Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Allergy and Infectious Diseases (NIAID)
Funding Opportunity Title	NIAID Division of Allergy, Immunology and Transplantation: Statistical and Clinical Coordinating Center (UM2)
Activity Code	UM2 Program Project or Center with Complex Structure Cooperative Agreement
Announcement Type	New
Related Notices	June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number	RFA-AI-14-016
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 Statistical and Clinical Coordinating Center, NIAID Division of Allergy, Immunology and Transplantation. The awardee will provide a broad range of support critical for the design, development, implementation, monitoring and analysis of clinical research carried out by multiple Division-supported programs in three disease areas: asthma and allergic diseases, autoimmune diseases, and transplantation. The scope of support to be provided includes statistical design and analysis, protocol development, study initiation and management, data management, clinical site monitoring, safety monitoring, and final analysis of study findings. The types of research for which support will be provided include clinical trials, integrated studies of underlying mechanisms, clinical studies (e.g., longitudinal studies, genetic studies, etc.), and studies to identify and validate surrogates/biomarkers.

Posted Date	March 26, 2014
Open Date (Earliest Submission Date)	June 18, 2014
Letter of Intent Due Date(s)	June 18, 2014
Application Due Date(s)	July 18, 2014, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	November 2014
Advisory Council Review	January 2015
Earliest Start Date	April 2015
Expiration Date	July 19, 2014
Due Dates for E.O. 12372	Not Applicable

NIH’s new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically; paper applications will not be accepted. ASSIST replaces the Grants.gov downloadable forms currently used with most NIH opportunities and provides many features to enable electronic multi-project application submission and improve data quality, including: pre-population of organization and PD/PI data, pre-submission validation of many agency business rules and the generation of data summaries in the application image used for review.

Required Application Instructions

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

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

The purpose of this FOA is to solicit applications for the Statistical and Clinical Coordinating Center (SACCC - hereinafter referred to as Center for the purposes of this FOA), NIAID Division of Allergy, Immunology and Transplantation (DAIT). The objective of the Center is to provide a broad range of support critical for the design, development, execution, monitoring, and analysis of clinical research sponsored by the Division in three disease areas: asthma and allergic diseases; autoimmune diseases; and transplantation of cells, tissues and solid organs. The scope of clinical research to be supported by the Center includes: (i) clinical trials at all phases to evaluate the safety and efficacy of investigational products and innovative approaches for disease treatment and prevention; (ii) studies of underlying mechanisms as integral components of clinical trials; (iii) clinical studies (e.g., longitudinal birth cohort studies, genetic studies, etc.); and (iv) surrogate/biomarker studies. The scope of statistical and clinical coordination functions to be performed by the Center includes: statistical design and analysis; protocol development; study initiation and management; clinical site monitoring; data management; and safety oversight and reporting.

Research supported and conducted by the NIAID, National Institutes of Health (NIH) strives to better understand, treat, and ultimately prevent immunologic, infectious, and allergic diseases. The NIAID Division of Allergy, Immunology, and Transplantation (DAIT) supports extramural basic, pre-clinical and clinical research through a variety of research grants and contracts that focuses on immune-mediated diseases. A critical component of the Division’s mission focuses on clinical research to develop new and/or improved therapies and prevention strategies through rigorous evaluations of the safety and efficacy of investigational products and approaches, studies to elucidate underlying mechanisms, studies to develop and evaluate surrogate/biomarkers of disease stage, severity and progression, and clinical studies of natural history, genetics, etc.

Major research programs are supported in three disease areas: asthma and allergic diseases; autoimmune diseases; and transplantation. Responsibility for these clinical research programs rests with multiple DAIT organizational components: the Asthma, Allergy and Airway Biology Branch; the Autoimmunity and Mucosal Immunology Branch; the Transplantation Branch; and the Clinical Research Operations Program.

In order to provide for critical clinical research support, DAIT has established multiple Statistical and Clinical Coordinating Centers (SACCCs) dedicated to specific research programs. Through this FOA, DAIT intends to consolidate such support under a single multi-component cooperative agreement.

The DAIT-supported clinical research programs to be supported by the Center include, but are not limited to, those described below under each of the three disease areas.

One DAIT-supported clinical research program, the Collaborative Network for Clinical Research on Immune Tolerance (hereinafter referred to as ITN for Immune Tolerance Network), focuses on mechanisms underlying the induction, maintenance and loss of immune tolerance in humans, with clinical research conducted in all three disease areas. This Network consists of an international consortium of clinical and basic scientists in the U.S., Canada, Mexico, Europe, and Australia dedicated to the clinical evaluation of novel, tolerance-inducing therapies in asthma and allergic diseases, autoimmune diseases, and transplantation. The research carried out by this Network encompasses clinical trials at all phases to evaluate investigational products and approaches for the induction and maintenance of immune tolerance, mechanistic studies and the development of tolerance assays as integral components of the clinical trials undertaken. Information about the Network’s clinical research is included under each of the three disease areas below. More information about this research program is located at www.immunetolerance.org .

Asthma and Allergic Diseases Clinical Research Programs

• Asthma and Allergic Diseases Cooperative Research Centers (AADCRCs). Through a network of 11 U.S. academic institutions, the AADCRC research program conducts innovative, multidisciplinary basic and clinical investigations of the biological mechanisms, immunologic basis, diagnosis, treatment and prevention of asthma and a broad spectrum of allergic diseases, focusing on allergic rhinitis, chronic rhinosinusitis, atopic dermatitis, and food allergy. The research objectives of the AADCRCs include: (i) defining the role of the immune system in the development, progression, treatment and prevention of asthma and allergic diseases; (ii) determining how respiratory viral infections, including influenza, and immune responses to infections may contribute to the development or worsening of these diseases; (iii) identifying how various types of immune cells are affected; and (iv) understanding the association between environmental exposures to inhaled pollutants, toxins, and bacterial products and the development and severity of asthma. The scope of research conducted includes Phase I/II clinical trials of promising therapeutic and preventive interventions and clinical studies (cross-sectional studies, short-term longitudinal observational studies, and genetic studies) to test novel therapeutic approaches or mechanistic hypotheses. This long-standing NIAID research program is cosponsored by the NIH Office of Research on Women’s Health (ORWH).
• Atopic Dermatitis Research Network (ADRN). Through the ADRN, NIAID supports clinical research and closely related animal research on the immunopathogenesis of atopic dermatitis (AD), the relevance of immunologic, skin barrier, genetic and other factors in this disease, as well as the underlying mechanisms for susceptibility of individuals with AD to cutaneous infectious diseases. The ADRN focuses on four major research areas to better understand host defense mechanisms and immune system responses to viral and bacterial infections in healthy individuals and in individuals with AD: (i) susceptibility to eczema vaccinatum and eczema herpeticum; (ii) susceptibility to staphylococcal colonization and infections, including methicillin-resistant staphylococcus aureus; (iii) susceptibility to colonization and infection with other organisms, including commensals; and (iv) immune responses to vaccines. Investigations in these four major research areas include Phase I/II clinical trials, clinical studies using human samples, and integrated studies of underlying mechanisms. The scope of the ADRN’s clinical research includes: (i) host responses to novel or established anti-vaccinia or anti-herpes simplex agents and vaccines; (ii) host responses to anti-staphylococcal agents and/or vaccines; (iii) epidemiological studies to identify genes and/or proteins associated with AD subjects that increase susceptibility to eczema colonization and infection; and (iv) longitudinal studies of the immunopathology, clinical status, and severity of AD. Animal studies, including research using existing animal models and new animal model development, and preclinical safety studies in support of clinical trials are also supported. The ADRN currently consists of eight clinical sites with the capacity to add clinical sites when necessary to complete clinical trials and clinical studies in a timely manner.

The current ADRN SACCC maintains a registry of AD subjects and controls with patient-specific information and results from laboratory tests. More information about this research program is available at http://www.nationaljewish.org/adrn/index/sites/.

• Consortium of Food Allergy Research (CoFAR). This collaborative clinical research program focuses on: (i) developing new approaches to treat and prevent IgE-mediated food allergy, including food allergy-associated anaphylaxis and food allergy-associated eosinophilic gastrointestinal disease; (ii) identifying mechanisms underlying the natural histories of these disorders; and (iii) defining the genetic components of these disorders. The scope of clinical research carried out includes: (i) single and multi-site Phase I and Phase II clinical trials of therapeutic and preventive approaches; (ii) Phase III clinical trials in instances where a Phase II clinical trial has been successfully completed and NIAID approval has been granted; (iii) observational/natural history studies using human subjects and integrated mechanistic studies; and (iv) genetic studies using human subjects and including replication and/or functional studies. This research program currently supports six clinical sites and is cosponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). More information about this research program is available at http://www.cofargroup.org.
• Inner City Asthma Consortium (ICAC). ICAC is a nationwide network of clinical and basic research sites focused on the disproportionate burden of asthma among children residing in the inner city. Major program goals include: (i) improving asthma control; (ii) developing more efficacious treatment approaches; (iii) evaluating strategies to prevent asthma development; (iv) defining asthma phenotypes; and (v) enhancing understanding of the specific factors involved in the immunopathogenesis of asthma. The scope of clinical research carried out includes: (i) clinical trials at all phases to improve asthma control using immunomodulatory therapies and to prevent asthma development using immunomodulatory, pharmacologic or environmental interventions; (ii) cross-sectional phenotyping studies to improve asthma immunophenotyping and to identify differences leading to improved understanding of specific phenotype pathophysiology and the design of phenotype-specific therapeutic interventions; (iii) longitudinal birth cohort studies; (iv) mechanistic studies to improve understanding of the immunopathogenesis of asthma in these populations, elucidate the mechanisms and predict the efficacy of immunotherapeutic modalities, and identify and evaluate potential biomarkers of the induction, maintenance and loss of immune tolerance induced by such modalities; and (v) the development, validation, and implementation of basic science methodology to support the primary outcomes of mechanistic studies. This Consortium is composed of eight Clinical Study Sites for the conduct of clinical trials and clinical studies, and two Basic Science Sites for the design of studies to test mechanistic hypotheses on asthma immunopathogenesis, develop, validate, and implement basic science methodology for mechanistic studies, and serve as core laboratories for the measurement of laboratory outcomes.

The current ICAC SACCC maintains a Clinical Specimen Repository of biological samples from all Consortium studies.

• ITN - Asthma and Allergic Diseases. Network clinical trials, mechanistic studies and assay development activities in asthma and allergic diseases focus on tolerance induction through innovative allergen immunotherapy strategies, including but not limited to: selectively amplifying responses, making immunotherapy more robust and durable; shortening time required to achieve beneficial and long-lasting immune responses; bringing greater safety to the clinical practice of immunotherapy; and applying immunotherapeutics more widely, e.g., where no safe, effective treatments are available, to prevent/delay disease development, and to use well characterized and purified antigens which facilitate dosing strategies as interventions. More information about this research program is available at http://www.immunetolerance.org/researchers/clinical-trials/allergy-asthma.

Autoimmune Diseases Clinical Research Programs

• Autoimmunity Centers of Excellence (ACE). Two closely related research programs provide support to institutions dedicated to fostering collaborations among basic and clinical scientists to advance understanding of autoimmunity and accelerate the development of improved therapies for autoimmune diseases.

ACE Basic Research Program investigates autoimmune disease in humans to identify common and distinct mechanisms in disease pathogenesis, e.g., mechanisms of action of existing therapies, biomarkers of disease status, cellular analysis for diagnosis or therapy, etc.

ACE Clinical Research Program supports single and multi-site clinical trials to evaluate promising strategies and approaches for the treatment and prevention of a broad range of autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, and scleroderma. The scope of clinical strategies/approaches includes: (i) investigational drugs; (ii) combinations of approved drugs; (iii) comparative effectiveness studies using approved drugs; and (iv) re-purposing drugs approved for other indications based on biological mechanisms. All ACE clinical trials include integrated mechanistic studies designed to enhance understanding of the mechanisms of action of the interventions being evaluated. Support is also provided for preclinical safety studies in support of clinical trials and for collaborative projects, using samples from previously completed clinical trials, in multiple areas of interest, including but not limited to: (i) pathogenesis of human autoimmune disease; (ii) mechanisms of action of existing therapies; (iii) biomarkers of disease status, including disease progression, prediction of remission or relapse, and therapeutic response; (iv) cellular analyses for diagnosis or therapy; and (v) analyses of genetic variations. More information about this research program is available at www.autoimmunitycenters.org.

• Hematopoietic Stem Cell Therapy Consortium (HSCTC). Through the HSCTC, DAIT supports two clinical trials to evaluate autologous stem cell transplantation for the treatment of autoimmune diseases: (i) HALT-MS (High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis), conducted by the ITN, has completed enrollment with follow-up of 24 subjects to be completed in 2015, and (ii) SCOT (Scleroderma Cyclophosphamide or Transplantation) has completed enrollment of 75 subjects and is now in the clinical follow-up phase with estimated completion in 2016. These complex clinical trials also include studies of the underlying mechanisms of these diseases and treatments. Center support will be provided for the closure of these two studies, including data clean-up and analysis, site closure, preparation of the final study report and preparation of ClinicalTrials.gov results.
• ITN Autoimmune Diseases. Network clinical trials, mechanistic studies and assay development activities in autoimmune diseases focus on immune-based approaches to restore tolerance, while preserving protective immunity, targeting T and B cell subsets and pathways, including: 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, and antigen specific therapies to modulate autoreactive immune responses. More information about this research program is available at http://www.immunetolerance.org/researchers/clinical-trials/autoimmune-disease.

Transplantation Clinical Research Programs

• Clinical Trials in Organ Transplantation (CTOT). The CTOT is a collaborative consortium, composed of 57 clinical sites in the U.S. and Canada, for the conduct of cooperative, multi-center Phase I, II and III clinical trials, associated mechanistic studies, and observational clinical studies in adult candidates for and recipients of heart, liver, lung and kidney transplants. The overall goals of this research program are to target immune-mediated causes of morbidity and mortality in transplant recipients and to improve long-term outcomes through the evaluation of interventions to address those causes. The CTOT’s 27 research laboratories perform a wide variety of tests in blood, urine, and tissue samples from study subjects, including cellular assays, assays of antibodies and gene expression, genomic and proteomic studies, and histopathology. The scope of clinical research carried out by the CTOT includes: (i) evaluations of improved, less toxic, and more specific immunosuppressive agents; (ii) protocols to minimize pharmacologic immune suppression; (iii) interventions in the donor that will result in improved recipient outcomes; (iv) identification and validation of biomarkers to enable accurate non- or minimally-invasive monitoring of the recipient’s immunoreactive state in order to individualize therapy; and (v) standardizing the process and procedures for diverse assays used. More information about the CTOT is available at www.ctotstudies.org.
• Clinical Trials in Organ Transplantation in Children (CTOT-C). The CTOT-C is a collaborative consortium, composed of 16 clinical sites in the U.S. and Canada, for the conduct of cooperative, multi-center Phase I, II and III clinical trials, associated mechanistic studies, and observational clinical studies to improve long-term graft acceptance and patient/graft survival in children who have undergone heart, lung, liver, small intestine, and kidney transplantation. The scope of clinical research carried out by the CTOT-C includes: (i) evaluations of new therapies and approaches to overcome immunological barriers to long-term graft and patient survival; (ii) evaluations of novel approaches to treat or prevent immune-mediated complications; (iii) investigations of underlying mechanisms of action for pathological processes and therapeutic regimens under evaluation; (iv) development of diagnostic and critical biomarkers that will facilitate routine surveillance, early diagnosis, and ongoing monitoring of processes contributing to post-transplantation morbidity and mortality; (v) evaluations of therapies for promoting the development of allograft tolerance; and (vi) standardizing the process and procedures for diverse assays used. The CTOT-C’s 15 research laboratories perform a wide variety of tests in blood, urine, and tissue samples from study subjects, including cellular assays, assays of antibodies and gene expression, genomic and proteomic studies, and histopathology. More information about the CTOT-C is available at www.ctotc.org.
• Genomics of Transplantation Cooperative Research Program (GTCRP). Through this cooperative, interdisciplinary research program, DAIT supports large-scale, broad scope genomic studies in clinical transplantation of solid organs, tissues, and cells. The objectives of this research program are to identify and characterize gene polymorphisms and gene expression patterns that: (i) correlate with and/or predict transplantation outcomes; (ii) define immune responses relating to the onset and severity of acute and chronic graft rejection; (iii) predict responses to immunosuppression to allow tailoring of therapy; and (iv) elucidate the genetic basis of variability in graft survival between populations or individuals. The long-term goal of the program is to understand the genetic basis of immune-mediated graft rejection and differences in transplant outcomes to provide a rational basis for developing more effective treatments, to design prevention strategies to improve long-term graft survival, and to improve quality of life for transplant recipients. Recipient and donor samples, coupled with clinical data, are employed for prospective and/or retrospective genomic studies addressing multiple issues in clinical transplantation, including the identification of: (i) unique immune response genes or gene expression patterns during acute and chronic graft rejection; (ii) genetic variations that influence or determine the response to immunosuppressive therapeutics; and (iii) SNPs, haplotypes, or microsatellite polymorphisms that correlate with and/or predict differences in transplant outcomes in individuals due to race, gender, or ethnicity. The GTCRP supports research at nine institutions.
• ITN Transplantation. Network clinical trials, mechanistic studies and assay development activities in transplantation focus on tolerogenic approaches to improve long-term graft survival and decrease the rates of acute and chronic rejection, including: co-stimulatory blockade regimens to inhibit T cell activation; cell-based therapies; bone marrow chimerism to induce tolerance in solid organ transplantation; and observational studies of transplant recipients who are functionally tolerant. More information about the CTOT-C is available at http://www.immunetolerance.org/researchers/clinical-trials/transplantation.

Applicants are advised to refer to http://www.niaid.nih.gov/about/organization/dait/Documents/ClinicalWorkBreakdownSfc.pdf for additional information on DAIT-supported clinical research programs and other clinical research support organizations.

The Center will consist of nine functional entities grouped as follows:

Leadership Group

One Leadership Group, headed by the Leadership Group Director, will have overall responsibility for planning, directing, coordinating, managing and evaluating Center activities.

Disease-Specific Groups

Three Disease-Specific Groups, each headed by a Group Leader, will provide services in three functional areas: (i) statistical design and analysis; (ii) protocol development; and (iii) study initiation and management. The three Disease-Specific Groups are:

• Asthma and Allergic Diseases Group
• Autoimmune Diseases Group
• Transplantation Group

Centralized Groups

Five Centralized Groups, each headed by a Group Leader, will provide support for DAIT clinical research programs for all three disease areas. The five Centralized Groups are:

• Clinical Site Monitoring Group
• Data Management and Reporting Group
• Safety Oversight and Reporting Group
• Ancillary Services Group
• Bioinformatics Group

The awardee will be expected to support the personnel, consultants and other resources necessary for statistical and clinical coordination support for (i) the continuation and completion of ongoing clinical trials, mechanistic studies, and clinical studies, and (ii) new clinical research projects approved for implementation by DAIT.

In addition, statistical and clinical coordination responsibilities will be carried out for all DAIT-supported clinical research programs with some exceptions. Those exceptions, where applicable, are noted under the descriptions of Center functions below.

The LG will be responsible for overall planning, direction, coordination, management and evaluation of the Center’s activities and for the performance of certain technical, operational, administrative and fiscal functions for the project as a whole.

LG Membership

Members of the LG will include the Disease-Specific Group Leaders as well as NIAID staff representing: (i) each of the three clinical disease areas; (ii) a bioinformatician; (iii) a regulatory officer; and (iv) on an ad hoc basis, a biostatistician. The awardee may elect to appoint Centralized Group Leaders to serve on the LG on a temporary or permanent basis.

LG Functions

The LG will be responsible for carrying out the functions specified below. The awardee may elect to establish short- and long-term LG committees focused on specific processes and procedures to guide and manage the Center’s activities.

• Establishing and implementing effective processes for decision-making and for communication within the LG, between the LG and other Center groups, with DAIT-supported clinical research programs and investigators, with other DAIT clinical research support contractors, and with multiple DAIT Branches, Offices and personnel involved in clinical research planning, execution, oversight and reporting
• Assessing the personnel and other resources required to provide support for approved clinical trials, mechanistic studies, and clinical studies across all disease areas, allocating necessary resources for specific projects, periodically reviewing the adequacy of allocated resources, and determining the need for and making adjustments in resources when appropriate
• Implementing and managing an information system to support the day-to-day activities of the Center, including hardware and software support
• Establishing, managing and updating on an ongoing basis, internet-based, password-protected collaboration portals to house study-specific documents and materials (e.g., Case Report Forms (CRFs), Investigator Brochures (IBs), informed consent forms, etc.)
• Establishing financial management capacity and systems to support a high volume of clinical research projects, timely review of expenditures and financial projections, and tracking of Center financial resources
• Establishing and implementing processes and procedures, including project management tracking and reporting system(s), for overseeing the effective implementation of clinical research support across all disease areas to ensure compliance with established timelines and DAIT, NIAID, NIH, DHHS, and other Federal regulations and requirements; identifying problems/deficiencies; and determining the need for and implementing corrective actions and/or additional training to ensure appropriate compliance
• Assisting DAIT in managing Conflict of Interest (COI) processes and procedures, including developing and coordinating the distribution and submission of disclosure forms for Data and Safety Monitoring Board (DSMB) and Safety Monitoring Committee (SMC) members
• Providing centralized technical and administrative services for planning, scheduling, materials preparation and on-site facilities and personnel needed for meetings and teleconferences of the Steering Committees for DAIT-supported clinical research programs
• Reporting to and obtaining input from the PDs/PIs of DAIT-supported clinical research programs with respect to Center procedures, processes, communications and support for specific clinical trials/studies
• Developing and implementing processes and procedures to evaluate overall Center performance, including appropriate metrics across multiple functions; conducting periodic performance evaluations; and implementing improvements when necessary
• Determining the value and feasibility of incorporating new and/or improved techniques and approaches for Center functions, e.g., statistical design and analysis, bioinformatics, etc., and overseeing their incorporation into appropriate clinical research projects
• Maintaining surveillance over changes in Federal, NIAID, NIH, and DHHS requirements for human subjects research and overseeing their timely implementation for study development, implementation and monitoring

Structure

Three Disease-Specific Groups Asthma and Allergic Diseases Group, Autoimmune Diseases Group, and Transplantation Group - will be responsible for providing support in three functional areas: (i) statistical design and analysis; (ii) protocol development; and (iii) study initiation and management. Responsibility for overall planning, tracking, managing and coordinating the activities of the Disease-Specific Groups will rest with the Group Leaders. In addition, these Group Leaders may serve as voting members of the Steering Committees for DAIT-supported clinical research programs or may delegate that role to other senior staff in their Group with NIAID approval. In addition, each Disease-Specific Group will provide appropriate project management staff for day-to-day operations. Within each Disease-Specific Group, the awardee may elect to establish additional organizational entities, e.g., sub-groups, teams, etc., to participate in planning, conducting and managing Group activities.

Disease-Specific Group Functions

All three Disease-Specific Groups will provide support for the following functions common to all three Groups:

Statistical Design and Analysis

Statistical Design

• Assist in the preparation and/or review of the appropriateness and adequacy of statistical designs for proposals from DAIT-supported investigators for clinical trials/studies
• Develop and refine study designs and statistical analysis plans for approved clinical trials/studies
• Arrange for and participate in the review of successive versions of clinical protocols and recommend improvements and modifications in statistical design and statistical analysis plans.

Statistical Analysis

• Prepare Interim and Final Statistical Analyses of all clinical trial/study data in collaboration with DAIT-supported investigators
• Participate in preparing scientific manuscripts and reports for publication and presentation
• Review the accuracy and completeness of statistical data for abstracts, manuscripts and presentations reporting on the results of research conducted by DAIT-supported clinical research programs
• Provide statistical assistance in connection with certain regulatory requirements and activities for clinical trials conducted under Investigational New Drug Applications (INDs) (e.g., materials preparation and oral presentations on statistical design and analysis plans and issues for discussions with and inquiries from the U.S. Food and Drug Administration (FDA) and other Regulatory Health Authorities
• Prepare regular statistical reports such as periodic study status reports, DSMB/SMC reports, mechanistic analysis reports and components of Interim and Final Clinical Study Reports
• Assist in preparing materials for and make oral presentations at DSMB/SMC meetings/teleconferences regarding interim and final safety data and, on an as-needed basis, in preparing written summaries of DSMB/SMC deliberations

Protocol Development

Development of Clinical Protocols and Protocol-Related Documents

In collaboration with investigators and DAIT staff:

• Take primary responsibility for preparing clinical protocols and protocol-related documents required for study implementation, e.g., CRFs, IBs, Manuals of Operations (MOOs), including protocol components to address clinical, medical, pharmacological/pharmacokinetic, toxicologic, chemistry and manufacturing aspects
• Review successive draft protocols and protocol-related documents and make recommendations for modifications/improvements
• Arrange for and coordinate the review of successive versions and final clinical protocols and protocol-related documents by investigators and DAIT staff

Primary responsibility for protocol development for ITN clinical trials and mechanistic studies rests with the Network’s Clinical Trial Group, with this Center providing expert advice and assistance in this area on an as-needed basis.

Study Initiation and Management

Study Initiation and Training of Clinical Site Personnel

• Assist in planning and developing materials for and participate in study initiation meetings, teleconferences, webcasts and videocasts, to provide standard and study-specific training for clinical site personnel in multiple areas, e.g., key features, procedures and requirements for study implementation, data collection instruments and procedures for data collection, entry, management, validation, quality control and submission, and standard and study-specific procedures and instructions for AE and SAE reporting. Coordinate planning and materials development for study initiation activities with other appropriate Center Groups, DAIT staff and clinical site investigators.
• Plan and conduct training programs for clinical site personnel covering regulatory requirements and standard practices for human subject research, DHHS (Department of Health and Human Services), NIH and NIAID policies, and policies and procedures used by DAIT and DAIT-supported clinical research programs for protocol development, implementation, monitoring and reporting.
• Prepare and provide to clinical site personnel Standard Operating Procedures (SOPs) covering all such policies, procedures and requirements, and working with DAIT and clinical site staff to identify site-specific training needs.
• Assess the thoroughness and quality of the training conducted.

Study Management

Manage, coordinate and monitor the implementation and conduct of clinical trials/studies, including:

• Participating in the development of Data and Safety Monitoring Plans (DSMPs)
• Establishing Study Management Teams (SMTs) for each clinical trial/study to include Center staff, Protocol Chairs and DAIT staff, and planning, scheduling and developing materials/data for SMT meetings and teleconferences
• Conducting regular reviews of active clinical trials to assess multiple performance factors, e.g., subject accrual and retention, adherence to protocol-specific requirements, etc.
• Documenting action items, problems and deficiencies and recommending improvements
• Assisting in preparing and presenting to Steering Committees for DAIT-supported clinical research programs status reports on specific clinical trials/studies

Asthma and Allergic Diseases Group Additional Functions

In addition, the Asthma and Allergic Diseases Group will have the following responsibilities and functions:

Atopic Dermatitis Research Network (ADRN) Subject Registry

• Operate, maintain and update a computerized registry database management system for the collection, storage, management, tracking, quality control and reporting of data on subjects participating in ADRN clinical research, including subjects with atopic dermatitis and controls. Key system features include but are not limited to the following: remote data entry and transmission of data by ADRN clinical sites; system security and integrity; secure, password-protected read access for designated DAIT staff and ADRN investigators; and customizable report generation capabilities by multiple parameters
• Develop and monitor adherence to qualify assurance/quality control procedures
• Develop and implement SOPs and instructions on the use of the tracking and inventory data management system by ADRN clinical site personnel, and provide training in system use

Inner City Asthma Consortium (ICAC) Clinical Specimen Repository

• Operate and maintain a repository for the receipt, storage, tracking and management of biological specimens from ICAC-supported clinical trials/studies, including a computerized database management system with multiple features/capabilities, e.g., password-protected read access for designated DAIT staff and clinical site investigators, provision of appropriate labeling, storage, handling and disposal of sensitive or controlled data, and customizable report generation
• Develop and implement SOPs and instructions on the use of the database management system by clinical site personnel, and provide training in system use

Clinical Site Monitoring Group (CSMG)

The Clinical Site Monitoring Group (CSMG) will perform the functions delineated below for all DAIT-supported clinical research programs with the exception of clinical site monitoring support for the ITN and AADCRCs, which will be supported through a separate contract. The Center will be required to collaborate and coordinate with the ITN Clinical Site Monitoring Center contractor with respect to ensuring compliance with Federal regulatory requirements and NIH and NIAID policies and procedures.

Standard Operating Procedures (SOPs)

• Develop and implement SOPs governing all aspects of the support to be provided, e.g., all types of visits, descriptions of each aspect of clinical trial conduct and clinical site operations to be reviewed, detailed work instructions, etc.
• Develop and implement SOPs to provide monitoring reports and other related data to DAIT utilizing the NIAID Clinical Research Management System (also known as the DAIT Clinical Research Information System (CRIS)).
• Keep abreast of all changes in Federal and country-specific requirements for human subject research and good practice guidelines, update SOPs as necessary, and ensure appropriate training of CSMG staff on new requirements/guidelines.

Site Establishment Visits

• Plan for, conduct and report the findings of site establishment visits for any new clinical sites to assess the adequacy of all site facilities, personnel and operating procedures.
• Recommend and assist in implementing necessary corrective/remedial actions.

Interim Site Monitoring Visits

• Plan for and conduct interim site monitoring visits to assess site performance/operations, e.g., the accuracy, completeness and timeliness of data collection and entry, adherence to inclusion and exclusion criteria, accuracy and completeness of reporting SAEs and protocol violations, documentation of informed consent and adherence to informed consent procedures, pharmacy operations, sample storage and GLP audits as needed.
• Prepare written reports on the findings of interim site monitoring visits, identify site-specific problems/deficiencies, and provide recommendations for improvements and remedial/corrective actions.
• Present findings from interim site monitoring visits to DAIT staff, PD(s)/PI(s), and Steering Committees for DAIT-supported clinical research programs upon request.
• Assist in implementing approved corrective/remedial actions through a variety of methods and arrange for the participation of other Center staff when appropriate to carry out such actions.

Additional Site Visits

• Plan, conduct and report the findings of additional types of site visits and, where appropriate, recommend and assist in implementing corrective actions. This includes remedial/for cause visits in instances of suspected non-performance and/or non-compliance with regulatory requirements, and site and study closeout visits to confirm proper closeout of specific protocols.
• Assist clinical sites in preparing for audits from the FDA and other Regulatory Health Authorities with respect to regulatory requirements for the conduct of human subject research.

Site Monitor Training

• Develop and implement a plan for the training of site monitors providing for initial and continuing training activities to be carried out both in-house and through outside organizations; frequency; methods/approaches; curricula, duration and instructors; and evaluation plans.

Data Management and Reporting Group (DMRG)

The Data Management and Reporting Group (DMRG) will perform the following functions for all three disease areas specified in this FOA.

Data Management System Clinical and Laboratory Study Data

Establish and operate a computer-based system, with appropriate system security and integrity provisions, to create databases for all clinical and laboratory study data providing for multiple features and capabilities, including:

• a central facility for the receipt, entry, verification, processing, correcting, storing, tracking, and reporting on all clinical data and clinical laboratory data;
• computerized registration and randomization of the majority of subjects and non-computerized methods on a limited basis;
• computerized study forms and systems for remote data entry and transmission, via the internet, of subject data from study sites and laboratories and non-computerized transmission methods when necessary;
• data links to DAIT CRIS to provide enrollment and study status updates;
• real-time electronic notification to DAIT staff and clinical investigators in instances where one or more protocol-specific or NIAID safety review committee-specific data trigger halting rule(s); and
• generation of periodic reports on status of specific studies and across the data for multiple parameters.

Data Management System Safety Data

Establish and operate a computer-based system, with appropriate system security and integrity procedures, to monitor, track, archive and report Serious Adverse Events (SAEs) from all clinical sites providing for multiple features and capabilities, including:

• an internet-based tracking system for the receipt, reporting and disposition of SAEs;
• real-time electronic notification of SAEs to DAIT medical and scientific staff, clinical investigators, DAIT DSMBs/SMCs and SACCC staff; and
• compliance with U.S. and non-U.S. regulations and requirements for the collection, verification and processing of SAE Reports and safety information.

Data Quality Control

(i) Establish a quality control system for all clinical, laboratory and SAE data providing for verification of 100 percent of study data and multiple features and capabilities, including:

• computerized validation and error-checking;
• strategies to assure uniform, standardized data collection and appropriate conduct of multi-center studies across participating study sites;
• ongoing quality assurance checks and summaries of results; and
• a computerized data query system for aberrant and/or missing data.

(ii) Prepare and review and revise on an annual basis manuals and procedures documenting data collection, editing and validation standards and procedures.

Training of Clinical Site Personnel

Provide training to clinical site personnel on the design of data collection instruments and procedures for data collection, entry, management, validation, quality control and submission through user manuals and participation in Study Initiation activities.

Data Management System Improvements

Investigate and assess the benefits and applicability of new and improved technologies to enhance the efficiency and ease of use of the two data management systems, and provide written recommendations to DAIT for proposed enhancements and improvements.

Safety Oversight and Reporting Group (SORG)

The Safety Oversight and Reporting Group (SORG) will perform the following functions for all three disease areas specified in this FOA.

Safety Reporting

Establish and operate a Safety Reporting Center for all clinical trials to provide the following:

• work flow processes utilizing established safety data management systems for collecting SAE Reports from participating clinical sites, SOPs for SAE reporting, and training clinical site personnel in system use;
• protocol-specific SAE reporting forms and instructions;
• a telephone help line to respond to inquiries about clinical events and obtain SAE Report information;
• evaluation of all SAE Reports submitted, within one business day of receipt, by Center nursing/safety desk staff; and
• provide SAE documents and disposition forms to DAIT utilizing, in part, the DAIT CRIS.

DAIT Data and Safety Monitoring Boards (DSMBs)

Provide support for certain functions associated with safety monitoring by independent DSMBs/SMCs established by DAIT in each of the three disease areas to review final clinical protocols and interim and final study data to ensure the safety of clinical trial subjects, including:

• assembling materials for DSMB/SMC review (e.g., final draft clinical protocols, protocol amendments, statistical analyses, etc.);
• establishing and maintaining web portals;
• archiving DSMB/SMC materials; and
• assisting in preparing and coordinating communications with DAIT staff, Steering Committees for DAIT-supported clinical research programs, and clinical site personnel in instances where DAIT accepts a DSMB/SMC recommendation to change an ongoing study.

Ancillary Services Group (ASG)

The Ancillary Services Group (ASG) will perform the following functions for all three disease areas specified in this FOA.

Sample Tracking

Establish and operate one or more computerized database systems for the site- and study-specific tracking and reporting/reconciliation of specimen collection, sample processing, inter-laboratory shipping and receipt, final specimen disposition, and facilitation of data handling for core mechanistic laboratory results, e.g., proteomic array, ELISPOT data.

Provision of Materials for Laboratory Testing

Purchase, package and ship kit materials required for protocol-specific specialized (core/mechanistic) laboratory tests, ensure intact receipt, and maintain a computerized inventory of all materials distributed.

Bioinformatics Group (BG)

The primary role of the Bioinformatics Group (BG) is to foster the long-term capacity for data exchange and utilization for DAIT-supported clinical research programs and the immunological community in general. Internally, the BG will work with the DMRG and other Center Groups to facilitate data collection and integration, including complex clinical and mechanistic studies from the three disease-specific areas specified in this FOA. The BG will also be a resource for appropriate data exchange and advice for external investigators and data repositories. Collectively, the BG should bring together individuals with expertise in biostatistics, systems immunology, data management, programming, and high performance computing.

To facilitate broad and optimal utility of data collected by DAIT-supported clinical research programs, the BG will participate/advise on aspects of experiment planning, building of computational infrastructure, data management and analysis, and collaboration with domain specialists and/or the bioinformatics staff of DAIT-supported clinical research programs, as needed, to address the increasingly complex and big data needs.

Specific functions of the BG pertaining to supporting the collection, storage, retrieval, archiving, integration of generated data and computing infrastructure include:

• Adopting and establishing uniform community data standards and exchange formats, including developing and implementing Standard Operating Procedures (SOPs)
• Adapting and making available software tools, databases and content management systems
• Establishing and maintaining a tracking system and associated documentation with the capacity to reproduce data modifications and analysis
• Disseminating summaries and reports, including assisting with managing these materials for completed studies for distribution to the general scientific community
• Developing and implementing strategies for the long-term maintenance and reusability of the data, software tools and the data systems by coordinating with public repositories
• Securely managing computer resources and SACCC infrastructure to accommodate both legacy and new data, as well as building sufficient expansion to accommodate future growth and expanded data management and analysis needs

In addition, leveraging on its unique position of interacting and overseeing multiple studies, the BG will support and assist with the utilization of Center information resources and infrastructure for primary and secondary data analyses, including:

• Keeping abreast of emerging technologies and data analysis methods
• Providing input into the development, review and implementation of proposed studies/sub-studies
• Sharing data analysis best practices to empower investigators to perform analyses, annotations and comparisons of clinical and mechanistic studies
• Participating in the preparation of manuscripts and timely release of data into public repositories such as ImmPort
• Offering training and consultation on using Center-supported data, software and computing resources to the end users

Note that mechanistic and clinical data integration from ITN-supported clinical trials is under the purview of the ITN’s Bioinformatics Group. The BG should include collaboration and coordination with the ITN Bioinformatics Group as part of its functions.

Regulatory Sponsorship and Support

It is anticipated that, with rare exceptions, the NIAID will serve as the regulatory sponsor for 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. In addition, the Center will coordinate and collaborate with DAIT’s Regulatory Management Center (RMC) contractor responsible for providing 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).

Clinical Products Center

A separate contract provides support for all DAIT clinical research programs with respect to the receipt, storage, inventory, packaging, quality assurance, distribution and disposal of study products. The Center will collaborate with this contractor to ensure appropriate management of study products.

Bioinformatics Support Contract (BISC)

BISC provides resources for all DAIT-supported clinical research programs, including resources for data standard and exchange format development, long-term data archive, and public data sharing. The Center will collaborate with the BISC contractor with respect to the transfer of clinical and mechanistic study data, in accordance with data standard and exchange formats, for long-term archiving and for public data sharing.

ITN Clinical Site Monitoring Support

A separate contract will provide clinical site monitoring support for the ITN and AADCRC and will not be funded under this FOA.

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 scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The NIAID intends to commit $16.5 million in total costs in FY 2015 to fund one award.
Award Budget	Application budgets are limited to $16.5 million per year in total costs.
Award Project Period	The scope of the proposed project should determine the project period. The maximum project period is 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)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

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

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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 can access the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

Most applicants will use NIH’s ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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

The letter of intent should be sent to:

Paul Amstad, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Room 3121, MSC-7616
6700B Rockledge Drive
Bethesda, MD 20892-7616
Zip Code for express couriers: 20817-7616
Telephone: 301-402-7098
Fax: 301-480-2408
Email: [email protected]

Component Types Available in ASSIST	Research Strategy/Program Plan Page Limits
Overall	30 pages
Admin Core - In ASSIST select component type Admin Core for Leadership Group	12 pages
Complex Component -- In ASSIST select component type Complex Component for the Disease-Specific Component Autoimmune Disease Group: A. ADG Structure and Staffing B. Statistical Design and Analysis for Clinical Research on Autoimmune Diseases C. Protocol Development for Clinical Research on Autoimmune Diseases D. Study Initiation and Management for Clinical Research on Autoimmune Diseases	A. 6 pages B. 30 pages C. 12 pages D. 12 pages
Complex Component - In ASSIST select component type Complex Component for the Disease-Specific Component Transplantation Group: A. TG Structure and Staffing B. Statistical Design and Analysis for Clinical Research in Transplantation C. Protocol Development for Clinical Research in Transplantation D. Study Initiation and Management for Clinical Research in Transplantation	A. 6 pages B. 30 pages C. 12 pages D. 12 pages
Complex Component - In ASSIST select component type Complex Component for the Disease-Specific Component Asthma and Allergic Diseases Group: A. AADG Structure and Staffing B. Statistical Design and Analysis for Clinical Research on Asthma and Allergic Diseases C. Protocol Development for Clinical Research on Asthma and Allergic Diseases D. Study Initiation and Management for Clinical Research on Asthma and Allergic Diseases E. Atopic Dermatitis Research Network (ADRN) Subject Registry F. Inner City Asthma Consortium (ICAC) Clinical Specimen Repository	A. 6 pages B. 30 pages C. 12 pages D. 12 pages E. 6 pages F. 6 pages
Core - In ASSIST select component type Core when preparing the following five Centralized Group Components: Clinical Site Monitoring Group Data Management and Reporting Group Safety Oversight and Reporting Group Ancillary Services Group Bioinformatics Group	12 pages 12 pages 12 pages 12 pages 12 pages

Additional page limits described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

• Overall Component: required
• Leadership Group Component: required
• Autoimmune Diseases Group Component: required
• Transplantation Group Component: required
• Asthma and Allergic Diseases Group Component: required
• Clinical Site Monitoring Group Component: required
• Data Management and Reporting Group Component: required
• Safety Oversight and Reporting Group Component: required
• Ancillary Services Group Component: required
• Bioinformatics Group Component: required

When preparing your application in ASSIST, use Component Type Overall .

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.. Not Applicable to any of the components listed in this FOA.

Research & Related Other Project Information (Overall)

Follow standard instructions.

Project/Performance Site Location(s) (Overall)

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Research & Related Senior/Key Person Profile (Overall)

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/ for the entire application.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

Budget (Overall)

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

PHS 398 Research Plan (Overall)

Specific Aims: Briefly describe the specific aims of the proposed Center.

Research Strategy: The Overall section of the application should describe proposed plans for the organization and staffing of the Center, how the components of the organization, including key personnel, will interact and ensure efficient cooperation, communication and coordination, and how the proposed organization of Center components will create an integrated entity capable of effectively providing support for DAIT-sponsored clinical trials and clinical studies.

Include the following:

(i) An overall organizational chart showing the nine required Center Group Components and any additional organizational entities proposed (e.g., sub-groups, committees, etc.), and identifying the names and degrees of the proposed PD(s)/PI(s), the Group Leaders, and Group staff serving in a senior role;

(ii) A description of overall plans for the governance of the Center, including lines of authority and reporting, decision-making processes, and communication processes within the Center and with DAIT senior officials, research program PDs/PIs, and other DAIT clinical research support organizations, including proposed processes for resolving operational issues and problems.

(iii) A discussion of the rationale for the proposed mix of expertise and experience represented by the Disease-Specific and Centralized Group Leaders and personnel serving in a senior role with respect to the Center’s scientific, clinical, technical and operational support responsibilities;

(iv) An overall discussion of considerations of particular relevance and importance for the design, development, initiation, monitoring and analysis of clinical trials and clinical studies for each of the three disease areas, including the applicability of current and new innovative strategies, methodologies and approaches to overcome common problems and difficulties in human subjects research for these diseases;

(v) A discussion of bioinformatics approaches/methodologies applicable to the analysis of combined mechanistic and clinical data, including new innovative strategies relevant for the three disease areas; and

(vi) A detailed description of the relevant expertise, experience and accomplishments of the applicant organization in the planning, direction, coordination, management and provision of the full scope of clinical research support provided for in this FOA in all the three disease areas. Include the following:

Clinical Research Programs/Projects. A listing of the clinical research programs/projects, both ongoing and completed, for which statistical and clinical coordination support has been provided by the applicant organization over the past five years, including programs/projects sponsored by public and private sector organizations/entities. For each program/project, provide the following information; (i) the title of the clinical research program/project; (ii) the name of the research program/project sponsor; (iii) the scope of statistical and clinical coordination support provided; and (iv) the time period of support.

Accomplishments. A brief summary of the accomplishments of the applicant organization with respect to the provision of statistical and clinical coordination support over the past five years for both completed and ongoing clinical research programs/projects, e.g., number of clinical trials/studies for which statistical design and analysis support has been provided, number of clinical protocols developed, number of clinical trials for which clinical site monitoring has been conducted, number of data management systems established and operated, etc.

Support for Specific Clinical Trials/Studies. A listing of individual clinical trials, mechanistic studies and clinical studies, both ongoing and completed, for which the applicant organization has provided support over the past five years in the three disease areas within the scope of this FOA. Display information by specific disease area, i.e., asthma and allergic diseases, autoimmune diseases and transplantation, and provide the following for each clinical trial/study: (i) study title, including clinical trial phase where applicable, and study sponsor and/or IND sponsor; (ii) sample size and number of participating clinical sites and laboratories; (iii) specific support functions performed (e.g., statistical design and analysis, protocol development, clinical site monitoring, data management, etc.); and (iv) for each specific support function performed, the names of all senior personnel proposed for this FOA with primary responsibility for overall direction/management and for the actual performance of the support function.

Multiple PD/PI Leadership Plan: Identify the PD/PI proposed to serve as the Director of the Leadership Group (LG), describe his/her qualifications for carrying out LG responsibilities, and describe the roles and responsibilities of those PDs/PIs not designated to serve as the LG Director.

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 SF424 (R&R) 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 as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type Admin Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Leadership Group)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Leadership Group)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Leadership Group)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Leadership Group)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Leadership Group)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• If the award provides for a single PD/PI, that individual will serve as the Director of the LG. If the award provides for multiple PDs/PIs, the PDs/PIs will select a single PD/PI from among themselves who has the qualifications indicated below to serve as the LG Director. This individual will also serve as the contact PD/PI for the award.
• LG Director’s qualifications include: (i) a Doctorate degree in quantitative sciences; (ii) extensive experience and expertise relative to the overall design, execution, monitoring and analysis of clinical research, particularly with respect to immune-mediated diseases; (iii) experience in the design, management and oversight of computer-based systems and databases for clinical research, the management and coordination of safety oversight and reporting functions for human subjects research, clinical site monitoring and training; (iv) demonstrated capability and experience to plan, implement, track, coordinate, and manage multiple diverse activities in support of large and complex clinical research programs; (v) considerable skill and experience in communicating and interacting effectively with research program sponsors, investigators, and other clinical research service organizations; and (vi) the ability to manage and assess the performance of a diverse staff of scientific, technical and administrative personnel.
• The LG Director may not also serve as one of the Disease-Specific Group Leaders.
• The LG will include a Senior Project Manager with responsibility for overseeing day-to-day operations for the project as a whole. The qualifications of the Project Manager include: relevant education, training, expertise and recent experience. Indicate recent projects of similar scope and complexity and the level and scope of responsibility for each project.

Budget (Leadership Group)

Budget forms appropriate for the specific component will be included in the application package.

Budget for staffing of the LG should be included and limited to the activities of this Group. The Director of the Leadership Group (LG) will be required to commit not less than 3.6 calendar months per year to the project. Additional support for activities covered in later Group descriptions should be requested for the budgets for those Groups. Infrastructure support related to LG functions should be included here as well.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Leadership Group)

Specific Aims: Briefly describe the specific aims of the LG.

Research Strategy:

LG Structure and Staffing. Describe in detail plans for the structure and staffing of the LG. Additional organizational entities, e.g., groups, sub-groups, committees, etc., may be established to carry out specific scientific, technical, and administrative responsibilities and/or to participate in the planning, conduct and management of Center activities. The use of tables, diagrams, flow charts and organizational charts is strongly recommended. Include: (i) descriptions of recent projects of similar scope and complexity and the level and scope of responsibility for each project of all key LG personnel serving in a senior role; and (ii) descriptions of the responsibilities of all proposed functional entities within the LG, and delineation of lines of authority and reporting among proposed Center personnel serving in a senior role.

LG Functions. Provide proposed plans, procedures and processes for the performance of LG functions. Include:

(i) project management and tracking systems for overseeing the effective implementation of clinical research support across all clinical research projects and disease areas;

(ii) assessing, allocating and adjusting Center resources across all clinical research projects and disease areas;

(iii) financial management, tracking and reporting systems and processes;

(iv) information system(s) to support day-to-day activities of the project as a whole, as well as study-specific collaboration portals;

(v) metrics, process(es) and schedules for evaluating Center performance, as well as approaches for implementing necessary improvements;

(vi) assisting in the management of Conflict of Interest (COI); and

(vii) technical and administrative support for meetings/teleconferences.

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 SF424 (R&R) Application Guide, with the following modification:

Generally, Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and GWAS Sharing Plan) are expected, but they are not applicable for this component.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Leadership Group)

Not Applicable

PHS 398 Cumulative Inclusion Enrollment Report (Leadership Group)

Not Applicable

When preparing your application in ASSIST, use Component Type Complex Component.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Autoimmune Diseases Group)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Autoimmune Diseases Group)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Autoimmune Diseases Group)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Autoimmune Diseases Group)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Autoimmune Diseases Group)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• Autoimmune Diseases Group Leader’s qualifications include: (i) a Doctorate degree in Statistics or equivalent; (ii) substantial experience and expertise in the statistical design, development, implementation, monitoring and analysis of clinical research on autoimmune diseases; (iii) expertise and experience in the management, coordination and oversight of statistical design and analysis components of IND and IDE submissions; (iv) demonstrated capability and experience to plan, implement, track, coordinate, and manage multiple diverse activities in support of large and complex clinical research programs; (v) considerable skill and experience in communicating and interacting effectively with research program sponsors, investigators, and other clinical research support organizations; and (vi) the ability to manage and assess the performance of a diverse staff of scientific, clinical, technical and administrative personnel. In addition, demonstrate a working understanding of disease pathogenesis and of currently available therapies and prevention strategies, and knowledge of the populations affected.
• The Autoimmune Diseases Group Leader may not also serve as the Leadership Group Director.

Budget (Autoimmune Diseases Group)

Budget forms appropriate for the specific component will be included in the application package.

At the time of the publication of this FOA, the autoimmune disease portfolio is comprised of 32 clinical trials and studies, of which 30 are interventional (23 under IND) and 2 are observational. Further information about the details of these studies is available at http://www.niaid.nih.gov/about/organization/dait/Documents/ClinicalWorkBreakdownSfc.pdf. Information about related manuscripts and reports can also be found at that site.

Clinical study summary:

• 3 are in development
• 9 are enrolling
• 7 are in follow-up and
• 11 are in analysis.

The interventional trials range in size from 10 to 200 subjects, but average around 100. The duration of individual participation ranges from approximately 12 weeks to 5 years, with an average of 12 months. As for the number of sites, the average is 11, but ranges from 1 to 26. All interventional trials include mechanistic studies requiring collection of immunologic data.

The applicant should assume the following during the period of the award:

• Approximately 3 (1 ITN) interventional trials will be developed per year
• The size of the interventional will vary but will average around 100 subjects
• The duration of individual participation in the trials will vary but will be 12 months on average
• The trials will be with novel interventions in a diverse population of pediatric and adult patients with autoimmune diseases requiring on average monthly safety monitoring reports and team meetings
• Trials will require 12 sites on average for completion; typically sites managed by this grant will be in North America
• All interventional trials will include mechanistic studies requiring collection and analysis of clinical and immunologic data; an exception is that the ITN has independent support for data dense (microarray; mechanistic multiparameter flow cytometry beyond standard clinical applications; etc.) correlative analyses that should not be budgeted here
• Two purely mechanistic or observational studies will be developed and managed annually

Budget for staffing related to the activities of the ADG should be included here as well as travel ADG leadership and administrative staff needed to support the activities of Network meetings. The autoimmune diseases group leader will be required to commit not less than 7.2 calendar months per year to the project. For travel purposes, assume two ACE Steering Committee meetings and 3 ITN related meetings per year. At least two will be in the metropolitan Washington, D.C. region.

If consortium agreements are proposed to conduct Group activities include budget information here. Budget information for proposed consortium agreements is required.

Note: Of the four subsections of the ADG, Section C. Protocol Development for Clinical Research on Autoimmune Diseases; and Section D. Study Initiation and Management for Clinical Research on Autoimmune Diseases are less relevant to ITN studies since ITN has additional support for these areas. ADG participation in study conference calls, meetings, etc. in support of these areas should be budgeted.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Autoimmune Diseases Group)

Specific Aims: Briefly describe the specific aims of the ADG.

Research Strategy: The Research Strategy consists of the following four subsections uploaded as a single pdf: A. ADG Structure and Staffing; B. Statistical Design and Analysis for Clinical Research on Autoimmune Diseases; C. Protocol Development for Clinical Research on Autoimmune Diseases; and D. Study Initiation and Management for Clinical Research on Autoimmune Diseases.

A. ADG Structure and Staffing.

Describe in detail plans for the structure and staffing of the ADG. Additional organizational entities, e.g., groups, sub-groups, committees, etc., may be established to carry out specific scientific, technical, and administrative responsibilities and/or to participate in the planning, conduct and management of Center activities. Include: (i) descriptions of recent projects of similar scope and complexity and the level and scope of responsibility for each project of all key ADG personnel serving in a senior role; (ii) descriptions of the responsibilities of all proposed functional entities within the ADG, and delineation of lines of authority and reporting among proposed Center personnel serving in a senior role; (iii) proposed processes for decision-making, for resolving operational issues/problems, and for communication within the ADG, between the ADG and other Center groups, with multiple DAIT Branches and Offices involved in clinical research planning, execution, oversight and reporting, with PDs/PIs and senior investigators of DAIT-supported clinical research programs, and with other DAIT-supported clinical research support organizations; and (iv) proposed processes and procedures to ensure the timely and effective implementation of Group functions across all clinical research programs and projects, track progress, identify and resolve technical and operational issues, and monitor the use and adequacy of allocated resources.

The use of tables, diagrams, flow charts and organizational charts is strongly recommended in describing the proposed structure and staffing of the Group.

B. Statistical Design and Analysis for Clinical Research on Autoimmune Diseases

(i) Provide in-depth discussions of the following:

• statistical design and analysis considerations of particular relevance and importance for the full scope of clinical research in this disease area, including: clinical trials at all phases to evaluate investigational products/approaches for treatment and prevention, mechanistic studies, clinical studies (e.g., genetic variations), and identification and validation of biomarkers;
• methodologies considered to be high priority for the statistical design and analysis of the full scope of clinical research on autoimmune diseases and the rationale for their selection;
• common statistical design and analysis problems and difficulties associated with such clinical trials/studies in general and in relation to differences among these diseases and the populations affected;
• approaches recommended to overcome and/or improve identified problems/difficulties and optimize the yield from experimental strategies; and
• emerging methodologies for the statistical design and analysis of clinical research and their applicability to this disease area.

(ii) Provide proposed plans and procedures for performing statistical design and analysis functions for the full scope of clinical research on autoimmune diseases, including: developing and/or assessing the appropriateness and feasibility of statistical designs for proposed clinical trials/studies; developing and refining study designs and statistical analysis plans for approved clinical trials/studies in collaboration with clinical investigators and senior DAIT officials; conducting interim and final statistical analyses and preparing Interim and Final Statistical Analysis Reports; providing assistance for regulatory requirements/activities associated with the statistical design and analysis of clinical trials conducted under INDs, e.g., written materials and oral presentations; preparing regular statistical reports; preparing materials for and making presentation to DSMBs; and participating in the preparation of scientific manuscripts and reports and reviewing the accuracy and completeness of statistical data and data analyses for abstracts, manuscripts and presentations.

C. Protocol Development for Clinical Research on Autoimmune Diseases

(i) Provide in-depth discussions of the following: critical aspects and considerations for preparing protocols and protocol-related documents (e.g., CRFs, IBs, Manuals of Operations) for the full scope of clinical research on autoimmune diseases, including clinical, medical, pharmacological/pharmacokinetic, toxicologic, chemistry and manufacturing aspects of protocols; common problems and difficulties encountered in developing these aspects of protocols and protocol-related documents for autoimmune diseases and also for clinical trials/studies involving multiple senior officials of research program sponsors, clinical sites and laboratories, and approaches recommended to overcome and/or reduce identified problems and difficulties.

(ii) Provide proposed plans and procedures for collaborating with clinical investigators and senior DAIT officials to develop, review and revise initial and successive drafts of protocols and protocol-related documents in this disease area, including processes for obtaining and documenting input and deliberating and achieving consensus on appropriate modifications/refinements to produce final documents.

D. Study Initiation and Management for Clinical Research on Autoimmune Diseases

(i) Study Initiation and Training of Clinical Site Personnel

• Provide in-depth discussions of critical aspects and considerations for planning, materials development, and conduct of study initiation and clinical site personnel training activities covering both standard and study-specific procedures and requirements for clinical trials/studies in autoimmune diseases. Include: a discussion of critical aspects and considerations for clinical trial/study initiation and clinical site training in this disease area for research involving multiple sites, laboratories and senior officials of research program sponsors, complex clinical research incorporating mechanistic and biomarker studies, as well as any relevant characteristics of the populations affected; regulatory requirements and standard practices for human subjects research, DHHS (Department of Health and Human Services), NIH and NIAID policies, and policies and procedures used by DAIT and DAIT-supported clinical research programs for protocol development, implementation, monitoring and reporting; data collection instruments and procedures for data collection, entry, management, validation, quality control and submission, and standard and study-specific procedures and instructions for AE and SAE reporting; a discussion of the most common training needs encountered during both study initiation and study implementation/conduct, as well as recurring problems and approaches recommended to overcome and/or resolve recurring problems; methods/venues for conducting study initiation and training activities and a description of their effectiveness, efficiency and limitations; and metrics and methods for assessing the thoroughness and quality of training activities.
• Provide proposed plans and procedures for providing study initiation and clinical site training support for clinical trials/studies focused on autoimmune diseases, including: planning; materials development; selection of appropriate venues; coordination with other Center groups, DAIT staff and clinical site investigators; methods to identify training needs of clinical sites personnel; and conduct of study initiation and training activities.

(ii) Study Management

• Provide in-depth discussions of critical aspects and considerations for managing, coordinating and monitoring the implementation and day-to-day conduct of clinical trials/studies in autoimmune diseases. Address critical study management aspects and considerations for clinical trials/studies in this disease area involving multiple sites, laboratories and senior officials of research program sponsors, complex clinical research incorporating mechanistic and biomarker studies, as well as any relevant characteristics of the populations affected. Include discussions of the following: approaches for ensuring effective communication and coordination among multiple parties; methods for ensuring consistency in study implementation across multiple sites/laboratories; and effective processes and procedures for the ongoing review of study implementation. In addition, describe common problems, difficulties and deficiencies encountered in study implementation and conduct in this disease area, as well as approaches recommended to overcome/resolve/eliminate such problems, difficulties and deficiencies, particularly for large and complex clinical research programs.
• Provide proposed plans and procedures for performing study management functions for clinical trials/studies focused on autoimmune diseases, including: establishing Study Management Teams (SMT), obtaining and disseminating relevant data for ongoing SMT monitoring of study implementation and site performance, documenting actions, problems, deficiencies and follow-up activities, and recommending and participating in the implementation of any necessary corrective/remedial actions; assisting in Data and Safety Monitoring Plans (DSMP) preparation; and assisting in the preparation and presentation of status reports on study-specific progress, problems and their resolution.

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 SF424 (R&R) 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 as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Autoimmune Diseases Group)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Autoimmune Diseases Group)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type Complex Component.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Transplantation Group)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Transplantation Group)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Transplantation Group)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Transplantation Group)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Transplantation Group)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• Transplantation Group Leader’s qualifications include: (i) a Doctorate degree in Statistics or equivalent; (ii) substantial experience and expertise in the statistical design, development, implementation, monitoring and analysis of clinical research on transplantation; (iii) expertise and experience in the management, coordination and oversight of statistical design and analysis components of IND and IDE submissions; (iv) demonstrated capability and experience to plan, implement, track, coordinate, and manage multiple diverse activities in support of large and complex clinical research programs; (v) considerable skill and experience in communicating and interacting effectively with research program sponsors, investigators, and other clinical research support organizations; and (vi) the ability to manage and assess the performance of a diverse staff of scientific, clinical, technical and administrative personnel. In addition, demonstrate a working understanding of disease pathogenesis and of currently available therapies and prevention strategies, and knowledge of the populations affected.
• The Transplantation Group Leader may not also serve as the Leadership Group Director.

Budget (Transplantation Group)

Budget forms appropriate for the specific component will be included in the application package.

At the time of the publication of this FOA, the transplantation portfolio is comprised of 34 clinical trials and studies, of which 18 are interventional (13 under IND) and 16 are observational. Further information about the details of these studies is available at http://www.niaid.nih.gov/about/organization/dait/Documents/ClinicalWorkBreakdownSfc.pdf. Information about related manuscripts and reports can also be found at that site.

Clinical study status:

• 6 are in development
• 12 are enrolling
• 9 are in follow-up and
• 7 are in analysis.

The trials vary in size from 12 to 5000 subjects, with most studies under 500 subjects. The duration of individual participation ranges from one to three years. All trials, whether interventional or observational, include in-depth studies of immunologic mechanisms requiring extensive data and specimen collection.

The applicant should assume the following during the period of the award:

• Approximately 4 to 5 trials will be developed in the first year, including one ITN trial; in subsequent years, one to three new trials will be developed each year.
• The size of the trials will vary from approximately 12 to up to 600 subjects
• The duration of individual participation in the trials will vary but will be three to four years.
• The trials will involve novel interventions in a diverse population of pediatric and adult subjects undergoing organ or vascularized composite allograft transplantation, with or without ancillary bone marrow transplantation, and requiring weekly to monthly team meetings.
• Trials will require two to 20 sites for completion. [Typically sites managed by this grant will be in North America.]
• All trials will include mechanistic studies requiring collection and analysis of clinical and immunologic data. An exception is that the ITN has independent support for data dense (microarray; mechanistic multiparameter flow cytometry beyond standard clinical applications; etc.) correlative analyses that should not be budgeted here.

Budget for staffing related to the activities of the TG should be included here as well as travel for TG leadership and administrative staff needed to support the activities of Network meetings. The transplantation group leader will be required to commit not less than 7.2 calendar months per year to the project. For travel purposes, assume twice annual Network meetings and 3 ITN related meetings per year. At least two will be in the metropolitan Washington, D.C. region.

If consortium agreements are proposed to conduct Group activities include budget information here. Budget information for proposed consortium agreements is required.

Note: Of the four subsections of the TG, Section C. Protocol Development for Clinical Research in Transplantation; and Section D. Study Initiation and Management for Clinical Research in Transplantation are less relevant to ITN studies since ITN has additional support for these areas. TG participation in study conference calls, meetings, etc. in support of these areas should be budgeted.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Transplantation Group)

Specific Aims: Briefly describe the specific aims of the TG.

Research Strategy: The Research Strategy consists of the following four subsections uploaded as a single pdf: A. TG Structure and Staffing; B. Statistical Design and Analysis for Clinical Research in Transplantation; C. Protocol Development for Clinical Research in Transplantation; and D. Study Initiation and Management for Clinical Research in Transplantation.

A. TG Structure and Staffing.

Describe in detail plans for the structure and staffing of the TG. Additional organizational entities, e.g., groups, sub-groups, committees, etc., may be established to carry out specific scientific, technical, and administrative responsibilities and/or to participate in the planning, conduct and management of Center activities. Include: (i) descriptions of recent projects of similar scope and complexity and the level and scope of responsibility for each project of all TG personnel serving in a senior role; (ii) descriptions of the responsibilities of all proposed functional entities within the TG, and delineation of lines of authority and reporting among proposed Center personnel serving in a senior role; (iii) proposed processes for decision-making, for resolving operational issues/problems, and for communication within the TG, between the TG and other Center groups, with multiple DAIT Branches and Offices involved in clinical research planning, execution, oversight and reporting, with PDs/PIs and senior investigators of DAIT-supported clinical research programs, and with other DAIT-supported clinical research support organizations; and (iv) proposed processes and procedures to ensure the timely and effective implementation of Group functions across all clinical research programs and projects, track progress, identify and resolve technical and operational issues, and monitor the use and adequacy of allocated resources.

The use of tables, diagrams, flow charts and organizational charts is strongly recommended in describing the proposed structure and staffing of the Group.

B. Statistical Design and Analysis for Clinical Research in Transplantation

(i) Provide in-depth discussions of the following:

• statistical design and analysis considerations of particular relevance and importance for the full scope of clinical research in transplantation, including: clinical trials at all phases to evaluate investigational products/approaches to prevent immune-mediated graft rejection and improve long-term graft and patient survival, associated mechanistic studies, observational clinical studies, genetic studies to understand the genetic basis of immune-mediated graft rejection, and studies to identify and validate biomarkers;
• methodologies considered to be high priority for the statistical design and analysis of the full scope of clinical research in transplantation and the rationale for their selection;
• common statistical design and analysis problems and difficulties associated with such clinical trials/studies in general and in relation to differences in transplanted organs, tissues and cells and the populations affected;
• approaches recommended to overcome and/or improve identified problems/difficulties and optimize the yield from experimental strategies; and
• emerging methodologies for the statistical design and analysis of clinical research and their applicability to this disease area.

(ii) Provide proposed plans and procedures for performing statistical design and analysis functions for the full scope of clinical research in transplantation, including: developing and/or assessing the appropriateness and feasibility of statistical designs for proposed clinical trials/studies; developing and refining study designs and statistical analysis plans for approved clinical trials/studies in collaboration with clinical investigators and senior DAIT officials; conducting interim and final statistical analyses and preparing Interim and Final Statistical Analysis Reports; providing assistance for regulatory requirements/activities associated with the statistical design and analysis of clinical trials conducted under INDs, e.g., written materials and oral presentations; preparing regular statistical reports; preparing materials for and making presentation to DSMBs; and participating in the preparation of scientific manuscripts and reports and reviewing the accuracy and completeness of statistical data and data analyses for abstracts, manuscripts and presentations.

C. Protocol Development for Clinical Research in Transplantation

(i) Provide in-depth discussions of the following: critical aspects and considerations for preparing protocols and protocol-related documents (e.g., CRFs, IBs, Manuals of Operations) for the full scope of clinical research in transplantation, including clinical, medical, pharmacological/pharmacokinetic, toxicologic, chemistry and manufacturing aspects of protocols; common problems and difficulties encountered in developing these aspects of protocols and protocol-related documents for transplantation and also for clinical trials/studies involving multiple senior officials of research program sponsors, clinical sites and laboratories, and approaches recommended to overcome and/or reduce identified problems and difficulties.

(ii) Provide proposed plans and procedures for collaborating with clinical investigators and senior DAIT officials to develop, review and revise initial and successive drafts of protocols and protocol-related documents in this disease area, including processes for obtaining and documenting input and deliberating and achieving consensus on appropriate modifications/refinements to produce final documents.

D. Study Initiation and Management for Clinical Research in Transplantation

(i) Study Initiation and Training of Clinical Site Personnel

• Provide in-depth discussions of critical aspects and considerations for planning, materials development, and conduct of study initiation and clinical site personnel training activities covering both standard and study-specific procedures and requirements for clinical trials/studies in transplantation. Include: a discussion of critical aspects and considerations for clinical trial/study initiation and clinical site training in this disease area for research involving multiple sites, laboratories and senior officials of research program sponsors, complex clinical research incorporating mechanistic and biomarker studies, as well as any relevant characteristics of the populations affected; regulatory requirements and standard practices for human subjects research, DHHS (Department of Health and Human Services), NIH and NIAID policies, and policies and procedures used by DAIT and DAIT-supported clinical research programs for protocol development, implementation, monitoring and reporting; data collection instruments and procedures for data collection, entry, management, validation, quality control and submission, and standard and study-specific procedures and instructions for AE and SAE reporting; a discussion of the most common training needs encountered during both study initiation and study implementation/conduct, as well as recurring problems and approaches recommended to overcome and/or resolve recurring problems; methods/venues for conducting study initiation and training activities and a description of their effectiveness, efficiency and limitations; and metrics and methods for assessing the thoroughness and quality of training activities.
• Provide proposed plans and procedures for providing study initiation and clinical site training support for clinical trials/studies focused on transplantation, including: planning; materials development; selection of appropriate venues; coordination with other Center groups, DAIT staff and clinical site investigators; methods to identify training needs of clinical sites personnel; and conduct of study initiation and training activities.

(ii) Study Management

• Provide in-depth discussions of critical aspects and considerations for managing, coordinating and monitoring the implementation and day-to-day conduct of clinical trials/studies in transplantation. Address critical study management aspects and considerations for clinical trials/studies in this disease area involving multiple sites, laboratories and senior officials of research program sponsors, complex clinical research incorporating mechanistic and biomarker studies, as well as any relevant characteristics of the populations affected. Include discussions of the following: approaches for ensuring effective communication and coordination among multiple parties; methods for ensuring consistency in study implementation across multiple sites/laboratories; and effective processes and procedures for the ongoing review of study implementation. In addition, describe common problems, difficulties and deficiencies encountered in study implementation and conduct in this disease area, as well as approaches recommended to overcome/resolve/eliminate such problems, difficulties and deficiencies, particularly for large and complex clinical research programs.
• Provide proposed plans and procedures for performing study management functions for clinical trials/studies focused on transplantation, including: establishing SMTs, obtaining and disseminating relevant data for ongoing SMT monitoring of study implementation and site performance, documenting actions, problems, deficiencies and follow-up activities, and recommending and participating in the implementation of any necessary corrective/remedial actions; assisting in DSMP preparation; and assisting in the preparation and presentation of status reports on study-specific progress, problems and their resolution.

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 SF424 (R&R) 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 as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Transplantation Group)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Transplantation Group)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type Complex Component.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Asthma and Allergic Diseases Group)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Asthma and Allergic Diseases Group)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Asthma and Allergic Diseases Group)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Asthma and Allergic Diseases Group)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Asthma and Allergic Diseases Group)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• Asthma and Allergic Diseases Group Leader’s qualifications include: (i) a Doctorate degree in Statistics or equivalent; (ii) substantial experience and expertise in the statistical design, development, implementation, monitoring and analysis of clinical research on asthma and allergic diseases; (iii) expertise and experience in the management, coordination and oversight of statistical design and analysis components of IND and IDE submissions; (iv) demonstrated capability and experience to plan, implement, track, coordinate, and manage multiple diverse activities in support of large and complex clinical research programs; (v) considerable skill and experience in communicating and interacting effectively with research program sponsors, investigators, and other clinical research support organizations; and (vi) the ability to manage and assess the performance of a diverse staff of scientific, clinical, technical and administrative personnel. In addition, demonstrate a working understanding of disease pathogenesis and of currently available therapies and prevention strategies, and knowledge of the populations affected.
• The Asthma and Allergic Diseases Group Leader may not also serve as the Leadership Group Director.
• Senior staff for the ADRN Subject Registry and the ICAC Clinical Specimen Repository should be included as Senior/Key Personnel. In the Biographical Sketch, indicate recent experience of the proposed technical, operational and project management staff, including descriptions of projects of similar scope and complexity and the level and scope of responsibility for each project.

Budget (Asthma and Allergic Diseases Group)

Budget forms appropriate for the specific component will be included in the application package.

At the time of the publication of this FOA, the AADG portfolio is comprised of 22 clinical trials and studies, of which 12 are interventional (9 under IND) and 10 are observational. Further information about the details of these studies is available at http://www.niaid.nih.gov/about/organization/dait/Documents/ClinicalWorkBreakdownSfc.pdf. Information about related manuscripts and reports can also be found at that site.

Clinical study summary:

• 5 are in development
• 10 are enrolling
• 9 are in follow-up and
• 2 are in analysis.

The interventional trials range in size from 40 600 subjects but average around 250 subjects. The duration of individual participation in interventional trials ranges from 12 weeks to 5 years. All interventional trials include mechanistic studies requiring collection of immunologic data. Ten of the studies in the portfolio are observational or mechanistic in nature and, with the exception of 2 longitudinal observational studies that include multiple visits and more intensive evaluations, may only require 1-2 visits and less clinical data collection and oversight. The size of observational studies ranges from 50 to 800 subjects with an average of around 400. The duration of individual participation in these studies ranges from a single visit to several years (e.g., the URECA birth cohort study of ICAC).

The applicant should assume the following during the period of the award:

• Approximately 4 (1 ITN) interventional trials will be developed per year
• The size of the interventional trials will vary but will average around 250 subjects
• The duration of individual participation in the trials will vary but will be 52 weeks on average
• The trials will be with novel interventions in a diverse population of primarily pediatric and patients having asthma, food allergies and atopic dermatitis and requiring on average monthly safety monitoring reports and weekly team meetings. A few small trials may also be conducted in adults
• Trials will require 7 sites on average for completion. Typically sites managed by this grant will be in North America but some of the current portfolio of studies is taking place in Europe.
• All interventional trials will include mechanistic studies requiring collection and analysis of clinical, immunologic, genomic or microbiom data. An exception is that the ITN has independent support for data dense (microarray; mechanistic multiparameter flow cytometry beyond standard clinical applications; etc.) correlative analyses that should not be budgeted here.
• Three purely mechanistic or observational trials will be developed and managed annually
• In addition to the above, an average of 2 interventional or observational studies per year that are to be conducted by the Asthma and Allergic Diseases Cooperative Research Centers (AADCRC) will require support for protocol development, sample size calculations and case report form development.

The applicant should also assume costs for the existing Inner City Asthma Consortium biologic sample repository of approximately 450,000 samples with 35,000 new samples per year. Most of these samples require deep-freezing (-80 C) storage facilities and will remain in storage for approximately 5 years. For samples stored on-site with various investigators in all 3 AADG Consortia (ICAC, CoFAR, ADRN), the applicant should propose and assume costs for a computerized sample tracking system for approximately 20,000 new samples per year.

The applicant should budget appropriate costs for the ADRN Subject Registry. The Registry currently has about 2,000 enrollments and expects to enroll about 200 new participants per year.

Budget for staffing related to the activities of the AADG should be included here as well as travel for AADG leadership and administrative staff needed to support the activities of Network meetings. The asthma and allergic diseases group leader will be required to commit not less than 7.2 calendar months per year to the project. For travel purposes, assume 9 Network meetings and 3 ITN related meetings per year. At least two will be in the metropolitan Washington, D.C. region.

If consortium agreements are proposed to conduct Group activities include budget information here. Budget information for proposed consortium agreements is required.

Note: Of the six subsections of the AADG, Section C. Protocol Development for Clinical Research in Asthma and Allergic Diseases; and Section D. Study Initiation and Management for Clinical Research in Asthma and Allergic Diseases are less relevant to ITN studies since ITN has additional support for these areas. AADG participation in study conference calls, meetings, etc. in support of these areas should be budgeted.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Asthma and Allergic Diseases Group)

Specific Aims: Briefly describe the specific aims of the AADG.

Research Strategy: The Research Strategy consists of the following six subsections uploaded as a single pdf: A. AADG Structure and Staffing; B. Statistical Design and Analysis for Clinical Research on Asthma and Allergic Diseases; C. Protocol Development for Clinical Research on Asthma and Allergic Diseases; D. Study Initiation and Management for Clinical Research on Asthma and Allergic Diseases; E. Atopic Dermatitis Research Network Subject Registry; and F. Inner City Asthma Consortium Clinical Specimen Repository.

A. AADG Structure and Staffing.

Describe in detail plans for the structure and staffing of the AADG. Additional organizational entities, e.g., groups, sub-groups, committees, etc., may be established to carry out specific scientific, technical, and administrative responsibilities and/or to participate in the planning, conduct and management of Center activities. Include: (i) descriptions of recent projects of similar scope and complexity and the level and scope of responsibility for each project for of all key AADG personnel serving in a senior role; (ii) descriptions of the responsibilities of all proposed functional entities within the AADG, and delineation of lines of authority and reporting among proposed Center personnel serving in a senior role; (iii) proposed processes for decision-making, for resolving operational issues/problems, and for communication within the AADG, between the AADG and other Center groups, with multiple DAIT Branches and Offices involved in clinical research planning, execution, oversight and reporting, with PDs/PIs and senior investigators of DAIT-supported clinical research programs, and with other DAIT-supported clinical research support organizations; and (iv) proposed processes and procedures to ensure the timely and effective implementation of Group functions across all clinical research programs and projects, track progress, identify and resolve technical and operational issues, and monitor the use and adequacy of allocated resources.

The use of tables, diagrams, flow charts and organizational charts is strongly recommended in describing the proposed structure and staffing of the Group.

B. Statistical Design and Analysis for Clinical Research on Asthma and Allergic Diseases

(i) Provide in-depth discussions of the following:

• statistical design and analysis considerations of particular relevance and importance for the full scope of clinical research on asthma and allergic diseases, including: clinical trials at all phases to evaluate investigational products/approaches for treatment and prevention, clinical studies, e.g., cross-sectional phenotyping studies and longitudinal birth cohort studies, to identify mechanisms underlying the natural histories of these disorders, define genetic components, etc., and mechanistic studies to improve understanding of disease pathogenesis, elucidate the mechanisms and efficacy of therapeutic modalities, and identify and evaluate potential biomarkers;
• methodologies considered to be high priority for the statistical design and analysis of the full scope of clinical research on asthma and allergic diseases and the rationale for their selection;
• common statistical design and analysis problems and difficulties associated with such clinical trials/studies in general;
• approaches recommended to overcome and/or improve identified problems/difficulties and optimize the yield from experimental strategies; and
• emerging methodologies for the statistical design and analysis of clinical research and their applicability to this disease area.

(ii) Provide proposed plans and procedures for performing statistical design and analysis functions for the full scope of clinical research on asthma and allergic diseases, including: developing and/or assessing the appropriateness and feasibility of statistical designs for proposed clinical trials/studies; developing and refining study designs and statistical analysis plans for approved clinical trials/studies in collaboration with clinical investigators and senior DAIT officials; conducting interim and final statistical analyses and preparing Interim and Final Statistical Analysis Reports; providing assistance for regulatory requirements/activities associated with the statistical design and analysis of clinical trials conducted under INDs, e.g., written materials and oral presentations; preparing regular statistical reports; preparing materials for and making presentation to DSMBs; and participating in the preparation of scientific manuscripts and reports and reviewing the accuracy and completeness of statistical data and data analyses for abstracts, manuscripts and presentations.

C. Protocol Development for Clinical Research on Asthma and Allergic Diseases

(i) Provide in-depth discussions of the following: critical aspects and considerations for preparing protocols and protocol-related documents (e.g., CRFs, IBs, Manuals of Operations) for the full scope of clinical research on asthma and allergic diseases, including clinical, medical, pharmacological/pharmacokinetic, toxicologic, chemistry and manufacturing aspects of protocols; common problems and difficulties encountered in developing these aspects of protocols and protocol-related documents for asthma and allergic diseases and also for clinical trials/studies involving multiple senior officials of research program sponsors, clinical sites and laboratories, and approaches recommended to overcome and/or reduce identified problems and difficulties.

(ii) Provide proposed plans and procedures for collaborating with clinical investigators and senior DAIT officials to develop, review and revise initial and successive drafts of protocols and protocol-related documents in this disease area, including processes for obtaining and documenting input and deliberating and achieving consensus on appropriate modifications/refinements to produce final documents.

D. Study Initiation and Management for Clinical Research on Asthma and Allergic Diseases

(i) Study Initiation and Training of Clinical Site Personnel

• Provide in-depth discussions of critical aspects and considerations for planning, materials development, and conduct of study initiation and clinical site personnel training activities covering both standard and study-specific procedures and requirements for clinical trials/studies in allergy and allergic diseases. Include: a discussion of critical aspects and considerations for clinical trial/study initiation and clinical site training in this disease area for research involving multiple sites, laboratories and senior officials of research program sponsors, complex clinical research incorporating mechanistic and biomarker studies, as well as any relevant characteristics of the populations affected; regulatory requirements and standard practices for human subjects research, DHHS (Department of Health and Human Services), NIH and NIAID policies, and policies and procedures used by DAIT and DAIT-supported clinical research programs for protocol development, implementation, monitoring and reporting; data collection instruments and procedures for data collection, entry, management, validation, quality control and submission, and standard and study-specific procedures and instructions for AE and SAE reporting; a discussion of the most common training needs encountered during both study initiation and study implementation/conduct, as well as recurring problems and approaches recommended to overcome and/or resolve recurring problems; methods/venues for conducting study initiation and training activities and a description of their effectiveness, efficiency and limitations; and metrics and methods for assessing the thoroughness and quality of training activities.
• Provide proposed plans and procedures for providing study initiation and clinical site training support for clinical trials/studies focused on allergy and allergic diseases, including: planning; materials development; selection of appropriate venues; coordination with other Center groups, DAIT staff and clinical site investigators; methods to identify training needs of clinical sites personnel; and conduct of study initiation and training activities.

(ii) Study Management

• Provide in-depth discussions of critical aspects and considerations for managing, coordinating and monitoring the implementation and day-to-day conduct of clinical trials/studies in allergy and allergic diseases. Address critical study management aspects and considerations for clinical trials/studies in this disease area involving multiple sites, laboratories and senior officials of research program sponsors, complex clinical research incorporating mechanistic and biomarker studies, as well as any relevant characteristics of the populations affected. Include discussions of the following: approaches for ensuring effective communication and coordination among multiple parties; methods for ensuring consistency in study implementation across multiple sites/laboratories; and effective processes and procedures for the ongoing review of study implementation. In addition, describe common problems, difficulties and deficiencies encountered in study implementation and conduct in this disease area, as well as approaches recommended to overcome/resolve/eliminate such problems, difficulties and deficiencies, particularly for large and complex clinical research programs.
• Provide proposed plans and procedures for performing study management functions for clinical trials/studies focused on allergy and allergic diseases, including: establishing SMTs, obtaining and disseminating relevant data for ongoing SMT monitoring of study implementation and site performance, documenting actions, problems, deficiencies and follow-up activities, and recommending and participating in the implementation of any necessary corrective/remedial actions; assisting in DSMP preparation; and assisting in the preparation and presentation of status reports on study-specific progress, problems and their resolution.

E. Atopic Dermatitis Research Network (ADRN) Subject Registry

(i) ADRN Subject Registry Structure and Staffing. Describe plans for the structure and staffing of the ADRN Subject Registry. Include descriptions of the responsibilities of all proposed functional entities within the Subject Registry; and delineation of lines of authority and reporting.

(ii) ADRN Subject Registry Functions. Describe the computerized database management system proposed for the collection, storage, tracking, updating, management, quality control and reporting of data on subjects enrolled in ADRN clinical research. Include key system capabilities, e.g., system security; secure, password-protected read access for designated DAIT staff and ADRN investigators; integrity and compatibility, remote data entry and transmission of clinical specimen data, customizable report generation, etc. Describe proposed quality assurance/quality control procedures to ensure the accuracy and completeness of subject data, provide brief descriptions of proposed SOPs and instructions on system use, and provide plans for training of clinical site personnel.

F. Inner City Asthma Consortium (ICAC) Clinical Specimen Repository

(i) ICAC Clinical Specimen Repository Structure and Staffing. Describe plans for the structure and staffing of the ICAC Clinical Specimen Repository. Include descriptions of the responsibilities of all proposed functional entities within the repository; and delineation of lines of authority and reporting.

(ii) ICAC Clinical Specimen Repository Functions. Describe the proposed computerized database management system(s), including key features and capabilities, e.g., remote data entry and transmission for designated DAIT staff and clinical site investigators, provisions for appropriate labeling, storage, handling and disposal of sensitive or controlled data, and customizable report generation, etc. Describe proposed quality assurance/quality control procedures. Provide: a listing, with brief descriptions, of proposed SOPs; the Table of Contents for an example of instructions on system use developed for clinical site personnel; and proposed plans and methods for training clinical site personnel.

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 SF424 (R&R) 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 as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Asthma and Allergic Diseases Group)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Asthma and Allergic Diseases Group)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Clinical Site Monitoring Group)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Clinical Site Monitoring Group)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Clinical Site Monitoring Group)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Clinical Site Monitoring Group)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Clinical Site Monitoring Group)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Clinical Site Monitoring Group will be led by a single Group Leader.
• Clinical Site Monitoring Group Leader’s qualifications include: (i) a minimum of a Bachelor’s degree or higher and CRA certification; (ii) extensive expertise and experience in planning, implementing, managing, tracking and reporting on clinical site monitoring activities, particularly for large, complex clinical research programs involving multiple clinical sites and laboratories; (iii) the capacity to serve as a subject matter expert with respect to Federal regulations and requirements and standard guidelines for human subjects research; (iv) considerable expertise and experience in training clinical site monitors to assess study conduct and to identify and correct clinical site problems and deficiencies; and (v) substantial experience and skill in directing and managing clinical and technical personnel for the provision of site monitoring services.

Budget (Clinical Site Monitoring Group)

Budget forms appropriate for the specific component will be included in the application package.

Budget for the staffing and travel associated with site monitoring activities should be included here. The Clinical Site Monitoring Group Leader will be required to commit not less than 2.4 months per year to the project.

On average, the total number of site visits per year conducted in support of DAIT studies by research area are:

• Asthma and Allergy 100
• Autoimmunity 60
• Transplantation 90

Further information about these site visits is available at http://www.niaid.nih.gov/about/organization/dait/Documents/ClinicalWorkBreakdownSfc.pdf.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Clinical Site Monitoring Group)

Specific Aims: Briefly describe the specific aims of the CSMG.

Research Strategy:

CSMG Structure and Staffing:

Describe in detail plans for the structure and staffing of the CSMG. Additional organizational entities, e.g., groups, sub-groups, committees, etc., may be established to carry out specific scientific, technical, and administrative responsibilities and/or to participate in the planning, conduct and management of Center activities. Include: (i) descriptions of recent projects of similar scope and complexity and the level and scope of responsibility for each project of all key CSMG personnel serving in a senior role; (ii) descriptions of the responsibilities of all proposed functional entities within the CSMG, and delineation of lines of authority and reporting among proposed Center personnel serving in a senior role; (iii) proposed processes for decision-making, for resolving operational issues/problems, and for communication within the CSMG, between the CSMG and other Center groups, with multiple DAIT Branches and Offices involved in clinical research planning, execution, oversight and reporting, with PDs/PIs and senior investigators of DAIT-supported clinical research programs, and with other DAIT-supported clinical research support organizations; and (iv) proposed processes and procedures to ensure the timely and effective implementation of Group functions across all clinical research programs and projects, track progress, identify and resolve technical and operational issues, and monitor the use and adequacy of allocated resources.

The use of tables, diagrams, flow charts and organizational charts is strongly recommended in describing the proposed structure and staffing of the Group.

CSMG Functions:

• Standard Operating Procedures (SOPs). Provide a listing, with brief descriptions, of proposed SOPs to be used to govern all aspects of clinical site monitoring functions, including all types of site visits.
• Site Visit Planning, Conduct and Reporting. Describe common clinical site performance and compliance problems and deficiencies and remedial actions recommended to correct identified problems and deficiencies (e.g., the accuracy, completeness and timeliness of data collection and entry, adherence to inclusion and exclusion criteria, accuracy and completeness of reporting SAEs and protocol violations, documentation of informed consent and adherence to informed consent procedures, pharmacy operations, sample storage and GLP audits). Identify those strategies/methods that have been most effective for ensuring the appropriate implementation of remedial/corrective actions and full resolution of problems/deficiencies. Include a discussion of any problems/deficiencies in clinical site performance and compliance that may arise due to the nature of the specific diseases and/or study populations for DAIT-supported clinical research programs. Provide proposed plans and procedures for planning, conducting and reporting on all types of site visits (e.g., site establishment, interim site monitoring, for cause, and site/study closeout). Reports and other relevant information will be submitted to DAIT through the site monitoring module of the DAIT CRIS.
• Clinical Site Audits. Describe proposed plans and procedures for assisting clinical sites in preparing for audits from Regulatory Health Authorities as well as pharmaceutical partners. Identify clinical site standards, operations and performance of primary importance in preparing for such audits and advice provided/actions recommended to ensure a favorable outcome.
• Site Monitor Training. Provide a brief description of proposed training of site monitors, both on staff and new hires, including initial and continuing training activities to be carried out both in-house and through outside organizations. Describe the frequency, methods/approaches, curricula, duration and instructors, and evaluation plans.

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 SF424 (R&R) Application Guide, with the following modification:

Generally, Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and GWAS Sharing Plan) are expected, but they are not applicable for this component.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Clinical Site Monitoring Group)

Not Applicable

PHS 398 Cumulative Inclusion Enrollment Report (Clinical Site Monitoring Group)

Not Applicable

When preparing your application in ASSIST, use Component Type Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Data Management and Reporting Group)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Data Management and Reporting Group)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Data Management and Reporting Group)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Data Management and Reporting Group)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Data Management and Reporting Group)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Data Management and Reporting Group will be led by a single Group Leader.
• Data Management and Reporting Group Leader’s qualifications include: (i) a Master’s degree or higher in computer science/information technology or related fields; (ii) extensive experience and expertise in the use of state-of-the-art, computer-based systems for the collection, storage, tracking and management of clinical research data, including data from clinical trials, mechanistic studies, clinical studies and surrogate/biomarker studies; (iii) substantial expertise and experience in operating large, complex databases involving the transmission of clinical, laboratory and safety data from multiple clinical sites and laboratories; (iv) expert knowledge of and experience in methods for data validation and system security; and (v) substantial experience and skill in directing and managing technical personnel for the provision of data management and reporting services.

Budget (Data Management and Reporting Group)

Budget forms appropriate for the specific component will be included in the application package.

Provide a unified budget for the staffing necessary to conduct the functions of the CDMG for all three subject area groups ADG, TG and AADG. The Data Management and Reporting Group Leader will be required to commit not less than 2.4 calendar months per year to the project.

Budget assumptions should include transition of the different datasets and functions performed by the incumbents. The current data management systems and formats utilized for ITN studies below are representative of most of the data platforms:

• The current clinical ITN database uses a combination of Rho EDC (for legacy trials) and Medidata Rave (for all new trials starting in late 2011) as a commercially-available and configurable platform with web-based interface systems for capturing, managing, and reporting clinical research data following CDISC standards in electronic or paper formats.
• The current safety ITN database uses Oracle Argus (Ver 5.1.3.3 moving to 7.X) as a comprehensive global pharmacovigilance platform for safety report collection, analysis, query-resolution, and safety reporting

Budgets should also include costs associated with data transfers.

• DAIT CRIS supports the business functions, management and oversight responsibilities of DAIT, such as enrollment information, study status, sites, serious adverse events, and monitoring data.
• An automated clinical research information system for tracking/managing clinical protocols, site monitoring, master contact data, and serious adverse events. Successful applicants will be required to interface, integrate or adapt their information system(s) to interact with DAIT CRIS as necessary to exchange data. Currently, DAIT uses XML data formats and November Research WebReports as a customized ad hoc reporting tool to provide data streams directly to DAIT CRIS in XML format.
• ITN TrialShare: ITN TrialShare is a clinical trials research web portal developed to aid researchers and study management teams in conducting trials by facilitating clinical and mechanistic data integration by the ITN Bioinformatics Group, and to share information about the Immune Tolerance Network’s clinical studies and bio-repository with the scientific community. Data and analysis code underlying ITN-published manuscripts are made publicly available via TrialShare. Data are transferred from the data center to ITN TrialShare using SAS transport files.
• For all non-ITN networks, data are transferred directly from the data centers to ImmPort at the DAIT Bioinformatics Integration Support Contractor (BISC). Data are loaded into ImmPort at the BISC by BISC staff.
• For all ClinicalTrial.gov registered research, preparation of data for transfer of safety and efficacy results to ClinicalTrials.gov.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Data Management and Reporting Group)

Specific Aims: Briefly describe the specific aims of the DMRG.

Research Strategy:

DMRG Structure and Staffing:

Describe in detail plans for the structure and staffing of the DMRG. Additional organizational entities, e.g., groups, sub-groups, committees, etc., may be established to carry out specific scientific, technical, and administrative responsibilities and/or to participate in the planning, conduct and management of Center activities. Include: (i) descriptions of recent projects of similar scope and complexity and the level and scope of responsibility for each project for all key DMRG personnel serving in a senior role; (ii) descriptions of the responsibilities of all proposed functional entities within the DMRG, and delineation of lines of authority and reporting among proposed Center personnel serving in a senior role; (iii) proposed processes for decision-making, for resolving operational issues/problems, and for communication within the DMRG, between the DMRG and other Center groups, with multiple DAIT Branches and Offices involved in clinical research planning, execution, oversight and reporting, with PDs/PIs and senior investigators of DAIT-supported clinical research programs, and with other DAIT-supported clinical research support organizations; and (iv) proposed processes and procedures to ensure the timely and effective implementation of Group functions across all clinical research programs and projects, track progress, identify and resolve technical and operational issues, and monitor the use and adequacy of allocated resources.

The use of tables, diagrams, flow charts and organizational charts is strongly recommended in describing the proposed structure and staffing of the Group.

DMRG Functions:

• Data Management System Clinical and Laboratory Study Data. Describe in detail the computer-based system (hardware and software) proposed for the assembly of clinical and laboratory study data in databases, including (i) the central facility for receipt, entry, verification, processing, correcting, storage, tracking, transmission and reporting, (ii) key system capabilities, e.g., computerized registration and randomization, computerized study forms and systems for remote data entry, real time electronic notifications to DAIT staff and clinical investigators in instances where one or more protocol-specific or NIAID safety review committee-specific data trigger halting rule(s), report generation features, etc., and (iii) provisions for system security and integrity, including an off-site storage facility for system back-ups.
• Data Management System Safety Data. Describe in detail the computer-based system (hardware and software) proposed for the assembly of safety data in databases, including (i) the central facility for receipt, entry, tracking, archiving and reporting Serious Adverse Events (SAEs), (ii) key system capabilities, e.g., internet-based tracking system, real-time electronic notification of SAEs to DAIT medical and scientific staff, clinical investigators, DAIT DSMBs and SACCC staff, and compliance with U.S. and non-U.S. regulations and requirements, etc., and (iii) provisions for system security and integrity, including an off-site storage facility for system back-ups.
• Data Quality Control. (i) Describe in detail the quality control system proposed for verification of 100% of clinical, laboratory and safety data, including key system capabilities, e.g., computerized validation and error-checking, procedures to ensure uniform, standardized data collection, computerized data query system for aberrant and/or missing data, etc. (ii) Provide a listing, with brief descriptions, of the components of the proposed manual(s) documenting data collection, editing and validation standards and procedures.
• Training of Clinical Site Personnel. Discuss proposed plans for providing training to clinical site personnel on the design of data collection instruments and procedures for data collection, entry, management, validation, quality control and submission.

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 SF424 (R&R) Application Guide, with the following modification:

Generally, Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and GWAS Sharing Plan) are expected, but they are not applicable for this component.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Data Management and Reporting Group)

Not Applicable

PHS 398 Cumulative Inclusion Enrollment Report (Data Management and Reporting Group)

Not Applicable

When preparing your application in ASSIST, use Component Type Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Safety Oversight and Reporting Group)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Safety Oversight and Reporting Group)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Safety Oversight and Reporting Group)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Safety Oversight and Reporting Group)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Safety Oversight and Reporting Group)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Safety Oversight and Reporting Group will be led by a single Group Leader.
• Safety Oversight and Reporting Group Leader’s qualifications include: (i) a Bachelor’s degree or higher; (ii) considerable experience and expertise in the use and management of computerized database systems for clinical specimen tracking, reporting/reconciliation of sample collection, and inter-laboratory shipping, receipt and final disposition; (iii) considerable experience and expertise in the purchase, packaging, shipping and inventory of laboratory testing kits; and (iv) experience in working with multiple clinical sites and laboratories in the provision of support for ASG functions.

Budget (Safety Oversight and Reporting Group)

Budget forms appropriate for the specific component will be included in the application package.

Provide a unified budget for the staffing necessary to conduct the functions of the CSOG for all three subject area groups ADG, TG and AADG. The Safety Oversight and Reporting Group leader will be required to commit not less than 2.4 calendar months per year to the project.

Safety Reporting:

On average, the number of initial SAEs received per year is:

• Autoimmunity - 30
• Transplantation - 83
• Asthma and Allergy 38

Further information about SAEs processed by the Safety Reporting Center is available at http://www.niaid.nih.gov/about/organization/dait/Documents/ClinicalWorkBreakdownSfc.pdf.

Data and Safety Monitoring Boards:

• Budget for the support of SORG activities associated with a total of 6 DSMB/SMCs having on average a total of 20 meetings per year involving 75 protocol reviews.

Further information about DSMB/SMCs activities is available at http://www.niaid.nih.gov/about/organization/dait/Documents/ClinicalWorkBreakdownSfc.pdf.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Safety Oversight and Reporting Group)

Specific Aims: Briefly describe the specific aims of the SORG.

Research Strategy:

SORG Structure and Staffing:

Describe in detail plans for the structure and staffing of the SORG. Additional organizational entities, e.g., groups, sub-groups, committees, etc., may be established to carry out specific scientific, technical, and administrative responsibilities and/or to participate in the planning, conduct and management of Center activities. Include: (i) descriptions of recent projects of similar scope and complexity and the level and scope of responsibility for each project of all key SORG personnel serving in a senior role; (ii) descriptions of the responsibilities of all proposed functional entities within the SORG, and delineation of lines of authority and reporting among proposed Center personnel serving in a senior role; (iii) proposed processes for decision-making, for resolving operational issues/problems, and for communication within the SORG, between the SORG and other Center groups, with multiple DAIT Branches and Offices involved in clinical research planning, execution, oversight and reporting, with PDs/PIs and senior investigators of DAIT-supported clinical research programs, and with other DAIT-supported clinical research support organizations; and (iv) proposed processes and procedures to ensure the timely and effective implementation of Group functions across all clinical research programs and projects, track progress, identify and resolve technical and operational issues, and monitor the use and adequacy of allocated resources.

The use of tables, diagrams, flow charts and organizational charts is strongly recommended in describing the proposed structure and staffing of the Group.

SORG Functions:

• Safety Reporting. Describe in detail proposed plans and procedures for operating a Safety Reporting Center to provide an internet-based data entry system for collection of SAE Reports, a telephone help line and the work flow process associated with an immediate SAE notification system. Provide a listing, with brief descriptions, of proposed SOPs for SAE reporting. Describe the proposed process to be used to evaluate SAE reports within one business day of receipt. Describe proposed plans and methods for providing training to clinical site personnel on the use of the data entry system as well as study-specific SAE reporting procedures and forms. Identify common problems/deficiencies in clinical site performance with respect to the completeness, accuracy and timeliness of AE and SAE reporting and provide recommendations for resolving problems and correcting deficiencies.
• Data and Safety Monitoring Boards and Safety Monitoring Committees. Provide proposed plans and procedures for supporting safety oversight functions of independent DSMBs/SMC, including: assembling materials for DSMB review; establishing and maintaining web portals; archiving DSMB/SMC materials; and assisting in preparing and coordinating communications with DAIT staff, Steering Committees for DAIT-supported clinical research programs, and clinical site personnel in instances where DAIT accepts a DSMB/SMC recommendation to change on ongoing study.

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 SF424 (R&R) Application Guide, with the following modification:

Generally, Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and GWAS Sharing Plan) are expected, but they are not applicable for this component.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Safety Oversight and Reporting Group)

Not Applicable

PHS 398 Cumulative Inclusion Enrollment Report (Safety Oversight and Reporting Group)

Not Applicable

When preparing your application in ASSIST, use Component Type Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Ancillary Services Group)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Ancillary Services Group)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Ancillary Services Group)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Ancillary Services Group)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Ancillary Services Group)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Ancillary Services Group will be led by a single Group Leader.
• Ancillary Services Group Leader’s qualifications include: (i) a Bachelor’s degree or higher; (ii) considerable experience and expertise in the use and management of computerized database systems for clinical specimen tracking, reporting/reconciliation of sample collection, and inter-laboratory shipping, receipt and final disposition; (iii) considerable experience and expertise in the purchase, packaging, shipping and inventory of laboratory testing kits; and (iv) experience in working with multiple clinical sites and laboratories in the provision of support for ASG functions.

Budget (Ancillary Services Group)

Budget forms appropriate for the specific component will be included in the application package.

Provide a unified budget for the staffing necessary to conduct the functions of the ASG for all three subject area groups ADG, TG and AADG. The Ancillary Services Group leader will be required to commit not less than 2.4 calendar months per year to the project.

Sample tracking:

• A specific sample tracking program is required for the ongoing needs of CTOT and CTOT-C sampleminded . Support for the other Networks should be proposed with the exception of the ITN, which has separate resources for sample tracking.

Materials for laboratory testing:

• Budgets should assume that all studies with the exception of ITN will require this support.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Ancillary Services Group)

Specific Aims: Briefly describe the specific aims of the ASG.

Research Strategy:

ASG Structure and Staffing:

Describe in detail plans for the structure and staffing of the ASG. Additional organizational entities, e.g., groups, sub-groups, committees, etc., may be established to carry out specific scientific, technical, and administrative responsibilities and/or to participate in the planning, conduct and management of Center activities. Include: (i) descriptions of recent projects of similar scope and complexity and the level and scope of responsibility for each project of all key ASG personnel serving in a senior role; (ii) descriptions of the responsibilities of all proposed functional entities within the ASG, and delineation of lines of authority and reporting among proposed Center personnel serving in a senior role; (iii) proposed processes for decision-making, for resolving operational issues/problems, and for communication within the ASG, between the ASG and other Center groups, with multiple DAIT Branches and Offices involved in clinical research planning, execution, oversight and reporting, with PDs/PIs and senior investigators of DAIT-supported clinical research programs, and with other DAIT-supported clinical research support organizations; and (iv) proposed processes and procedures to ensure the timely and effective implementation of Group functions across all clinical research programs and projects, track progress, identify and resolve technical and operational issues, and monitor the use and adequacy of allocated resources.

The use of tables, diagrams, flow charts and organizational charts is strongly recommended in describing the proposed structure and staffing of the Group.

ASG Functions:

• Sample Tracking. Describe in detail the proposed computerized database system(s) for tracking samples from subjects in clinical trials/studies, including key features and capabilities, e.g., label generation, sample collection, processing/aliquoting, shipping from collection site to central core laboratories, transfer between core laboratories, and sample disposition. Describe system(s) capabilities for maintaining site-specific and study-specific reconciliation of physical samples, and reconciliation of data results corresponding to physical samples. Provide an example of instructions on system use developed for sample tracking system users and a description of plans and methods for training users.
• Provision of Materials for Laboratory Testing. Describe proposed methods for the design, purchase, packaging and shipping of materials required for protocol-specific, specialized (i.e., core/mechanistic) laboratory tests. Describe proposed methods for an inventory of distributed materials.

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 SF424 (R&R) 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 as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Ancillary Services Group)

Not Applicable

PHS 398 Cumulative Inclusion Enrollment Report (Ancillary Services Group)

Not Applicable

When preparing your application in ASSIST, use Component Type Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Bioinformatics Group)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Bioinformatics Group)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Bioinformatics Group)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Bioinformatics Group)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Bioinformatics Group)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Bioinformatics Group will be led by a single Group Leader.
• Bioinformatics Group Leader’s qualifications include: (i) a Ph.D. degree in bioinformatics, biomedical informatics, biostatistics, or related quantitative sciences (computer sciences, mathematics, physics and engineering) with at least 5 years of relevant work experience; (ii) evidence at a senior level of experience and expertise in integrating and interpreting large datasets of biomedical data, such as genomics, proteomics, metabolomics, imaging data and clinical study data; (iii) in-depth technical knowledge and experience of bioIT areas, including programming, systems and database architecture, high performance computing (HPC) and networking technologies; (iv) considerable skill and experience in communicating and interacting effectively with research program sponsors, investigators, and other clinical research service organizations; and (v) the ability to manage and assess the performance of a diverse staff of scientific, technical and administrative personnel in a complex customer oriented environment.

Budget (Bioinformatics Group)

Budget forms appropriate for the specific component will be included in the application package.

Provide a unified budget for the staffing necessary to conduct the functions of the BG for all three subject area groups ADG, TG and AADG. The Bioinformatics Group leader will be required to commit not less than 2.4 calendar months per year to the project.

Assume that the BG phases-in over two years. Plan to initially provide a collaborative portal space for data review and analyses as well as displays of sample storage (dates, quantity, type of biologic sample, etc.)

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Bioinformatics Group)

Specific Aims: Briefly describe the specific aims of the BG.

Research Strategy:

BG Structure and Staffing:

Describe in detail plans for the structure and staffing of the BG. Additional organizational entities, e.g., groups, sub-groups, committees, etc., may be established to carry out specific scientific, technical, and administrative responsibilities and/or to participate in the planning, conduct and management of Center activities. Include: (i) descriptions of recent projects of similar scope and complexity and the level and scope of responsibility for each project of all key BG personnel serving in a senior role; (ii) descriptions of the responsibilities of all proposed functional entities within the BG, and delineation of lines of authority and reporting among proposed Center personnel serving in a senior role; (iii) proposed processes for decision-making, for resolving operational issues/problems, and for communication within the BG, between the BG and other Center groups, with multiple DAIT Branches and Offices involved in clinical research planning, execution, oversight and reporting, with PDs/PIs and senior investigators of DAIT-supported clinical research programs, and with other DAIT-supported clinical research support organizations; and (iv) proposed processes and procedures to ensure the timely and effective implementation of Group functions across all clinical research programs and projects, track progress, identify and resolve technical and operational issues, and monitor the use and adequacy of allocated resources.

The use of tables, diagrams, flow charts and organizational charts is strongly recommended in describing the proposed structure and staffing of the Group.

BG Functions:

• Bioinformatics Data Management System and Software Development. Describe in detail the data management system and software tools proposed for the collection, integration, annotation, analysis, storage, retrieval, and presentation of data and meta-data from mechanistic and clinical studies from the disease-specific areas specified in this FOA. Provide proposed procedures for data quality assurance, quality control and verification in collaboration with originating laboratories and relevant function groups of the SACCC. Include a description of timely data and software dissemination and public sharing plans that follow community standards, ensure reproducibility, and contribute to DAIT-sponsored and public repositories such as ImmPort. Describe computing infrastructure and administration plans to provide sufficient system security, computing power and data transfer capacity.
• Primary and Secondary Analyses. Provide plans for interacting with DAIT- supported investigators, Center and DAIT staff for the development, review and implementation of proposed studies/sub-studies, including assessing feasibility and suggesting appropriate technologies to use. Provide plans for collaborating with domain specialists or investigators bioinformatics staff on in-depth analysis of mechanistic and clinical study data. Provide proposed plans for meta-analysis across multiple studies for the purposes of developing best practices, generating summaries/reports, or identifying patterns and trends beyond the primary goals of individual studies. Provide proposed plans for training and consultation on using Center-supported data, software, SOPs, and computing resources to the end users.

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 SF424 (R&R) 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 as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Bioinformatics Group)

Not Applicable

PHS 398 Cumulative Inclusion Enrollment Report (Bioinformatics Group)

Not Applicable

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

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 submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

Important reminders:
All PD(s)/PI(s) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management (SAM). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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-13-030.

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 Center 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 Center 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 Center that by its nature is not innovative may be essential to advance a field.

Significance

Does the Center address an important problem or a critical barrier to progress in the field? If the aims of the Center 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? Does the application as a whole demonstrate a sound and thorough understanding of key problems and difficulties in conducting human subjects research for immune-mediated diseases? Does the Center have the potential to lead to improvements in the design, conduct and analysis of clinical research in the three disease areas?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Center? 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 Center 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 Center? Are the qualifications of the PD/PI proposed to serve as the Director of the Leadership Group (LG) well documented and appropriate for directing, managing and coordinating the Center’s scientific, technical, operational and fiscal support activities, particularly for large, complex and multifaceted clinical research programs, and will this individual devote adequate time and effort? For applications proposing multiple PDs/PIs, are the roles and responsibilities of PD(s)/PI(s) not proposed to serve as the LG Director clearly defined and well justified relative to the full scope of Center responsibilities? Do these PD(s)/PI(s) have well documented qualifications to perform the responsibilities proposed, and will they devote adequate time and effort? Is the proposed mix of expertise and experience represented by the Disease-Specific and Centralized Group Leaders and senior personnel well justified and well suited to the scope of the Center s scientific, clinical, technical and operational support functions?

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? Does the application as a whole demonstrate a sound understanding of innovative approaches to study design and statistical analysis of clinical research and mechanistic data, including the use of innovative bioinformatics tools and methodologies for the study of immune-mediated diseases?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center? Are potential problems, alternative strategies, and benchmarks for success presented? If the Center is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the Center involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Is the overall plan for the organization of the Center comprehensive? Does it provide for a well-integrated entity with an effective governance structure and clearly defined processes for decision-making, collaboration, coordination and communication? Are there sound, appropriate, feasible standards and criteria for evaluating the importance and relevance of the design, development, initiation, monitoring and analysis of clinical research in the three disease areas? Does the Center have appropriate experience with respect to statistical and clinical coordination of programs/projects of the similar size and scope in all three disease areas?

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 Center proposed? Will the Center benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Do the accomplishments, experience and expertise of the applicant organization demonstrate the capability to effectively and efficiently support the full scope of statistical and clinical coordination functions in each of the three disease areas?

This component will receive one individual score; the subcategories listed will be assessed but not scored separately.

Structure and Staffing

Is the proposed LG structure clearly defined and does it provide for effective and efficient planning, direction and management of the scientific, clinical, operational and administrative activities of the Center as a whole? Are proposed processes for decision-making, resolving technical and operational issues, and communication clearly articulated and appropriate? Do the LG Director, Senior Project Manager, and other senior LG staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Functions

Are proposed project management and tracking systems clearly defined, feasible and appropriate for overseeing effective planning and implementation of the full scope of Center activities? Are proposed plans for managing Center resources, including financial management capacity and systems, fully defined and feasible, particularly for a high volume of clinical research projects; will they contribute to maximizing the efficient use of available resources across all disease areas and clinical research programs? Does the application propose effective, efficient and reliable information management system(s) to support day-to-day Center activities and study-specific collaboration portals? Are there appropriate plans and meaningful metrics for evaluating Center performance and productivity, and is the proposed frequency of such evaluations adequate? Are there appropriate and efficient plans for assisting in COI management and providing technical and administrative support for meetings/teleconferences?

This component will receive one individual score; the subcategories listed will be assessed but not scored separately.

Structure and Staffing

Is the proposed ADG structure, including all functional entities, clearly defined and does it provide for effective and efficient planning, implementation, management and tracking of Group functions? Are the lines of authority clearly delineated? Does the application clearly articulate appropriate processes within the Group for decision-making, communication, collaboration, resolution of technical and operational issues, and monitoring the use and adequacy of allocated resources? Do the proposed Group Leader and other senior ADG staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Statistical Design and Analysis

Does the application demonstrate a sound and comprehensive understanding of the statistical design and analysis considerations of particular relevance and importance for the full scope of clinical research in this disease area? Are statistical design and analysis methodologies identified as high priority scientifically sound and well justified? Does the application demonstrate a sound and thorough understanding of common statistical design and analysis problems and difficulties in this disease area, and are approaches recommended to overcome/improve identified problems and difficulties well founded and likely to optimize the yield from experimental strategies? Does the application demonstrate a solid understanding of emerging statistical design and analysis methodologies and their applicability to autoimmune diseases? Are the plans and procedures proposed for performing the full scope of statistical design and analysis functions clearly defined and appropriate to ensure a high level of quality for clinical protocols, statistical analyses, assistance with reports needed for regulatory requirements and safety monitoring, and publication/presentation of study results?

Protocol Development

Does the application demonstrate a sound and thorough understanding of critical aspects, considerations, and common problems and difficulties involved in protocol development for the full scope of research and research programs in this disease area? Are approaches recommended to overcome/mitigate common problems and difficulties sound and appropriate? Are the plans and procedures proposed for performing protocol development functions clearly defined and likely to contribute to both the quality of clinical protocols and the efficiency of the protocol development process?

Study Initiation and Management

Does the application demonstrate a sound and thorough understanding of critical aspects and considerations for study initiation, clinical site training, and study management, coordination and conduct for the full scope of research and research programs in this disease area? Does the application adequately identify and propose effective approaches to overcome/mitigate common problems and deficiencies in study initiation and conduct, including clinical site training? Are the plans and procedures proposed for supporting study initiation and management activities sound and thorough; will they contribute to ensuring effective communication and coordination; consistency in study implementation across multiple sites/laboratories; appropriate review of study implementation on an ongoing basis; and the efficient implementation of strategies to correct/improve study performance and productivity?

This component will receive one individual score; the subcategories listed will be assessed but not scored separately.

Structure and Staffing

Is the proposed TG structure, including all functional entities, clearly defined and does it provide for effective and efficient planning, implementation, management and tracking of Group functions? Are the lines of authority clearly delineated? Does the application clearly articulate appropriate processes within the Group for decision-making, communication, collaboration, resolution of technical and operational issues, and monitoring the use and adequacy of allocated resources? Do the proposed Group Leader and other senior TG staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Statistical Design and Analysis

Does the application demonstrate a sound and comprehensive understanding of the statistical design and analysis considerations of particular relevance and importance for the full scope of clinical research in this disease area? Are statistical design and analysis methodologies identified as high priority scientifically sound and well justified? Does the application demonstrate a sound and thorough understanding of common statistical design and analysis problems and difficulties in this disease area, and are approaches recommended to overcome/improve identified problems and difficulties well founded and likely to optimize the yield from experimental strategies? Does the application demonstrate a solid understanding of emerging statistical design and analysis methodologies and their applicability to transplantation? Are the plans and procedures proposed for performing the full scope of statistical design and analysis functions clearly defined and appropriate to ensure a high level of quality for clinical protocols, statistical analyses, assistance with reports needed for regulatory requirements and safety monitoring, and publication/presentation of study results?

Protocol Development

Does the application demonstrate a sound and thorough understanding of critical aspects, considerations, and common problems and difficulties involved in protocol development for the full scope of research and research programs in this disease area? Are approaches recommended to overcome/mitigate common problems and difficulties sound and appropriate? Are the plans and procedures proposed for performing protocol development functions clearly defined and likely to contribute to both the quality of clinical protocols and the efficiency of the protocol development process?

Study Initiation and Management

Does the application demonstrate a sound and thorough understanding of critical aspects and considerations for study initiation, clinical site training, and study management, coordination and conduct for the full scope of research and research programs in this disease area? Does the application adequately identify and propose effective approaches to overcome/mitigate common problems and deficiencies in study initiation and conduct, including clinical site training? Are the plans and procedures proposed for supporting study initiation and management activities sound and thorough; will they contribute to ensuring effective communication and coordination; consistency in study implementation across multiple sites/laboratories; appropriate review of study implementation on an ongoing basis; and the efficient implementation of strategies to correct/improve study performance and productivity?

This component will receive one individual score; the subcategories listed will be assessed but not scored separately.

Structure and Staffing

Is the proposed AADG structure, including all functional entities, clearly defined and does it provide for effective and efficient planning, implementation, management and tracking of Group functions? Are the lines of authority clearly delineated? Does the application clearly articulate appropriate processes within the Group for decision-making, communication, collaboration, resolution of technical and operational issues, and monitoring the use and adequacy of allocated resources? Do the proposed Group Leader and other senior AADG staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Statistical Design and Analysis

Does the application demonstrate a sound and comprehensive understanding of the statistical design and analysis considerations of particular relevance and importance for the full scope of clinical research in this disease area? Are statistical design and analysis methodologies identified as high priority scientifically sound and well justified? Does the application demonstrate a sound and thorough understanding of common statistical design and analysis problems and difficulties in this disease area, and are approaches recommended to overcome/improve identified problems and difficulties well founded and likely to optimize the yield from experimental strategies? Does the application demonstrate a solid understanding of emerging statistical design and analysis methodologies and their applicability to autoimmune diseases? Are the plans and procedures proposed for performing the full scope of statistical design and analysis functions clearly defined and appropriate to ensure a high level of quality for clinical protocols, statistical analyses, assistance with reports needed for regulatory requirements and safety monitoring, and publication/presentation of study results?

Protocol Development

Does the application demonstrate a sound and thorough understanding of critical aspects, considerations, and common problems and difficulties involved in protocol development for the full scope of research and research programs in this disease area? Are approaches recommended to overcome/mitigate common problems and difficulties sound and appropriate? Are the plans and procedures proposed for performing protocol development functions clearly defined and likely to contribute to both the quality of clinical protocols and the efficiency of the protocol development process?

Study Initiation and Management

Does the application demonstrate a sound and thorough understanding of critical aspects and considerations for study initiation, clinical site training, and study management, coordination and conduct for the full scope of research and research programs in this disease area? Does the application adequately identify and propose effective approaches to overcome/mitigate common problems and deficiencies in study initiation and conduct, including clinical site training? Are the plans and procedures proposed for supporting study initiation and management activities sound and thorough; will they contribute to ensuring effective communication and coordination; consistency in study implementation across multiple sites/laboratories; appropriate review of study implementation on an ongoing basis; and the efficient implementation of strategies to correct/improve study performance and productivity?

Atopic Dermatitis Research Network (ADRN) Subject Registry

Is the proposed structure of the ADRN Subject Registry clearly defined and does it provide for effective and efficient planning, implementation, management and tracking of registry functions? Do the senior staff proposed possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort? Is the computerized database management system proposed effective, efficient and reliable; does it provide for the necessary system capabilities; and are appropriate quality assurance/quality control procedures in place to ensure data accuracy and completeness? Are descriptions of proposed SOPs, instructions on system use, and plans for clinical site training appropriate and sufficient to ensure smooth functioning?

Inner City Asthma Consortium (ICAC) Clinical Specimen Repository

Is the proposed structure of the ICAC Clinical Specimen Repository clearly defined and does it provide for effective and efficient planning, implementation, management and tracking of repository functions? Do the senior staff proposed possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort? Is the computerized database management system(s) proposed effective, efficient and reliable; does it provide for the necessary system capabilities; and are appropriate quality assurance/quality control procedures in place? Are descriptions of proposed SOPs, instructions on system use, and plans for clinical site training appropriate and sufficient to ensure smooth functioning?

This component will receive one individual score; the subcategories listed will be assessed but not scored separately.

Structure and Staffing

Is the proposed CSMG structure, including all functional entities, clearly defined and does it provide for effective and efficient planning, implementation, management and tracking of Group functions? Does the application clearly articulate appropriate processes for decision-making, communication, collaboration, resolution of technical and operational issues, and monitoring the use and adequacy of allocated resources? Do the proposed Group Leader and other senior CSMG staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Functions

Does the application demonstrate a sound and thorough understanding of common clinical site performance and compliance problems and deficiencies in general and for the three specific disease areas, and identify effective strategies for ensuring appropriate corrective/remedial actions? Are the SOPs, plans and procedures proposed for performing the full scope of clinical site monitoring functions, including preparing clinical sites for external audits (e.g., FDA, pharmaceutical partners) clearly defined and appropriate to ensure full compliance with regulatory requirements and guidelines and NIH and NIAID policies? Are proposed plans for training site monitors clearly articulated and will they ensure adequate capability to provide the full scope of clinical site monitoring support?

This component will receive one individual score; the subcategories listed will be assessed but not scored separately.

Structure and Staffing

Is the proposed DMRG structure, including all functional entities, clearly defined and does it provide for effective and efficient planning, implementation, management and tracking of Group functions? Does the application clearly articulate appropriate processes within the Group for decision-making, communication, collaboration, resolution of technical and operational issues, and monitoring the use and adequacy of allocated resources? Do the proposed Group Leader and other senior DMRG staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Functions

Are the data management system and procedures proposed for both clinical and laboratory study data and safety data effective, efficient and reliable; do they provide for the necessary system capabilities; and are appropriate quality assurance/quality control procedures in place? Is the data quality control system proposed comprehensive, efficient and reliable; does it provide for standardization in data collection and other necessary system capabilities; and are components of proposed manuals documenting standards and procedures comprehensive and appropriate? Are adequate and reasonable plans in place for training clinical site personnel on all aspects of data management and submission?

This component will receive one individual score; the subcategories listed will be assessed but not scored separately.

Structure and Staffing

Is the proposed SORG structure, including all functional entities, clearly defined and does it provide for effective and efficient planning, implementation, management and tracking of Group functions? Does the application clearly articulate appropriate processes within the Group for decision-making, communication, collaboration, resolution of technical and operational issues, and monitoring the use and adequacy of allocated resources? Do the proposed Group Leader and other senior SORG staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Functions

Are proposed plans and procedures for operating the Safety Reporting Center comprehensive and appropriate with a well-defined list of SOPs on SAE reporting, a sound and efficient process for evaluating SAE Reports, and effective plans for clinical site training on system use? Does the application demonstrate a thorough and sound understanding of common problems/deficiencies in clinical site performance with respect to SAE reporting and provide effective recommendations for resolving problems/deficiencies? Are proposed plans and procedures for supporting DSMB activities clearly defined and appropriate; will they contribute to smooth functioning and careful records maintenance?

This component will receive one individual score; the subcategories listed will be assessed but not scored separately.

Structure and Staffing

Is the proposed ASG structure, including all functional entities, clearly defined and does it provide for effective and efficient planning, implementation, management and tracking of Group functions? Does the application clearly articulate appropriate processes within the Group for decision-making, communication, collaboration, resolution of technical and operational issues, and monitoring the use and adequacy of allocated resources? Do the proposed Group Leader and other senior ASG staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Functions

Is the proposed computerized database system(s) for sample tracking effective, efficient and reliable; does it provide for the necessary system capabilities, including site and study-specific reconciliation of samples and data results? Are instructions for use of the sample tracking system complete and well documented, and are proposed plans for training users effective? Are efficient and comprehensive methods proposed for the design, purchase, packing and shipping of materials for specialized laboratory tests? Is the proposed plan for provision of materials for laboratory testing comprehensive and appropriate?

This component will receive one individual score; the subcategories listed will be assessed but not scored separately.

Structure and Staffing

Is the proposed BG structure, including all functional entities, clearly defined and does it provide for effective and efficient planning, implementation, management and tracking of Group functions? Does the application clearly articulate appropriate processes within the Group for decision-making, communication, collaboration, resolution of technical and operational issues, and monitoring the use and adequacy of allocated resources? Do the proposed Group Leader and other senior BG staff possess the expertise and experience relevant for their roles/responsibilities and devote adequate effort?

Functions

Do the proposed data management system and software tools provide effective data integration and analysis support for the disease-specific areas specified? Is the quality management plan proposal sufficient to assure confidence in the data being analyzed from different laboratories? Is the plan for data dissemination to a wide variety of data users clear and effective? Is the description of the infrastructure for the BG sufficient to support the scope of the activities that are required? Are the plans that are provided in support of DAIT-funded investigators developing study proposals; collaborations with investigators for in-depth analyses; and analyses across individual studies clearly articulated and effective? Does the application adequately plan to provide training to users of the proposed resources?

As applicable for the Center 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 Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

When the proposed Center involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

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 Center 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. Applications 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. 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.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other DHHS, 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(s)/PI(s) will have the primary responsibility for:

• Directing the activities of the Center Leadership Group, including: (i) establishing and implementing processes for decision-making, communication and collaboration; (ii) establishing and implementing processes and systems for tracking the implementation of Center support functions, identifying problems/deficiencies, and determining the need for and implementing corrective actions; (iii) assessing and allocating resources, reviewing their adequacy, and determining needed adjustments; (iv) establishing and implementing financial management capacity and systems to track and project Center resources and expenditures; (v) implementing and managing an information system to support day-to-day Center activities; (vi) establishing and managing collaboration portals for study-specific documents/materials; (vii) reporting to and obtaining input from clinical research program PDs/PIs; and (viii) establishing procedures and metrics for assessing Center progress and productivity.
• Providing the full scope of statistical and clinical coordination support through the Disease-Specific and Centralized Groups; ensuring appropriate and effective coordination and collaboration with senior DAIT officials, research program PDs/PIs and clinical investigators, and other DAIT-supported clinical research organizations; and ensuring that the performance of support functions complies with all Federal and, where appropriate, country-specific regulatory requirements and guidelines for the conduct of human subjects research, as well as NIH and NIAID policies and procedures.
• Providing reports to DAIT staff regarding Group activities described earlier (e.g. SAE and adverse event listings, tabular summaries of study progress, protocol deviation and site monitoring reports, etc.) as well as budgetary summaries as requested.
• Transfer study related data, as required, in formats compliant with the DAIT CRIS, ImmPort, ClinicalTrials.gov, DAIT supported clinical research programs and pharmaceutical collaborators.
• Ensuring the appropriate training/certification of Center staff designated to provide statistical and clinical coordination support, and including a list of all training programs and written assessments in the Annual Progress Report.

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

NIAID staff assistance will be provided by NIH Project Scientists in each of the three disease areas who 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. These staff will be identified at the time of award and their roles and responsibilities will be addressed in the Notice of Grant Award. It is anticipated that decisions regarding Center activities will be reached by consensus and that the NIH Project Scientists will participate in this process. In various matters related to clinical study approval and oversight, NIH Project Scientists will have final decision authority, as described below.

• Concept Proposals and Study Protocols: NIH Project Scientists will: (i) participate in the review and approval of Concept Proposals for clinical trials, clinical studies and mechanistic studies; (ii) provide final approval of clinical trials/studies to be supported by the Center; (iii) in collaboration with research program PDs/PIs, establish timelines for protocol development, implementation and completion; and (iv) participate in the development, review and approval of study protocols.
• IND/IDE Sponsorship: It is anticipated that, with rare exceptions, NIAID will serve as the regulatory sponsor for clinical trials conducted under INDs/IDEs. As part of NIAID’s regulatory sponsorship responsibilities, NIH Project Scientists/Medical Monitors will obtain, through the Center, regular reports on serious adverse events and protocol deviations, and will decide on the final disposition of SAE Reports for all IND/IDE studies.
• Study Monitoring and Management: (i) NIAID will be responsible for monitoring compliance with regulatory requirements and GCP and ICH guidelines for human subject research, accurate protocol implementation and internal quality assurance. This includes: participating in the development of and approving DSMPs prior to study initiation; establishing and managing the activities of independent DSMBs to review interim and final study data and monitor the safety of clinical trial subjects; and determining the need to conduct for cause clinical site visits, participating in such visits, and approving recommendations for remedial actions. (ii) NIAID will also be responsible for establishing and coordinating the activities of Study Management Teams to manage the day-to-day implementation of clinical trials/studies.
• Study Termination: NIAID reserves the right to terminate, curtail or suspend a clinical trial/study for any reason, including but not limited to risks to subject safety, scientific question is no longer relevant or the objectives will not be met, failure to comply with Federal regulations, GCP, or Terms and Conditions of Award, occurrence of unforeseen drug safety issues or data from preclinical studies indicate a presence of unanticipated toxicity, and reaching a major study endpoint before schedule with persuasive statistical significance.
• Access to Data: NIAID will have the right of access to all data (raw and analyzed) generated under this cooperative agreement and may periodically review these data.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

• NIH Project Scientists will serve as voting members of the Center Leadership Group and, in collaboration with the PD/PI serving as the Leadership Director and other Center Leadership Group members, will participate in deliberations and decision-making regarding the multiple substantive, operational, financial and administrative responsibilities of this Group.
• NIH Project Scientists and/or their designees will collaborate with Center staff to ensure the provision of appropriate information, materials and training regarding NIH and NIAID policies and procedures for the conduct of human subject research.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Center, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

All PD(s)/PI(s) must include a list of training programs conducted for clinical site personnel and written assessments in their Annual Progress Report.

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.

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Finding Help Online: http://grants.nih.gov/support/index.html

TTY: 301-451-5939
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

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

Leighton Thomas
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3522
Email: [email protected]

Paul Amstad, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-402-7098
Email: [email protected]

Tina M. Carlisle
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-402-6579
Email: [email protected]

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

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