Collaborative Network for Clinical Research on Immune Tolerance

Collaborative Network for Clinical Research on Immune Tolerance is sponsored by National Institute of Allergy and Infectious Diseases (NIAID) / NIH. This program aims to enhance understanding of the underlying mechanisms of immune tolerance, and to develop improved tolerogenic interventions for the prevention and treatment of immune system mediated diseases, including transplant rejection, autoimmune diseases, and asthma and…

Expired RFA-AI-12-043: Collaborative Network for Clinical Research on Immune Tolerance (UM1) This notice has expired. Check the NIH Guide for active opportunities and notices. of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) of Participating Organizations National Institute of Allergy and Infectious Diseases ( NIAID ) Funding Opportunity Title Collaborative Network for Clinical Research on Immune Tolerance (UM1) UM1 Multi-Component Research Project Cooperative Agreements December 06, 2019 - This RFA has been reissued as RFA-AI-19-068 .

Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity Additional Information on Eligibility . Catalog of Federal Domestic Assistance (CFDA) Number(s) Funding Opportunity Purpose The purpose of this FOA is to solicit applications for the Collaborative Network for Clinical Research on Immune Tolerance.

The major goal of this Network is to develop new tolerogenic approaches for the treatment and prevention of disease in three clinical areas: asthma and allergic diseases; autoimmune diseases; and immune-mediated rejection of transplanted solid organs, tissues and cells.

The scope of research to be carried out includes: 1) the design and conduct of clinical trials at all phases to evaluate the safety and efficacy of investigational products and approaches for the induction and maintenance of immune tolerance in humans; 2) the design and conduct of mechanistic studies and the development of tolerance assays as integral components of the clinical trials undertaken, including establishing and directing a consortium of laboratories; and 3) the provision of bioinformatics, data collection, validation and analysis resources.

In addition, on a limited basis, the Network may support focused product development and nonclinical studies (e.g., toxicology, pharmacology, pharmacokinetics, etc.) essential for the subsequent evaluation of promising tolerance induction approaches in humans.

Letter of Intent Due Date(s) AIDS Application Due Date(s) Required Application Instructions It is critical that applicants follow the instructions in Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced.

While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV . When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Looking ahead : NIH is committed to transitioning all grant programs to electronic submission using the SF424 Research and Related (R&R) format and is currently investigating solutions that will accommodate NIH’s multi-project programs. NIH will announce plans to transition the remaining programs in the NIH Guide to Grants and Contracts and on NIH’s Applying Part 1. Overview Information Part 2.

Full Text of Announcement Section I. Funding Opportunity Description Section II. Award Information Section III.

Eligibility Information Section IV. Application and Submission Section V. Application Review Information Section VI.

Award Administration Information Section VII. Agency Contacts Section VIII. Other Information Full Text of Announcement Section I.

Funding Opportunity Description The purpose of this FOA is to solicit applications for the Collaborative Network for Clinical Research on Immune Tolerance (hereinafter referred to as 'Network').

The major objective of the Network is to develop new tolerogenic approaches for the treatment of disease in three clinical areas: asthma and allergic diseases; autoimmune diseases; and immune-mediated rejection of transplanted solid organs, tissues and cells.

The scope of research to be carried out by the Network includes: 1) the design and conduct of clinical trials at all phases to evaluate the safety and efficacy of investigational products and approaches for the induction and maintenance of immune tolerance in humans; 2) the design and conduct of mechanistic studies and the development of tolerance assays as integral components of the clinical trials undertaken; and 3) the provision of bioinformatics, data collection, validation and analysis resources.

On a selective basis, the Network may also support limited product development and nonclinical studies (e.g., toxicology, pharmacology, pharmacokinetics, etc.) essential for the subsequent evaluation of promising tolerance induction approaches in humans.

For the purpose of this FOA and the resulting grant award, immune tolerance is broadly defined as a selective elimination of pathogenic immune responses to relevant antigens (e.g., alloantigens, autoantigens or allergens) by any of a variety of approaches, including deletion, induction of anergy, immune deviation, sequestration, or suppression, while preserving protective immunity and does not require ongoing treatment with the intervention.

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

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

Operations Group with responsibility for clinical site assessments and other pre-study initiation requirements, assistance in the development of clinical protocols, and study implementation and monitoring. Laboratory Group with responsibility for the conduct of mechanistic studies and the performance of tolerance assays to assess the induction, maintenance and loss of tolerance.

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

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

The successful induction of immune tolerance is a major therapeutic goal for the treatment of immune-mediated diseases, including asthma and allergic diseases; autoimmune disorders, such as rheumatoid arthritis and type 1 diabetes; and immune-mediated rejection of transplanted solid organs, tissues, and cells.

Tolerance induction strategies aim to selectively block or prevent deleterious immune responses, while leaving protective immunity intact.

More than two decades of highly intensive and productive basic research in immunology have provided a solid foundation of knowledge and understanding that will enable the application of promising tolerance induction strategies to the treatment of immune-mediated diseases and transplantation, and enhanced understanding of the underlying mechanisms of disease and therapeutic effect.

Asthma and allergic diseases are among the major causes of illness and disability in the U.S., affecting nearly 1 in 5 Americans. Asthma afflicts over 24 million Americans or 8. 2 percent of the U.S. population; chronic sinusitis afflicted 12.

9 percent of Americans age 18 and older in 2009; and food allergy was reported to afflict 3 million children under the age of 18 in 2007. In asthma and allergic diseases, the goal of tolerance research is to develop methods to block immune responses, especially allergic (IgE) responses, to allergens such as cockroach, house dust mite, and peanut that cause or exacerbate these diseases.

Autoimmune diseases are chronic disabling disorders in which underlying defects in the immune response lead the body to attack its own organs and tissues. More than 80 autoimmune diseases have been identified and, for reasons that are not clear, the prevalence of these diseases is rising.

Collectively, autoimmune diseases affect approximately 14-22 million people in the U.S., and represent a significant physical, emotional, social, and fiscal burden for patients and their families and to society. These diseases can affect any organ or organ system, and all ages are affected, with onset from childhood to late adulthood.

In autoimmune diseases, novel approaches to block immune responses that cause the body to mistakenly attack its own organs, tissues, or cells are evaluated. The benefits of organ transplantation, as evidenced by prolonged survival and/or improved quality of life, have been clearly demonstrated for children and adults suffering from a wide range of congenital and acquired diseases.

In 2011, 30,986 transplants were performed in the U.S., with 14,146 organ donors; in 2011, there were 113,237 candidates on the transplant waiting list.

Although one-year survival after transplantation has improved markedly for every organ, barriers to long-term graft and patient survival include incompatibility between donor and recipient, acute rejection, chronic graft dysfunction, and complications of long-term use of immunosuppressive drugs.

In transplantation, donor-specific immune tolerance - a selective blockade of immune responses directed against the graft - would enable long-term graft survival without the complications and risks of systemic immunosuppressive therapy (e.g., infection, malignancy, and The NIAID has a long-standing commitment to supporting basic, translational and clinical research on immune tolerance with the ultimate goal of developing novel, efficacious therapies for the induction and maintenance of antigen-specific immune tolerance in humans.

The NIAID Plan for Research on Immune Tolerance and the Report of the NIAID Expert Panel on Immune Tolerance are located on the NIAID website at http://www. niaid. nih.

gov/topics/immuneTolerance/researchplan/Pages/immuneToleranceReport.

aspx In 1999, the NIAID awarded a seven-year contract to establish the Collaborative Network for Clinical Research on Immune Tolerance - a major program resulting from the scientific planning process, designed to: (1) develop a long-term scientific agenda for clinical trials and mechanistic studies; (2) design and conduct clinical trials at all phases to determine the safety, toxicity and efficacy of tolerogenic treatment strategies for multiple immune system diseases; and (3) design and conduct research to delineate the underlying mechanisms of immune tolerance as an integral part of the clinical trials undertaken by the Network, as well as clinical trials sponsored by other Federal and private sector organizations and companies.

In 2007, the contract was recompeted and expanded to include nonclinical research and product development, as well as bioinformatics, data collection and analysis.

The contract (N01-AI-15416) is currently held by the University of California San Francisco, with Dr. Jeffrey Bluestone as the contract Principal Investigator and Dr. Gerald Nepom, of the Benaroya Research Institute, as the Network Since the establishment of this Network in 1999, substantial progress has been made in evaluating diverse tolerogenic products and approaches for a broad range of immune-mediated diseases, enhancing our understanding of underlying mechanisms, and assessing the induction, maintenance and loss of tolerance through multiple assays.

Achieving complete tolerance in a single human trial is quite challenging; studies that provide step-wise advances towards achieving this goal have been an important strategy in advancing tolerance research.

The Network has initiated 43 clinical trials with associated mechanistic studies, and 13 tolerance assay studies: 9 clinical trials and 3 tolerance assay studies in asthma and allergic diseases; 18 clinical trials and 8 tolerance assay studies in autoimmune diseases, with approximately 47% of each in type 1 diabetes; and 16 clinical trials and 2 tolerance assay studies in transplantation.

It is anticipated that 15 studies will be ongoing at the completion of the current contract and will be continued and completed during the new award period. Additional information about the research activities of the current Network, publications, the status of the studies, as well as information on organizational structure and membership, may be obtained from the Network website at http://www. immunetolerance.

org . Research Scope and Priorities Scope: The scope of research to be performed by the Network Trials.

The design and conduct of Phase I-IV clinical trials to evaluate the safety and efficacy of investigational products, approaches and techniques intended to lead to a functional state of immune tolerance in three clinical areas: autoimmune diseases; asthma and allergic diseases; and immune-mediated rejection of transplanted solid organs, tissues and cells.

Tolerogenic strategies may target antigen specific receptors, molecules of the co-stimulation pathways, homing molecules, or other relevant approaches; may use any of a variety of agents including antigens, peptides, altered peptides, monoclonal antibody blockade, cytokines, molecularly engineered cells or tissues, DNA vectors, or other relevant molecules; and may be administered by a variety of routes.

Tolerance studies may include projects that are intended to achieve incremental advances and are clear steps towards tolerance. In addition, the Network will be responsible for the continuation and completion of ongoing clinical trials and integrated mechanistic studies being conducted under the current Network contract. Additional information on responsibilities for ongoing clinical trials is provided under Section VI.

Award Administration Information, item 2. Administrative and National Policy Requirements Cooperative Agreement Terms and Conditions of Award . Studies.

The design and conduct of mechanistic studies and the development and evaluation of assays to measure/assess stages of disease and likelihood of progression, effect of treatment on immunological status and/or clinical outcome, maintenance of protective immunity, and safety of immunosuppressive withdrawal, and to identify and evaluate potential immune/surrogate markers of the induction, maintenance, and loss of tolerance.

Such assays include, but are not limited to: microarray and PCR analyses of gene expression, quantitative assays of T cell reactivity, assays of B cell activity, assays of cytokines and other proteins, and novel tissue morphology studies to analyze tissue changes due to disease progression and therapeutic effect.

These studies are performed, often through central laboratory resources, as integral components of the clinical trials undertaken. Resources. The provision of biostatistics, data collection, validation and analysis resources for integrated mechanistic and clinical data analyses, including analyses across Network studies.

Studies and Product Development. On a limited basis, support for product development activities and the design and conduct of nonclinical studies essential for the subsequent evaluation of promising tolerance induction strategies in humans.

Such activities may include, but are not limited to: proof-of-principle studies and pharmacokinetics and pharmacodynamics animal studies; and nonclinical toxicity studies in suitable animal models; and production. Manufacturing and laboratory studies will be conducted under current Good Manufacturing Practices (cGMP) or Good Clinical Laboratory Practices (GCLP), as appropriate.

Research Priorities: Research priorities within each of the three clinical areas include, but are not limited to, the following: Allergic Diseases and Asthma Tolerance induction through innovative allergen immunotherapy strategies, including but not limited to: Selectively amplify responses, making immunotherapy more robust Shorten time required to achieve beneficial and long-lasting Bring greater safety to the clinical practice of immunotherapy Apply immunotherapeutics more widely: safe and effective treatments are available, such as food allergy prevent or delay the development of disease, such as asthma and food allergy well characterized and purified antigens (allergens) which facilitate dosing strategies as interventions immunosuppressive interventions are generally not considered safe for use in treating allergic diseases, other immunomodulatory approaches are encouraged Immune-based approaches to restore tolerance, while preserving protective immunity, targeting T and B cell subsets and pathways, including but not limited to: Co-stimulatory blockade to inhibit T cell activation Cytokine modulation to induce immune deviation and suppression Depletion of autoreactive lymphocyte populations to promote Cellular therapies to restore the balance of regulatory cells Antigen specific therapies to modulate autoreactive immune Tolerogenic approaches to improve long-term graft survival and decrease the rates of acute and chronic rejection, including but not Costimulatory blockade regimens to inhibit T cell activation Cell-based therapies, including, e.g., T regulatory cells or Bone marrow chimerism to induce tolerance in solid organ Strategies using potentially tolerogenic induction immunotherapeutic approaches Strategies involving novel tolerogenic agents Observational studies of transplant recipients who are Detailed mechanistic analyses to increase understanding of the Structure and Governance.

The Network will consist of four functional elements: (i) the Leadership Group, composed of national and international clinical investigators and basic scientists with the full range of expertise and experience necessary to plan and direct the implementation of oversee the development, implementation, and monitoring of clinical trials; (iii) the Core Laboratory Group to perform mechanistic studies and tolerance assays for all Network clinical trials/studies; and (iv) the Bioinformatics Group to collect, validate and analyze mechanistic data, and integrate these mechanistic data with clinical data.

Additional committees, subcommittees and/or functional components may be established to carry out specific scientific, technical and administrative responsibilities.

Each organizational entity must: establish and define effective communication and decision-making processes; identify clear lines of authority; establish processes to identify and resolve operational issues; and coordinate and collaborate effectively both within the Network and with other Federal and private sector research organizations/programs.

The Network should use effective approaches to project management, including project plans with identified key milestones, provide for ongoing evaluation of projections against actual performance, adjust project plans as necessary, and develop and implement contingency plans. Time Commitment. The PD/PI will be required to commit not less than 3.

6 person months per year to the project. Resources. The NIAID will provide certain contract resources to support the design, development, implementation, and monitoring of Network clinical trials and the analysis of final study data.

The Network will cooperate with NIAID contractors to ensure that clinical research complies with Federal regulatory requirements as well as NIAID policies and procedures.

and Data Coordinating Center contract to provide a broad range of support services, including: assistance in the development of statistical design and analysis plans and other clinical protocol components (e.g., data and safety monitoring plans); a central data management system for the collection, storage, quality control and retrieval of clinical and other trial related data; a safety database system for the receipt, reporting and disposition of Serious Adverse Events (SAEs); and the analysis of final clinical study data and preparation of final clinical study reports.

The Request for Proposals can be found at https://www. fbo. gov/index?

s=opportunity&mode=form&id=4402094af6db51fefb94671d355adebc&tab=core&_cview=0 . The contract is held by Rho ( http://www. rhoworld.

com/ ). Site Monitoring Center contract to assist in monitoring the conduct of clinical trials in accordance with protocol-specific and regulatory requirements, including initial site assessments, interim site monitoring of ongoing clinical trials, and site and study close-out. The Request for Proposals can be found at https://www.

fbo. gov/index? s=opportunity&mode=form&id=07021adff3bc56d94503c38c83f32bdb&tab=core&_cview=1 .

The contract is held by PPD ( http://www. ppdi. com/ ).

Products Center contract for the receipt, storage, inventory, packaging/repackaging, quality assurance, distribution and disposal of study products. The Request for Proposals can be found at https://www. fbo.

gov/index? s=opportunity&mode=form&id=96d65718068fb0a5d34086876b3f8a11&tab=core&_cview=1 . The contract is held by Eminent Services Corporation ( http://www.

eminentservices. com/ ).

Management Center contract to provide technical and administrative assistance for a broad range of functions pertaining to regulatory sponsorship, including preparation of regulatory submissions, reports and other materials, communications with Regulatory Health Authorities, implementation of protocol-specific site registration requirements, and maintenance and management of Sponsor Essential Clinical Documents (SECDs).

The Request for Proposals can be found at https://www. fbo. gov/index?

s=opportunity&mode=form&id=ffaa80e09ae0c5c612502ac077bcca97&tab=core&_cview=1 . The contract is held by PPD ( http://www. ppdi.

com/ ). In addition, it is anticipated that, with rare exceptions, the NIAID will serve as the regulatory sponsor for Network clinical trials conducted under Investigational New Drug (IND) Applications, Investigational Device Exemptions (IDEs), and Biologic Licensing Agreements (BLAs) with full responsibility for carrying out sponsor regulatory requirements.

The NIAID will also coordinate the activities of independent Data and Safety Monitoring Boards (DSMBs) to review final clinical protocols and interim and final study data to ensure the safety of clinical trial subjects.

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

Agenda. The Network will develop and implement a Research Agenda to advance immune tolerance induction strategies through clinical trials and to integrate studies of underlying mechanisms of the induction, maintenance and loss of tolerance.

It is anticipated that Network research will evolve during the award period as new investigational products/approaches and developing technologies provide additional opportunities, and as findings eliminate some approaches from further consideration. Therefore, the Network is expected to refine and revise the Research Agenda as necessary to accommodate new opportunities and expanded knowledge.

The Research Agenda will include the following: A description of the state-of-the-art of research to induce immune tolerance and define underlying mechanisms in animal models and human studies, including discussions of: safety concerns; knowledge gaps; scientific opportunities relevant to the clinical application of tolerance induction strategies in human immune-mediated diseases and transplantation; and reasons for the failure of past approaches.

Delineation of promising investigational approaches to tolerance induction for the prevention and treatment of asthma, allergic and autoimmune diseases, and for the prevention of immune-mediated rejection of solid organ, tissue and cell transplants.

A description of: (i) the state-of-the-art of research on the identification, assessment and validation of immune/surrogate markers, biological samples (e.g., blood, tissue, cellular isolates), and existing and new techniques for measuring tolerant states; (ii) knowledge gaps and opportunities relevant to further development and improvement in immune/surrogate markers, samples and techniques, including the major sources of variability that may confound clinical applications (biological and sampling diversity, specimen handling, shipping, storage and variability of detection procedures), validation against acknowledged disease endpoints, and proposed strategies for overcoming and/or reducing variability; and (iii) the use of bioinformatics tools to analyze combined mechanistic and clinical data.

A detailed description of research priorities for both clinical trials and mechanistic studies and the rationale for their selection.

Identification of the immediate and long-range goals of the Network, potential barriers to success, and potential solutions to overcome Delineation of approaches to identify and capitalize on opportunities for industry partnerships to accomplish the research goals of the standards, policies, criteria and processes for implementing the Research Agenda with respect to: (i) setting scientific priorities and refining priorities based on new opportunities and findings; (ii) identifying and integrating new clinical strategies and technologies; (iii) soliciting, evaluating and making funding decisions for proposed clinical trials, integrated mechanistic studies, and tolerance assays; (iv) assessing the productivity, continued need for, and continued relevance of approved trials/studies, and discontinuing unneeded or unproductive research projects; (v) assessing the soundness, feasibility and anticipated contributions of proposed bioinformatics projects for the analysis of combined mechanistic and clinical data; and timelines and milestones to assess success in meeting the major objectives of the Research Plan.

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

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

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

Under the overall direction of the PD/PI, the Steering Committee will serve as the primary governing body for clinical trials, mechanistic studies and tolerance assays, nonclinical research and product development, and bioinformatics/data analyses.

Specific functions include: (i) developing and implementing a process for the solicitation, preparation and submission of proposals from Network and non-Network investigators, including standardized requirements, templates and instructions; (ii) conducting reviews to assess the scientific merit, soundness and feasibility of all proposed studies, including the adequacy and appropriateness of the number and capabilities of proposed clinical sites; (iii) preparing written reports to document the results of all reviews; (iv) making recommendations to the Executive Committee on support of proposed projects; and (v) directing and overseeing the implementation of approved studies, including adherence to established timelines and milestones.

Steering Committee members must represent the breadth of clinical and scientific expertise and experience necessary to: evaluate proposals for clinical trials and mechanistic studies for asthma and allergic diseases, autoimmune diseases, and transplantation; assess the need for further nonclinical studies and product development; and determine feasibility and value of proposed analyses of combined clinical and A Clinical Operations Group (COG) will be established to assist investigators and institutions in the development, implementation and monitoring of Network-funded clinical trials.

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

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

All laboratories must meet Good Clinical Laboratory Practices (GCLP) or equivalent standards. A consortium of multi-disciplinary experts will be established to serve as the Bioinformatics Group (BG), including experts in statistics, epidemiology, data modeling and marginal structural modeling, etc., in the context of biomedical research and, more specifically, in the context of clinical trials and mechanistic studies.

The BG will develop and operate a data management system for mechanistic study data and clinical data derived from the Network Statistical and Data Coordinating Center and conduct and/or participate in the design and conduct of data analyses.

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