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	December 06, 2019 - This RFA has been reissued as RFA-AI-19-068.
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.

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.

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

The 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.

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

• Clinical Trials. The design and conduct of Phase I-IV clinical trials to evaluate the safety and efficacy of investigational products, approaches and techniques intended to lead to a functional state of immune tolerance in three clinical areas: autoimmune diseases; asthma and allergic diseases; and immune-mediated rejection of transplanted solid organs, tissues and cells. Tolerogenic strategies may target antigen specific receptors, molecules of the co-stimulation pathways, homing molecules, or other relevant approaches; may use any of a variety of agents including antigens, peptides, altered peptides, monoclonal antibody blockade, cytokines, molecularly engineered cells or tissues, DNA vectors, or other relevant molecules; and may be administered by a variety of routes. Tolerance studies may include projects that are intended to achieve incremental advances and are clear steps towards tolerance. In addition, the Network will be responsible for the continuation and completion of ongoing clinical trials and integrated mechanistic studies being conducted under the current Network contract. Additional information on responsibilities for ongoing clinical trials is provided under Section VI. Award Administration Information, item 2. Administrative and National Policy Requirements Cooperative Agreement Terms and Conditions of Award.
• Mechanistic Studies. The design and conduct of mechanistic studies and the development and evaluation of assays to measure/assess stages of disease and likelihood of progression, effect of treatment on immunological status and/or clinical outcome, maintenance of protective immunity, and safety of immunosuppressive withdrawal, and to identify and evaluate potential immune/surrogate markers of the induction, maintenance, and loss of tolerance. Such assays include, but are not limited to: microarray and PCR analyses of gene expression, quantitative assays of T cell reactivity, assays of B cell activity, assays of cytokines and other proteins, and novel tissue morphology studies to analyze tissue changes due to disease progression and therapeutic effect. These studies are performed, often through central laboratory resources, as integral components of the clinical trials undertaken.
• Bioinformatics Resources. The provision of biostatistics, data collection, validation and analysis resources for integrated mechanistic and clinical data analyses, including analyses across Network studies.
• Nonclinical Studies and Product Development. On a limited basis, support for product development activities and the design and conduct of nonclinical studies essential for the subsequent evaluation of promising tolerance induction strategies in humans. Such activities may include, but are not limited to: proof-of-principle studies and pharmacokinetics and pharmacodynamics animal studies; and nonclinical toxicity studies in suitable animal models; and production. Manufacturing and laboratory studies will be conducted under current Good Manufacturing Practices (cGMP) or Good Clinical Laboratory Practices (GCLP), as appropriate.

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:

• Selectively amplify responses, making immunotherapy more robust and durable
• Shorten time required to achieve beneficial and long-lasting immune responses
• Bring greater safety to the clinical practice of immunotherapy
• Apply immunotherapeutics more widely:
  • where no safe and effective treatments are available, such as food allergy
  • to prevent or delay the development of disease, such as asthma and food allergy
  • that use well characterized and purified antigens (allergens) which facilitate dosing strategies as interventions
  • although immunosuppressive interventions are generally not considered safe for use in treating allergic diseases, other immunomodulatory approaches are encouraged

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:

• Co-stimulatory blockade to inhibit T cell activation
• Cytokine modulation to induce immune deviation and suppression
• Depletion of autoreactive lymphocyte populations to promote immune homeostasis
• Cellular therapies to restore the balance of regulatory cells
• Antigen specific therapies to modulate autoreactive immune responses

Transplantation

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

• Costimulatory blockade regimens to inhibit T cell activation
• Cell-based therapies, including, e.g., T regulatory cells or mesenchymal stem cells
• Bone marrow chimerism to induce tolerance in solid organ transplantation
• Strategies using potentially tolerogenic induction immunotherapeutic approaches
• Strategies involving novel tolerogenic agents
• Observational studies of transplant recipients who are functionally tolerant
• Detailed mechanistic analyses to increase understanding of the tolerant state

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:

• Statistical and Data Coordinating Center contract to provide a broad range of support services, including: assistance in the development of statistical design and analysis plans and other clinical protocol components (e.g., data and safety monitoring plans); a central data management system for the collection, storage, quality control and retrieval of clinical and other trial related data; a safety database system for the receipt, reporting and disposition of Serious Adverse Events (SAEs); and the analysis of final clinical study data and preparation of final clinical study reports. The Request for Proposals can be found at https://www.fbo.gov/index?s=opportunity&mode=form&id=4402094af6db51fefb94671d355adebc&tab=core&_cview=0. The contract is held by Rho (http://www.rhoworld.com/).
• Clinical Site Monitoring Center contract to assist in monitoring the conduct of clinical trials in accordance with protocol-specific and regulatory requirements, including initial site assessments, interim site monitoring of ongoing clinical trials, and site and study close-out. The Request for Proposals can be found at https://www.fbo.gov/index?s=opportunity&mode=form&id=07021adff3bc56d94503c38c83f32bdb&tab=core&_cview=1. The contract is held by PPD (http://www.ppdi.com/).
• Clinical Products Center contract for the receipt, storage, inventory, packaging/repackaging, quality assurance, distribution and disposal of study products. The Request for Proposals can be found at https://www.fbo.gov/index?s=opportunity&mode=form&id=96d65718068fb0a5d34086876b3f8a11&tab=core&_cview=1. The contract is held by Eminent Services Corporation (http://www.eminentservices.com/).
• Regulatory Management Center contract to provide technical and administrative assistance for a broad range of functions pertaining to regulatory sponsorship, including preparation of regulatory submissions, reports and other materials, communications with Regulatory Health Authorities, implementation of protocol-specific site registration requirements, and maintenance and management of Sponsor Essential Clinical Documents (SECDs). The Request for Proposals can be found at https://www.fbo.gov/index?s=opportunity&mode=form&id=ffaa80e09ae0c5c612502ac077bcca97&tab=core&_cview=1. The contract is held by PPD (http://www.ppdi.com/).

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. 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:

• A description of the state-of-the-art of research to induce immune tolerance and define underlying mechanisms in animal models and human studies, including discussions of: safety concerns; knowledge gaps; scientific opportunities relevant to the clinical application of tolerance induction strategies in human immune-mediated diseases and transplantation; and reasons for the failure of past approaches.
• Delineation of promising investigational approaches to tolerance induction for the prevention and treatment of asthma, allergic and autoimmune diseases, and for the prevention of immune-mediated rejection of solid organ, tissue and cell transplants.
• A description of: (i) the state-of-the-art of research on the identification, assessment and validation of immune/surrogate markers, biological samples (e.g., blood, tissue, cellular isolates), and existing and new techniques for measuring tolerant states; (ii) knowledge gaps 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 (biological and sampling diversity, specimen handling, shipping, storage and variability of detection procedures), validation against acknowledged disease endpoints, and proposed strategies for overcoming and/or reducing variability; and (iii) the use of bioinformatics tools to analyze combined mechanistic and clinical data.
• A detailed description of research priorities for both clinical trials and mechanistic studies and the rationale for their selection.
• Identification of the immediate and long-range goals of the Network, potential barriers to success, and potential solutions to overcome those barriers.
• Delineation of approaches to identify and capitalize on opportunities for industry partnerships to accomplish the research goals of the Network.

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

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:

• Developing and updating, as necessary, the Research Agenda
• Developing the Strategic Plan to implement the Research Agenda, including the establishment of standards, policies, criteria and processes for the submission, evaluation, prioritization and funding of proposed clinical trials and associated mechanistic studies
• Reviewing and assessing proposed clinical trials and mechanistic studies with respect to: soundness, feasibility and relevance to achieving the goals of the Research Agenda; adequacy and appropriateness of the number and capabilities of proposed clinical sites; and ethical considerations
• Determining those clinical trials and mechanistic studies to be supported
• Managing the implementation and monitoring of clinical trials and mechanistic studies, including establishing and directing a network of core laboratories
• Providing a network architecture capable of managing complex and dispersed information communication systems with secure, access controlled storage of data and other confidential information as well as arrangements for secure back-up of data
• Implementing and managing an information system to support the day-to-day activities of the Network Clinical Operations and Core Laboratory Groups, including hardware and software support
• Determining the need for additional nonclinical studies and product development services for high priority clinical trials and directing the implementation of approved studies and product development activities
• Assessing the soundness, feasibility and value of proposed biostatistical analyses and determining those analyses to be conducted
• Establishing and implementing other research-related policies and procedures, including: publication of the research results; communications with scientific and lay audiences, including a publicly accessible website on Network goals, composition and research activities; and conflict of interest
• Establishing and implementing collaborations with other Federal and non-Federal research programs and with industry partners
• Directing activities associated with the administrative and fiscal planning and management of the Network
• Establishing financial management capacity and systems to support a high volume of sub-awards and the timely review of invoices; disbursement of funds; and tracking of Network financial resources

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.

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.

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

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

• System for Award Management (SAM) must maintain an active entity registration (formerly CCR registration), to be renewed at least annually. Use the Sam.gov Manage Entity function to manage your entity registrations. See the Grants Registration User Guide at SAM.gov for additional information.
• eRA Commons

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.

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.

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

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

NIH will not accept any application 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:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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

It is critical that applicants follow the instructions in the 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.

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

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

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

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

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

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:

• Component 1. Research Agenda and Strategic Plan: Total page limit is 30 pages
• Component 2. Concept Proposals for Clinical Trials and Integrated Mechanistic Studies: Total page limit is 30 pages
• Component 3. Leadership Group (LG) - Structure and Governance: Total page limit is 30 pages
• Component 4. LG Assessment of Clinical Research Capacity Needs: Total page limit is 6 pages
• Component 5. LG Collaborations and Communications: Total page limit is 6 pages
• Component 6. Clinical Operations Group (COG): Total page limit is 30 pages
• Component 7. Core Laboratory Group (CLG) Structure and Governance, and Research Approach and Methodologies: Total page limit is 12 pages
• Component 8. CLG Quality Management, Evaluation and Improvements, and Communications and Clinical Site Laboratory Capacity/Training: Total page limit is 6 pages
• Component 9. Bioinformatics Group (BG): Total page limit is 12 pages

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

• Using PHS 398 Form Page 2; provide a succinct but accurate description (abstract) of the OVERALL multi-component application addressing the major, common theme of the program. Do not exceed the space provided.
• List the known performance sites where the research will be conducted.
• Under "Key Personnel", list the PD/PI of the multi-component application, followed by the Component Leaders of the functional components, and co-investigators.

PHS 398 Form Page 3 - Table of Contents

• The table of contents for the application should match the order of the table of contents provided above.

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:

• Research Approach. Discuss the CLG’s research approach, its significance and expected contributions to the field, emphasizing how this approach supports and integrates with the Research Agenda to achieve Network goals.
• Protocol-Specific Testing. Discuss the approach to making decisions on the selection of specialized assays, procedures, and analyses for performance of protocol-specific testing.
• Laboratory Selection. Describe the approach for making decisions on the selection of laboratories to perform specialized assays, including determining laboratory readiness and ensuring ongoing quality.
• New Assay Development. Describe how new assays will be assessed and implemented for use with clinical specimens from Network-supported clinical trials, including how decisions will be made on the use of new and non-FDA- approved test methods for IND and non-IND studies, and procedures for transitioning from existing to new technologies.

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:

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

Appendix

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS 398 Application Guide.

Part I. Overview Information contains information about Key Dates.

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS 398 Application Guide.

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

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

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).

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?

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?

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

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.

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:

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

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:

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

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.

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.

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

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

• Identifying and implementing a clinical research agenda that addresses research areas of highest priority in promoting research on new tolerogenic approaches for the treatment or prevention of asthma and allergic diseases, autoimmune diseases, and immune-mediated rejection of transplanted solid organs, tissues and cells
• Chairing the Network Executive Committee and ensuring the effective implementation of Committee responsibilities
• Collaborating with NIAID and the Network Statistical and Data Coordinating Center (SDCC) to set Network clinical research priorities in accordance with available SDCC resources
• Establishing policies and procedures for decision-making that are adaptable to changing research priorities
• Participating in the design, conduct, analysis, and publication of clinical trial and mechanistic research findings/results
• Establishing procedures and metrics for the assessment of Network progress and productivity in achieving the objectives of the Research Agenda
• Ensuring the participation and appropriate training of Network-supported investigators
• Providing bylaws, policies and standard operating procedures to the DAIT Program Officer within 90 days of issuance of an award, to include, at a minimum, a Conflict of Interest (COI) Policy consistent with NIH policy as well as DHHS and FDA regulations to ensure adequate protection of the rights and safety of subjects involved in the research and a description of lines of authority and communication within the Network

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:

• Developing and implementing procedures for selecting and prioritizing proposed clinical trials and mechanistic studies
• Providing all Network personnel, consultants and research support services necessary for the continuation and completion of ongoing clinical trials and mechanistic studies being supported by the current Network, including the execution and management of sub-awards for participating clinical sites and laboratories
• Ensuring that protocol development is initiated only when:
  • there are sufficient preclinical safety and supportive scientific data for the proposed study
  • there is a commitment of sufficient study product supply and financial resources
  • there is a thorough evaluation of the overall feasibility of the proposed study, including an assessment of the performance of potential clinical trial sites that shows proposed study viability
• Developing protocol documents collaboratively with the input of investigators, statisticians, and NIAID staff
• Ensuring that protocol implementation and oversight adhere to the following:
  • criteria for determining operational futility and when primary endpoints will not be reached within a pre-defined time boundary, prior to protocol initiation
  • protocol approval by NIAID prior to protocol implementation
  • mechanisms for monitoring study progress and participant safety (in collaboration with the SDCC), and provision of status reports to NIAID on an agreed upon schedule
  • provision of results to study participants and the research community as soon as can be accomplished
• Implementing procedures for regular assessment of performance, to include processes for the addition, reduction, expansion or elimination of Network trial sites and laboratories
• Submitting required information to NIAID in order to meet administrative, oversight, and regulatory requirements, including, but are not limited to:
  • Reports, as required by the IND sponsor, to fulfill its regulatory requirements compliant with federal regulations and NIAID procedures for clinical trials.
  • Protocol documents; information concerning Network trial sites and laboratory names; contact and additional information requested of all senior/key personnel; and training records
  • Annual progress reports summarizing all research accomplishments and providing detailed metrics on Network performance as a whole and for Network trial sites and laboratories. These annual reports will also discuss activities, difficulties, corrective actions, and future directions with complete budget justifications. These reports will be due concurrently with the annual Non-Competing Grant Progress Report (PHS 2590)
• Developing a plan for sharing of archived laboratory specimens obtained during the conduct of Network clinical studies across Network investigators, as well as for external investigators, to promote laboratory investigations to better understand immune tolerance promoting interventions
• Obtaining NIAID approval prior to submission of publications

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:

• Setting laboratory priorities for mechanistic studies that are based on Network research priorities and integrated in clinical trials
• Ensuring that laboratories conduct operations in accordance with GCLP when appropriate
• Ensuring, wherever appropriate, that new assays are qualified or validated per FDA and GCLP guidance
• Engaging, where appropriate, non-Network expert investigators and laboratories and other NIH-supported resources when identifying, evaluating and implementing new tests, reagents and instruments for mechanistic studies of tolerance promoting strategies
• Ensuring that laboratories supported by the Network have the necessary SOPs, permits, personnel, data management system and other resources to perform and report the results of laboratory assays to support Network operations in a timely manner and in accordance with required standards:
  • Laboratories that perform any tests on materials derived from the human body for the purpose of providing information for the diagnosis, prevention or treatment of any disease or impairment, or the assessment of the health of human beings must be CLIA-accredited/College of American Pathologists (CAP) certified or equivalent.
  • Clinical laboratories conducting tests for protocols being carried out under an Investigational New Drug Application (IND), New Drug Application (NDA) or Biologics License Application (BLA) shall use FDA-approved tests and reagents. When not feasible, appropriate validation processes should be used with approval from NIAID Program Officer
• Ensuring that laboratories supported by the Network:
  • Provide scientific expertise to the design and execution of clinical protocols, including evaluation of laboratory data
  • Ensure security of any personally identifiable information associated with test specimens
• Ensuring that the bioinformatics group has all the necessary SOPs, personnel, data management, statistical and communication expertise and systems to support Network operations and meet NIAID requirements, to include:
  • Ensuring timeliness, accuracy, confidentiality and integrity of data transferred among the Network members
  • Providing access to data visualization tools to facilitate the sharing and integration of clinical and mechanistic data
  • Providing statistical expertise for combined mechanistic and clinical database analyses

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:

• Ensure that Network research efforts are consistent with that of the NIAID agenda for immune tolerance clinical research, and complement those of other NIH and NIAID programs
• Facilitate coordination among the NIAID- and other NIH-supported clinical trials Networks and other research groups
• Communicate the NIAID scientific priorities and how they impact Network priorities
• Serve as members of protocol teams in the roles of Medical Monitors, Project Managers and Regulatory Officers
• Track protocol development, implementation, and study conduct
• Attend and participate in meetings, trainings, and conference calls
• Serve as resources for scientific and policy information
• Share information regarding promising new agents, strategies, and developments when appropriate
• Identify scientific gaps and organize meetings to facilitate exchange of scientific and regulatory information, including during Network meetings
• Oversee contract resources that:
  • provide statistical and data management services
  • provide regulatory services
  • conduct external site monitoring
  • manage and distribute investigational agents
  • collect SAE reports
• Participate on committees as voting members
• Participate in the presentation of research results, including publications
• Monitor progress of medical, laboratory, and operational aspects of clinical trials
• Oversee clinical site operations to include: development of template informed consent documents as well as review of site-specific consents for IRB submission; operational activation of Network clinical sites; and review and evaluation of site monitoring reports
• Perform Medical Monitor activities for the evaluation of study participant safety during the conduct of Network clinical trials

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:

• Research Plans. Implementing, monitoring, and updating the clinical research plan for the Network to ensure consistency and relevance with the NIAID scientific priorities
• Research Activities. Reviewing the Network's research activities and goals on an agreed upon schedule (but no less than once every year)

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.

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.

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

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

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

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

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

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

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