NIH/NIAID Partnerships for Diagnostics to Address Antimicrobial Resistance of Select Bacterial Pathogens (R01)

Funding Opportunity Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to solicit research applications for projects focused on development and/or production of diagnostics that will enable rapid, sensitive, specific, culture-independent detection of high-priority antimicrobial-resistant Gram-negative bacterial pathogens. This FOA is focused on select healthcare-associated bacteria where resistance compromises effective treatment, including: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species and extra-intestinal pathogenic Escherichia coli. Applications must include a Product Development Strategy and demonstrate substantive participation by at least one industrial participant.

Key Dates

Open Date (Earliest Submission Date)	May 19, 2014
Letter of Intent Due Date(s)	May 19, 2014
Application Due Date(s)	June 19, 2014, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
Scientific Merit Review	October 2014
Advisory Council Review	January 2015
Earliest Start Date	April 2015
Expiration Date	June 20, 2014

Award Information

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIAID intends to commit $12 million in FY 2015 to fund 10 - 15 awards.
Award Budget	Budgets for direct costs of up to $750,000 per year may be requested. In addition, applicants may request up to a total of $300,000 for major equipment in the first year of the award to ensure that research aims can be met and biohazards can be contained. Consortium F&A is not included in the direct cost limitation.
Award Project Period	The scope of the proposed project should determine the project period. The maximum period is 5 years.

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Full Text of Announcement

Funding Opportunity Description

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to solicit research applications for projects focused on development and/or production of medical diagnostics that permit rapid species identification, and optimally, corresponding antibacterial susceptibility profiles for one or more of the following causes of antibacterial-resistant infections in hospital settings: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and extra-intestinal pathogenic Escherichia coli. The primary goal of such diagnostics is to facilitate antibacterial stewardship, thereby reducing selective pressure and improving patient outcomes. A secondary goal, centered on increasing treatment options, is to facilitate enrollment in clinical trials for new antibacterial therapeutics against these pathogens. The proposed diagnostic must be designed to detect the target pathogen(s) in normally sterile sample types, such as blood, cerebral spinal fluid (CSF), and pleural fluid, but may also include the detection of the target pathogen(s) in the context of non-sterile sample types, such as those analyzed for hospital- and/or ventilator-associated pneumonia (HAP/VAP). The proposed diagnostic platforms and/or technologies must be supported by proof-of-concept data demonstrating feasibility. Examples of research areas supported include, but are not limited to: assay/prototype development; sample preparation; development of broad-spectrum platforms and/or production technologies; adaptation of products or platform technologies to new applications; optimization of products or technologies; process development; manufacturing; and diagnostic validation. 

Industrial Participation

All applications submitted to this FOA by academic organizations must demonstrate substantive investment and participation in the project by at least one industry participant. For the purpose of this FOA, "industry" is defined as large or small, domestic or foreign, pharmaceutical, biotechnology, bioengineering, and/or chemical companies, or non-profit agencies with demonstrated experience in product development. “Substantive investment" is defined as a commitment of one or more resources including, but not limited to: product/prototype development support/guidance, personnel, in kind contributions of materials and/or reagents [i.e., chemical libraries, innovative biotechnology platforms, scale up of Good Manufacturing Process (cGMP) chemical synthesis or production, etc.], provision of animal or other laboratory models for evaluation, subcontracts, data management resources or regulatory support. Support for industrial partner activities may be included in the project budget. The Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) of the project may be affiliated with either an academic organization or industry. Applications submitted by industrial institutions or product development non-profit agencies do not require an additional partner.

Background

Escalating resistance to antibacterial agents is an increasing contributor to morbidity, mortality, and rising healthcare costs. Emerging pan-drug resistance has been documented for a subset of hospital-associated infections, such as those caused by the Gram-negative pathogensKlebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species and extra-intestinal pathogenic Escherichia coli. The emergence of these untreatable infections highlights the importance of antimicrobial stewardship and the need to develop new therapeutics against the causative pathogens. Development of rapid and informative diagnostics will help address this growing public health challenge by allowing clinicians to quickly determine the most effective treatment for infected individuals and will facilitate antimicrobial stewardship by reducing the empiric use of broad-spectrum antimicrobials. Additionally, such diagnostics would benefit development and approval of new antibacterials by reducing the diagnostic uncertainty that necessitates enrollment of large numbers of patients who may not be evaluable in pivotal efficacy trials. Hence, rapid diagnostics should provide a means to reduce the size and cost of antibacterial clinical trials. Accordingly, development of new diagnostics that will enable enrichment of evaluable subjects in therapeutic clinical trials are of particular interest. An FDA Draft Guidance released in July 2013 provides information related to the development of diagnostics for this use (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM359184.pdf). It is expected that proposed diagnostics will be developed with the ultimate goal of obtaining FDA clearance; however such clearance need not be the final result of the proposed research project.

Research Objectives

The objective of this FOA is to solicit research that will advance the development and/or production of diagnostics that will enable rapid, sensitive, specific, culture-independent species identification of key Gram-negative hospital-associated pathogens (listed below). Priority will be given to diagnostics that additionally provide corresponding antibacterial susceptibility profiles for the targeted pathogen(s). Each application must propose a research and development project whose goal is to advance a diagnostic platform/technology. Research projects are not required to result in a "final" product. Moreover, it is not necessary to propose to complete the product development process up to the point of readiness for validation within the time frame of the project. Applications for projects that would significantly advance a candidate diagnostic product/platform toward clinical utility are responsive and encouraged.

Applications must include plans to detect one or more of the following Gram-negative bacteria pathogens:

• Klebsiella pneumoniae,
• Acinetobacter baumannii
• Pseudomonas aeruginosa
• Enterobacter species
• Extra-intestinal pathogenic Escherichia coli

Diagnostic platforms/technologies intended for differential diagnosis and/or clinical decision making must incorporate multiple bacterial targets, including at least one of the Gram-negative species listed above and may include diagnosis of additional pathogens. Detection of host factors predictive of bacterial infection that may provide clinically actionable information may also be included. A proposed diagnostic intended solely to facilitate clinical trial enrollment for a pathogen-specific drug may target a single Gram-negative species from the above list and optimally would report antibacterial susceptibility profiles.

The proposed diagnostic technologies must detect the target pathogen(s) from at least one normally sterile specimen type, such as blood, CSF, or pleural fluid. Focusing on these sample types will allow validation of the technology in a setting where colonizing organisms are not a complicating factor. There are a number of other types of hospital-associated infections where rapid diagnostics are also needed, but where the presence of commensal/colonizing organisms makes interpretation of test results difficult. Therefore, applications may also include plans to include detection of the target pathogen(s) in non-sterile sample types such as those analyzed for HAP/VAP; for such plans, applicants must specify how contamination with colonizing organisms will be addressed.

For the purposes of this FOA, the following test characteristics are of greatest importance:

• Rapid: Proposed diagnostic test time of < 3 hours for clinical diagnostics that identify species and resistance profile information or < 1 hour for clinical trial enrichment tools, which includes the time required to process the clinical sample (if appropriate) through detection and final test result;
• Culture-independent: the diagnostic should focus on direct detection of the target pathogen(s) from normally sterile samples;
• Sensitive: sensitivity should be equivalent to or exceed sensitivity of FDA-cleared tests for proposed agent(s) from the same sample type; and
• Specific: specificity should be equivalent to or exceed specificity of FDA-cleared tests for proposed agent(s) from the same sample type.

In addition, the following characteristics are desirable, but not essential to prototype diagnostics developed under this FOA:

• Easy to use: i.e.,  integrated, closed sample-to-answer system with automated data analyses and/or result presentation and with minimal operator training and expertise required;
• Random Access: the instrument should allow samples to be run as needed;
• Adaptable: capable of integrating new diagnostic tests for agents as required, including detection of modified or new targets;
• Non-nucleic acid amplification-based: due to failures of previous Nucleic Acid Amplification Tests (NAATs) in detecting bacteria from normally sterile sites, non-NAAT approaches are of higher priority unless a strong rationale is presented that documents why the proposed technology will overcome the challenges of predecessor NAATs; and
• Cost-effective: projected production and operating costs should be consistent with commonly used platforms for detecting hospital-associated infections.

 Examples of potential activities to be supported include, but are not limited to:

• Use of nanotechnology, microfluidic-based systems or any other novel or innovative system to process large numbers of patient samples;
• Integrated sample-to-answer technologies for rapid, multiplexed antigen or other analyte detection using novel and improved sample processing and detection methods and reagents;
• Integrated sample-to-answer technologies capable of high throughput multiplex screening using  analytes or signature biomarkers to identify human immune or other physiological response to infection;
• Technologies capable of detecting drug-resistance/drug-susceptibility, relevant to clinical decision making;
• Technologies and capacity for high throughput, automated data management, output and analyses; and
• In vivo imaging methods and development of contrast reagents for visualization of pathogens or host immune responses in vivo.

NOTE: PD(s)/PI(s) are strongly encouraged to obtain expertise in regulatory matters and reimbursement topics associated with product development. Expertise may be retained as defined effort or may be included as periodic consultation on specific issues.

NOTE: The following application types will be considered non-responsive and will not be reviewed:

• Applications proposing development of a diagnostic that lacks the required capability to detect at least one of the following pathogens: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and extra-intestinal pathogenic Escherichia coli.
• Applications proposing the development of a diagnostic that lacks the required capability to detect the specified pathogen from a normally sterile site, such as blood, CSF, or pleural fluid.
• Applications lacking proof-of-concept data for proposed diagnostic platforms/technologies.
• Applications that do not have the ultimate goal of detection and identification of pathogens in human clinical samples, or those which are focused on development of environmental or workplace pathogen/toxin detection technologies.
• Applications that propose clinical trial(s). While clinical development strategies may be included within an overall project, this FOA will NOT support clinical trials. Utilization of human-derived material in pre-clinical studies in support of compliance with regulatory requirements is permitted and encouraged.