Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Allergy and Infectious Diseases (NIAID)

Funding Opportunity Title

Collaborative Network for Clinical Research on Immune Tolerance (UM1)

Activity Code

UM1 Multi-Component Research Project Cooperative Agreements

Announcement Type

New 

Related Notices

None

Funding Opportunity Announcement (FOA) Number

RFA-AI-12-043

Companion Funding Opportunity

None 

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.855; 93.856 

Funding Opportunity Purpose

The purpose of this FOA is to solicit applications for the Collaborative Network for Clinical Research on Immune Tolerance.  The major goal of this Network is to develop new tolerogenic approaches for the treatment and prevention of disease in three clinical areas: asthma and allergic diseases; autoimmune diseases; and immune-mediated rejection of transplanted solid organs, tissues and cells.  The scope of research to be carried out includes: 1) the design and conduct of clinical trials at all phases to evaluate the safety and efficacy of investigational products and approaches for the induction and maintenance of immune tolerance in humans; 2) the design and conduct of mechanistic studies and the development of tolerance assays as integral components of the clinical trials undertaken, including establishing and directing a consortium of laboratories; and 3) the provision of bioinformatics, data collection, validation and analysis resources.  In addition, on a limited basis, the Network may support focused product development and nonclinical studies (e.g., toxicology, pharmacology, pharmacokinetics, etc.) essential for the subsequent evaluation of promising tolerance induction approaches in humans.

Key Dates
Posted Date

November 5, 2012

Letter of Intent Due Date(s)

February 7, 2013

Application Due Date(s)

March 7, 2013   

AIDS Application Due Date(s)

Not Applicable 

Scientific Merit Review

July, 2013   

Advisory Council Review

October, 2013 

Earliest Start Date

December, 2013 

Expiration Date

March 8, 2013 

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS 398 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.

Looking ahead: NIH is committed to transitioning all grant programs to electronic submission using the SF424 Research and Related (R&R) format and is currently investigating solutions that will accommodate NIH’s multi-project programs. NIH will announce plans to transition the remaining programs in the NIH Guide to Grants and Contracts and on NIH’s Applying Electronically website.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The purpose of this FOA is to solicit applications for the Collaborative Network for Clinical Research on Immune Tolerance (hereinafter referred to as 'Network').  The major objective of the Network is to develop new tolerogenic approaches for the treatment of disease in three clinical areas: asthma and allergic diseases; autoimmune diseases; and immune-mediated rejection of transplanted solid organs, tissues and cells.  The scope of research to be carried out by the Network includes: 1) the design and conduct of clinical trials at all phases to evaluate the safety and efficacy of investigational products and approaches for the induction and maintenance of immune tolerance in humans; 2) the design and conduct of mechanistic studies and the development of tolerance assays as integral components of the clinical trials undertaken; and 3) the provision of bioinformatics, data collection, validation and analysis resources.  On a selective basis, the Network may also support limited product development and nonclinical studies (e.g., toxicology, pharmacology, pharmacokinetics, etc.) essential for the subsequent evaluation of promising tolerance induction approaches in humans.  For the purpose of this FOA and the resulting grant award, immune tolerance is broadly defined as a selective elimination of pathogenic immune responses to relevant antigens (e.g., alloantigens, autoantigens or allergens) by any of a variety of approaches, including deletion, induction of anergy, immune deviation, sequestration, or suppression, while preserving protective immunity and does not require ongoing treatment with the intervention.

Network Structure:  The Network will consist of multiple functional elements to carry out the broad scope of research delineated above.  These components include:

Leadership Group – with responsibility for:  1) scientific planning and priority setting; 2) soliciting and evaluating proposed research projects and determining those projects to be supported; 3) directing and managing the implementation of approved research projects; 4) establishing and implementing collaborations with other Federal and non-Federal organizations/institutions for the co-sponsorship of research in areas of mutual interest; 5) establishing and implementing industry collaborations for the evaluation of specific products/approaches; and 6) planning and directing the technical, operational, administrative and fiscal aspects of the Network’s activities.

Clinical Operations Group – with responsibility for clinical site assessments and other pre-study initiation requirements, assistance in the development of clinical protocols, and study implementation and monitoring.

Core Laboratory Group – with responsibility for the conduct of mechanistic studies and the performance of tolerance assays to assess the induction, maintenance and loss of tolerance.

Bioinformatics Group – with responsibility for establishing and maintaining a data management system for the collection, storage, archiving and exchange of mechanistic data, and integration of mechanistic and clinical data derived from the Network Statistical and Data Coordinating Center, and for conducting analyses of such data across Network clinical trials and mechanistic studies.

In addition, the Network will function as a cross-disciplinary, open consortium with proposals for clinical trials and integrated mechanistic studies accepted from investigators both within and outside of the Network’s infrastructure and with support provided to Network and non-Network institutions and researchers.

Background

The successful induction of immune tolerance is a major therapeutic goal for the treatment of immune-mediated diseases, including asthma and allergic diseases; autoimmune disorders, such as rheumatoid arthritis and type 1 diabetes; and immune-mediated rejection of transplanted solid organs, tissues, and cells.  Tolerance induction strategies aim to selectively block or prevent deleterious immune responses, while leaving protective immunity intact.  More than two decades of highly intensive and productive basic research in immunology have provided a solid foundation of knowledge and understanding that will enable the application of promising tolerance induction strategies to the treatment of immune-mediated diseases and transplantation, and enhanced understanding of the underlying mechanisms of disease and therapeutic effect.

Asthma and allergic diseases are among the major causes of illness and disability in the U.S., affecting nearly 1 in 5 Americans.  Asthma afflicts over 24 million Americans or 8.2 percent of the U.S. population; chronic sinusitis afflicted 12.9 percent of Americans age 18 and older in 2009; and food allergy was reported to afflict 3 million children under the age of 18 in 2007.  In asthma and allergic diseases, the goal of tolerance research is to develop methods to block immune responses, especially allergic (IgE) responses, to allergens such as cockroach, house dust mite, and peanut that cause or exacerbate these diseases.  Autoimmune diseases are chronic disabling disorders in which underlying defects in the immune response lead the body to attack its own organs and tissues.  More than 80 autoimmune diseases have been identified and, for reasons that are not clear, the prevalence of these diseases is rising.  Collectively, autoimmune diseases affect approximately 14-22 million people in the U.S., and represent a significant physical, emotional, social, and fiscal burden for patients and their families and to society.  These diseases can affect any organ or organ system, and all ages are affected, with onset from childhood to late adulthood.  In autoimmune diseases, novel approaches to block immune responses that cause the body to mistakenly attack its own organs, tissues, or cells are evaluated.  The benefits of organ transplantation, as evidenced by prolonged survival and/or improved quality of life, have been clearly demonstrated for children and adults suffering from a wide range of congenital and acquired diseases.  In 2011, 30,986 transplants were performed in the U.S., with 14,146 organ donors; in 2011, there were 113,237 candidates on the transplant waiting list.  Although one-year survival after transplantation has improved markedly for every organ, barriers to long-term graft and patient survival include incompatibility between donor and recipient, acute rejection, chronic graft dysfunction, and complications of long-term use of immunosuppressive drugs.  In transplantation, donor-specific immune tolerance - a selective blockade of immune responses directed against the graft - would enable long-term graft survival without the complications and risks of systemic immunosuppressive therapy (e.g., infection, malignancy, and atherosclerosis).

The NIAID has a long-standing commitment to supporting basic, translational and clinical research on immune tolerance with the ultimate goal of developing novel, efficacious therapies for the induction and maintenance of antigen-specific immune tolerance in humans.  The NIAID Plan for Research on Immune Tolerance and the Report of the NIAID Expert Panel on Immune Tolerance are located on the NIAID website at http://www.niaid.nih.gov/topics/immuneTolerance/researchplan/Pages/immuneToleranceReport.aspx

In 1999, the NIAID awarded a seven-year contract to establish the Collaborative Network for Clinical Research on Immune Tolerance - a major program resulting from the scientific planning process, designed to: (1) develop a long-term scientific agenda for clinical trials and mechanistic studies; (2) design and conduct clinical trials at all phases to determine the safety, toxicity and efficacy of tolerogenic treatment strategies for multiple immune system diseases; and (3) design and conduct research to delineate the underlying mechanisms of immune tolerance as an integral part of the clinical trials undertaken by the Network, as well as clinical trials sponsored by other Federal and private sector organizations and companies.  In 2007, the contract was recompeted and expanded to include nonclinical research and product development, as well as bioinformatics, data collection and analysis.  The contract (N01-AI-15416) is currently held by the University of California San Francisco, with Dr. Jeffrey Bluestone as the contract Principal Investigator and Dr. Gerald Nepom, of the Benaroya Research Institute, as the Network Director.

Since the establishment of this Network in 1999, substantial progress has been made in evaluating diverse tolerogenic products and approaches for a broad range of immune-mediated diseases, enhancing our understanding of underlying mechanisms, and assessing the induction, maintenance and loss of tolerance through multiple assays.  Achieving complete tolerance in a single human trial is quite challenging; studies that provide step-wise advances towards achieving this goal have been an important strategy in advancing tolerance research.  The Network has initiated 43 clinical trials with associated mechanistic studies, and 13 tolerance assay studies: 9 clinical trials and 3 tolerance assay studies in asthma and allergic diseases; 18 clinical trials and 8 tolerance assay studies in autoimmune diseases, with approximately 47% of each in type 1 diabetes; and 16 clinical trials and 2 tolerance assay studies in transplantation.  It is anticipated that 15 studies will be ongoing at the completion of the current contract and will be continued and completed during the new award period.  Additional information about the research activities of the current Network, publications, the status of the studies, as well as information on organizational structure and membership, may be obtained from the Network website at http://www.immunetolerance.org.

Research Scope and Priorities

Research Scope:  The scope of research to be performed by the Network includes:

Disease-specific Research Priorities:  Research priorities within each of the three clinical areas include, but are not limited to, the following:

Allergic Diseases and Asthma

Tolerance induction through innovative allergen immunotherapy strategies, including but not limited to:

Autoimmune Diseases

Immune-based approaches to restore tolerance, while preserving protective immunity, targeting T and B cell subsets and pathways, including but not limited to:

Transplantation

Tolerogenic approaches to improve long-term graft survival and decrease the rates of acute and chronic rejection, including but not limited to:

Overall Requirements

Network Structure and Governance.  The Network will consist of four functional elements: (i) the Leadership Group, composed of national and international clinical investigators and basic scientists with the full range of expertise and experience necessary to plan and direct the implementation of the Research Agenda and Strategic Plan; (ii) the Clinical Operations Group to oversee the development, implementation, and monitoring of clinical trials; (iii) the Core Laboratory Group to perform mechanistic studies and tolerance assays for all Network clinical trials/studies; and (iv) the Bioinformatics Group to collect, validate and analyze mechanistic data, and integrate these mechanistic data with clinical data.  Additional committees, subcommittees and/or functional components may be established to carry out specific scientific, technical and administrative responsibilities.  Each organizational entity must: establish and define effective communication and decision-making processes; identify clear lines of authority; establish processes to identify and resolve operational issues; and coordinate and collaborate effectively both within the Network and with other Federal and private sector research organizations/programs.  The Network should use effective approaches to project management, including project plans with identified key milestones, provide for ongoing evaluation of projections against actual performance, adjust project plans as necessary, and develop and implement contingency plans.

PD/PI Time Commitment.  The PD/PI will be required to commit not less than 3.6 person months per year to the project.

NIAID Resources.  The NIAID will provide certain contract resources to support the design, development, implementation, and monitoring of Network clinical trials and the analysis of final study data.  The Network will cooperate with NIAID contractors to ensure that clinical research complies with Federal regulatory requirements as well as NIAID policies and procedures.  These resources include:

In addition, it is anticipated that, with rare exceptions, the NIAID will serve as the regulatory sponsor for Network clinical trials conducted under Investigational New Drug (IND) Applications, Investigational Device Exemptions (IDEs), and Biologic Licensing Agreements (BLAs) with full responsibility for carrying out sponsor regulatory requirements.  The NIAID will also coordinate the activities of independent Data and Safety Monitoring Boards (DSMBs) to review final clinical protocols and interim and final study data to ensure the safety of clinical trial subjects.

Funding

The NIAID will provide funds to the Leadership Group (LG) to support personnel, consultants, and other research-related resources for:  (i) continuation and completion of ongoing clinical trials and mechanistic studies; (ii) review and evaluation of proposed research projects; (iii) study design and development for new clinical trials and mechanistic studies; (iv) new clinical trials and mechanistic studies to cover the costs associated with implementation, follow-up, and analysis of final integrated study data; and (v) centralized operational, administrative and fiscal support.

Research Agenda and Strategic Plan

Research Agenda.  The Network will develop and implement a Research Agenda to advance immune tolerance induction strategies through clinical trials and to integrate studies of underlying mechanisms of the induction, maintenance and loss of tolerance.  It is anticipated that Network research will evolve during the award period as new investigational products/approaches and developing technologies provide additional opportunities, and as findings eliminate some approaches from further consideration.  Therefore, the Network is expected to refine and revise the Research Agenda as necessary to accommodate new opportunities and expanded knowledge.

The Research Agenda will include the following:

Strategic Plan.  The Network will develop a Strategic Plan delineating standards, policies, criteria and processes for implementing the Research Agenda with respect to: (i) setting scientific priorities and refining priorities based on new opportunities and findings; (ii) identifying and integrating new clinical strategies and technologies; (iii) soliciting, evaluating and making funding decisions for proposed clinical trials, integrated mechanistic studies, and tolerance assays; (iv) assessing the productivity, continued need for, and continued relevance of approved trials/studies, and discontinuing unneeded or unproductive research projects; (v) assessing the soundness, feasibility and anticipated contributions of proposed bioinformatics projects for the analysis of combined mechanistic and clinical data; and timelines and milestones to assess success in meeting the major objectives of the Research Plan.

Leadership Group, Clinical Operations Group, Core Laboratory Group, and Bioinformatics Group

Leadership Group

The Leadership Group (LG) will be responsible for planning and directing the implementation of the Network’s research activities and for carrying out multiple technical and centralized operational, administrative and fiscal functions.  LG responsibilities include:

An Executive Committee and a Steering Committee will be established to carry out the LG functions specified below.

Executive Committee

The Executive Committee, chaired by the PD/PI, will be responsible for providing scientific leadership and overall governance of the Network, including: (i) developing the Research Agenda and the Strategic Plan for the implementation of the Research Agenda; (ii) serving as the main decision-making body and providing for the second-level of review and for the approval of recommendations for research support emanating from the Steering Committee and other organizational entities; (iii) establishing and implementing collaborations with other Federal and non-Federal organizations for support of research in areas of mutual interest; (iv) establishing and implementing industry partnerships for the evaluation of specific products/approaches in Network clinical trials; and (v) assessing the performance, productivity, continued need for, and continued value of Network-sponsored research, discontinuing unproductive/unneeded projects, and redirecting research resources as necessary to achieve the goals of the Research Agenda.

Steering Committee

Under the overall direction of the PD/PI, the Steering Committee will serve as the primary governing body for clinical trials, mechanistic studies and tolerance assays, nonclinical research and product development, and bioinformatics/data analyses.  Specific functions include: (i) developing and implementing a process for the solicitation, preparation and submission of proposals from Network and non-Network investigators, including standardized requirements, templates and instructions; (ii) conducting reviews to assess the scientific merit, soundness and feasibility of all proposed studies, including the adequacy and appropriateness of the number and capabilities of proposed clinical sites; (iii) preparing written reports to document the results of all reviews; (iv) making recommendations to the Executive Committee on support of proposed projects; and (v) directing and overseeing the implementation of approved studies, including adherence to established timelines and milestones.  Steering Committee members must represent the breadth of clinical and scientific expertise and experience necessary to:  evaluate proposals for clinical trials and mechanistic studies for asthma and allergic diseases, autoimmune diseases, and transplantation; assess the need for further nonclinical studies and product development; and determine feasibility and value of proposed analyses of combined clinical and mechanistic data.

Clinical Operations Group

A Clinical Operations Group (COG) will be established to assist investigators and institutions in the development, implementation and monitoring of Network-funded clinical trials.  Specific functions of the COG include: (i) performing detailed feasibility assessments of proposed research projects and ongoing protocols as needed and submitting documentation to the LG; (ii) participating in the preparation of draft and final clinical protocols and protocol-related documents and coordinating their review and modification; (iii) assessing the adequacy and appropriateness of the capabilities of approved clinical sites with respect to staffing, standard operating procedures, data management systems, and clinical, laboratory and pharmacy facilities; (iv) monitoring overall progress in clinical trial implementation, including clinical site performance with respect to subject screening and enrollment and the ongoing adequacy of site-specific recruitment and retention plans; (v) working with clinical site staff to address problems and deficiencies in adherence to protocol-specific requirements; and (vi) serving as the primary contact for NIAID project managers, medical monitors and regulatory affairs officers.

Core Laboratory Group

A consortium of institutions/organizations will be established to serve as the Core Laboratory Group (CLG).  Specific functions of the CLG include: (i) designing and conducting mechanistic studies and evaluations of immune/surrogate markers of the induction, maintenance and loss of tolerance as integral components of clinical trials for asthma and allergic diseases, autoimmune diseases, and transplantation; (ii) establishing and operating a repository of clinical specimens for Network-supported clinical trials and mechanistic studies; (iii) developing and implementing laboratory performance standards and metrics, including new performance standards for emerging technologies; (iv) developing and implementing standard operating procedures for the conduct of mechanistic studies and assays, including quality assurance and quality control, and timelines for generating and reporting on mechanistic data from each clinical trial; (v) developing protocol-specific instructions for clinical sites regarding the collection, storage, inventory, packaging and shipping of clinical specimens and distributing sample collection kits; (vi) collaborating in the preparation of interim and final analyses of study data; (vii) assessing and implementing new technologies and transitioning from existing to new technologies; and (viii) participating in NIAID collaborations with other Federal and non-Federal organizations to assist in the design and conduct of mechanistic studies.  All laboratories must meet Good Clinical Laboratory Practices (GCLP) or equivalent standards.

Bioinformatics Group

A consortium of multi-disciplinary experts will be established to serve as the Bioinformatics Group (BG), including experts in statistics, epidemiology, data modeling and marginal structural modeling, etc., in the context of biomedical research and, more specifically, in the context of clinical trials and mechanistic studies.  The BG will develop and operate a data management system for mechanistic study data and clinical data derived from the Network Statistical and Data Coordinating Center and conduct and/or participate in the design and conduct of data analyses.

Specific functions of the BG pertaining to the data management system include: (i) establishing and operating a system for the collection, storage, retrieval, archiving and exchange of data from Network-supported mechanistic studies, and integrating mechanistic data with clinical data derived from the Network Statistical and Data Coordinating Center, including genetic, cellular, and molecular data; (ii) utilizing open source/customizable off the shelf software for data capture, storage, query and analysis, as well as for disseminating data to the scientific community; (iii) building a scalable network and computer infrastructure to meet the needs of end users, e.g., Network staff, Network-supported investigators, and NIAID staff; (iv) creating an integrated electronic data repository of relevant scientific data for each research subject or patient sample, including clinical, laboratory and other information, in a format that permits rapid and efficient production of files for analysis, and verifying all repository data in collaboration with originating laboratories and the Statistical and Data Coordinating Center; (v) developing and implementing standard operating procedures for the collection, storage, archiving and exchange of data for participating laboratories and the Statistical and Data Coordinating Center; (vi) designing and implementing a reliable system for data quality control and system security; (vii) developing and implementing a plan for the long-term maintenance and survival of the data and the data system; (viii) documenting systems and software developed; and (ix) establishing and maintaining an end-to-end tracking system for laboratory samples with the capacity to generate audit trails and reports at any point in the process.

Specific functions of the BG pertaining to primary and secondary data analyses include: (i) providing input into the development, review and implementation of proposed studies/sub-studies, e.g., defining research questions, selecting appropriate study populations and control/comparison groups, developing innovative statistical methods, alternative study designs, and data analysis plans, assessing the feasibility of access to appropriate data for retrospective analyses, and ensuring the availability of the necessary number, type and volume of clinical samples; (ii) conducting analyses of mechanistic study data and combined clinical and mechanistic data; and (iii) participating in the preparation of manuscripts.

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New

The OER Glossary and the PHS 398 Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

NIAID intends to commit $27 million in FY 2014.

Award Budget

Application budgets are limited to $27 million per year in total costs .

Award Project Period

The total project period for an application submitted in response to this FOA 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.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

Foreign Institutions

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

Required Registrations

Applicant organizations must complete the following registrations as described in the PHS 398 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.

All Program Directors/Principal Investigators (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 least6 weeks prior to the application due date.

Eligible Individuals (Program Director/Principal Investigator)

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.

Multiple PD(s)/PI(s) are not allowed for this FOA.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

Section IV. Application and Submission Information

1. Address to Request Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the PHS 398 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.

Letter of Intent

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:

The letter of intent should be sent to:

Priti Mehrotra, M. Sc., Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases (NIAID)
Room 3138, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
For Express Couriers: 20817-1824
Telephone: 301-435-9369, 301-496-2550
Fax: 301-480-2408
Email: pmehrotra@NIAID.nih.gov

Application Submission

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 all copies of the Appendix files must be sent to:

Priti Mehrotra, M. Sc., Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases (NIAID)
Room 3138, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
For Express Couriers: 20817-1824
Telephone: 301-435-9369, 301-496-2550
Fax: 301-480-2408
Email: pmehrotra@NIAID.nih.gov

Page Limitations

All page limitations described in the PHS 398 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements for the Research Strategy Component subsections listed below:

Application Format

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

The multi-component grant application should be assembled and paginated as one complete document.

Use the table of contents and instructions below as a supplemental guide to the PHS 398 instructions to assemble the multi-component application:

ITEM

Application Package Cover Letter

Face Page (PHS 398 Form Page 1).  This is the first page of the application; number all succeeding pages consecutively.

Description, Project/Performance Sites, Senior Key Personnel and Key Personnel, Other Significant Contributors, Human Embryonic Stem Cell statement if applicable (PHS 398 Form Page 2).

Detailed Budget for Initial Budget Period (use PHS 398 Form Page 4).  See below.

Composite Budget for Entire Proposed Project Period (Do not use PHS 398 Form Page 5).  See below.

Biographical Sketch (Biographical Sketch Format Page).  Provide biographical sketches of all senior/key professional personnel for all Components at the end of the application.  Place PD/PI biographical sketch first, followed by those of other senior/key personnel in alphabetical order.

Resources (Resources Format Page).  Complete the resources available for each Component.

Research Plan:

Specific Aims (Overall)

Research Strategy

Note:  For each Component subsection below, include a Cover Page and information as described under detailed component headings.  Do not use PHS 398 Form Page 1.

Component 1:  Research Agenda and Strategic Plan

Component 2:  Concept Proposals for Clinical Trials and Integrated Mechanistic Studies

Component 3:  Leadership Group - Structure and Governance

Component 4:  Leadership Group – Assessment of Clinical Research Capacity Needs

Component 5:  Leadership Group – Collaborations and Communications

Component 6:  Clinical Operations Group

Component 7:  Core Laboratory Group – Structure and Governance, and Research Approach and Methodologies

Component 8:  Core Laboratory Group - Quality Management, Evaluation and Improvements, and Communications and Clinical Site Laboratory Capacity/Training

Component 9:  Bioinformatics Group

Bibliography and References Cited

Protections for Human Subjects

Inclusion of Women and Minorities

Targeted/Planned Enrolllment Table

Inclusion of Children

Vertebrate Animals

Select Agent Research

Consortium/Contractual Agreements

Letters of Support (e.g. Consultants)

Resource Sharing Plan

Checklist (Checklist Form Page)

Appendix

PHS 398 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.

PHS 398 Form Page 2

PHS 398 Form Page 3 - Table of Contents

PHS Form Page 4 and Form Page 5

1.  Overall Budget Assumptions:  For purposes of this FOA, propose a budget in which costs for the entire Collaborative Network for Clinical Research on Immune Tolerance program are included and consolidated within the budgets for Components 3 through 9, herein referred to as the Network Functional Components.  Costs for the entire Collaborative Network for Clinical Research on Immune Tolerance program include: (a) the continuation and completion of ongoing clinical trials and mechanistic studies; (b) the planning, conduct, and completion of new clinical trials and mechanistic studies; (c) the infrastructure and core support functions, including Network personnel, consultants and related research support resources, required to carry out and complete both new and ongoing clinical trials and mechanistic studies; and (d) study-specific costs for all participating clinical sites and mechanistic studies provided through sub-awards.  The proposed budget should be an estimate appropriate for all Network activities, and should be developed in terms of the magnitude and complexity of the current Network and based on assessments of the research to be conducted and the allocation of available resources to carry out that research.  Additional budget information will be requested just-in-time to accommodate the status and more accurate estimates of ongoing costs that will be known closer to the time of award.

Guidance is provided below to assist applicants in budgeting cost for continuation and completion of ongoing clinical trials and mechanistic studies.

2.  Detailed Budget: Use PHS 398 Form Page 4 to provide detailed budgets for the proposed direct costs for the initial budget period (first year) for each individual Network Functional Component (Components 3 through 9).

In addition, use PHS 398 Form Page 4 to provide a summary budget of all seven Network Functional Components that indicates the proposed total direct costs for the initial budget period (first year).

Place together all individual Component and summary budgets with justifications in the budget section of the application.  Do not place the individual Component budgets within each individual Component section.

Do not provide individual budgets for Component 1: Research Agenda and Strategic Plan or for Component 2: Concept Proposals for Clinical Trials and Integrated Mechanistic Studies.

Do not list individual Consortium Agreements.  Instead, under Consortium/Contractual Costs (PHS 398 Form Page 4) provide an estimate of the total sub-award costs for ongoing clinical trials and mechanistic studies based on the information provided in the website cited below and for proposed new clinical trials and mechanistic studies.  Include this estimate within the proposed budget for Component 3: Leadership Group – Structure and Governance.

3.  Composite Budget: Do not use PHS 398 Form Page 5.  Instead, use the suggested format presented below to prepare a Composite Budget for All Proposed Years of Support for the Network Functional Components 3 through 9.  Justification for budget items should be presented here and not in the individual Component sections of the application.

The total direct costs (up to seven years) for the entire Collaborative Network for Clinical Research on Immune Tolerance program (i.e., the total direct costs for Network Functional Components 3 through 9) plus Institutional F&A may not exceed $27 million per year.

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

Cost Categories         

Yr 1

Yr 2

Yr 3

Yr 4

Yr 5

Yr 6

Yr 7

All Years

Network Functional Components (Indicate Direct Costs for each Component):

Leadership Group (Component 3)

Leadership Group (Component 4)

Leadership Group (Component 5)

Clinical Operations Group (Component 6)

Core Laboratory Group (Component 7)

Core Laboratory Group (Component 8)

Bioinformatics (Component 9)

F&A Costs

Total





















4.  New Clinical Trials and Mechanistic Studies.  Costs for new clinical trials and mechanistic studies should be apportioned across the costs for the Network Functional Components.  To estimate costs for new trials and studies assume that: (a) one new clinical trial and associated mechanistic study in each of the three disease areas (total three trials/studies) will open late in the first budget year; (b) on average three to four additional new clinical trials and associated mechanistic studies will open in each of the following proposed years of support; and (c) at any given time during all proposed years of support a mixture of early and later phase studies will be in progress.

5.  Ongoing Clinical Trials and Mechanistic Studies.  Information about the required continuation and completion of ongoing clinical trials and associated mechanistic studies can be found at this website (http://www.immunetolerance.org/professionals/researchers/research/niaid-rfp).  Additional clinical trial details for these studies can be found at www.clinicaltrials.gov.  Assume that ongoing clinical trials and associated mechanistic studies at the time of award will account for approximately 80% of the total costs for the first year.  Anticipate an annual decline in support for ongoing studies at a rate of 20-25% of the previous year’s cost per year.

Include these estimated costs for ongoing clinical trials and mechanistic studies when developing the proposed budgets for the Network Functional Components.  Do not include budgets for individual ongoing clinical trials and mechanistic studies.  Do not include detailed budgets for Consortium Agreements.

Costs for ongoing clinical trials and mechanistic studies within each Network Functional Component will vary depending on where the study is in its life cycle.  For example, Network staff time and site costs might be higher earlier in a study than Network staff and laboratory costs later in a study.

Costs associated with Consortium Agreements for participating clinical sites for both new and ongoing clinical trials and mechanistic studies should be included within the proposed budget for Component 3: Leadership Group – Structure and Governance.

6.  Sub-awards Required to Support Network Activities.  The following information is provided to assist in the estimation of consortia (sub-award) capacity needed to support the Network.  The current Network manages a portfolio of subcontracts as follows: (a) since the most recent Network contract recompetition in 2007, a total of nearly 600 subcontracts have been executed, of which approximately one third consist of new subcontracts and two thirds involve modifications to existing subcontracts; (b) the NIAID estimates that there will be in excess of 300 active subcontracts at the time of the new award, which represents approximately 75% of the 80% of total costs for the ongoing clinical trial and mechanistic studies noted above for the first year; and (c) of the 300 active subcontracts, approximately 70% are to clinical sites and 30% are for laboratory and other support services.

Biographical Sketch Format Page

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

Resources Format Page

Essential information is to be presented for each Network Functional Component in the relevant Component section of the application.

Research Plan

Specific Aims (Overall):

List the Specific Aims of the Network focusing on the overall research agenda and strategic plan.

Research Strategy:

This section consists of the Component subsections 1 through 9 described below.

Component 1.  Research Agenda and Strategic PlanResearch Agenda.  Present the proposed Network Research Agenda to advance immune tolerance induction strategies through clinical trials and to integrate studies of underlying mechanisms of the induction, maintenance and loss of tolerance.  Include the following:  (i) a brief description of research strategies to induce tolerance in human clinical studies, including underlying mechanisms, and scientific opportunities relevant to the clinical application of tolerance induction strategies in human immune-mediated diseases and transplantation; (ii) a brief description of the state of current research on the identification, assessment and validation of immune/surrogate markers, existing and new techniques for measuring tolerant states and opportunities relevant to further development and improvement in immune/surrogate markers, samples and techniques, including the major sources of variability that may confound clinical applications, strategies for overcoming and/or reducing variability, and validation against acknowledged disease endpoints, as well as the use of bioinformatics tools to analyze combined mechanistic and clinical data; (iii) delineation of promising investigational tolerogenic approaches for the treatment of asthma, allergic and autoimmune diseases, and for the prevention of immune-mediated rejection of solid organ, tissue and cell transplants; (iv) a description of the immediate and long-range goals of the Network, including completion of ongoing clinical trials and mechanistic studies supported under the current Network, potential barriers to success, and potential solutions to overcome those barriers; (v) delineation of approaches to identify and capitalize on opportunities for industry partnerships to accomplish the research goals of the Network; and (vi) timelines and milestones to assess success in meeting the major objectives of the Research Agenda.

In the final section of the Research Agenda, provide a detailed description of research priorities for both clinical trials and mechanistic studies and the rationale for their selection with respect to the significance, soundness and innovation of approaches, strategies and techniques designated as high priority.  In addition, explain how the environment at the applicant institution will contribute to ensuring the effective implementation of research priorities and provide the flexibility necessary to respond to emerging scientific opportunities and integrate new and promising approaches and techniques.

Strategic Plan.  Provide a proposed Strategic Plan for the implementation of the Network Research Agenda.  Include a detailed description of standards, policies, criteria, procedures and processes for: (i) setting scientific priorities and refining priorities based on new opportunities and findings; (ii) identifying and integrating new clinical strategies and technologies; (iii) soliciting, evaluating and making funding decisions for proposed clinical trials and integrated mechanistic studies; (iv) assessing the productivity, continued need for, and continued relevance of approved trials/studies, and discontinuing unneeded or unproductive research projects; and (v) assessing the soundness, feasibility and anticipated contributions of proposed bioinformatics projects for the analysis of mechanistic data and combined mechanistic and clinical data.  Identify the proposed frequency or define the proposed time frames/milestones associated with carrying out these various functions.

Component 2.  Concept Proposals for Clinical Trials and Integrated Mechanistic Studies

Provide a total of three Concept Proposals for clinical trials and integrated mechanistic studies - one Concept Proposal for each clinical area within the purview of the Network, i.e., asthma and allergic diseases, autoimmune diseases, and transplantation.

For each Concept Proposal, include the following:  (i) a description of the clinical and mechanistic rationale for the study and overall objectives; (ii) a description of the study population and inclusion/exclusion criteria; (iii) a description of the investigational product/approach and the rationale for its use in the specific study population and clinical area, including safety data and, if available, preliminary efficacy data; (iv) sample size estimations and justification; (v) control/comparison groups; (vi) primary and secondary outcomes and outcome measures; (vii) routine protocol-specific tests; (viii) study events, study flow and timeline; (ix) potential risks and methods to reduce such risks; (x) safety assessments and safety monitoring plan; (xi) data analysis plan; (xii) feasibility considerations, including the number of required clinical sites, methods to determine availability of, access to, and ability to recruit eligible subjects, potential recruitment and retention problems, and approaches to overcome/mitigate such problems; and (xiii) a description of the design of integrated mechanistic studies, including proposed assays for measuring the induction, maintenance and loss of tolerance, the rationale for the use of validated assays and/or data and justification for the use of novel assays for the specific disease and investigational product/approach selected, and type, number, and volume of clinical specimens required.

Component 3.  Leadership Group (LG) - Structure and Governance

Describe in detail plans for the structure and governance of the LG and for the management of Network activities with respect to: (i) scientific planning, priority setting and decision making; (ii) the provision of operational support; and (iii) resource planning and management for all research projects, including the continuation and completion of ongoing clinical trials and mechanistic studies supported by the current Network.  Tables, diagrams, flow charts and organizational charts are strongly recommended.  Include the information delineated below, as well as  an overall organizational chart showing the Network’s four functional elements and any additional functional elements, committees and/or subcommittees proposed, with the names, degrees and titles of proposed Network personnel and consultants serving in a leadership role.

Executive Committee (EC).  (i) Identify the proposed EC members with degrees, institutional affiliations and level of effort, and describe their relevant experience/qualifications for performing the functions of the EC.  (ii) Identify and describe the responsibilities and authorities of any additional subcommittees and/or organizational entities proposed to assist in implementing EC responsibilities, identify individuals to serve as leaders for any additional subcommittees and/or organizational entities and their level of effort, and describe their relevant experience/qualifications for the roles proposed.  (iii) Describe how the EC will be governed, including lines of authority, effective communications processes within the EC, between the EC and the Steering Committee, and with all other functional elements of the Network, decision making processes, procedures to identify and resolve operational issues, and the process for setting EC meetings (e.g., frequency, agendas and participants).  (iv) Describe plans for, frequency of, and metrics to be used to evaluate overall Network performance and productivity.

Steering Committee (SC).  (i) Identify the proposed SC members with degrees, institutional affiliations and level of effort, and describe their relevant experience/qualifications for performing the functions of the SC.  (ii) Identify and describe the responsibilities and authorities of any additional subcommittees and/or organizational entities proposed to implement and/or assist in implementing the scientific responsibilities of the SC, identify individuals proposed to serve as leaders for any additional SC subcommittees and/or organizational entities and their level of effort, and describe their experience/qualifications for the roles proposed.  (iii) Describe how the SC will be governed, including lines of authority, communications processes within the SC, between the SC and the EC, and with other functional elements of the Network, decision making processes, and the process for setting SC meetings (e.g., frequency, agendas and participants).

Centralized Operations. (i) Identify and describe the responsibilities and authorities of organizational elements proposed to provide centralized operational support for the implementation and management of research-related policies and procedures (e.g., submission, distribution and review of proposed clinical trials/studies, publications, conflict of interest, and agreements with Federal, non-Federal and industry collaborators).  (ii) Identify leaders and key personnel for each proposed operational element and their level of effort, and describe their relevant experience/qualifications for the responsibilities proposed.  (iii) Describe the information system, including hardware, software, support, maintenance, and information and system security procedures to support the day-to-day activities of the Clinical Operations and Core Laboratory Groups.

Resource Management and Study-Specific Funds.  (i) Provide a structure for and describe how Network resources will be managed, including lines of authority, decision making, tracking and reporting processes.  (ii) Identify leaders and key personnel including key resource management personnel, provide their level of effort, and describe specific financial management roles and responsibilities, and experience/qualifications.  (iii) Describe procedures for determining and calculating the amount of study-specific funds, including any formulas or templates to be used; and (iv) provide a financial management plan to administer and track the Network budget and associated expenditures and reports.  Include a description of the capacity to execute and manage sub-awards and oversee the technical, administrative and operational activities of Network contracts.

Cross-Network Integration.  Describe proposed approaches to integrating all Network functional elements (Leadership Group, Clinical Operations Group, Core Laboratory Group and Bioinformatics Group), and plans for coordinating with the clinical sites participating in Network-approved studies.  Discuss how the proposed approaches will facilitate efficient decision-making and the ability to effectively drive studies through to completion, and highlight any innovative aspects for the integration of a multi-component clinical research program.

Component 4.  LG – Assessment of Clinical Research Capacity Needs

Provide proposed plans and procedures for ensuring the adequacy of clinical research capacity for Network-supported clinical trials.  Include the following:  (i) a description of proposed plans and procedures for assessing the adequacy of clinical research capacity for clinical trial proposals from both investigators within the Network Executive and Steering Committees and outside investigators, including the number of clinical sites, their access to appropriate subjects, and their recruitment and retention capabilities; (ii) in instances where the LG determines that additional clinical research capacity is required, explain how additional clinical sites will be identified and recruited to participate in specific clinical trials, including institutions represented by the members of the Network Executive and Steering Committees; (iii) a brief description of the clinical research capacity of Network member institutions for participation in clinical trials in the three disease areas within the purview of the Network; and (iv) in instances where additional research capacity is required and Network member institutions are qualified to participate as clinical sites, identify those factors/circumstances that the LG would consider acceptable for non-participation.

Component 5.  LG – Collaborations and Communications

Collaborations.  Describe proposed plans to identify opportunities for collaborating with other Federal and private sector research organizations/programs and to establish joint sponsorship arrangements in order to capitalize on non-Network clinical research resources, coordinate clinical research in areas of mutual interest, and avoid duplication of effort.  Identify and briefly describe specific Federal and non-Federal research organizations/programs that provide opportunities for collaboration with the Network.

Communications.  (i) Provide a proposed plan for communicating with a broad spectrum of audiences, including the scientific community, other Federal and non-Federal research organizations/programs, private foundations, patient advocacy groups, the media, and the general public.  Include proposed strategies and communication tools to describe research funding opportunities and procedures, identify opportunities for participation in clinical trials, and disseminate the results of Network research.  Identify the leader(s), key personnel, and infrastructure required to implement and manage the communications plan, provide level of effort, and describe relevant staff experience and qualifications.  (ii) Provide a plan delineating how the NIAID Program Officer and other NIAID staff responsible for facilitating the research conducted by the Network will be integrated into Network activities.  (iii) Provide a plan for cooperating and coordinating Network clinical research activities with NIAID support contractors, i.e., Statistical and Data Coordinating Center, Clinical Site Monitoring Center, Clinical Products Center and Regulatory Management Center, and with NIAID staff responsible for directing and managing these support contracts.

Component 6.  Clinical Operations Group (COG)

Structure and Governance.  Describe in detail plans for the structure and governance of the COG.  Tables, diagrams, flow charts and organizational charts are strongly recommended.  (i) Describe the proposed organization of the COG, delineating the responsibilities and authorities of all functional elements.  (ii) Identify proposed COG leader(s) and key personnel with level of effort, and discuss their relevant experience/qualifications.  (iii) Describe proposed plans for the governance of the COG, including:  lines of authority; project management approaches, including the establishment of timelines/milestones and the evaluation of COG performance; communication processes within the COG and between the COG, the LG and other Network functional elements; decision-making processes; methods to identify and resolve operational issues; and general procedures for communicating, cooperating and interacting with NIAID staff and NIAID support contractors.

Clinical Site Assessments.  (i) Identify proposed clinical site assessment staff with level of effort, and describe their roles, responsibilities and relevant experience/qualifications.  (ii) Describe proposed plans and procedures for: assessing the adequacy and appropriateness of the capabilities of clinical sites approved for participation in Network clinical trials; identifying appropriate actions to improve clinical research capabilities when necessary, assist clinical sites in implementing appropriate actions, and coordinating clinical site assessment activities and actions with the NIAID Clinical Site Monitoring Center and responsible NIAID staff.  (iii) Explain how performance will be managed, including processes and procedures to ensure the timely initiation, conduct and completion of clinical site assessments.

Protocol Development.  (i) Identify proposed staff to assist in the development of protocols and protocol-related documents with level of effort, and describe their roles, responsibilities and relevant experience/qualifications.  (ii) Describe in detail the processes to be used to develop, review, revise and finalize protocols, including the involvement of appropriate staff of NIAID and NIAID support contractors.  The use of flow charts/diagrams is highly recommended to delineate the steps involved in implementing the processes proposed.  (iii) Explain how performance will be managed, including processes and procedures to:  ensure adherence to approved protocol timelines/milestones; identify and resolve obstacles to timely protocol development; and develop and implement contingency plans when necessary.

Protocol Implementation and Monitoring.  (i) Identify proposed staff to assist in implementing and monitoring Network-approved clinical trials with level of effort, and describe their roles, responsibilities and relevant experience/qualifications.  (ii) Describe in detail the processes to be used to oversee timely clinical trial initiation and conduct in accordance with NIAID and Network policies and procedures, monitor subject accrual and retention, assess adherence to approved protocol timelines/milestones, identify problems/obstacles, and develop and implement actions to resolve identified problems/obstacles.  (iii) Explain how performance will be managed, including processes and procedures to assess clinical site progress and staff effectiveness and productivity.  (iv) Describe plans and procedures for coordinating Network protocol implementation and monitoring functions with appropriate staff of NIAID and NIAID clinical research support contractors.

Component 7.  Core Laboratory Group (CLG) – Structure and Governance, and Research Approach and Methodologies

Structure and Governance.  Describe in detail plans for the structure of the CLG.  Tables, diagrams, flow charts and organizational charts are strongly recommended.   (i) Identify the number, types, roles and significance of each proposed laboratory and clinical specimen repository, and the proposed leaders and key senior personnel for each, with level of effort and a description of responsibilities and relevant experience/ qualifications.  (ii) Describe any proposed CLG 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. 

Describe in detail plans for the governance of the CLG.  Include the following: (i) lines of authority; (ii) decision making process for responding to changes in testing needs and capacity; (iii) requirements and processes for developing and implementing laboratory SOPs, the approach for specimen handling, acquisition, processing, shipping, tracking, testing, storage and retrieval, the proposed laboratory data management system and responsible personnel, and how specimen repositories will be managed; (iv) requirements for protocol-specific laboratory documents and processes for document development and implementation; and (v) how performance will be managed, including processes and procedures to ensure adherence to approved timelines/milestones, identify and resolve obstacles to the timely initiation, conduct and completion of laboratory studies, and develop and implement contingency plans when necessary.

Research Approach and Methodologies:

Component 8.  CLG – Quality Management, Evaluation and Improvements, and Communications and Clinical Site Laboratory Capacity/Training

Quality Management, Evaluation and Improvements.  (i) Describe how all aspects of the CLG will be evaluated and improved, including the process, metrics and frequency for evaluating the CLG effort, and resolving problems/deficiencies.  (ii) Describe laboratory quality management procedures, including requirements for external quality assurance (EQA), validations, reference range studies and laboratory audits.  (iii) Describe the process for determining the need for and development and implementation of alternative EQA.  Do not include names of external advisors  not associated with the Network Executive Committee and Steering Committee.

Communications and Clinical Site Laboratory Capacity/Training.  (i) Describe procedures for interactions among CLG laboratories, with other Network functional elements, and with participating clinical site laboratories for performing routine, non-specialized testing, and for collecting, processing and shipping specimens.  (ii) Describe how the CLG will establish and maintain communication and transmission of assay information and data between the CLG and the Bioinformatics Group.  (iii) Describe and discuss the proposed data input methodology for clinical site laboratories, how assay capacity assessment and clinical site training will be accomplished, how clinical site laboratories will be evaluated, and problem resolution processes and procedures.  (iv) Discuss the ability, capacity and willingness of the CLG to perform testing and provide training on specific assays for laboratory personnel of other Federal and non-Federal clinical research programs.

Component 9.  Bioinformatics Group (BG)

Structure and Governance.  Describe in detail plans for the structure and governance of the BG.  Tables, diagrams, flow charts and organizational charts are strongly recommended.  (i) Describe the proposed organization of the BG, including all proposed functional elements.  (ii) Identify proposed leader(s) and key personnel with level of effort, discuss their relevant experience/qualifications, and provide the rationale for the mix of disciplines represented.  (iii) Describe proposed plans for the governance of the BG, including:  lines of authority;  project management approaches, including the establishment of timelines/milestones and the evaluation of BG performance; communication processes within the BG and between the COG, the CLG, and the LG and other Network functional elements; decision-making processes; methods to identify and resolve operational issues; and general procedures for communicating, cooperating and interacting with NIAID staff and NIAID support contractors.

Bioinformatics Data Management System.  (i) Describe in detail the data management system proposed for the collection, storage, retrieval, archiving and exchange of data from Network-supported mechanistic studies and for the integration of mechanistic data with clinical data derived from the Network Statistical and Data Coordinating Center.  Include a description of software proposed for data capture, storage, query and analysis, as well as for disseminating data to Network-supported investigators, NIAID staff, and the scientific community.  (ii) Include detailed plans for an integrated electronic data repository of relevant scientific data for each research subject or patient sample, and discuss how this plan will permit rapid and efficient production of files for analysis.  (ii) Provide proposed procedures for data quality control and verification in collaboration with originating laboratories and the Network Statistical and Data Coordinating Center.  (iii) Describe methods to be used to ensure system security and provide for the long-term maintenance and survival of data and the data system.

Primary and Secondary Analyses.  (i) Provide plans for interacting with Network-supported investigators, the Network Statistical and Data Coordinating Center, and NIAID staff for the development, review and implementation of proposed studies/sub-studies, including assessing feasibility.  (ii) Discuss relevant statistical methods and study designs for the analysis of mechanistic data and combined mechanistic and clinical data.  Include examples of analyses performed.

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 PHS 398 Application Guide, with the following modification:

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 PHS 398 Application Guide.

3. Submission Dates and Times

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 PHS 398 Application Guide.

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

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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.

6. Other Submission Requirements and Information

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.  

Post Submission Materials

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

Section V. Application Review Information

1. Criteria

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.

Overall Impact - Overall

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Network   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 Network   proposed).

Scored Review Criteria - Overall

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, a Network Functional Component or a specific set of responsibilities  that by its nature is not innovative may be essential to advance a field.

Significance

Does the Network   address an important problem or a critical barrier to progress in the field? If the aims of the Network   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? Is the Network research program as a whole scientifically compelling? Are the overall Network goals, as articulated in the Research Agenda, significant and how well do they (i) address key roadblocks to the development of tolerogenic treatment and prevention approaches in the three disease areas, and (ii) support multiple approaches to achieving long-term tolerance? Does the application have a high likelihood of developing critical new knowledge about tolerance induction in humans, as well as underlying mechanisms and therapeutic effect for multiple diseases?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Network ? 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/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Does the PD/PI have documented experience in directing large, complex, integrated and multifaceted clinical research activities and will the PD/PI devote adequate time and effort to the Network? Are the qualifications, competence, and commitment of the Executive Committee and Steering Committee members and key clinical, scientific and technical personnel appropriate?

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 Network  ? 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 Network   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 plans and processes for setting scientific priorities and integrating new opportunities sound, appropriate and feasible? Are there sound, appropriate and feasible standards, criteria, processes and timelines for evaluating and funding research projects, assessing productivity/continued relevance, discontinuing projects when necessary, and reallocating research funds? Are plans and metrics for evaluating overall Network performance and productivity sound, appropriate and meaningful? Are plans for the overall operation, management and coordination of the Network appropriate?

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?

Review Criteria - Individual Application Components

Reviewers will consider the review criteria below for each Component 1 through 9 in the determination of scientific merit, and give a separate score for each Component.

Component 1.  Research Agenda and Strategic Plan

Research Agenda. Does the Research Agenda demonstrate a sound and thorough understanding of clinical research on immune tolerance, including reasons for failure of past approaches, and address important knowledge gaps in the clinical application of tolerance induction strategies? Are short- and long-term goals and scientific opportunities for clinical trials feasible, scientifically sound, and likely to lead to improved treatment/prevention approaches? Are clinical strategies proposed as high priority feasible, sound, and based on adequate preliminary data; are they well suited for and do they demonstrate a thorough understanding of the three disease areas within the Network’s purview? Are potential barriers to clinical success and solutions to overcoming barriers sound, feasible, and well justified? Are safety concerns adequately articulated?

Does the Research Agenda demonstrate a sound and thorough understanding of research on the identification, assessment, and validation of approaches to measuring tolerant states? Are important knowledge gaps relevant to measuring tolerant states adequately addressed? Are major sources of variability and approaches for overcoming/reducing variability feasible and appropriate? Are the short- and long-term goals, scientific opportunities, and research priorities for mechanistic studies feasible, scientifically sound, and likely to lead to improved methods for measuring the induction, maintenance and loss of tolerance in humans; are they well suited for and do they demonstrate a thorough understanding of the three disease areas within the Network’s purview?

Is the overall approach to the use of bioinformatics appropriate and feasible for analyzing mechanistic data and combined clinical and mechanistic data?

Are the approaches proposed to capitalize on opportunities for industry partnerships effective and likely to succeed?

Strategic Plan. Are the standards, policies, criteria, procedures and processes proposed appropriate and will they be effective in ensuring sound scientific priority setting, the flexibility to integrate new clinical strategies and technologies, thorough and meaningful evaluation of proposed clinical trials and mechanistic studies, and funding of the most promising clinical trials and mechanistic studies? Does the Strategic Plan provide appropriate standards and criteria for assessing the productivity and continued need for and relevance of the research supported, and effective procedures/processes for discontinuing clinical trials and mechanistic studies when necessary? Are there adequate criteria and procedures in place to assess the soundness, feasibility, and anticipated contributions of proposed bioinformatics analyses? Are the timelines and milestones identified for scientific planning and the evaluation of proposed and ongoing clinical trials and mechanistic studies feasible and appropriate? Are timelines and milestones for assessing success in meeting Research Agenda objectives feasible and appropriate?

Component 2.  Concept Proposals for Clinical Trials and Integrated Mechanistic Studies

Clinical Trials:  Is the rationale for each proposed clinical trial sufficient to demonstrate an understanding of the important clinical questions in immune tolerance? Do the clinical trials proposed show sufficient understanding of the Network’s priorities and short- and long-term goals? Are the data on safety and, if available, efficacy of the tolerance induction strategies proposed sound and adequate to justify testing in humans? Are the strategies proposed appropriate for the study populations selected, and is there a reasonable likelihood that these strategies will be effective for the disease indications chosen? Are key study design features adequately addressed and justified, e.g., sample size, control/comparison groups, primary/secondary outcomes? Are potential risks thoroughly identified, are methods proposed to reduce such risks adequate, and are safety monitoring plans appropriate? Do Concept Proposals adequately demonstrate study feasibility (e.g., number of clinical sites, access to eligible subjects, etc.)? Have risks to clinical trial success been adequately identified?

Mechanistic Studies: Is the rationale for each proposed mechanistic study sufficient to demonstrate an understanding of the important mechanistic questions in immune tolerance? Do the mechanistic studies proposed show sufficient understanding of the Network’s priorities and short- and long-term goals? Are the mechanistic studies proposed well integrated into the clinical trials? Are the key design features sound and appropriate for measuring the induction, maintenance and/or loss of tolerance within the context of each proposed clinical trial? Is there a sound justification for the use of validated assays and/or novel assays?

Component 3.  Leadership Group (LG) – Structure and Governance

Executive Committee (EC):  Do the proposed EC members represent the breadth of expertise and disciplines appropriate to implement the Network’s Research Agenda, possess relevant experience and qualifications to perform the full scope of other EC functions, and devote adequate effort? If additional EC subcommittees or organizational entities are proposed, are their responsibilities clearly defined and appropriate, and do the proposed leaders possess relevant expertise and experience and devote adequate effort? Are plans for the governance of the EC clearly articulated, feasible and appropriate, with defined lines of authority and effective communication and decision-making processes? Is the process for setting EC meetings appropriate for carrying out the scope of its responsibilities? Are there appropriate plans and meaningful metrics for evaluating Network performance and productivity, and is the proposed frequency of such evaluations adequate?

Steering Committee (SC): Do the proposed SC members represent the breadth of expertise and disciplines appropriate to implement the full scope of committee functions, possess relevant experience and qualifications, and devote adequate effort? If additional SC subcommittees or organizational entities are proposed, are their responsibilities clearly defined and appropriate, and do the proposed leaders possess relevant expertise and experience and devote adequate effort? Are plans for the governance of the SC clearly articulated and appropriate, with defined lines of authority and effective communication and decision-making processes? Is the process for setting SC meetings appropriate for carrying out the scope of its responsibilities?

Centralized Operations: Are the organizational entities proposed for centralized operational support appropriate and adequate to assist in implementing and managing research-related policies and procedures? Are responsibilities and authorities clearly defined and appropriate for the type and level of support required? Do proposed leaders and key personnel possess relevant experience, expertise and qualifications and is their level of effort adequate? Is the proposed information system for managing day-to-day activities of the Clinical Operations and Core Laboratory Groups effective, efficient, and reliable?

Resource Management and Study-Specific Funds: Are the structure and plans for managing Network resources clearly defined, feasible and adequate, with appropriate lines of authority and effective processes and procedures for decision-making, tracking and reporting? Do proposed leaders and key personnel possess appropriate expertise and experience and devote adequate effort? Are proposed procedures for determining the amount of study-specific funds required reasonable; will they be effective in maximizing the efficient use of Network resources and ensuring the effective management of resource utilization? Does the application demonstrate adequate capacity and appropriate plans for executing and managing a large volume of sub-awards and contracts, and for overseeing the technical, administrative and operational activities of Network sub-awards and contracts?

Cross-Network Integration: Are proposed approaches to integrating all Network functional elements and plans for coordinating with clinical sites appropriate; will they be effective in facilitating efficient decision-making and driving studies through to completion? Are there any innovative aspects to proposed approaches and plans for integration within a multi-component clinical research program?

Component 4.  LG – Assessment of Clinical Research Capacity Needs

Are proposed plans and procedures for ensuring the adequacy of clinical research capacity for Network-supported clinical trials clearly defined and appropriate; will they contribute substantially to driving clinical trials to completion within approved timelines? Are adequate plans, standards and criteria in place for identifying and selecting additional clinical sites when necessary for specific protocols; do standards and criteria adequately consider performance and available capacity among Network member institutions? For qualified Network member institutions that elect not to participate in clinical trials, are the factors/circumstances considered acceptable for non-participation well-articulated and justified?

Component 5.  LG – Collaborations and Communications

Collaborations: Are proposed plans to identify collaborative opportunities and establish joint sponsorship arrangements well-articulated, sound and feasible; will they facilitate the Network’s ability to capitalize on private sector and other Federal clinical research resources, coordinate research in areas of mutual interest, maximize efficiency, and avoid duplication? Have relevant and appropriate opportunities for collaboration with specific Federal and non-Federal research organizations/programs been identified?

Communications:  Are proposed communication plans, procedures and tools well defined and appropriate for a broad spectrum of scientific and lay audiences; are they appropriately tailored for specific types of organizations/groups and for specific purposes? Is the Network infrastructure proposed for designing and implementing communication plans and tools adequate for the scope of audiences; do proposed leader(s) and key personnel possess appropriate expertise and experience, and devote adequate effort? Are there appropriate and effective plans for integrating NIAID staff into Network activities, and for cooperating and coordinating Network clinical research activities with NIAID support contractors?

Component 6.  Clinical Operations Group (COG)

Structure and Governance:  Are the proposed COG structure, organization, and responsibilities and authorities of functional elements clearly defined and appropriate for the scope of activities to be undertaken? Do the proposed COG leader and leaders for each COG functional element possess appropriate experience and qualifications for their respective roles, and devote adequate effort? Are plans for the governance of the COG clearly articulated and appropriate, with defined lines of authority, project management approaches, effective communication and decision-making processes, and milestones for performance evaluation?

Clinical Site Assessments: Do proposed key personnel possess the experience and qualifications appropriate for their roles and responsibilities, and devote adequate effort? Are there clearly defined and appropriate plans and procedures for assessing clinical site capabilities, identifying and assisting in the implementation of necessary actions to improve site capabilities when warranted, and effectively coordinating clinical site assessment activities and actions with NIAID staff and support contractors? Are there appropriate and effective processes and procedures to manage performance and ensure timely completion of clinical site assessments?

Protocol Development: Do proposed key personnel possess the experience and qualifications appropriate for their roles and responsibilities, and devote adequate effort? Are there clearly defined and appropriate processes to develop, review, revise and finalize protocols and ensure the effective involvement of NIAID staff and support contractors? Are there appropriate and effective processes and procedures to manage performance, ensure adherence to approved timelines/milestones, and develop and implement contingency plans when necessary?

Protocol Implementation and Monitoring: Do proposed key personnel possess the experience and qualifications appropriate for their roles and responsibilities, and devote adequate effort? Are there clearly defined and appropriate processes to oversee timely clinical trial initiation and conduct, monitor subject recruitment and retention, assess adherence to approved timelines/milestones, and develop and implement actions to resolve identified problems/obstacles? Are there appropriate and effective processes and procedures to manage clinical site performance/progress and COG staff productivity and coordinate protocol implementation and monitoring activities with NIAID staff and support contractors?

Component 7.  Core Laboratory Group (CLG) – Structure and Governance, Clinical Specimen Repository, and Research Approach and Methodologies

Structure and Governance.  Are the proposed structure, organization, responsibilities and authorities of the CLG clearly defined and appropriate for the scope of activities to be undertaken? Are the number, types and roles of the proposed laboratories appropriate to carry out the breadth of mechanistic studies anticipated? Do proposed CLG leaders and key personnel possess appropriate training, experience and qualifications for their respective roles and devote adequate effort? Is the proposed laboratory data management system appropriate for the type and volume of studies anticipated; is data management personnel adequately trained and experienced? Are there adequate and sound requirements and processes for developing and implementing laboratory SOPs and protocol-specific documents? Are plans for the governance of the CLG clearly articulated and appropriate, with defined lines of authority, project management approaches, effective communication and decision-making processes, and milestones for performance evaluation?

Clinical Specimen Repository. Are there sound and appropriate plans for the operation of the clinical specimen repository, including specimen acquisition, processing, shipping, tracking, testing, storage, retrieval and quality control? Are the proposed repository facilities and equipment adequate for the scope and volume of work anticipated? Do key repository personnel possess appropriate training, expertise and experience?

Research Approach and Methodologies:

Research Approach.  Does the research approach of the CLG address an important problem or critical barrier to progress in the field? If the aims of the CLG are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved?  Is the CLG research approach well integrated into the Network’s proposed Research Agenda, and sufficiently flexible to accommodate new findings and refined research priorities?

Protocol-Specific Testing.  Does the application provide a feasible and sound approach for decision-making on the selection of specialized assays, procedures and analyses for performance of protocol-specific testing? Are decision-making criteria clearly articulated and appropriate?

Laboratory Selection.  Does the application provide a feasible and sound approach for decision-making on the selection of laboratories to perform specialized assays, including laboratory readiness and ensuring ongoing quality? Are decision-making criteria clearly articulated and appropriate?

New Assay Development.  Are the proposed processes and procedures for assessing new assays sound, feasible and appropriate? Are there well justified and sound criteria for decision-making on the use of new assays in Network-supported studies? Are plans/procedures for transitioning from existing to new technologies clearly defined, efficient and appropriate?

Component 8.  CLG – Quality Management, Evaluation and Improvements, and Communications and Clinical Site Laboratory Capacity/Training

Quality Management, Evaluation and Improvements.  Are the proposed processes, metrics and frequency of evaluating the CLG effort sound, feasible and appropriate for the scope of laboratory activities to be undertaken? Does the application provide adequate plans for making improvements, resolving problems and correcting deficiencies in a timely and satisfactory fashion? Are proposed laboratory quality management procedures feasible and appropriate, including requirements for external quality assurance (EQA), validations, reference range studies and audits? Are proposed processes and criteria for determining the need for and development and implementation of alternative EQA appropriate for the range of laboratory studies anticipated?

Communications and Clinical Site Laboratory Capacity/Training.  Does the application provide clearly defined, appropriate and effective procedures for interactions among CLG laboratories, with other Network functional elements, and with participating clinical site laboratories, and for collecting processing and shipping specimens? Are there appropriate and efficient plans/processes for communication and transmission of assay information and data between the CLG and the Bioinformatics Group?  Is the proposed data input methodology for clinical site laboratories clearly defined, sound and efficient? Are there well defined and effective processes, standards and criteria for (i) assessing assay capacity of clinical sites, (ii) determining clinical site training needs and implementing training activities, and (iii) evaluating clinical site laboratory performance and resolving problems/deficiencies? Are there appropriate CLG ability, capacity and willingness to perform testing and provide training on specific assays for laboratory personnel of other Federal and non-Federal clinical research programs?

Component 9.  Bioinformatics Group (BG)

Structure and Governance.  Are the proposed structure, organization, responsibilities and authorities of the BG clearly defined and appropriate for the scope of activities to be undertaken? Do proposed BG leaders and key personnel provide the necessary mix of disciplines, possess appropriate experience and qualifications for their respective roles, and devote adequate effort? Are plans for the governance of the BG clearly articulated and appropriate, with defined lines of authority, project management approaches, effective communication and decision-making processes, and milestones for performance evaluation?

Bioinformatics Data Management System.   Does the application propose a sound, feasible, effective and efficient system for the collection, storage, retrieval, archiving and exchange of mechanistic data and the integration of clinical data? Will the system provide for secure and efficient dissemination of data to NIAID and the scientific community? Are there sound plans for an integrated electronic data repository of relevant scientific data for each research subject/patient sample that will permit rapid and efficient production of files for analysis? Are plans for data quality control and verification well defined, sound, comprehensive and appropriate for originating laboratories and the Network Statistical and Data Coordinating Center? Are sound and effective methods proposed to ensure system security and provide for the long-term maintenance and survival of data and the data system?

Primary and Secondary Analyses.  Does the application provide well defined, appropriate and effective plans for interacting with Network-supported investigators, the Network Statistical and Data Coordinating Center, and NIAID staff for the development, review and implementation of proposed studies/sub-studies? Are the proposed statistical methods and study designs for analyzing mechanistic data and combined mechanistic and clinical data sound, well justified, and likely to produce relevant information on specific studies as well as approaches to measuring immune tolerance?

Additional Review Criteria - Overall

As applicable for the Network   proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact 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 Network   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

Additional Review Considerations - Overall

As applicable for the Network   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 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.   

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the NIAID  in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

Appeals of initial peer review will not be accepted for applications submitted in 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:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI 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.

Section VI. Award Administration Information

1. Award Notices

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,  SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

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.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, other 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.

The PD/PI of the Network will have primary responsibility for the overall performance of the Network, including, but not limited to:

The PD/PI of the Network will have primary responsibility for the scientific leadership, administration and coordination of all Network activities, including, but not limited to:

The PD/PI of the Network will have the primary responsibility for the overall planning, execution and review of all mechanistic laboratory and bioinformatics activities including, but not limited to:

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

Program Official and Project Scientists. NIAID staff assistance will be provided by a DAIT Program Official and Project Scientists 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 NoA. These staff members will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond the normal program stewardship role for grants:

Clinical Trials Agreements. NIAID will negotiate and execute Clinical Trials Agreements (CTAs) with pharmaceutical companies for the use of investigational products in Network-supported clinical trials.

Clinical Trial Sponsorship.  It is anticipated that, with rare exceptions, NIAID will serve as the regulatory sponsor for Network clinical trials conducted under IND and IDE. NIAID will advise  investigators on the specific regulatory requirements for IND sponsorship. In situations where NIAID is the regulatory 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 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 all adverse events in NIAID-supported trials. Final disposition of serious adverse event (SAE) reports will be decided by NIAID staff for all IND studies held by NIAID.

Clinical Trial Monitoring.  NIAID staff will oversee an external clinical site monitoring contract that evaluates GCP, regulatory compliance, protocol implementation, internal quality assurance, and test article accountability at the Network clinical sites. The monitoring contractor, with or without accompanying NIAID staff, will visit Network clinical sites periodically to review selected protocols, provide training on general protocol conduct, review internal QA/QC plans, and audit pharmacies.  Site monitoring reports will be reviewed and evaluated by NIAID Project Managers.

Training.  NIAID staff will provide a variety of training activities to appropriate Network personnel to assist the Network in ensuring that consistent standards for protection of human subjects and clinical trial conduct and documentation are achieved across the Network. 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 staff will review and 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 protocol design, 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, biologics, or other clinical interventions. 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 final safety monitoring plans, including the composition of review committees, by NIAID is required prior to study initiation. NIAID independently supports Data and Safety Monitoring Boards (DSMB) that oversee clinical trials at the discretion of NIAID.

Study Termination.  NIAID staff reserves the right to terminate or curtail a clinical study for any reason.  Examples include, but are not limited to, risks to subject safety, failure to achieve recruitment goals, and reaching a major study endpoint substantially before schedule with persuasive statistical significance.

Data Access.  NIH will have the right of access to all data generated (raw and analyzed) and may periodically review these data. This includes a review of data as recorded on the case report forms or in the central databases, and external checking against the original source documentation as required by Federal regulation and NIAID as the regulatory sponsor. NIAID staff may request from the Network specific data analysis needed for programmatic activities or for issues related to NIAID plans with other partners. The NIH requires public access to selected data sets generated with the use of public funds within a reasonable time after the primary analysis and publication.

Areas of Joint Responsibility between NIH and Awardees include:

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 the award recipient and the NIH may be brought to Dispute Resolution.  A Dispute Resolution Panel will be convened.  It will have three members:  a designee of the Executive 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 appear 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.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590 or RPPR) annually and financial statements as required in the NIH Grants Policy Statement. Progress reports should briefly describe the status of pilot projects (awardee-selected projects involving new clinical trials and mechanistic studies), including data and safety monitoring, and should notify NIH of serious adverse events and unanticipated problems.

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. 

Section VII. Agency Contacts

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

Application Submission Contacts

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

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: commons@od.nih.gov

Scientific/Research Contact(s)

James McNamara, M.D.
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases (NIAID)
Room 6806, MSC 6601
6610 Rockledge Drive
Bethesda, MD  20892
Telephone: 301-402-5386
Email: jmcnamara@mail.nih.gov 

Peer Review Contact(s)

Priti Mehrotra, M. Sc., Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases (NIAID)
Room 3138, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
For Express Couriers: 20817-1824
Telephone: 301-435-9369, 301-496-2550
Fax: 301-480-2408
Email: pmehrotra@NIAID.nih.gov

Financial/Grants Management Contact(s)

Julie Waugh
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases (NIAID)
Room 2239, MSC-7614
6700B Rockledge Drive
Bethesda, MD, 20892
Telephone (301)-451-7381
E-mail: WaughJ@niaid.nih.gov 

Section VIII. Other Information

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.

Authority and Regulations

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.


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