minutes or, if no meeting minutes are available, synopses from discussions with the FDA (CBER/CDER/CDRH), that are relevant to development activities for the proposed product.

f. A description of activities that are part of the critical product development strategy through submission of a BLA or NDA.

3.2.2.1.6.2 - PRODUCT DEVELOPMENT PLAN

Technical Proposals must include a Product Development Plan that describes the critical path for the proposed lead series/lead/candidate product to eventual licensure and identifies the decision points/gates for progress of the lead series/lead/candidate/product. Offerors should point out areas of significant uncertainty and propose likely alternatives.

The Product Development Plan should detail the specific tasks and stages to be performed with contract funding that can be reasonably completed within the period of performance. The Product Development Plan should include a summary of the following (AS APPLICABLE - based on the stage of development of the proposed work:

a. A description of the lead series/lead/candidate product as it is currently configured.

b. The intended use/indication of the proposed lead series/lead/candidate product and the public health gap the product is intended to fill.

c. A Target Product Profile for the lead/ candidate product, the performance specifications and features the candidate/product should have including potential stability, dosing and safety.

d. Data to support the characterization and selection of the lead series/lead/ candidate product for further development. A summary of the data that demonstrates activity in an appropriate animal model.

e. Discussions with FDA, if available, that are relevant to development activities for the proposed candidate product.

f. A description of activities that are part of the critical product development strategy through submission of a BLA or NDA.

g. As relevant, plans for the development, submission, and sponsorship of an

Investigational New Drug (IND)/combination product application, including compliance with all regulatory requirements.

h. As relevant, plans for the design, conduct, and completion of a Phase 1, Phase

1/2 and/or Phase 2 clinical trial for the candidate product.

3.2.2.1.6.3 - WORK PLAN (For the implementation of the…