Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Allergy and Infectious Diseases (NIAID))
Funding Opportunity Title	Leadership Group for a Clinical Research Network on Antibacterial Resistance (UM1)
Activity Code	UM1 Multi-Component Research Project Cooperative Agreements
Announcement Type	New
Related Notices	July 9, 2018 - This RFA has been reissued as RFA-AI-18-036. April 10, 2012 - See issuance of RFA-AI-12-018, Clinical Trials Units for NIAID Networks (UM1). The NIAID is soliciting concurrent Leadership Group applications for the following areas: Clinical Research Network on HIV/AIDS and HIV-associated Infections in Pediatric and Maternal Populations (RFA-AI-12-001), Clinical Research Network on Integrated Strategies to Prevent HIV Infection (RFA-AI-12-011), Clinical Research Network on Microbicides to Prevent HIV Infection (RFA-AI-12-008), Clinical Research Network on Therapeutics for HIV/AIDS and HIV associated Infections in Adults (RFA-AI-12-004), and Clinical Research Network on Vaccines to Prevent HIV Infection (RFA-AI-12-012).
Funding Opportunity Announcement (FOA) Number	RFA-AI-12-019
Companion FOA	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.855; 93.856
FOA Purpose	The purpose of this FOA is to encourage submission of applications for the Leadership Group for a Clinical Research Network on Antibacterial Resistance. The Leadership Group (LG) will have overall responsibility for designing, prioritizing, implementing and managing the network’s clinical research agenda to address antibacterial resistance (AR) scientific priorities. Applications for the LG must include an overview component and three functional components: a Leadership and Operations Center (LOC), a Laboratory Center (LC) and a Statistics and Data Management Center (SDMC).

Posted Date	January 13, 2012
Letter of Intent Due Date	May 1, 2012
Application Due Date(s)	June 1, 2012
AIDS Application Due Date(s)	Not Applicable.
Scientific Merit Review	January, 2013
Advisory Council Review	October, 2013
Earliest Start Date(s)	December, 2013
Expiration Date	June 2, 2012
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS398 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. While some links are provided, 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.

Part 1. Overview Information
Part 2. Full Text of 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

The National Institute of Allergy and Infectious Diseases (NIAID) invites grant applications from domestic institutions/organizations to serve as the Leadership Group for the Clinical Research Network on Antibacterial Resistance (AR). The purpose of this initiative is the design, prioritization, implementation and management of an integrated, clinical research program that could lead to the reduction of AR. The Leadership Group (LG) will be responsible for the network’s overarching research agenda to address AR as well as contingencies to address changing needs in AR. The LG, coupled with affiliated clinical research sites, will constitute the Clinical Research Network on AR. Priority will be placed on relevance to US public health and the feasibility of implementing the overarching research agenda where AR is endangering the advances of modern medicine and the ability to treat formerly treatable infections.

Creation of a LG represents the first NIAID clinical trials network focused on an overarching clinical research agenda for AR in bacteria (background and information can be found on the NIAID Clinical Trials Network. However, NIAID has relevant prior experience in clinical research related to AR. In 2001, NIAID created the Bacteriology and Mycology Study Group (BAMSG) that included a focus on AR. This group undertook studies that would not readily be conducted by the pharmaceutical industry alone, such as those to assess reduced or no drug use. In addition, these studies were confounded by the prevalence of empiric antibacterial drug use in intensive care units.

In 2007, building on the BAMSG experience, the NIAID launched a series of initiatives to support targeted clinical trials to reduce the risk of antimicrobial resistance. These initiatives are designed to provide vital information on the optimal use of currently available antibacterial drugs in a variety of clinical settings. The goal of this concerted effort is to find treatment regimens that limit the emergence of drug resistance. Ongoing clinical trials under this program each target a particular disease and strategy, such as:

• Use of oral antimicrobials (e.g., clindamycin; trimethaprim sulfamethoxasole) for uncomplicated skin and soft tissue infection in the era of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).
• Alternative treatment duration for staphylococcal bloodstream infections.
• Alternative treatment duration for pediatric urinary tract infections.
• Optimization of treatment for multi-drug resistant Acinetobacter baumanii invasive infection.
• Use of PK/PD to inform optimal treatment for ventilator-associated pneumonia with multi-drug resistant Acinetobacter baumanii or Psudomonas aeruginosa.
• Optimization of treatment for pediatric acute otitis media with a goal of reducing drug exposure.
• Optimization of rapid diagnostic point-of-care tests to guide optimal therapy for community-acquired pneumonia.

DMID also has clinical infrastructure that continues to contribute to our knowledge on AR, including the Vaccine and Treatment Evaluation Units (VTEUs), which conduct a broad range of studies of products against infectious diseases in people of all ages and risk categories, and Phase 1 Clinical Trial Units for Therapeutics. In addition, DMID supports disease-specific clinical efforts relevant to AR through the Sexually Transmitted Infections Clinical Trials Group (STICTG), the Tuberculosis Research Unit, and the Bacterial Respiratory Pathogens Research Unit (BRPRU). AR-related clinical trials currently supported under these DMID programs include:

• Study of photodynamic treatment of endotracheal tubes for reducing microbial pathogens.
• Phase 1 clinical trial of a novel class of compound for Clostridium difficile infection.
• Phase 1 clinical trial of the pharmacokinetics of inhalational Colistin
• Safety and efficacy trial of two dual therapy regimens, azithromycin/gentamicin and azithromycin/gemifloxacin, for treatment of uncomplicated urogenital gonococcal infection.
• Early clinical trials to develop new broad-spectrum drugs against a wide range of multi-drug resistant, gram-negative organisms (Pseudomonas, Acinetobacter and Enterobacteriaceae), as well as multi-drug resistant gram-positive bacteria (MRSA- and vancomycin-resistant Staphylococcus strains).

For further details on these clinical research programs see: http://www.niaid.nih.gov/about/organization/dmid/pages/programs.aspx.

All of these efforts are consistent with NIAID’s Strategic Plan for Biodefense Research Update (http://www.niaid.nih.gov/topics/BiodefenseRelated/Biodefense/Documents/biosp2007.pdf)

and the HHS Public Health Emergency Medical Countermeasure Enterprise Implementation Plan for Chemical, Biological, Radiological and Nuclear Threats (https://www.medicalcountermeasures.gov/BARDA/documents/phemce_implplan_041607final.pdf), both published in 2007, and NIAID’s Research Agenda on Antimicrobial Resistance, published in 2008 (http://jid.oxfordjournals.org/content/197/8/1087.full).

Other Available Resources

Concomitant with the renewed focus on clinical research for AR, NIAID has been expanding resources for researchers. These resources, which include those for both preclinical and clinical efforts, are designed to help lower the risk for entry into the product development pathway. For a comprehensive list of resources, see: http://www.niaid.nih.gov/labsandresources/resources/dmid/Pages/default.aspx.

Additionally, in an effort to facilitate the efficient and cost-effective conduct of high quality clinical studies and trials, DMID has centralized many of its clinical research support services, including regulatory affairs, statistics and data management, and clinical research operations and management support, and made them available to DMID-supported clinical investigators.

In general, the studies and trials supported by DMID fall into one of two categories high resource, which require a high level of support services, or low resource, which require a low level of support services. The designated resource level determines the type of clinical services and support provided by DMID, and this determination is made in consultation with DMID staff prior to study initiation.

High-resource trials generally include those that involve administration of an unapproved product, procedures that differ from standard of care, invasive procedures, or trials conducted under an Investigational New Drug (IND). For high-resource clinical trials conducted under the auspices of the LG, DMID will provide support services including IND sponsorship, data management and statistical support, and clinical site monitoring; the specific clinical support services to be provided for each trial will be determined in consultation with DMID staff.

All clinical studies and trials not designated as high-resource are considered low-resource. The LG must provide the statistics and data management support for low-resource studies and trials. DMID will not provide clinical site monitoring for low-resource studies and trials. Further discussion about the utilization of these programs by the LG can be found in Section 3, Scientific Scope.

Related to this effort, the NIAID is soliciting concurrent LGs for the following areas in companion Funding Opportunity Announcements: Leadership Group for the Clinical Research Network on Integrated Strategies to Prevent HIV Infection, Leadership Group for the Clinical Research Network on Microbicides to Prevent HIV Infection, Leadership Group for the Clinical Research Network on HIV/AIDS and HIV Associated Infections in Pediatric and Maternal Populations, Leadership Group for the Clinical Research Network on Therapeutics for HIV/AIDS, and Leadership Group for the Clinical Research Network on HIV Vaccines to Prevent HIV Infection. In addition, NIAID plans to recompete the Clinical Trials Units program, which supports the clinical research site infrastructure necessary to conduct clinical trials developed and implemented by the networks. Further information about these funding opportunities will be posted on the NIAID web site in early 2012.

Antimicrobial resistance is a global public health threat recently elevated to the top three threats identified by the WHO, and subject of numerous national and international government activities, including both the US Interagency Task Force on Antimicrobial Resistance, and the Trans-Atlantic Task Force on Antimicrobial Resistance established by the US and EU presidencies. Antimicrobial resistance is multifactorial, cross-cutting, and unavoidable. Therefore, most experts feel the best approach is an integrated program aimed at reducing the overall risk of antimicrobial resistance.

The focus of this initiative is the creation and implementation of a LG on AR. The NIAID has chosen AR for this activity in order to maximize the potential for reaching a critical mass in a top priority area. The LG must design, implement and manage a clinical research agenda that identifies the top priorities in the realm of AR in order to contribute to the knowledge base in the most important areas that drive resistance and that have the best potential for effecting gains in the reduction of resistance.

When developing the research agenda, the LG must be aware not only of the most important public health needs, but also of the current efforts and opportunities underway by the pharmaceutical and biotechnology industries, and the government (especially NIAID), in order to complement ongoing research activities and maximize the uniqueness of their contribution toward impacting the problem. All efforts should be generalizable to the US experience with AR. Efforts could include, but are not limited to:

• early clinical evaluation of new antibacterial drugs;
• comparative effectiveness or efficacy trials;
• strategy trials to optimize currently licensed antibacterials (dose, duration, need for drug) to reduce the risk of resistance;
• clinical algorithm testing strategies;
• treatment-based prevention measures;
• diagnostics testing in the context of treatment trials, epidemiologic elements, or behavioral modification;
• effective infection control programs which include surveillance for resistant organisms, outbreak investigation, and antibiotic stewardship to prevent the development and spread of resistant organisms;
• novel facilities level activities to prevent the development of resistance.

In general, performance sites for implementation of the research agenda will occur at separately awarded NIAID-supported clinical research sites. Possible clinical research sites could include the NIAID VTEUs (current sites: http://www.niaid.nih.gov/LabsAndResources/resources/dmid/resources/Pages/default.aspx) and the HIV/AIDS Network Clinical Trials Units (CTU) and Clinical Research Sites (CRS) (current sites: http://www.niaid.nih.gov/about/organization/daids/Networks/Pages/daidsnetworkunits.aspx), as well as LG affiliated clinical research sites. All network investigators must develop their clinical protocols and associated documents such as the Data and Safety Monitoring Plan in accordance with DMID standardized protocol development processes and templates (http://www3.niaid.nih.gov/research/resources/DMIDClinRsrch/ ), and must ensure that clinical trials are conducted in accordance with all Federal regulations, NIAID Clinical Terms of Award (http://www.niaid.nih.gov/researchfunding/sci/human/pages/clinterm.aspx)

and the International Conference on Harmonization ICH-E6-GCP guidelines.

Leadership Group Structure

Applications for the LG must comprise an overview component and three functional components: a Leadership and Operations Center (LOC), a Laboratory Center (LC) and a Statistics and Data Management Center (SDMC). The multi-component cooperative agreement (UM1) mechanism will be used to support the multiple components of this large-scale complex clinical research network to carry out the functions that are essential to achieving the network s clinical research agenda. Applications may include multiple PD(s)/PI(s). Submissions that do not contain the required four components will be returned without review.

The LG will be responsible for all network activities and ensure that the network’s components fulfill their respective responsibilities in the most efficient and effective manner possible. NIAID will expect the LG components LOC, LC, and SDMC to demonstrate scientific leadership, effective management and efficient utilization of resources. NIAID will require the following:

Leadership. Applications proposing Multiple PD(s)/PI(s) are permitted, but the roles and responsibilities of multiple PD(s)/PI(s) should be clearly delineated and justified in the context of the LG proposed.

Research Agenda/Scientific Priorities. The network’s clinical research agenda should be clearly articulated and directly related to other ongoing NIAID scientific activities, as outlined in Section 3, Scientific Scope. The research agenda should include at a minimum an overarching research strategy, goals and implementing actions, and types of studies anticipated. The LG is required to monitor and evaluate the need to refine and revise the network s research priorities and to actively engage researchers and AR communities within and outside of the network.

Governance and Management. Each functional LG component must establish effective communication and decision making in its areas of responsibility, identify clear lines of authority, coordinate and collaborate effectively with other components of the network and with other NIAID-sponsored networks, avoid redundancies and ensure efficiencies. Governance or management by committee is permitted as long as the structure, authority and composition of any proposed committee are clearly defined.

Each functional LG component must have staff and an organizational structure that promote the utilization of key principles of project management, including development of project plans with identification of key milestones; ongoing evaluation of projections against actual data and adjustments to project plans; and development and implementation of contingency plans. The LG should work synergistically and seamlessly with the clinical research sites in driving protocols through to completion. In addition, each LG component must establish processes to identify and resolve operational issues, including, for example, those arising from QA/QC programs, site monitoring reports, network performance evaluations and data management issues; and identify and develop training programs in its area of responsibility.

Policies, by-laws and standard operating procedures (SOPS), including a Conflict of Interest (COI) Policy, must be developed, implemented and updated by each LG component as necessary (http://grants.nih.gov/grants/policy/coi/index.htm; and http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=54). All aspects of network activities that are the responsibility of that LG component should be covered.

Resource Utilization and Allocation. Each functional LG component must ensure optimal utilization of resources and ensure that resource allocation within its area of responsibility is harmonized with current network research priorities.

Collaborative Responsibilities. The LG will be strongly encouraged to collaborate with other NIH-supported networks and other Federal and private sector clinical research programs, and to interact with government and non-government organizations and committees to effectively develop and implement a clinically relevant, interdisciplinary and cost-efficient clinical research network. Such collaborations and interactions are essential for the development and implementation of a comprehensive research agenda that utilizes the strengths, experience and expertise of the various collaborating organizations. The sharing of expertise, resources and procedures is expected in key areas, including: harmonization of laboratory resources and specimen management, and harmonization of common data elements and data entry interfaces. Examples of additional entities the LG will need to collaborate and/or communicate with include, but are not limited to: the NIAID Strategic Working Group, LG Program Officers and Project Scientists, the DMID Office of Clinical Research Affairs (OCRA), the DMID Office of Regulatory Affairs (ORA), and the other HIV/AIDS Clinical Research Network leadership groups.

NIAID Strategic Working Group (SWG). The NIAID SWG is a subcommittee of the NIAID AIDS Research Advisory Committee. The Strategic Working Group (SWG) provides expert advice on the scientific priorities of the NIAID-funded HIV/AIDS Clinical Trials Networks. In consultation with DMID, PD/PIs should attend the SWG and participate in the discussion of resource allocation.

Safety Oversight. DMID monitors safety and efficacy of all clinical trials funded by DMID. DMID monitors Phase II, Phase III and Phase IV multicenter randomized clinical trials primarily through Data and Safety Monitoring Boards (DSMBs). DMID monitors Phase I and small Phase II clinical trials primarily through Safety Monitoring Committees (SMCs) in conjunction with Independent Safety Monitors (ISMs). (http://www.niaid.nih.gov/LabsAndResources/resources/DMIDClinRsrch/pages/safetyoversight.aspx).

In addition to the Overview Component (Component 1) and to the requirements described above, the functional LG components have the following specific responsibilities:

Component 2: Leadership and Operations Center (LOC)

The LOC provides for the overall scientific and administrative leadership for the network. This requires coordination with the LC, SDMC and the network-affiliated clinical research sites. The LOC provides leadership and broad oversight of all network activities, including research concept prioritization, protocol development and implementation, and timely publication and communication of results. The LOC is also responsible for defining and implementing network governance and resource distribution policies and procedures. In addition, the LOC leads the ongoing refinement and revision of the network’s research plan, and oversees and regularly evaluates all aspects of the network’s operations and performance. The LOC also has resource allocation responsibilities described below (Section 6); ensuring efficient use of resources that support the network’s highest scientific priorities is paramount, and maximizing the unique contributions of the LG relative to other NIAID AR clinical research activities. Finally, the LOC must provide non-protocol training and mentoring for network staff.

Component 3: Laboratory Center (LC)

The LC contributes to the development of the network s research agenda, and leads the development, implementation and evaluation of the laboratory research that is essential to the successful execution of that research agenda. The LC manages and oversees relevant laboratory services, including any necessary PK services and any network specimen characterization, and provides adequate storage facilities necessary to accomplish the network s clinical research agenda, laboratory quality management programs, the monitoring and evaluation of all specialized laboratories in the network, and sharing of specimens outside the network if it becomes scientifically necessary. LC leadership fosters collaboration and harmonization of laboratory activities within the network, including clinical research site-affiliated laboratories.

Component 4: Statistics and Data Management Center (SDMC)

The SDMC will provide leadership in biostatistics, in study design, in analysis, in interpretation and publication of results, including innovative statistical methods in the field of AR, along with state-of-the-art clinical and laboratory data management systems to ensure complete, high-quality data. The SDMC must ensure the integrity of study design, data management and data analyses. The SDMC will provide data management training and education for network-affiliated clinical research sites and laboratory staff and investigators. The SDMC has a central role in standardizing and harmonizing statistics and data management activities both within the network and with other NIAID-sponsored networks as required for low resources studies. As noted above in Section 3. Scientific Scope, DMID will provide additional support services including Investigational New Drug (IND) sponsorship, data management and statistics support, and clinical site monitoring; the specific clinical support services to be provided will be determined in collaboration with DMID staff for high-resource clinical trials conducted under the auspices of the Leadership Group.

Funding to carry out the network’s clinical research agenda falls into two categories:

• Core Funds (Grant Awards)

NIAID will provide funds to the LG LOC on an annual basis in the Notice of Grant awards. These funds are to support the activities of the LG as determined by the proposed research agenda. [This should include support for clinical research and low resource clinical trials.]

• Protocol funds

For high resource clinical trials, funding may be provided by NIAID directly to the clinical research sites to support protocol participant accrual and study-related expenses. These clinical research sites could include the VTEUs and appropriate CTUs, or LG-affiliated sites.

DMID reserves the right to modify these general guidelines on a case-by-case basis.

Funding Instrument	Cooperative Agreement
Application Types Allowed	New The OER Glossary and the PHS398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIAID intends to commit up to an estimated $10 million total cost in FY 14 to fund 1 multi-component award.
Award Budget	Application budgets are limited to $10 million per year in total costs.
Award Project Period	The total project period for an application submitted in response to this funding opportunity may not exceed seven years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant organizations must complete the following registrations as described in the PHS398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• Central Contractor Registration (CCR) must maintain an active registration, to be renewed at least annually
• eRA Commons

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least4-6 weeks prior to the application due date.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS398 Application Guide.

Note that the multiple PD(s)/PI(s) option may only be used for the overall LG leader. The multiple PD(s)/PI(s) option is not available for the individual components within a UM1 multi-component application.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

It is critical that applicants follow the instructions in the PHS398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed research
• Name, address, and telephone number of the PD(s)/PI(s)
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

The letter of intent should be sent to:

Edward Schroder, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3116, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616 (for Express Mail 20817)
Telephone 301-435-8537
FAX: 301-480-2310
Email: [email protected]

Applications must be prepared using the PHS 398 research grant application forms and instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

At the time of submission, two additional paper copies of the application and five identical CDs containing all appendix material must be sent to:

Edward Schroder, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3116, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616 (for Express Mail 20817)
Telephone 301-435-8537
FAX: 301-480-2310
Email: [email protected]

All page limitations described in the PHS398 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirement:

• Follow the instructions below for page limits specific to Research Plan sections associated with each component of the application.

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions:

The following section supplements the instructions found in Form PHS 398 for preparing a multi-component grant application (UM1) and must be followed:

All applications must be submitted on Form PHS 398. The multi-component grant application should be assembled and paginated as one complete document.

See text below for page limitations associated with multi-component applications.

1. Form Page 1 - Face Page

Items 1 - 14: complete these items as instructed. This should be the first page of the entire application and all succeeding pages should be numbered consecutively.

2. Form Page 2

Using Page 2 of Form 398; provide a succinct but accurate description (abstract) of the OVERALL multi-component application addressing the major, common theme of the program. Do not exceed the space provided.

List the performance sites where the research will be conducted.

Under "Key Personnel", list the PD(s)/PI(s) of the multi-component application, followed by the Component Leaders of the functional components, and co-investigators.

3. Form Page 3 - Table of Contents

Do not use Form Page 3 of the PHS 398; a more comprehensive table of contents is needed for a multi-component application.

Prepare a detailed Table of Contents that will enable reviewers to readily locate specific information pertinent to the overall application as well as to each component. A page reference should be included for the budget for each functional component (LOC, LC and SDMC). The page location of the overall COMPOSITE BUDGET should also be indicated in the "Table of Contents."

4. Composite Budget

Do not use Form Page 4 of PHS Form 398. Instead, using the suggested format presented below, prepare a Composite Budget for All Proposed Years of Support only for the functional components (LOC, LC and SDMC). (Justification for budget elements should not be presented here but in the individual budgets of the components.)

SAMPLE TEMPLATE: Consolidated Direct Cost Budget (in thousands) for All Proposed Years of Support

Component	Year 1	Year 2	Year 3	Year 4	Year 5	Year 6	Year 7	All Years
Leadership and Operations Center
Laboratory Center
Statistics and Data Management Center
Totals

5. Form Page 5

Complete the Total Direct Cost line entries for all requested budget periods (years) and the Total Direct Cost for Entire Period of Support entry. Detailed budgets are required within the descriptions of each functional component. Also, use a second Form Page 5 to reflect the additional budget years requested. As noted above, application budgets are limited to $10 million per year in total costs.

6. Biographical Sketch Format Page

Biographical sketches of all key professional personnel for all components should be placed at the end of the application with the PD(s)/PI(s) first, followed by those of other key personnel in alphabetical order.

7. Resources Format Page

Essential information is to be presented in each functional component section of the application.

8. Component 1: Research Overview (Total page limit is 30 pages)

Specific Aims (Limit 1 page). Describe the specific scientific aims of the network.

Research Background and Objectives. Provide a brief history and background of the field of clinical research in AR, including a discussion of knowledge gaps and future opportunities, and briefly summarize the proposed scope of research of the network.

Research Agenda and Strategies.

• Clearly describe a comprehensive clinical research agenda that includes proposed low and high resource clinical studies and trials focused on AR, identify which objectives are the highest priority, and their significance to the field, and the anticipated contributions during the period of award.
• Explain how the proposed research agenda is innovative.
• Include specific strategies/approaches/clinical products or combinations that are considered meritorious for future evaluation and explain how such evaluations will advance the field.
• Provide milestones and timelines for completing key studies.
• Provide preliminary data/documentation of the feasibility of the proposed approaches.

Overall Scientific Priorities and Scientific Prioritization and Decision Making.

• Provide a summary of the proposed approach(s) to making high level scientific and management decisions for the network overall; include research prioritization, reassessment and redirection, involvement of key stakeholders, and how these decisions will be linked to cost effective management of network resources.
• Explain how the environment at the applicant institution will contribute to ensuring synergism among the LG components and a flexible network capable of responding to new scientific opportunities.

Proposed Network Leadership Group, Network and Cross-Network Integration. Provide a broad summary of the LG components. Include:

• A description of the roles and responsibilities of the network Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)), and, if designated, multiple PD(s)/PI(s), and the experience of each in leading and managing clinical research focused on AR.
• An organizational chart(s) showing personnel with time commitments for each leadership or decision-making position in the LOC, LG and SDMC, and how they will relate to each other.
• A description of the proposed approach to integrating all network components (Leadership and Operations Center, Laboratory Center, and Statistics and Data Management Center), and plans for coordinating with the clinical research sites and affiliated laboratories. Highlight structures that demonstrate how the proposed approach will facilitate efficient decision-making and the ability to effectively drive protocols through to completion. Point out any innovative aspects of the proposed organizational and management approach.
• Plans to ensure adequate representation of early career investigators, and diverse investigators of both genders.
• A description of the proposed approach to integrating with other networks in areas of shared responsibility.

Network Governance. Describe in detail the plans for overall network governance and management and the LOC structure. Tables, diagrams, flow charts and organizational charts are strongly recommended. This section should include, but is not limited to, the following:

• Detail the lines of authority; decision making processes; the processes and timelines for establishing by-laws, policies and standard operating procedures; any proposed governance/decision making committees and their authorities, and key personnel (level of effort, experience/qualifications) involved in key network-wide governance steps and/or committees.
• Describe how the utility and continued need for governance/decision making committees will be evaluated and, if necessary, committee restructuring or abolishment accomplished, and how the need for additional network committees will be assessed and formed or adapted.
• Name only staff and investigators supported by the LOC, LC and SDMC
• Detailed by-laws, policies and standard operating procedures should not be included in the application but must be provided to NIAID within 90 days of issuance of the Notice of Award.

Network Annual Meetings. The LG will meet at least annually or as needed to share scientific and programmatic information; to assess scientific progress; and to identify new research and development opportunities and potential avenues of collaborations. Requested budgets must include funds for travel by the PD(s)/PI(s) and key personnel to an annual meeting.

Communications and Collaborations. Provide proposed network communication and collaboration plans, including the roles and responsibilities of involved individuals, for ongoing interactions with other NIAID-supported clinical research networks or other potential collaborators. Provide a plan delineating how DMID Program Officers and other program staff responsible for facilitating the work conducted by the networks will be integrated into network activities.

Applicant Accomplishments. Describe previous experience in leading clinical trials of similar scope and complexity in the area of AR, including: (i) key contributions to the field, (ii) scientific strengths, and (iii) areas for improvement. In addition, describe collaborations established and implemented with other clinical trials and/or other clinical researchers, their value to the field, and any innovative scientific or administrative approaches undertaken.

Experience. Describe the relevant experience of LOC leadership in overseeing a clinical research leadership and operations group. Describe previous experience and performance in providing leadership and operations in managing antibacterial clinical research. In addition, identify any innovative approaches taken in the oversight of a complex clinical research network.

LOC Structure and Management Plan. Provide a plan for the structure and management of the day-to-day operations of the LOC. Include the following:

• A description of the organizational structure of the LOC, showing the lines of authority and decision making processes by which the day-to-day operations of the LOC will be managed.
• Identification of key personnel and a description of their management/operations responsibilities, level of commitment, training, experience and qualifications.
• A description of the role of LOC staff in communicating with and coordinating activities among the LOC, LC, SDMC, and the clinical research sites.

Future Research Directions.

Scheduled Assessments. Describe the process and frequency for obtaining external assessments of research plans and priorities. Include proposed methods/processes to be used to obtain input from the network investigators and the scientific community external to the network, including related NIAID networks. Do not name anticipated advisors; rather, list areas of expertise that will be sought, frequency of meetings, etc.

Reactive Assessments. Research priorities may shift considerably when results of major studies become known, or when new interventions become licensed and/or standard of care changes. Describe the approaches to assessing the need for major shifts in research priorities; any major shifts anticipated during the period of award; how the network will respond rapidly to major shifts in research priorities; and how the identified research will receive the appropriate scientific and operational support as related to the evolving research agenda.

Prioritization. Describe how specific research concepts that address the network’s research agenda will be solicited, reviewed and prioritized according to the research agenda. The proposed process should include plans for the solicitation and evaluation of research concepts from investigators within the network, including clinical research sites, and from investigators outside the network. Include the criteria to be used to assess the scientific merit and feasibility of the specific concepts.

Protocol Development and Implementation. Explain how performance will be managed using key principles of project management, including the processes and procedures to ensure that protocols are developed, initiated and completed on schedule, the roles and responsibilities of staff of the LOC, LC and SDMC and clinical research sites, and how the LOC will foster synergism among network components.. This should include, but is not limited to, the following:

Protocol Development. Describe the proposed approach to developing approved research concepts into protocols. Include descriptions of the following:

• How protocol development project plans, including identification of milestones and go/no go criteria and contingency plans will be developed,
• How the project plan will be monitored, including ongoing evaluation of projections against actual data and adjustments to project plans
• How decisions at each step in the protocol development process will be made and how decisions will be communicated to protocol teams, clinical research site investigators, collaborating entities and NIAID.
• The nature and process for interacting with representatives from the pharmaceutical industry to engage them very early in the protocol development process so that access to study product(s) is ensured.
• Plans for ensuring adherence to DMID standardized protocol development processes and templates (http://www.niaid.nih.gov/labsandresources/resources/dmidclinrsrch/Pages/default.aspx).
• How ancillary studies will be considered, approved, and integrated into the primary protocol, and managed during the protocol development process.

Protocol Implementation. Describe the proposed approach to protocol implementation. Specifically address the following:

• Critical Protocol Implementation Milestones. Describe how the network will identify and ensure adherence to critical milestones for protocol implementation, including the process for ongoing evaluation of projections against actual data. List the expected critical milestones for protocol implementation. Describe the consequences of missed milestones.
• Plans for Modifying Protocol Implementation Milestones and Timelines. Discuss how the network will develop and implement contingency plans, adjust funding when needed, and modify timelines and milestones to address unanticipated issues and how the effects of those modifications will be managed within the protocol team and across inter-network collaborations, where applicable.
• Clinical Research Site Selection. Describe the network s proposed process for selecting clinical research sites to implement specific protocols, conducting feasibility assessments, including how site capacity, capabilities, and needs will be assessed prior to the provision of protocol funds.
• New Clinical Research Sites/Venues. Describe how the network will solicit, review and support new protocol-specific clinical research sites and/or new venues, such as randomized communities, in instances where the existing clinical research sites are inadequate to implement and complete a specific protocol.

Fast Tracking of High Priority Protocols. Provide a description of the proposed process for fast tracking both the development and implementation of high priority protocols and managing the impact on other protocols.

Clinical Research Site Management and Oversight of Protocol Funds

Roles and Responsibilities. Provide a proposed structure for the overall financial management of network resources, including establishing consortium agreements with network-affiliated clinical research sites. Include lines of authority; decision making and management processes; and key personnel with level of commitment and a description of specific financial management roles and responsibilities, training, experience and qualifications. In addition, identify any innovative aspects in the proposed processes that are expected to result in savings of time and/or resources.

Policies and Procedures. Describe the policies and procedures that will be used to determine the distribution of core funds, monitor expenditures and communicate with the clinical research sites.

Overview of Clinical Research Sites. Describe the types of clinical research sites needed to accomplish the network’s research agenda in the first year; include the capacity requirements, the nature of the populations to be recruited and any other information pertinent to ensuring the network has access to clinical research sites needed to accomplish its first year research agenda. Describe the process and criteria by which clinical research sites will be selected to participate in specific protocols.

Protocol-Specific Training and Assessments. Describe protocol-specific training procedures. Include the source(s) of training; general format; plans for monitoring training needs; and how the need for retraining will be identified and implemented, if required.

Reassessments. Provide a plan for the ongoing reassessment of the capabilities, needs and performance of clinical research sites and how this process is supported by quality management planning and guidance from LOC staff. In addition, provide contingency plans and decision trees for shutting down or reducing clinical research site participation in a specific protocol.

Protocol-Specific Clinical Research Sites. Describe the policy and procedures for notifying the clinical research sites and NIAID of the site’s impending close-out, as well as the specific close-out procedures upon completion of protocol-specific activities.

Network Evaluation, Improvement and Training/Mentoring Plans. Describe in detail how the overall performance of the network will be evaluated and improved over the course of the award period. Explain the roles and responsibilities of staff of the LOC, LC and SDMC and clinical research site investigators but do not name investigators other than those supported by the LOC, LC or SDMC. Identify any innovative aspects to the proposed processes. Include the following:

Evaluation. Describe proposed policies, methods and approaches for evaluating the operational performance of the network as a whole, the clinical research sites, and each Leadership Group component (i.e., LOC, LC and SDMC) in the conduct of network and inter-network studies. Include distinct and measurable criteria for assessing performance; the LOC group(s)/individuals responsible for carrying out the evaluations showing level of commitment and describing training, experience, and qualifications; the process by which the evaluations will be conducted (e.g., site visit, questionnaire, etc); and the frequency and timelines for the conduct and completion of evaluations.

Problem Resolution and Improvement Plans. Describe proposed processes for the identification and resolution of performance problems for all network components, including the LOC, LC, SDMC, committees, protocol teams and clinical research sites and local laboratories, and proposed processes for the development of remediation/improvement plans to avoid the identified shortcomings in the future. Include the following:

Training and Mentoring.

Training. Describe how non-protocol-related training needs for network staff will be determined and provided, how value and effectiveness of training conducted will be reviewed and evaluated periodically, and how necessary changes in training programs/approaches will be decided and implemented.

Mentoring. Describe the mentoring process for early stage investigators (ESIs) and clinical research site PD(s)/PI(s) who have not previously worked in a network.

Describe previous relevant research experience and the anticipated scientific contributions of the proposed LC to implementing the research agenda of the network. This includes, but is not limited to, the following:

Relevant Experience and Scientific Contributions.

• Provide a summary of the experience and expertise of the laboratories and investigators proposed to be part of the LC.
• Provide documentation to clearly demonstrate the importance and contributions of the proposed LC components to accomplishing the clinical research objectives.
• Identify any innovative approaches for the provision of laboratory support services.

Research Strategy and Methodologies.

Research Contribution. Discuss how the LC will be integrated into the research agenda of the clinical trial network and synergized with other components to achieve network goals. Include a general description of the role of LC in protocol design and implementation, data analysis and publication. Identify any proposed innovations in the LC’s approach.

Protocol testing. Discuss the approach to making decisions on the selection of specialized assays, procedures, and analyses for performance of protocol-specified testing. Highlight any novel or innovative assays that are in place.

Laboratory Assessment. Describe the approach the LC will use in ensuring ongoing quality of all laboratory assays.

New Assay Development. Describe how new assays will be assessed and implemented for use with clinical specimens from network trials if their use is warranted. Describe any innovative assays that will be developed. Since some clinical trials may require the use of assays and test methods not approved by the US Food and Drug Administration (FDA) (e.g., international trials where FDA-approved tests are not available in some countries, but similar non-FDA-approved tests are available), describe how decisions will be made on the use of new and non-FDA-approved test methods in IND and non-IND trials.

Ancillary Studies. Given that important scientific questions can sometimes be answered through laboratory-centered ancillary studies, which are not included as part of any protocol, provide the following:

• A description of the significance of ancillary studies to the network and how such studies might advance the scientific field. Include examples of scientific questions that could potentially be addressed through network-approved ancillary studies, including any innovative approaches that might be used.
• A description of the LC’s approaches for conducting ancillary studies using pre-existing stored samples when available from network clinical trials.

Organizational Structure.

• Describe the overall LC structure, identifying the number and types of laboratories and repositories that will comprise the LC. A diagram showing the roles and relationships of each laboratory and repository is recommended. Describe the roles and significance of each laboratory, pointing out any synergisms, how the environment(s) will contribute to the success of the LC, and any innovative aspects of the proposed structure.
• Provide a LC staffing plan, identifying key personnel and providing descriptions of duties and responsibilities, a short summary of relevant training, experience and expertise, and time commitment. An organizational chart with key positions and the names of individuals who will hold those positions, if known, is highly recommended.
• Describe the approach to LC committees, including the structure and roles of each proposed committee and the procedures for establishing new committees and disbanding those that are no longer needed.

Do not include names of committee members from outside the LOC, LC and SDMC.

Quality Management.

• Describe network laboratory quality management procedures. Include general quality assurance (QA) and quality control (QC) procedures, as well as LC requirements for external quality assurance (EQA), validations, reference range studies and laboratory audits.
• If new assays require development of alternative EQA programs, describe the processes for determining alternative EQA needs and their development and implementation. Highlight any proposed innovative approaches to alternative EQA.

Evaluation and Improvement.

• Describe the process, metrics, and frequency for evaluating the entire LC effort. Provide information on how laboratory productivity, structure and activities will be evaluated, and include the process for obtaining external evaluation from DMID and from the scientific community. Do not include names of external advisors.
• Describe the problem resolution process as it relates to LC laboratories that do not meet or maintain required quality standards.

Clinical Research Site-Affiliated Laboratories: Relationships and Assessments. Describe the procedures and interactions among laboratories, network components and clinical sites for performing routine, non-specialized testing, collecting and processing specimens when necessary, and shipping to one of more laboratories within the LC for specialized testing or to a repository for storage.

Describe the previous relevant research experience and the anticipated contributions of the SDMC to implementing the research agenda of the network and providing statistics and data management support to proposed clinical studies and low resource clinical trials. This includes, but is not limited to, the following:

Relevant Research Experience and Scientific Contributions.

• Provide a summary of all relevant experience and expertise of the key personnel in this area with other networks or research groups, particularly in connection with cutting edge statistical research and the development, validation and utilization of data systems designed to support research in the AR area.
• Document scientific contributions to clinical research.

Research Strategy and Technical Capabilities. Describe the roles and responsibilities of SDMC staff in clinical research activities, including, but not limited to, the following:

• Protocol design and development, SAP development and implementation, preparation of data summaries (within and across protocols), and publication of results. Include a description of the milestones and timelines that will be used to ensure timely provision of data sets, tables and figures and publication of results.
• Development of data collection systems, forms and formats, as well as generic and protocol- specific instruments (paper and/or electronic), including items such as case report forms, questionnaires, electronic laboratory data, and other data collection tools. Identify any innovations in statistical methodologies or in adapting database systems and structures to accommodate network needs and potential multi-network and other collaborations.

Data Management Plans and Systems. Provide a plan for managing data generated in the context of research studies carried out in the network. This includes, but is not limited to, the following:

• A description of the data system and its components, their individual and integrated functional capabilities, and the method(s), requirements and compliance of data coding activities.
• A description of the processes (e.g., paper and/or electronic) that will be used to collect and manage data generated at clinical research sites, clinical laboratories and central network laboratories, including a description of how datasets will be transmitted, collated, reconciled and merged for purposes of efficient and valid analysis.
• A discussion of the day-to-day procedures that will be used to ensure data quality and validity (QA/QC), including the processes and proposed timelines for querying and resolving data discrepancies or irregularities or acquiring missing data. A description of the SDMC policies and plans to ensure the security and integrity of data and data systems at the SDMC and during the transmission of data from and to external systems, including the DMID clinical support contracts.
• A discussion of applicability and utilization of current and future data management standards and/or harmonization across protocols and with different collaborators.

Overall Organizational Structure. Describe the overall SDMC structure. Discuss how the statistics and data management staff will interface in a synergistic manner within the SDMC as well as with other network components, and provide a detailed description of the lines of authority. Inclusion of a diagram showing the roles and relationships of the statistics and data management staff within the SDMC and with other network components is encouraged.

Statistics Staff.

• Describe how the statistics staff is organized.
• Describe the duties, responsibilities, experience, expertise and time commitment of key staff. Define those staff with responsibility for contributing to the identification and resolution of statistics issues and those staff with data analysis responsibilities.

Data Management/IT Staff.

• Describe how the data management staff is organized.
• Describe the duties, responsibilities, experience, expertise and time commitment of key staff. Define the staff with responsibility for contributing to which data management decisions and functions.
• Describe the roles and activities of IT staff involved in the development and maintenance of computer programs and systems.

Management and Governance.

• Describe requirements and processes for development and implementation of SDMC SOPs. Do NOT include SOPs in the application package.
• Describe how personnel assignments will be made to ensure network needs are met in a timely manner.
• Discuss the approach to making decisions on the assessment and adaptation of new data management or statistics methods, procedures, designs or tools by the SDMC if and when warranted, including how decisions will be made on the level of validation required.
• Describe how decisions will be made for setting and adhering to timelines and consequences for failure to meet established timelines.
• Describe approaches to be used for establishing and maintaining cost efficiency, and explain why this approach was selected.
• Describe any committees proposed for use in the conduct the business of the SDMC, including structures and roles. Provide procedures for assessing the need for new committees, selecting committee members, and disbanding committees. DO not include names of committee members outside the LOC, LC and SDMC.

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS398 Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS398 Application Guide.

Part I. Overview Information contains information about Key Dates.

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS398 Application Guide.

Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be received on or before the due dates in Part I. Overview Information. If an application is received after that date, it will not be reviewed.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

Review of Individual Components:

Reviewers will evaluate the Overview/Scientific Strategy, Leadership Operations Center, Laboratory Center and Statistics and Data Management Center sections of the application first, providing overall impact scores for each section. The criteria to be applied are:

Component 1: Overview

• Are the proposed clinical research agenda and scientific priorities meritorious, innovative, feasible and flexible to address developing scientific opportunities?
• Is there an appropriate and clear organizational structure for the LG?
• Are the management and communication plans adequate to manage, support and track protocol development and implementation, communicate with DMID, and achieve the goals of the LG?
• Are there adequate lines of authority and a strong, feasible and fair governance plan for the LG?
• Are there appropriate and feasible procedures to measure and assess the productivity of the LG overall and each component individually?

Component 2: Leadership Operations Center

• Is there an appropriate plan for management of day-to-day operations, for evaluation of outcomes and prioritization and re-alignment of the scientific agenda in response to changing needs and unexpected findings?
• Are plans to apply key principles of program management to protocol development and implementation in place?
• Has the applicant proposed an appropriate CRS network including establishment of appropriate sites and management of funds across the sites?
• Are training and mentoring plans appropriate?

Component 3: Laboratory Center

• Are there strong, meritorious and appropriate plans for the assessment and implementation of new assays and technologies?Are the proposed number, type and location of laboratories adequate and appropriate to meet network research plans and will they allow for the sharing of specimens outside the network if it becomes scientifically necessary?
• Do the proposed laboratory services demonstrate scientific and technical merit, appropriateness and feasibility especially with respect to the facilities, staff, standard operating procedures, plans for laboratory data management, and specimen tracking?
• Are there strong, meritorious and appropriate plans for laboratory QA/QC, including plans for adherence to guidelines of regulatory agencies and for participation in external quality assurance programs?

Component 4: Statistics and Data Management Center

• Are there strong, meritorious, appropriate and feasible plans, procedures and equipment for providing all data management services required by the LG, including database design, security, confidentiality and administration, participant randomization/registration, data collection, quality control, data retrieval, report generation, and site training?
• Are there strong, meritorious, appropriate and feasible plans and procedures for planning and conducting interim and final analyses of clinical studies and for strict maintenance of blinding throughout the study?

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, an application that by its nature is not innovative may be essential to advance a field. The scored review criteria should be applied to the overall Leadership Group Application taking all required components into account.

Significance

• Does the project address an important problem or a critical barrier to progress in the field?
• If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved?
• How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
• Will the proposed clinical research agenda address the current and future US public health needs in the scientific area of AR?

Investigator(s)

• Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project?
• If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training?
• If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)?
• If the project is collaborative or multi-PD(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the network?
• Do the proposed PD(s)/PI(s) and key personnel have adequate time commitments, experience and vision for the design, coordination and direction of the LG and its various components?
• Is there adequate and appropriate leadership in biostatistics, clinical systems, study design, data analysis, data management, and result interpretation to ensure complete and high quality research data?

Innovation

• Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions?
• Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense?
• Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

• Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project?
• Are potential problems, alternative strategies, and benchmarks for success presented?
• If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?
• If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?
• Are the priorities clear and appropriate?
• Does the overall plan for operations of the LOC, LC and SDMC provide a suitable approach for scientific and administrative leadership of the network?
• Are research concept prioritization, protocol development/implementation and general governance procedures well thought-out and appropriate?
• Are procedures for harmonization and quality management properly addressed?

Environment

• Will the scientific environment in which the work will be done contribute to the probability of success?
• Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed?
• Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Impact-Overall Application (LG Network)

Reviewers will provide an overall impact/priority score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the component proposed). The overall impact evaluation for the entire application should take the individual review criterion assessments into account. In addition, reviewers should address:

• Is the Leadership Group application as a whole scientifically compelling?
• Do the overall proposed research agenda, structure and management plan for the clinical research network have a likelihood of shifting treatment paradigms so as to reduce the threat that AR will erode our ability to treat bacterial infections?
• Does the plan presented competently address the stated purpose and scientific scope of the solicitation with appropriate integration of existing DMID resources outlined therein?
• Is the plan for the three centers likely to result in synergy among the centers and harmonization of laboratory and data management procedures across research sites?
• Do the LG PD(s)/PI(s) have experience leading a multidisciplinary team and demonstrate the ability to establish and manage administrative functions across multiple sites?
• Do the LG PD(s)/PI(s) have the leadership and scientific ability to develop an integrated and focused network operation?
• Will the LG PD(s)/PI(s) devote adequate time and effort to the network operations?
• Are the administrative plans for the management of individual components, including plans for resolving conflicts and setting priorities, appropriate?

As applicable for the component proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed component involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

As applicable for the LG proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Institute of Allergy and Infectious Diseases,, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact/priority score.
• Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center and will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Allergy and Infectious Diseases Council l. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Resource Sharing Plan.

The NIAID reserves the right to conduct site visits or reverse site visits prior to award when deemed essential.

After the peer review of the application is completed, the PD(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

PD(s)/PI(s) of the Leadership Group will have primary responsibility for the overall performance of the network, including, but not limited to:

• Identifying and implementing a clinical research agenda that addresses AR scientific priorities.
• Participating in the design, conduct, analysis, and publication of clinical trial research.
• Collaborate and promote inter network interactions.
• Establishing policies and procedures for decision-making that are adaptable to changing research activities over time.
• Providing by-laws, policies and standard operating procedures to the DMID Program Officer within 90 days of issuance of an award, to include, at a minimum, the following:
  • A Conflict of Interest (COI) Policy consistent with NIH policy and FDA regulations (21CFR54);
  • Procedures to assure compliance with DAIDS Clinical Research Policies and Standard procedures and to ensure adequate protection of the rights and safety of subjects involved in the research; and
  • Description of lines of authority and communication within the network

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• Program Official and Project Scientist. NIAID staff assistance will be provided by a DMID Program Officer who may serve as a Project Scientist along with other NIH staff. These staff will be identified at the time of award and their roles and responsibilities will be addressed in the Notice of Grant award. These NIAID staff members will have substantial scientific/programmatic involvement during the conduct of this activity through provision of technical assistance, advice and coordination above and beyond the normal program stewardship role for grants:
  • Assure that network research efforts are consistent with that of the NIAID agenda for AR clinical research, and complement those of other NIH and NIAID programs;
  • Facilitate coordination among the NIAID- and other NIH-supported clinical trials networks, and research groups, and other U.S. Government agencies promoting collaborations and facilitating information exchange;
  • Communicate the NIAID scientific priorities;
  • Serve as members of protocol teams;
  • Track protocol development, implementation, and study conduct;
  • Participate in meetings, training activities, and conference calls;
  • Serve as resources for scientific and policy information;
  • Share information regarding promising new agents, strategies, and developments when appropriate;
  • Identify scientific gaps and organize meetings to facilitate exchange of scientific and regulatory information, including during network meetings;
  • Periodically conduct an independent review of the constituent parts of the network for reliability and compliance with clinical and regulatory requirements;
  • Oversee contract resources that facilitate the provision of investigational agents or to meet needs identified by the SWG or other advisory bodies;
  • Participate on scientific committees as a voting member;
  • Participate in the presentation of research results, including publications;
  • Monitor medical progress of clinical trials;
  • Hold responsibility for disposition of serious adverse events (SAEs)
• Clinical Trials Agreements. NIAID will serve as a liaison between pharmaceutical companies (or other providers of investigational agents) and network investigators, and will lead the negotiation of Clinical Trials Agreements (CTAs).
• Trial Sponsorship. NIAID will have the option to independently file an IND on investigational agents or an IDE on investigational devices evaluated in NIAID-supported clinical studies. NIAID will advise the investigators on the specific regulatory requirements for IND/IDE sponsorship. In situations where NIAID is the IND sponsor, NIAID through its contractors will also assemble, review, and submit the required regulatory documents to the FDA. When holding an IND or IDE, NIAID has responsibility for the data management and reporting of safety information in accordance with FDA requirements and preferences. In order to provide for consistent reporting of serious adverse experiences across the NIAID-supported clinical trial networks, NIAID will provide current policies and procedures that govern the reporting of adverse events in NIAID-supported trials.
• Pharmaceutical Support. For studies in which NIAID is the IND or IDE sponsor, NIAID staff and/or contractors will provide consultation on study treatment-related issues, including manufacturing, preparation, administration and availability of active dosage forms and placebo. NIAID staff and/or contractors may also interact with pharmaceutical company collaborators to facilitate adequate and timely supply of study product; and oversee the distribution of study product to the clinical research sites;
• Trial Monitoring. NIAID will oversee an external clinical site monitoring contract that evaluates GCP, regulatory compliance, protocol implementation, internal quality assurance, and test article accountability at the clinical research sites for high-resource clinical trials. The monitoring contractor, with or without accompanying NIAID staff, will visit the clinical research sites periodically to review selected protocols, provide training on general protocol conduct, review internal QA/QC plans, and audit pharmacies.
• Laboratory Oversight. NIAID staff and NIAID contract resources will provide oversight and monitoring of clinical research sites for GCLP and for the quality of subject diagnosis and safety tests (e.g. hematology, chemistry, liver function), as well as the quality of pharmacological tests (e.g. drug levels, drug interactions), end point tests and blood processing.
• Training. NIAID staff will provide a variety of training activities to appropriate network personnel to help the network ensure that consistent standards for protection of human subjects and clinical trial conduct and documentation are achieved across the NIAID-supported clinical trials networks. Training areas include, but are not limited to, regulatory requirements, GCP, adverse event reporting, human subject protections, informed consent, and NIAID and NIH policies and procedures.
• Protocol approval. NIAID will review and must approve all protocols. The Program Officer or designee will return comments and recommendations to the network after review. The network must address in writing all safety, regulatory, ethical, and conflict of interest concerns raised by NIAID to the satisfaction of NIAID before participant enrollment can begin. If a protocol is disapproved, NIAID will not provide investigational products or permit expenditure of NIH funds for the proposed investigation. If a protocol is not initiated within twelve months of NIAID approval, re-review and approval by NIAID will be required.
• Safety Monitoring. NIAID staff will participate in the development of appropriate safety monitoring plans for all planned clinical trials and must approve the plan for all trials involving investigational drugs, devices, or biologics and other clinical research perceived to involve more than a minimal risk. The frequency and intensity of safety monitoring will be based on individual study characteristics and past experience with study products and may require review by an Independent Safety Monitor, Safety Monitoring Committee (SMC) or Data and Safety Monitoring Board (DSMB). NIAID Medical Officers will be part of network organized protocol safety review teams to monitor the safety and efficacy of the intervention(s) for ongoing studies, and will be provided with appropriate reports. Approval of the final monitoring plan, including the composition of the review committee, by NIAID is required prior to study initiation. NIAID independently supports Data and Safety Monitoring Boards (DSMB) that oversee Phase IIb/III and other select clinical trials at the discretion of NIAID.
• Study Termination. NIAID reserves the right to terminate or curtail a clinical study for any of the following reasons:
  • risk to subject safety
  • the scientific question is no longer relevant or the objectives will not be met (i.e. slow accrual)
  • failure to comply with GCP, U.S. Federal regulations, or Terms and Conditions of Award
  • occurrence of unforeseen drug safety issues or data from preclinical studies indicate a presence of unanticipated toxicity
  • risks that cannot be adequately quantified
  • ethical concerns raised by the community or medical care/health care authorities
  • failure to remedy deficiencies identified through site monitoring
  • substandard data
  • reaching a major study endpoint substantially before schedule with persuasive statistical significance
• Data Access. The awardees retain the rights to the data, consistent with current DHHS, PHS, NIH and NIAID policies; however, NIH will have access to all data generated (raw and analyzed) and may periodically review it. This includes a review of data as recorded on the case report forms or in the central database, and external checking against the original source documentation as required by federal regulation and NIAID as the IND/IDE sponsor. NIAID may request from the network specific data analysis needed for programmatic activities or for issues related to NIAID plans with other partners. The NIH may provide public access to selected data sets generated with the use of public funds within a reasonable time after primary analysis and publication.

Areas of Joint Responsibility include:

• Research Plans. Implementing, monitoring, and updating the clinical research plan for the network to ensure consistency and relevance with the AR scientific priorities.
• Research Activities. Reviewing the network's research activities and goals on an agreed upon schedule (but no less than once every year).
• Strategic Working Group (SWG). Participating with external advisors selected by NIAID in the SWG, a subcommittee of the NIAID AIDS Research Advisory Committee, to promote optimal joint research activities among the NIAID-supported clinical trials networks when appropriate as determined by consultation with DMID. This will include maximizing use of clinical trial infrastructure and resources across networks through the coordination of plans to prevent duplication and to achieve efficiency and economy; and ensuring exchange of current information on the status of protocol development, study conduct and future plans across networks.
• Quality Assurance (QA) and Quality Control (QC). NIAID staff, NIAID contractors and the LC will collaborate in providing quality assurance and oversight for network-specific tests. Oversight will include assessment of laboratory ability, readiness and capacity to participate in NIAID study protocols; provision of training and trouble-shooting; and assistance in implementing general and study-specific QA/QC measures. When external proficiency testing programs do not exist for study-required tests, the NIAID, NIAID contractors and the LC may design and implement tools to evaluate the ability of laboratories to perform such tests, develop criteria for acceptable performance and determine consequences for unacceptable performance.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: [email protected]

Carolyn Deal, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone : 301-402-0443
Email: [email protected]

Edward Schroder, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-435-8537
Email: [email protected]

Victoria P. Connors
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-402-5065
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.