Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Allergy and Infectious Diseases (NIAID)
Funding Opportunity Title	Inner City Asthma Consortium (UM1)
Activity Code	UM1 Multi-Component Research Project Cooperative Agreements
Announcement Type	New
Related Notices	None
Funding Opportunity Announcement (FOA) Number	RFA-AI-13-036
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 Funding Opportunity Announcement (FOA) is to invite applications to conduct clinical research and assume the leadership and administrative responsibilities for the Inner City Asthma Consortium (ICAC). The selected applicant will continue the mission of the ICAC, which focuses on the prevention and treatment of asthma in inner-city populations by conducting clinical trials and mechanistic studies in order to understand the immunopathogenesis of the disease and to evaluate and develop effective interventions tailored to inner-city populations.

Posted Date	August 26, 2013
Letter of Intent Due Date(s)	November 20, 2013
Application Due Date(s)	December 20, 2013
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	April, 2014
Advisory Council Review	May, 2014
Earliest Start Date	July, 2014
Expiration Date	December 21, 2013
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS 398 Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Looking ahead: NIH is committed to transitioning all grant programs to electronic submission using the SF424 Research and Related (R&R) format and is currently investigating solutions that will accommodate NIH’s multi-project programs. See NOT-OD-13-075 and NIH’s Applying Electronically website for more information.

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

The purpose of this FOA is to invite applications to conduct clinical research and assume the leadership and administrative responsibilities for the Inner City Asthma Consortium (ICAC). The selected applicant will continue the mission of the ICAC, which focuses on the treatment and prevention of asthma in inner-city populations by conducting clinical trials and mechanistic studies in order to understand the immunopathogenesis of the disease and to evaluate and develop effective interventions tailored to inner-city populations. The ICAC will be supported by the following sub-sections: Leadership, Clinical Trials Operations, Mechanistic Studies Operations, Urban Environment and Childhood Asthma (URECA) Operations, and Laboratory Support.

The prevalence of asthma has continued to increase in the United States (US). The burden of asthma morbidity and mortality falls disproportionately on poor and minority groups. For example, for children and adolescents 0 to 17 years of age, asthma hospitalizations and emergency room visits are over 3 times more frequent among African Americans than among whites. NIAID has a long-standing interest in understanding and reducing the burden of asthma among inner city residents and has funded research initiatives towards this goal over the previous 2 decades. Previous NIAID-sponsored asthma-related initiatives include: a) the National Cooperative Inner City Asthma Study (NCICAS, 1991-1995) which identified cockroach as a major allergen for inner city asthma and demonstrated the effectiveness of an Asthma Counselor intervention; b) the Inner City Asthma Study (ICAS, 1996-2001), which demonstrated the effectiveness of an environmental intervention aimed at reducing allergen exposure among inner-city children; and c) the Inner City Asthma Consortium I (ICAC I, 2002-2008), which conducted clinical trials evaluating the biomarker exhaled nitric oxide as a guide for asthma therapy, and the use of omalizumab therapy for inner-city children with asthma. In addition, the initial safety dosing studies for cockroach sublingual immunotherapy were completed and the URECA birth cohort was established.

The current ICAC is comprised of 9 clinical sites and 2 mechanistic sites that support the following goals:

• To design and conduct clinical studies with the goal of:
  • improving asthma control;
  • improving asthma phenotyping using biomarkers; and
  • developing allergen immunotherapy approaches for cockroach allergy.
• To design and conduct mechanistic studies involving human subjects with the goal of elucidating the immunopathogenesis of asthma in the inner-city environment
• To develop, validate and implement basic science methodology to support the studies conducted under the above objectives
• To continue follow-up and monitoring of the ongoing URECA birth cohort through 10 years of age

Previous ICAC studies have identified risk factors and effective clinical strategies for asthma management and ongoing studies are expected to provide detailed information on inner-city childhood asthma phenotypes, safety and efficacy of therapies targeting seasonal asthma exacerbations, as well as preliminary data on cockroach allergen immunotherapy.

The goal of this FOA is to continue the work of the ICAC and to include further development of cockroach allergen immunotherapy and consideration of new allergen immunotherapies; for example to mouse allergens; the development and execution of clinical and mechanistic studies targeted to inner-city asthma phenotypes, and interventions designed to prevent the incidence of asthma or its progression. In addition, the URECA birth cohort study will be continued to the end of the grant, when the participants will range from 14 to 16 years of age, with the goal to provide information on the immunologic basis of late childhood and adolescence-onset asthma, as well as the remission of asthma during the same years.

The work of the ICAC will be conducted by clinical trial and mechanistic study sites. The clinical trial sites must have 1) ready access to inner-city patient populations to ensure timely screening and enrollment of appropriate study participants; 2) Site Leaders with a strong history and experience in successfully designing and conducting clinical trials and mechanistic studies; 3) support personnel and clinical research facilities to execute clinical trial and mechanistic study protocols; and 4) capabilities to collect and process the biologic samples required for mechanistic studies. The mechanistic study sites must provide 1) Site Leaders with a strong history and experience in conducting human mechanistic research necessary to carry out the scope of the ICAC’s immunologic research relevant to asthma immunopathogenesis and immunotherapeutics; 2) support personnel with immunology and molecular biology laboratory experience for research using human biologic samples, including appropriate International Conference on Harmonization-Good Clinical Practice (ICH-GCH) training in handling human biologic samples; and 3) support laboratory facilities equipped for immunologic experimentation using human biologic specimens.

The studies proposed should focus on children and adolescents less than 18 years of age residing in US inner cities. However, Phase I/II clinical trials or any mechanistic studies in adult subjects may be supported if such clinical trials involve unacceptable risk for pediatric participants or require methodology difficult to apply in children; for example, collection of large volumes of blood. The number of clinical trials sites participating in a study is not limited and it is expected that multiple studies will be performed concurrently.

All clinical trials to be designed by the ICAC must abide by the recommendations on asthma outcomes issued by the NIH-sponsored Asthma Outcomes Workshop that were published in the Journal of Allergy and Clinical Immunology, 2012 Mar;129(3 Suppl).

The applicant is required to submit 4 sample clinical trials and 3 sample mechanistic studies with the understanding that the specific studies to be conducted may be different as a result of peer review, external scientific advisory review, and/or the priorities of NIAID.

The following are the major research objectives of the ICAC:

• Develop allergen immunotherapy modalities to mitigate and/or prevent the effects of inner-city specific allergens on asthma
• Develop and implement other innovative, phenotype-specific, immunomodulatory clinical trials for the treatment of inner-city asthma
• Develop and implement clinical trials to prevent the incidence or progression of inner-city asthma
• Investigate the role of the microbiome of the host (GI, respiratory, skin) and of the home environment in inner-city asthma
• Investigate the pathogenesis and mechanisms of specific inner-city asthma phenotypes
• Continue the inner-city asthma birth cohort URECA through 14-16 years of age

This FOA will support basic research not involving human subjects/human samples ONLY if the studies are pivotal for the development of subsequent human research studies, or to provide clinical trials with validated laboratory methodologies.

The Leadership will be responsible for the overall scientific leadership and administrative functions of the ICAC and for coordination among the other activities. The Leadership responsibilities include:

• Overall scientific planning and priority setting including defining an agenda to advance research in the area of prevention and treatment of asthma in inner-city populations by recommending to NIAID priority clinical trials and mechanistic studies for design and implementation
• Establishing and maintaining clinical trial sites and mechanistic study sites to achieve the scientific goals of the ICAC
• Evaluating proposed clinical trials, mechanistic studies and laboratory monitoring/testing
• Establishing and implementing collaborations with other Federal and non-Federal organizations/institutions for the co-sponsorship of research in areas of mutual interest and collaborations with industry for the evaluation of specific products/approaches
• Planning and coordinating the ICAC’s technical, operational, administrative, and fiscal requirements
• Establishing a plan for efficient IRB review (within 30 calendar days from submission) and approval for multi-center studies using federated IRB models.
• Establishing plans and procedures to reduce redundancy, delays and excess due to duplicated infrastructure associated with a consortium of clinical trials and mechanistic study site
• Establishing and maintaining the functions of committees responsible for governance and management of the ICAC

Within the governance and management structure, the Leadership will have responsibility for establishing and maintaining several committees/groups. Brief descriptions of the committees/groups include:

Steering Committee

The voting members of the Steering Committee include the PD(s)/PI(s) of the ICAC, the PD/PI of the Inner-City Asthma Consortium Statistical and Clinical Coordinating (ICAC-SACCC), up to two NIAID-designated Project Scientists, and the Site Leaders of the clinical trials and mechanistic study sites. The Steering Committee responsibilities include: (i) making decisions regarding overall scientific direction, recommending specific studies for NIAID approval, and coordinating and managing approved studies; (ii) developing and implementing policies to ensure the efficient operation and effective management of ICAC functions, resolution of disputes and differences of opinion within the Steering Committee and between the Steering Committee and the External Scientific Advisory Group; (iii) establishing and implementing policies and procedures for publications and other forms of information dissemination pertaining to ICAC-supported studies and study data; (iv) developing and implementing policies and procedures for the identification, disclosure, reporting and management of potential and actual conflicts of interest for members of the ICAC and the External Scientific Advisory Group; (v) approving policies and procedures for the secure transfer of clinical and laboratory data to the central databases of the ICAC-SACCC prior to study implementation and for the transfer of all baseline and study outcomes data to NIAID databases for public access following the publication of the primary outcome results. On a yearly basis, the Steering Committee will select a Chairperson among the Site Leaders of the clinical trial and mechanistic study sites.

Executive Committee

The PD/PI of the ICAC will have the responsibility to serve as Chair of the Executive Committee. Other members include the Steering Committee Chairperson, NIAID project scientist(s), the PD/PI of the ICAC-SACCC, the Site Leaders of all approved studies, ongoing or under development, and a rotating representative of the mechanistic sites. The Executive Committee will have responsibility for: (i) updating the PD(s)/PI(s) of the ICAC in regards to the performance of the clinical trial and the mechanistic study sites; (ii) evaluating ICAC study problems and issues requiring immediate action, including problems with delayed IRB action for study approval, study participant recruitment and retention, progress and completion of protocol development, protocol approval, clinical trial site training and other study implementation milestones/tasks within timelines approved by the Steering Committee; (iii) formulating recommendations to the Steering Committee to resolve the issues and problems identified, (iii) reviewing site monitoring visit reports; (iv) managing personnel needs, resources and performance; and (v) monitoring the progress of manuscripts for publication under preparation for dissemination of the ICAC’s scientific findings.

External Scientific Advisory Group (ESAG)

The members of the ESAG will be selected from institutions outside those serving as members of the ICAC and include expertise in the areas of clinical trials for asthma, asthma pathophysiology and asthma immunopathogenesis and immunotherapeutics. ESAG appointments should be for one year with no restrictions on renewal. The role of the ESAG will be to review and provide recommendations on: studies proposed for implementation by the ICAC, final study protocols, major findings resulting from ICAC-sponsored studies, and specific studies and areas of research for ICAC consideration. The recommendations by the ESAG will be submitted to the Steering Committee Chairperson and the designated NIAID project scientist(s). All such recommendations will be considered advisory.

Potential ESAG members should NOT be identified in the application.

The Clinical Trials Operations will be responsible for establishing the processes and procedures for development and review of clinical trial protocols and conduct Phase I, II, III or IV clinical trials with the overall goals of a) improving asthma control and b) preventing the development or progression of asthma. Clinical trials should focus on immunomodulatory interventions, but other forms of interventions (e.g. pharmacologic, environmental) are acceptable as long as novel effects on immune function are postulated and assessed. It is expected that clinical trials will be based on asthma phenotypes that are important in the inner-city environment. Observational studies (cross-sectional or prospective) are not a priority of the ICAC and may only be included if required as part of a primary mechanistic study. To help overcome enrollment challenges, applicants are encouraged to adopt recommendations of the Institute of Medicine expert panels (Clinical Trials Workshop Summary), including:

• Identifying and engaging patients and physicians, through outreach to community clinics and practices;
• Promoting public involvement through web-based information (such as social media), education, and outreach; and
• Incorporating advanced clinical trial designs, such as adaptive design that uses information gathered in the course of a trial to adjust placebo and drug assignment groups.

In addition, the Clinical Trials Operations will have responsibility for the following activities:

Protocol Development:

• Establish a Protocol Team for each study protocol
• Assist the Protocol Team and the ICAC-SACCC in the development of the study protocol
• Assist the Protocol Team and the ICAC-SACCC in the preparation and approval of study informed consent forms, Case Report Forms, Standard Operating Procedures, Manuals of Operation, subject instructions, questionnaires, screening and recruitment logs, order forms for test articles and test article accountability logs
• Establish protocol-specific milestones, timelines and performance guidelines for both the protocol development process and for study initiation, execution, completion and analysis of final study data

Investigational New Drug and Investigational Device Exemption Applications: assist the NIAID in the preparation of IND and IDE applications and ensure compliance of ICAC personnel and activities with all regulatory requirements associated with IND/IDE sponsorship.

Clinical Trial Data and Safety Monitoring: prepare a Data and Safety Monitoring Plan (DSMP) to ensure adequate data collection and documentation and adequate protection of human subjects commensurate with the anticipated level of risk for each ICAC study in accordance with all applicable Federal regulations and requirements and ICH standards for human subjects research.

Data Safety Monitoring Board (DSMB) or Safety Monitoring Committee (SMC) Review and Monitoring: for the clinical trials that will be reviewed and monitored by the NIAID-assigned DSMB or SMC, assist in activities related to DAIT DSMB or SMC review and approval of final clinical study protocols and provide interim analyses, progress reports and safety updates as well as the final safety report and study results to the DAIT-assigned DSMB or SMC.

Protocol-specific Training: assist in the organization and conduct of protocol-specific training for the participating investigators and the relevant clinical and technical Clinical Trial Site and Mechanistic Study Site staff.

Clinical Trial Implementation and Management: assist with the coordination to execute the following activities:

• Initiate and complete clinical trial protocols and the clinical components of the mechanistic studies protocols
• Establish and implement policies and procedures for study management and continuous oversight to ensure adequate rates of human subject recruitment, timely and accurate data collection, and completion of all studies in compliance with NIH guidelines and Federal regulations, requirements and policies
• Establish and implement policies and procedures to ensure the safe and ethical conduct of clinical research in accordance to Federal regulatory requirements, GCP and ICH guidelines and study-specific DSMPs, including the recording and reporting of all Adverse Events (AEs) and Serious Adverse Events (SAEs)
• Establish and implement policies and procedures for the secure transfer of clinical and laboratory data to the central databases of the ICAC-SACCC

The Mechanistic Studies Operations will have responsibility for the design and conduct of mechanistic studies involving human subjects with the goals of: a) improving our understanding of the immunopathogenesis of asthma in the inner-city populations in relation to its various clinical and functional phenotypes; b) elucidating the mechanisms and predicting the efficacy of immunotherapeutic modalities, particularly allergen immunotherapy; and c) identifying and evaluating potential biomarkers of the induction, maintenance, and loss of immune tolerance induced by immunotherapeutic modalities.

Two types of mechanistic studies can be conducted:

• Stand-alone clinical studies designed with primary mechanistic hypotheses that will be tested in human subjects. These studies will be separate and distinct from the clinical trials to be conducted by the ICAC. It is anticipated that these studies will be designed by the mechanistic study sites, which will also carry out the primary mechanistic laboratory analyses. However, all clinical aspects (human subject recruitment and phenotyping characterization, monitoring, biologic sample collection) will be conducted by the clinical trial sites.
• Ancillary studies on therapeutic mechanisms or biomarker development designed as components of the clinical trials or the birth cohort study undertaken by the ICAC.

Limited support for basic research projects that do not involve human subjects will be provided only when such projects are pivotal for the development of subsequent human research studies, or to provide clinical trials with validated laboratory methodologies.

The URECA Operations will be responsible for the follow-up and monitoring of the ongoing URECA birth cohort under the existing, approved protocol through 10 years of age and designing and implementing a clinical protocol to follow the URECA birth cohort through the end of the grant when the participants will range from 14 to 16 years of age. The current URECA protocol is available at http://www.niaid.nih.gov/about/organization/dait/Documents/URECAIIIAdd508.pdf. The purpose of the new protocol is to employ innovative and state-of-the-art methodologies to address the following scientific topics:

• Natural history of asthma in adolescence and identification of factors that contribute to asthma progression or amelioration/resolution focusing on allergen-specific and overall immune responses, endocrine function/metabolism/obesity, the environment, and psychosocial factors
• Rate and risk factors for new asthma development in adolescence focusing on the same factors
• Natural history of allergic sensitization in adolescence and identification of factors that contribute to the development of new or the loss of existing IgE-mediated allergies
• Changes in the immune system that are associated with the onset, persistence, or remission of asthma and other allergic conditions (e.g. allergic rhinitis) during this time period and factors that influence those changes

The URECA study, initiated in February 2005, is a longitudinal birth cohort study designed to elucidate risk factors involved in the immunopathogenesis and the clinical manifestations of recurrent wheeze\asthma among inner city children. Pregnant women with and without a history of asthma or allergies were recruited in the later part of their pregnancies. The cohort completed recruitment in early 2007 with 609 infants enrolled (560 from allergic mothers and 49 from non-allergic mothers) and its current size is approximately 484 children (441 from allergic mothers and 43 from non-allergic mothers). At birth, cord blood was collected on all eligible newborns. Since birth, the cohort has been followed in a number of ways, including: (i) telephone interviews every 3 months to monitor respiratory symptoms, symptoms associated with various allergic diseases, and psychosocial factors; (ii) annual home visits to collect home environmental samples; (iii) nasal lavages performed on study participants reporting respiratory symptoms meeting pre-specified criteria to identify respiratory viruses; and (iv) annual clinic visits for detailed medical history, physical examination, nasal lavage, and the collection of blood samples for a variety of immunologic studies, such as determination of immunoglobulin levels as well as T cell phenotyping and stimulation. In addition, depending on the age of the study participant, other clinical tests, such as spirometry, allergen skin testing, and bioelectric impedance analysis, are performed during the annual clinical visit. By the time of award, all study participants will be between 7 and 9 years old.

The Laboratory Support will be responsible for performing common clinical and other routine laboratory services required for the clinical trials and mechanistic studies to be performed by the ICAC as well as for established clinical tests that will be used as outcomes in participant characterization and follow-up in all studies that will be supported under this award. Examples of such services include total and specific IgE, CBC, home dust analysis, and lung function measurements. The Laboratory Support will have the responsibility for the development and implementation of Standard Operating Procedures (SOPs) and Quality Assurance/Quality Control (QA/QC) plans for the performance of all protocol-specific laboratory tests conducted by the ICAC.

This FOA will not support:

• Animal model development
• Clinical studies/trials that are performed outside the United States

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the PHS 398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIAID intends to commit $10 million total cost yearly to fund 1 award.
Award Budget	Budgets for the URECA Management and Operations should not exceed $3 million total cost yearly and budgets for the Leadership and Laboratory Support combined should not exceed $1.5 million total cost yearly. The remaining $5.5 million total cost yearly should be apportioned between the Clinical Trials Operations and Mechanistic Studies Operations as required for the conduct of clinical trials and mechanistic studies.
Award Project Period	The scope of the proposed project should determine the project period The maximum project period is 7 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 not allowed.

Applicant Organizations

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

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

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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 PHS 398 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 are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

It is critical that applicants follow the instructions in the PHS 398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

• Descriptive title of proposed 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:

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

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

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

At the time of submission, two additional paper copies of the application and all copies of the Appendix files must be sent to:

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

All page limitations described in the PHS 398 Application Guide and the Table of Page Limits must be followed in addition to the following page limitations to the Research Strategy sub-sections listed below:

A. ICAC Overview: 30 pages

B. Leadership 12 pages

C. Clinical Trials: 12 pages each trial

D. Mechanistic Studies: 12 pages each study

E. URECA Operations: 30 pages

F. Laboratory Support: 6 pages

The following section supplements the instructions found in the PHS 398 Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

All instructions in the PHS398 Application Guide must be followed, with the following additional instructions, as noted.

Face Page

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

This is the first numbered page of the application; number all succeeding pages consecutively.

Description, Project/Performance Sites, Senior/Key Personnel, Other Significant Contributors, Human Embryonic Stem Cells

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

Description: Provide a succinct but accurate description (abstract) of the overall application addressing the major, common theme of the consortium. Do not exceed the space provided.

Project/Performance Site: List the performance sites where the research will be conducted. Applicants should include clinical research facilities suitable to execute each proposed clinical trial and mechanistic study protocol and laboratory facilities equipped for immunologic experimentation using human biologic specimens.

Senior/ Key Personnel: A single PD/PI will be required to commit a minimum of 4 calendar months per year. For institutions/organizations proposing multiple PDs/PIs the commitment will be a minimum of 2.4 person months per year for each PD/PI.

Applicants should propose clinical trial Site Leaders with a strong history and experience in successfully designing and conducting clinical trials and support personnel capable to execute the clinical trial and any associated mechanistic study, if applicable. Trial Sites Leaders should have demonstrated clinical expertise in the diagnosis, treatment and management of asthma and allergic diseases and at least 10 years' experience in the design and conduct of clinical trials and other studies in asthma and allergic diseases.

Applicants should propose mechanistic study Site Leaders with a strong history and experience in successfully designing and conducting mechanistic research in humans and support personnel capable to execute mechanistic study protocols. Mechanistic study Site Leaders should have a strong history and experience in conducting mechanistic research necessary to carry out the scope of the ICAC’s immunologic research relevant to asthma immunopathogenesis and immunotherapeutics and support personnel with immunology and molecular biology laboratory experience for research using human biologic samples, including appropriate GCP/ICH training in handling human biologic samples.

Table of Contents

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

Modify Form Page 3 of the PHS 398 to include the following sub-sections of the Research Strategy:

A. ICAC Overall

B. Leadership

C. Clinical Trials Operations

D. Mechanistic Studies Operations

E. URECA Operations

F. Laboratory Support

Detailed Budget for Initial Budget Period

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

Use Additional Form Pages 4 and 5 if needed to provide detailed separate budget information for initial budget period for the following individual application sub-sections:

• Leadership
• Clinical Trials Operations
• Mechanistic Studies Operations
• URECA Operations
• Laboratory Support

The budget estimates provided below should serve as guidelines, not strict caps. Nonetheless, substantial deviations from these guidelines should be justified.

Budgets for the URECA Operations should not exceed $3 million total cost yearly. The first 2 years of the URECA Operations budget should include the costs associated with the ongoing URECA protocol as well as the new, URECA continuation protocol.

Budgets for the Leadership and Laboratory Support combined should not exceed $1.5 million total cost yearly. This amount should be apportioned as necessary between the Leadership and Laboratory Support.

The remaining $5.5 million total cost yearly funds should be apportioned between the Clinical Trials Operations and Mechanistic Studies Operations as required for the conduct of clinical trials and mechanistic studies. Individual budgets for each sample trial should not be added into the Detailed Budget. Comprehensive information for EACH of the 4 sample trials and EACH of the 3 sample mechanistic studies costs should be included in the budget justification. For the 4 sample clinical trials, budget justifications should be based on per patient costs and include the other costs of performing the trial (clinical research tests, coordinator and Site Leader time, study and other drug costs if applicable, pharmacy costs, mechanistic study costs, etc.). It is anticipated that only 3 clinical trials will be carried out during the period of this award. For mechanistic studies, budgets should be based on per patient costs and include the other costs of performing the study (clinical research tests, coordinator and Site Leader time, drug costs if applicable, pharmacy costs, mechanistic assay or other test costs, etc.). Full development of clinical trials and mechanistic studies will begin soon after award, with the assistance of NIAID staff and the ICAC-SACCC.

Certain resources for the ICAC will be provided by NIAID and no costs for such resources should be requested in response to this FOA. These are:

• The ICAC-SACCC will be supported by an independent NIAID award and will provide a broad range of clinical research support services, including support for the design and organization of each ICAC protocol, development of protocol-related materials, data collection, management and quality control, clinical site monitoring, data analysis and manuscript development support.
• It is anticipated that, with rare exceptions, the NIAID will serve as the regulatory sponsor for the ICAC’s 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 support and coordinate the activities of an independent Data and Safety Monitoring Board (DSMB) or Safety Monitoring Committee (SMC) to review final clinical protocols and interim and final study data to ensure the safety of clinical trial subjects.
• All clinical trial data produced by the ICAC will be made publicly available by NIAID, through the ICAC-SACCC, within 18 months after database lock. NIAID will provide the resource for public access, either through Immport (https://immport.niaid.nih.gov) or through another NIAID resource.

Budget for Entire Proposed Period of Support

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

Use Additional Form Pages 4 and 5 to provide detailed separate budget information (first year and cumulative budgets for the entire project period) using the same categories as described above for the initial budget period. Individual budgets for each sample clinical trial and mechanistic study should not be added into the Budget for Entire Proposed Period of Support.

Biographical Sketch

All instructions in the PHS 398 Application Guide must be followed.

Resources

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

Provide information on resources available for each sample clinical trial or mechanistic study or laboratory service. Describe how the scientific environment in which the trial will be done contributes to the probability of success (e.g., institutional support, physical resources, and intellectual rapport.) For Early Stage Investigators, describe institutional investment in the success of the investigator. If there are multiple performance sites, describe the resources available at each site.

Describe any special facilities used for working with biohazards or other potentially dangerous substances.

Research Plan

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

Specific Aims: Applicants should list the Specific Aims of the ICAC focusing on the overall ICAC agenda and strategic plan including the plans for clinical trials and mechanistic studies.

Research Strategy: The Research Strategy must consist of the following sub-sections:

A. ICAC Overview

This narrative sub-section is an overview that discusses the overall strategic plan of ICAC. Applicants should describe their agenda to advance research in the area of prevention and treatment of asthma in inner-city populations and to understand the immunopathology of the disease and should discuss how this agenda will satisfy the stated goals of this FOA. Applicants should also discuss past experience or preliminary data focusing on how the proposed work is linked to this experience and on what the proposed work is expected to achieve that will inform future research in the field.

Describe the current state of knowledge in the field of inner-city asthma with regards to:

• Scope of the problem
• Major existing questions and needs
• Recent advances in identifying risk factors and clinical phenotypes, understanding the pathophysiology, improving management and addressing prevention of disease
• The applicant’s contributions to the above topics (insert a list of relevant publications)

Describe an overall strategy to advance research in inner city asthma and address the objectives of this FOA.

• Discuss what the proposed trials, mechanistic studies and the proposed URECA protocol try to accomplish and how they will advance the field
• Discuss how the proposed trials, mechanistic studies and the URECA protocol integrate
• Discuss the innovative aspects of the proposed trials, mechanistic studies and the proposed URECA protocol
• Discuss how the proposed trials, mechanistic studies and the proposed URECA protocol relate to previous work by the applicant and lessons learned
• Describe potential next steps if the proposed studies are conducted and support the tested hypotheses

Discuss how the strategy and direction of the Consortium may need to be modified, and towards what direction, if the outcomes of the studies conducted do not support the tested hypotheses

In addition, applicants should describe and discuss their strategy and approach in selecting the Clinical Trial Sites and the Mechanistic Study Sites for this application and their plans for organizing these sites into a functional and interactive consortium that can conduct state-of-the-art clinical research while abiding to GCP guidelines and ICH standards for the conduct of clinical research.

Clinical Trials Sites:

• Establishing Clinical Trial Sites in geographic areas of the United States with large inner city populations
• Identifying Clinical Trial Site Leaders with appropriate expertise
• Providing information on these sites previous record and achievements (participant recruitment and retention, experience in handling and processing human samples) in clinical trials
• Providing training in accordance with Federal regulatory requirements, GCP guidelines and ICH standards for subject screening, recruitment, enrollment and retention; informed consent; assessment and reporting of Adverse Events and Serious Adverse Events; collection of protocol-specific biologic specimens; receipt, storage, packaging, labeling and management of study products
• Collaborating with the ICAC-SACCC in the management of study data; data entry, and creation, maintenance and storage of research records
• Identifying the availability of clinical research facilities; clinical laboratory facilities for the conduct of protocol-specific laboratory tests; facilities for storage of clinical samples and for the packaging and shipping of clinical samples to mechanistic studies sites; research pharmacy facilities for the receipt, labeling, storage, distribution, inventory packaging, and for return or disposal of investigational products
• Demonstrating access to pediatric and adult clinic patients and/or to clinical research databases deriving from inner city populations adequate to ensure the timely screening and enrollment of study participants and, when necessary, access to non-inner city pediatric and adult patients

Mechanistic Studies Sites:

• Establishing Mechanistic Study Sites
• Identifying Mechanistic Study Site Leaders with appropriate expertise
• Providing training in accordance with Federal regulatory requirements, GCP guidelines and IHC standards in human subject samples receipt, storage, packaging, labeling and management of study products; collection, quality control and management of study data; data entry, and creation, maintenance and storage of research records
• Identifying the availability of research facilities including facilities for the conduct of state-of-the-art human sample evaluations, complex bioinformatics analyses; facilities for storage of clinical samples

Protocol Development:

• Establishing a Protocol Team for each approved clinical trial or stand-alone mechanistic study protocol
• Assisting in the development of the clinical trial protocols or stand-alone mechanistic studies
• Assisting in the development of mechanistic studies as parts of the clinical trials that are to be developed and executed by the Clinical Trials Operations
• Assisting in the preparation and approval of clinical trial informed consent forms, Case Report Forms, Standard Operating Procedures, Manuals of Operation, subject instructions, questionnaires, screening and recruitment logs, order forms for test articles and test article accountability logs
• Development of protocol-specific milestones, timelines and performance guidelines for both the protocol development process and for study initiation, execution, completion and analysis of final study data
• Investigational New Drug and Investigational Device Exemption Applications: assisting in the preparation of IND and IDE applications for all clinical trials and for the stand-alone mechanistic studies that are designed by the Mechanistic Studies Operations.
• Data and Safety Monitoring: preparing Data and Safety Monitoring Plans (DSMP) for all clinical trials and for stand-alone mechanistic studies that are designed by the Mechanistic Studies Operations.
• For all clinical trials and for the stand-alone mechanistic studies designed by the Mechanistic Studies Operations, assisting in DAIT DSMB review and approval of final clinical trial protocols and providing interim analyses, progress reports and safety updates and the final safety report and study results to the DAIT DSMB or SMC or the NIAID project scientist\medical officer;
• Protocol-specific Training: assisting in the organization and conduct of protocol-specific training for the participating investigators and the relevant clinical and technical clinical trial and mechanistic study site staff.
• Clinical Trial Implementation and Management: for all clinical trials and for the stand-alone mechanistic studies designed by the Mechanistic Studies Operations, assisting with the coordination of the following activities: (i) establish and implement policies and procedures for study management and oversight to ensure adequate rates of human subject recruitment, timely and accurate data collection; (ii) establish and implement policies and procedures to ensure the safe and ethical conduct of clinical research in accordance to Federal regulatory requirements, GCP and ICH guidelines and study-specific DSMPs, including the recording and reporting of all Adverse Events (AEs) and Serious Adverse Events (SAEs); (iii) establish and implement policies and procedures to ensure that all Clinical Trial Sites have the required supply of study materials for study initiation and conduct, and monitor supplies throughout the duration of the study and; (iv) establish and implement policies and procedures for the secure transfer of clinical and laboratory data to the central databases of the ICAC-SACCC. Note that training for site personnel in the use of these databases will be provided by the ICAC-SACCC. Note that the implementation and management of the clinical aspects of stand-alone mechanistic studies should be under the responsibility of the Clinical Trials Operations.
• Mechanistic Protocol Implementation and Management: directing, monitoring, and managing the implementation of the mechanistic research aspects of both the stand-alone mechanistic studies designed by the Mechanistic Studies Operations and the mechanistic studies that are part of the clinical trials designed by the Clinical Trials Operations.

B. Leadership

This narrative sub-section should detail the fiscal and administrative responsibilities and management of the ICAC.

Applicants should describe plans, processes, and procedures for the following activities:

• Managing the ICAC’s technical, operational, administrative, and fiscal requirements
• Establishing and implementing collaborations with other Federal and non-Federal organizations/institutions for the co-sponsorship of research in areas of mutual interest and collaborations with industry for the evaluation of specific products/approaches
• Reducing delays incurredwith the process of protocol approval at multiple, independent, Institutional Review Boards (IRBs) using federated IRB models
• Reducing redundancy, delays and excess due to duplicated infrastructure associated with a consortium of clinical sites
• Establishing and maintaining the functions of committees responsible for governance and management

Steering Committee: Applicants should identify the members of the Steering Committee and provide information that supports appropriate scientific and clinical research experience in asthma pathophysiology and treatment to implement the responsibilities of the Steering Committee.

Executive Committee: Applicants should identify any members of the Executive Committee that differ from those in the Steering Committee and provide information that supports appropriate scientific and clinical research experience in asthma pathophysiology and treatment to implement the responsibilities of this Committee.

External Scientific Advisory Group: Applicants should describe plans, processes, and procedures for selecting ESAG members from institutions outside those serving as members of ICAC that possess expertise in the areas of clinical trials for asthma, asthma pathophysiology and asthma immunopathogenesis and immunotherapeutics; Do NOT name potential members in the application.

Describe the internal institutional plans and procedures to ensure that all projects supported from this award will comply fully with all applicable Federal regulations, policies, and guidelines for research involving human subjects, including the evaluation of risks and protections, appropriate ethical oversight and funded projects, and plans for data and safety monitoring for clinical trials, if applicable.

Leadership Succession Plan: Applicants should provide a brief plan in the case the PD/PI moves to a different institution or is for any reason unable to continue as leader of the program.

C. Clinical Trials

Repeat this sub-section for each of the 4 required sample clinical trials.

Use the following format as the first page of each sample clinical trial:

Clinical Trial number and Title: (e.g., Clinical Trial 1. Immune Modulation with X in Asthma)

Name of Clinical Trial Site Leader: (e.g., Jones, Roberta A.);

Human Subjects: (Yes or No) If Yes: Exemption number, -or- IRB Approval Date (e.g., 12/13/2012, or "Pending"), and Federalwide Assurance (FWA) number;

Vertebrate Animals: (Yes or No) If Yes: IACUC Approval Date (e.g., 11/17/2012, or Pending) and Animal welfare assurance number

Proposed Period of Support:

From: (mmddyy - e.g., 09/01/2014)

To: (mmddyy - e.g., 08/30/2021)

Costs Requested for Initial Budget Period: (e.g. 09/01/2014-08/30/2015)

Direct Costs: (e.g., $250,000)

Total Costs: (e.g., $400,000)

Costs Requested for the Entire Budget Period: (e.g., 09/01/2014-08/30/2021)

Direct Costs: (e.g., $1,250,000)

Total Costs (e.g. $2,000,000)

Applicant Organization (Organization name; Street address; City, State, Zip code)

Applicants should propose 4 separate sample clinical trials. NIAID is interested in the following areas:

• Cockroach allergen immunotherapy treatment with consideration for other relevant allergens
• Immunomodulatory interventions aimed at asthma phenotypes that are prevalent in the inner city
• Interventions aimed at preventing either the onset (primary prevention) or progress (secondary prevention) of asthma
• Additional areas for intervention in the inner city asthma may be proposed as long as they fall under the general objectives of this FOA

Sample clinical trials should be submitted with the understanding that the trials to be conducted by the ICAC may be different as a result of peer review, external scientific advisory review, and/or the priorities of NIAID.

The clinical trials must not exceed the clinical and scientific resources of the applicant’s team of institutions (e.g., the applicant group must be able to recruit the required number of study subjects from within their collaborating institutions) and must not exceed 7 years in duration.

The sample clinical trial should be presented in sufficient detail to allow reviewers to judge significance, approach, innovation and environment. The applicant should not submit a detailed clinical trial protocol because this will be developed collaboratively as a result of peer review, external scientific advisory review, and/or the priorities of NIAID.

Describe how each clinical trial will contribute to meeting the ICAC goals and explain the approach and rationale for selecting the methods to achieve the goals. In addition to stating the biological significance of the research, indicate the clinical trial’s relevance to the primary theme of the consortium.

Provide details about the approach, the planned research, anticipated results and alternative approaches including past experience and preliminary data. Explain how results will be interpreted (e.g., what would support your hypothesis, what would disprove it?).

This section should include, as applicable to the specific proposed clinical trial, the following:

• A discussion of the significance of the problem being studied and the need for the trial
• A discussion of studies that led to the proposed clinical trial and information or data from preliminary studies which address the need for and the feasibility of the trial
• A discussion of how this trial fits the overall research strategy of ICAC and how it integrates with the other proposed clinical trials and mechanistic research studies
• A discussion of anticipated results focusing on what interpretations can be offered, what the impact on the overall strategy of the ICAC and what the next steps could be depending on the outcomes of the trial
• A concise description of the overall study design, its rationale, methodology and analyses to be used to accomplish the goals and specific aims of the trial and a discussion of how the trial will test the hypothesis (es) proposed. This should include:
  • Study hypothesis (es) and objectives (primary, secondary, include mechanistic hypothesis (es) and objectives, if applicable)
  • Population
  • Study eligibility criteria (inclusion/exclusion)
  • Clinical trial design (include a graphic design of the trial):

Study arms

Primary and secondary endpoints (include mechanistic endpoints, if applicable)

Anticipated duration of recruitment and of the study as a whole

Study visit schedule and primary evaluations, including laboratory evaluations

Any anticipated Human Subjects issues and how those issues will be resolved

Sample size (with justification)

• Intervention(s) and comparators
  • Include descriptions of investigational study drugs, potential toxicities and experience in the proposed population. The discussion of toxicities should include known events as well as concerns unique for the population being studied.
  • Plan for provision of investigational drugs with letter(s) of commitment from suppliers, if needed (note additional requirements in appendix).
• Feasibility Assessment
  • Discuss the availability of the overall research population - to include the standard of care alternatives to trial participation, likelihood of acceptance by study populations of the proposed interventions (e.g. intravenous administration, required hospitalization, requirement for procedures such as biopsies, bronchoscopies or repeated imaging)
  • Discuss interventions with similar mechanism of action currently under development and their potential influence on the proposed trial
  • Describe the participating clinical study sites:

Investigators and their experience in clinical trials in the proposed study area

Investigators participation in investigator initiated clinical trials

Availability of the potential study participants at that site

Competing clinical trials at the proposed sites

Availability of special services needed to complete the trial (e.g. investigational pharmacy, PET scanner)

• Availability of the proposed study intervention
• A concise description of the associated mechanistic study (ies), if applicable, its (their) rationale and its (their) integration with the clinical trial.
• A summary of the statistical analysis plan for the proposed primary endpoint, including a description of the outcome measures and the statistical tests that will be used for data analysis. A more detailed and complete statistical analysis plan will be developed when studies are finalized post-award, with the assistance of the ICAC-SACCC.
• A statement of how the proposed trial outcomes abide by the recommendations issued by the NIH-sponsored Asthma Outcomes Workshop published in the Journal of Allergy and Clinical Immunology, 2012 Mar;129(3 Suppl).
• To help overcome enrollment challenges, applicants are encouraged to adopt recommendations of the Institute of Medicine expert panels (Clinical Trials Workshop Summary), including:
  • Identifying and engaging patients and physicians, perhaps through outreach to community clinics and practices
  • Promoting public involvement through web-based information (such as social media), education, and outreach
  • Incorporating advanced clinical trial designs, such as adaptive design that uses information gathered in the course of the trial to adjust placebo and drug assignment groups

D. Mechanistic Studies

Repeat this sub-section for each of the 3 required sample mechanistic studies involving human subjects research.

Use the following format as the first page of each sample mechanistic study:

Mechanistic Study Number and Title: (e.g., Mechanistic Study 1. Immune Modulation with X in Asthma)

Name of Mechanistic Study Site Leader: (e.g., Jones, Roberta A.);

Human Subjects: (Yes or No) If Yes: Exemption number, -or- IRB Approval Date (e.g., 12/13/2012, or "Pending"), and Federalwide Assurance (FWA) number;

Vertebrate Animals: (Yes or No) If Yes: IACUC Approval Date (e.g., 11/17/2012, or Pending) and Animal welfare assurance number

Proposed Period of Support:

From: (mmddyy - e.g., 09/01/2014)

To: (mmddyy - e.g., 08/30/2021)

Costs Requested for Initial Budget Period: (e.g. 09/01/2014-08/30/2015)

Direct Costs: (e.g., $250,000)

Total Costs: (e.g., $400,000)

Costs Requested for the Entire Budget Period: (e.g., 09/01/2014-08/30/2021)

Direct Costs: (e.g., $1,250,000)

Total Costs (e.g. $2,000,000)

Applicant Organization (Organization name; Street address; City, State, Zip code)

Applicants should propose 3 separate, stand-alone, mechanistic studies. NIAID is interested in one or more of the following areas:

• Asthma immunopathogenesis
• The role of the microbiome in asthma pathogenesis
• Immune tolerance to allergens
• The influence of the epigenome on innate or adaptive immunity in asthma
• Systems biology and immune profiling in asthma clinical phenotypes

Additional areas for mechanistic research in inner city asthma may be proposed as long as they fall under the general objectives of this FOA.

Sample studies should be submitted with the understanding that the studies to be conducted by the ICAC may be different as a result of peer review, external scientific advisory review, and\or the priorities of NIAID.

The mechanistic studies must not exceed the clinical and scientific resources of the applicant’s team of institutions (e.g., the applicant group must be able to recruit the required number of study subjects from within their collaborating institutions) and must not exceed 7 years in duration.

The mechanistic studies proposed should be presented in sufficient detail to allow reviewers to judge significance, approach, innovation and environment. The applicant should not submit a detailed study protocol because this will be developed collaboratively as a result of peer review, external scientific advisory review, and\or the priorities of NIAID.

Note that, although the Mechanistic Studies Operations will design these studies and will manage and conduct their laboratory aspects, the Clinical Trials Operations will conduct all clinical aspects of the study (e.g. human subject recruitment and phenotyping, clinical and safety monitoring, biologic sample collection).

Describe how the proposed research will contribute to meeting the Program goals and explain the approach and rationale for selecting the methods to achieve the specific aims. In addition to stating the biological significance of the research, indicate the project's relevance to the primary theme of the consortium.

Provide details about the approach, the planned experiments, anticipated results and alternative approaches including past experience and preliminary data. Explain how results will be interpreted (e.g., what would support your hypothesis? What would disprove it?).

This sub-section should include as applicable to the specific mechanistic studies project the following:

• A discussion of the significance of the problem being studied and the need for the study
• A discussion of studies that led to the proposed project and information or data from preliminary studies which address the need for and the feasibility of the study
• A discussion of how this study fits the overall research strategy of ICAC and how it integrates with the other proposed clinical trials and mechanistic research studies
• A discussion of anticipated results focusing on what interpretations can be offered, what the impact on the overall strategy of the consortium and what the next steps could be depending on the outcomes of the study
• A concise description of the overall study design, its rationale, methodology and analyses to be used to accomplish the goals and specific aims of the study and a discussion of how the study will test the hypothesis (es) proposed. This should include as applicable:
  • Study hypothesis(es) and objectives (primary, secondary, include mechanistic hypothesis(es) and objectives, if applicable)
  • Population
  • Study eligibility criteria (inclusion/exclusion)
  • Clinical study design (include a graphic design of the study):

Study arms (if applicable)

Primary and secondary endpoints (include clinical endpoints, if applicable)

Anticipated duration of recruitment and of the study as a whole

Study visit schedule and primary evaluations, including laboratory evaluations

Any anticipated Human Subjects issues and how those issues will be resolved

Sample size (with justification)

• Feasibility Assessment:

Discuss the availability of the overall research population - to include likelihood of acceptance by study populations of the proposed procedures (e.g. biopsies, bronchoscopies or repeated imaging).

Discuss similar studies currently under development and their potential influence on the proposed study.

Describe the participating mechanistic and clinical study sites:

Investigators and their experience in the proposed study area;

Investigators participation in investigator-initiated clinical studies;

Availability of the potential study participants at that site

Competing studies or clinical trials at the proposed sites;

Availability of special services needed to complete the study (e.g.

specialized equipment, high quality bioinformatics support).

• A summary of the statistical analysis plan for the proposed primary endpoint, including a description of the outcome measures and the statistical tests that will be used for data analysis. A more detailed and complete statistical analysis plan will be developed when studies are finalized post-award, with the assistance of the ICAC-SACCC
• A statement of how the proposed study outcomes abide by the recommendations issued by the NIH-sponsored Asthma Outcomes Workshop for observational studies published in the Journal of Allergy and Clinical Immunology, 2012 Mar;129(3 Suppl)
• To help overcome enrollment challenges, applicants are encouraged to adopt recommendations of the Institute of Medicine expert panels (Clinical Trials Workshop Summary), including:
  • Identifying and engaging patients and physicians, perhaps through outreach to community clinics and practices and
  • Promoting public involvement through web-based information (such as social media), education, and outreach

E. URECA Operations

Use the following format as the first page of the URECA continuation protocol:

URECA study title:

Name of URECA Study Leader: (e.g., Jones, Roberta A.);

Human Subjects: (Yes or No) If Yes: Exemption number, -or- IRB Approval Date (e.g., 12/13/2012, or "Pending"), and Federalwide Assurance (FWA) number;

Vertebrate Animals: (Yes or No) If Yes: IACUC Approval Date (e.g., 11/17/2012, or Pending) and Animal welfare assurance number

Proposed Period of Support:

From: (mmddyy - e.g., 09/01/2014)

To: (mmddyy - e.g., 08/30/2021)

Costs Requested for Initial Budget Period: (e.g. 09/01/2014-08/30/2015)

Direct Costs: (e.g., $250,000)

Total Costs: (e.g., $400,000)

Costs Requested for the Entire Budget Period: (e.g., 09/01/2014-08/30/2021)

Direct Costs: (e.g., $1,250,000)

Total Costs (e.g. $2,000,000)

Applicant Organization (Organization name; Street address; City, State, Zip code)

This sub-section is to primarily describe the URECA study that will follow the ongoing observational URECA study and will observe the URECA participants through the end of the grant (approximately when they reach 14-16 years of age). The URECA continuation protocol should be presented in sufficient detail to allow reviewers to judge significance, approach, innovation and environment. Do not submit a detailed, final clinical protocol because it will be developed collaboratively as a result of peer review, external scientific advisory review, and/or the priorities of NIAID.

Use this section to describe how the proposed research will contribute to meeting the Program goals and explain the approach and rationale for selecting the methods to achieve the specific aims. In addition to stating the biological significance of the research, indicate the project's relevance to the primary theme of the application.

Provide details about the approach, the planned experiments, anticipated results and alternative approaches including past experience and preliminary data. Explain how results will be interpreted (e.g., what would support your hypothesis, what would disprove it?). This section should include the following:

• A short description of the history of URECA and its previous accomplishments
• A short description of the ongoing URECA protocol that will provide a context for the URECA continuation protocol http://www.niaid.nih.gov/about/organization/dait/Documents/URECAIIIAdd508.pdf
• A discussion of the significance of the problem being studied and the need for the study
• A discussion of studies that led to the proposed project and information or data from preliminary studies which address the need for and the feasibility of the study
• A discussion of how the proposed study fits the overall research strategy of ICAC and how it integrates with the proposed clinical trials and mechanistic research studies
• A discussion of anticipated results focusing on what interpretations can be offered, what the impact on the overall strategy of the consortium and what the next steps could be depending on the outcomes of the study
• Description of a URECA continuation protocol through which current URECA participants will be studied at least through 14-16 years of age. The URECA continuation protocol should focus on the mechanisms driving the changes in asthma prevalence and severity during adolescence.

The URECA continuation protocol must include the following information:

• Study hypothesis(es) and objectives (primary, secondary, include mechanistic hypothesis(es) and objectives, if applicable)
• Study objectives (primary, secondary; include mechanistic objectives)
• Clinical study design:
  • Primary and secondary endpoints (include mechanistic endpoints)
  • Anticipated study duration
  • Study visit schedule and study evaluations, including laboratory evaluations
  • Any anticipated Human Subjects issues and how those issues will be resolved
• Feasibility Assessment:
  • Discuss the availability of the overall research population and include likelihood of acceptance by the study population of the proposed study procedures (e.g. blood draws or repeated lung function measurements).
  • Discuss methods that will facilitate retention of the URECA population during adolescent years
  • Describe the participating clinical study sites:

Investigators and their experience in clinical studies in the proposed study area

Competing clinical studies at the proposed sites

Availability of special services needed to complete the study (e.g. peripheral blood processing facilities)

• Summary of the statistical analysis plan for the proposed primary endpoint, including a description of the outcome measures and the statistical tests that will be used for data analysis. A more detailed and complete statistical analysis plan will be developed when studies are finalized post-award, with the assistance of the SACCC

F. Laboratory Support

Use this sub-section to describe how the proposed services will contribute to meeting the ICAC goals and explain the approach and rationale for selecting the methods to achieve the specific aims. In addition to stating the biological significance of the services, indicate the relevance to the primary theme of the consortium.

Provide details about the approach and include the following:

• A description of the laboratory services required for the clinical trials and studies to be performed by the ICAC including processes and procedures for developing and validating laboratory methodologies and for the measurement of other laboratory outcomes in approved human studies
• A concise description of the laboratory tests to be used to accomplish the specific aim
• Plans for laboratory QA/QC, including plans for adherence to guidelines of regulatory agencies and for participation in external quality assurance programs
• Description and rationale for the number, type and location of laboratories to meet research plans

Letters of Support: Documentation of availability of interventional agents. Applicants should include letters of collaboration from pharmaceutical companies to assure the company’s interest in participation from a business as well as a medical perspective is recommended. The letters of collaboration should include a statement of willingness (1) to share the Investigator s Brochure and (2) to write a cross-reference letter for the IND 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 PHS 398 Application Guide, with the following modification:

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

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

Part I. Overview Information contains information about Key Dates.

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

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

This initiative is not subject to intergovernmental review.

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

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

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

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by NIAID, 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 Inner City Asthma Consortium 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 project 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 project that by its nature is not innovative may be essential to advance a field.

Significance

Does the Consortium address an important problem or a critical barrier to progress in the field? If the aims of the Consortium 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 proposed Research Agenda address important areas and will it advance knowledge and provide evidence for therapeutic approaches in the prevention and treatment of asthma in the inner-city populations by conducting relevant clinical trials and mechanistic studies?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Do the PD(s)/PI(s) have adequate and appropraite experience in administering clinical trials and mechanistic studies, including organization and management of the infrastructure required? Are other key personnel appropriately trained and well suited to carry out the work associated with the clinical trials, mechanistic studies and laboratory support?

Innovation

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

Approach

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

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Are the plans and procedures for the development and review of protocols and for implementation and execution of clinical trials and mechanistic studies appropriate and well-reasoned? Are the strategies, methodologies, and analyses proposed well-reasoned and appropriate to accomplish the goals of the individual clinical trials and mechanistic studies and the URECA continuation protocol? Are plans for establishing clinical trial and mechanistic study sites appropriate? Are procedures for identifying appropriate clinical trial and mechanistic studies Site Leaders adequate? Are plans for ready access to inner-city patient populations adequate to ensure timely screening and enrollment? Are adequate plans in place for training of investigators and staff at Clinical Trial and Mechanistic Study Sites?

Are the plans for management (including fiscal) and planning, initiation, implementation, tracking, and monitoring adequate and timely for completion of planned activities? Are plans for establishing and implementing collaborations with other Federal and non-Federal organizations/institutions for the co-sponsorship of research in areas of mutual interest and collaborations with industry for the evaluation of specific products/approaches adequate? Are plans for reducing start-up time of multi-site studies by increasing the efficiency of IRB review using federated IRB models, and for reducing redundancy, delays and excess due to duplicated infrastructure associated with a consortium of clinical sites adequate? Are plans for establishing and maintaining the functions of committees responsible for governance and management adequate?

Does the application clearly define the laboratory services to be provided for the clinical trials and mechanistic studies to be performed by the ICAC? Are the plans for laboratory QA/QC, including plans for adherence to guidelines of regulatory agencies and for participation in external quality assurance programs adequate? Are the description and rationale for the number, type and location of laboratories to meet network research plans well justified?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Are appropriate resources for identifying appropriate facilities to conduct clinical trials and mechanistic studies and laboratory services in place?

As applicable for the individual 4 sample clinical trials, 3 sample mechanistic studies, and URECA continuation protocol 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.

Clinical Trials Operations

Do the individual sample clinical trials address important areas of interest in the field of asthma treatment and prevention in inner city populations? How will successful completion of the aims of the individual sample clinical trial change the concepts, methods, technologies, treatments, services, or preventative interventions that drive the field?

Are adequate preliminary data or other background information presented justifying each of the proposed sample clinical trials? Are the design and analytical approach of each of the proposed sample clinical trials appropriate to address the objectives of the trial? Is the feasibility of each proposed trial adequately supported? Do the proposed clinical trials include valuable mechanistic studies and is the methodology of these studies appropriate for the questions asked? Is there adequate, in-depth discussion of possible outcomes and of their impact on the scientific direction of the ICAC?

Mechanistic Studies Operations

Do the individual sample mechanistic studies address important areas of interest in the field of asthma treatment and prevention in inner city populations? How will successful completion of the aims of the individual sample mechanistic study change the concepts, methods, technologies, treatments, services, or preventative interventions that drive the field?

Are adequate preliminary data or other background information presented justifying each of the proposed stand alone sample mechanistic studies? Are the design, the laboratory methodologies and the analytical approach of each of the proposed mechanistic studies appropriate to address the objectives of the study? Is the feasibility of each proposed mechanistic study adequately supported? Is there adequate, in-depth discussion of possible outcomes and of their impact on the scientific direction of the ICAC?

URECA Operations

Does the URECA continuation protocol address an important problem or a critical barrier to progress in the study of mechanisms driving the changes in asthma prevalence and severity of asthma during adolescence?

Are adequate preliminary data or other background information presented justifying the specific objectives of the URECA protocol? Are the design and analytical approach of the URECA continuation protocol appropriate to address the proposed objectives? Is the feasibility of the URECA continuation protocol adequately suppported? Is there adequate, in-depth discussion of possible outcomes and of their impact on the scientific direction of the ICAC?

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 project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the 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 project 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 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 response to this FOA.

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

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

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

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

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

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

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

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

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

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

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

The PD(s)/PI(s) will have the primary responsibility for:

The PD/PI will provide for the overall management, integration and coordination of all activities. The PD/PI will establish an Administrative Center composed of the PD/PI and financial and administrative personnel to carry out the following functions:

• Establish and maintain subcontracts with the clinical trials sites and the mechanistic sites.
• Develop, implement and manage a process for allocating ICAC resources for approved studies, including a plan to recommend reallocation of funds to achieve the scientific goals of the ICAC.
• Establish a plan that will ensure that all IRB primary reviews of any multi-center trial or study are conducted within 30 days from submission preferably using a federated IRB model.
• Establish a Steering Committee to serve as the governing body of the ICAC.
• Establish an Executive Committee.
• Establish, in consultation with the Steering Committee, an External Scientific Advisory Group (ESAG) composed of no less than 3 and no more than 5 clinical and basic science investigators.
• Participate in a one-day Initiation Meeting with the NIAID Program Officer and other NIAID staff designated by the Program Officer, to be held at the PI’s site.
• At a minimum of once a year, participate in a teleconference with key staff personnel and the NIAID Program Officer and other NIAID personnel designated by the Program Officer to review overall progress and future plans and to discuss any matters relevant to the scientific and financial administration of the grant.
• Participate in Annual Site Visits at the PD(s)/PI (s) sitefor NIAID staff to review and discuss: project progress; problems and obstacles and approaches to overcoming identified problems and obstacles; recommendations for modifications in project timelines, objectives, resource allocation, and research approaches/methodologies based on outcomes to date; and future plans. These site visits will be attended by the PD/PI, the PD/PI’s business representative, and all key personnel.

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

NIAID will assign one or more Project Scientists to the grant. Project Scientists will provide guidance and support in the design of research activities, will serve as a resource for protocol design and development, will provide scientific/programmatic support during the accomplishment of the research by participating in the design of the activities, will advise in the selection of sources or resources, and will advise in management and technical performance. The role of NIAID Project Scientists will be to facilitate and not direct activities. It is anticipated that decisions in all activities will be reached by consensus and that the NIAID Project Scientists will participate in this process. In various matters related to clinical study approval and oversight, NIAID Project Scientists will have final decision authority, as described below. Up to two NIAID Project Scientists will be designated voting members of the Consortium Steering Committee.

• Protocol Development, Review and Approval: NIAID Project Scientists and other NIAID staff will participate in the development, review, and approval of all clinical trials and mechanistic study protocols, as well as the URECA continuation protocol. All clinical trials, mechanistic study protocols and the URECA continuation protocol will be reviewed by NIAID and, depending on their level of complexity and risk, will be further reviewed by the DAIT/NIAID Clinical Research Committee and by the DAIT/NIAID Asthma and Allergy Data and Safety Monitoring Board (DSMB), Safety Monitoring Committee (SMC), or another monitoring body. Prior to study initiation, all clinical study protocols must be approved by an assigned NIAID Project Scientist who will be the Medical Monitor of the study, as well as by an assigned NIAID Regulatory Officer.
• IND/IDE: NIAID will serve as the IND/IDE sponsor for all Consortium clinical trials requiring an IND/IDE. As part of NIAID’s IND/IDE sponsor responsibilities, the NIAID Medical Monitor will obtain, through the ICAC-SDCC, regular reports on adverse events and protocol deviations and will review all serious adverse events. NIAID will be responsible for reporting safety information in accordance with FDA requirements. Also, NIAID, in cooperation with the ICAC-SACCC, will prepare and submit the final study reports to the FDA.
• Clinical Trial Monitoring: NIAID will be responsible for monitoring compliance with good clinical practices, regulatory compliance, accurate protocol implementation, internal quality assurance, and test agent accountability at the Clinical Study Sites. NIAID will convene an independent NIAID Data and Safety Monitoring Board (DSMB) or Safety Monitoring Committee (SMC) or another monitoring body to review and monitor any protocols deemed to possess more than minimal risks. At NIAID’s discretion, the NIAID Medical Monitor may request that the monitoring body convenes ad hoc to review a serious adverse event or a cluster of adverse events or serious adverse events. Furthermore, the NIAID Medical Monitor may request that the ICAC-SACCC conducts for cause monitoring visits to a Clinical Study Site. Depending on the seriousness of the problem, such visits may be conducted by the NIAID Medical Monitor and/or NIAID project management staff.
• Study Termination: NIAID reserves the right to terminate or suspend a clinical study for any of the following reasons: (1) risk to subject safety; (2) the scientific question is no longer relevant or the objectives will not be met; (3) failure to comply with Good Clinical Practices, federal regulations, or Terms and Conditions of Award; (4) occurrence of unforeseen drug safety issues or data from preclinical studies indicate a presence of unanticipated toxicity; (5) risks that cannot be adequately quantified; (6) failure to remedy deficiencies identified through site monitoring; (7) substandard data; (8) inadequate progress in fulfilling the research agenda; (9) slow accrual; or (10) reaching a major study endpoint substantially before schedule with persuasive statistical significance.
• Access to Data: The NIAID Project Scientists or designee will have access to all data generated under this cooperative agreement, and may review the data as recorded on the case report forms or in a database. Data must be available for external checking against the original source documentation.
• Scientific and Programmatic Oversight: An NIAID program official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. This stewardship includes monitoring program progress, approving changes and concurring in proceeding into study implementation stage. Release of each yearly funding increment will be based on a review of progress. The Government, via the NIAID program official, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. NIAID staff may use information obtained from the data for the preparation of internal reports on the activities of the study. However, awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies.

Areas of Joint Responsibility between NIH and Awardees include:

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

Steering Committee

The voting members of the Steering Committee will include the PD/PI of the ICAC, the PD/PI of the ICAC-SACCC, the Clinical Study Sites Project Leaders, the Mechanistic Study Sites Project Leaders, and up to two NIAID-designated Project Scientists. The Steering Committee will meet at least 2 times each year.

A Chairperson of the Steering Committee will be elected every year by the voting members. No single member of the Steering Committee will serve as chairperson for more than one year. The Chairperson will be responsible for managing and coordinating all Steering Committee responsibilities and functions, including presiding over meetings and teleconferences. The PD/Pl of the ICAC, the PD/PI of the SACCC and the NIAID Project Scientists cannot serve as Chairpersons of the Steering Committee.

The Steering Committee will: (i) make decisions regarding overall scientific direction, recommend specific studies for NIAID approval, and coordinate and manage approved studies; (ii) develop and implement policies to ensure the efficient operation and effective management of functions, including enforcement of Steering Committee decisions and resolution of disputes and differences of opinion within the Steering Committee and between the Steering Committee and the External Scientific Advisory Group.

Executive Committee

The Executive Committee will be chaired by the PD/PI of the UM1 and will consist of the Steering Committee Chairperson, the NIAID Project Scientists, the PD/PI of the ICAC-SACCC, the Project Leaders of all approved studies, ongoing or under development, and a rotating representative of the Mechanistic Study Sites.

The Executive Committee will be responsible for: (i) updating the PD/PI, on an ongoing basis, in regards to the performance of the Clinical Study Sites and the Mechanistic Study Sites, (ii) evaluating study problems and issues requiring immediate action, including problems with study participant recruitment and retention, progress and completion of protocol development, protocol approval, clinical site training and other study implementation milestones/tasks within timelines approved by the Steering Committee, (iii) formulating recommendations to the Steering Committee to resolve the issues and problems identified, (iii) reviewing site monitoring visit reports, and (iv) managing personnel needs, resources and performance.

The Executive Committee will not make decisions regarding the overall scientific direction, including study protocols, will not designate study Project Leaders or assign study sites or members of Protocol Teams, and will not decide upon or implement any study protocol changes.

External Scientific Advisory Group (ESAG)

The members of the ESAG will be selected from institutions outside those serving as members of the ICAC and will represent expertise in the areas of clinical trials for asthma, asthma pathophysiology and asthma immunopathogenesis and immunotherapeutics. Appointments will be for one year with no restrictions on renewal.

Responsibilities of the ESAG will include:

• Reviewing and recommending improvements/modifications to study protocols developed by Protocol Teams prior to final approval by the Steering Committee.
• Reviewing and advising the Steering Committee on the results obtained from studies undertaken by the ICAC.
• The recommendations by the ESAG will be submitted to the Steering Committee Chairperson and the NIAID Project Scientist.

The ESAG will meet at least once per year to review study protocols at early stage of development, and major findings from ICAC-sponsored studies. The members of the ESAG may also participate in a joint session with the Steering Committee to convey and discuss the rationale for the Group s recommendations. The NIAID Project Scientist may request meeting with the members of the ESAG in the absence of any members.

Public Access to Data Generated by the Consortium

Data generated by the Consortium will become available to the public through posting onto a public access database such as ImmPort [https://immport.niaid.nih.gov] or another resource designated by NIAID. Data will be posted 18 months after a clinical trial or a mechanistic study database is officially considered closed by the NIAID-supported Statistical and Clinical Coordinating Center (SACCC). Data uploading will be the responsibility of the SACCC. The Awardee will assist the SACCC and NIAID staff in the data uploading process.

Protocol Development

For each approved protocol, a Protocol Team will be established by the Steering Committee and will be responsible for the development of the study protocol, under the direction of the Project Leader and with the assistance of the ICAC-SCCC. All study informed consent forms, Case Report Forms, Standard Operating Procedures, Manuals of Operation, subject instructions, questionnaires, screening and recruitment logs, order forms for test articles and test article accountability logs will be prepared by the ICAC-SCCC with the input of the Protocol Team. The Project Leader and NIAID staff assigned to the Protocol Team, as designated by the NIAID Project Scientist, will approve study forms and documents. The Protocol Team will also be responsible for establishing and submitting, for Steering Committee approval, protocol-specific milestones, timelines and performance guidelines for both the protocol development process and for study initiation, execution, completion and analysis of final study data. Protocol development and execution for each approved study will be carried out in accordance with specific milestones, timelines and performance guidelines approved by the Steering Committee.

Study protocols will be submitted to the Steering Committee for review and modified in accordance with Steering Committee recommendations.

Study protocols will also undergo review by the ESAG and will be modified, as necessary, to accommodate any Steering Committee-approved ESAG recommendations.

Final study protocols or protocol amendments will proceed to the implementation phase only after Steering Committee and NIAID Project Scientist approval.

Protocol Implementation, Management and Oversight

Investigational New Drug and Investigational Device Exemption Applications

For studies requiring an Investigational New Drug (IND) and/or Investigational Device Exemption (IDE) application, including clinical trials, birth cohort studies, cross-sectional phenotyping studies, or mechanistic studies, NIAID will act as the IND and IDE sponsor. The Protocol Team, in coordination with the ICAC-SACCC, will assist the NIAID in the preparation of IND and IDE applications and will comply with all regulatory requirements associated with IND/IDE sponsorship.

Clinical Study Data and Safety Monitoring

The Protocol Development Team, with the support of the ICAC-SACCC, will be responsible for the preparation of a Data and Safety Monitoring Plan (DSMP) to ensure adequate data collection and documentation and adequate protection of human subjects commensurate with the anticipated level of risk for each clinical trial, mechanistic study or the URECA birth cohort in accordance with all applicable Federal regulations and requirements and ICH standards for human subjects research. All DSMPs will be reviewed and approved by the Steering Committee, the NIAID project scientist and the NIAID-designated Regulatory Affairs Officer.

Data and Safety Monitoring Board (DSMB) or Safety Monitoring Committee (SMC)

All clinical studies will be monitored by an independent DAIT/NIAID-appointed DSMB or SMC. All final clinical protocols will be reviewed by the DAIT DSMB or SMC and revised, as necessary, at the request of the NIAID project scientist, to address DSMB or SMC recommendations. In addition, the DSMB or SMC will review those protocol amendments which may increase the risk of the study or change the nature of information provided to study participants through the study consent form in the course of clinical studies. The Protocol Team, with the support of the ICAC-SACCC, will be responsible for the preparation of materials for review by the DAIT DSMB or SMC prior to study implementation. The Project Leader will present the final clinical protocol to the DSMB or SMC prior to study implementation, and will participate in the preparation of materials for and in responding to questions and recommendations emanating from DSMB or SMC deliberations. During the course of the study, the Protocol Team, with the support of the ICAC-SACCC will provide progress reports and safety data updates to the DAIT DSMB or SMC on at least an annual basis or more frequently as provided for in study-specific DSMPs or at the request of the DSMB or SMC. Interim data analyses will also be provided by the Protocol Team, with the support of the ICSC-SACCC, if specified in the DSMP or if requested by the DSMB or SMC or the Program Officer. At the completion of each study, the Project Leader will present a final safety report and study results to the DSMB or SMC. Any materials to be presented to the DSMB or SMC, including clinical study protocols, clinical study protocol amendments, interim data analyses, and safety data updates, will be submitted to the NIAID Project Scientist not less than 5 calendar days prior to DSMB or SMC submission.

Protocol-specific Training

Prior to the initiation of any clinical study, the Project Leader will organize and conduct, with the support of the ICAC-SACCC, protocol-specific training for the participating investigators and the relevant clinical and technical clinical study site and mechanistic site staff. Training will include face-to-face meetings and teleconferences.

Clinical Study Implementation and Management

The PD/PI will work in coordination with the ICAC-SACCC to execute the following tasks:

• Establish and implement policies and procedures for study management and continuous oversight to ensure adequate rates of human subject recruitment, timely and accurate data collection, and completion of all studies in compliance with NIH guidelines and Federal regulations, requirements and policies. This will include compliance with clinical site and study monitoring functions carried out by the ICAC-SACCC for: (i) site initiation visits, when deemed necessary; (ii) routine monitoring visits to the clinical study sites and the mechanistic sites on a protocol-specific basis; and (iii) specialized site visits, when deemed necessary (e.g., research pharmacy and laboratory operations and compliance with protocol-specific requirements, for cause or remedial site visits). This will also include PD/PI compliance with the NIAID-designated Medical Monitor-approved corrective/remedial actions resulting from clinical site and study monitoring activities.
• Establish and implement policies and procedures to ensure the safe and ethical conduct of clinical research in accordance to Federal regulatory requirements, GCP and ICH guidelines and study-specific DSMPs, including the recording and reporting of all Adverse Events (AEs) and Serious Adverse Events (SAEs). This will include policies for the preparation and submission of AE and SAE Reports to the ICAC-SACCC for initial review and assessment, followed by final assessment and classification by the NIAID-designated Medical Monitor.
• Establish and implement policies and procedures to ensure that all clinical study sites and mechanistic sites have the required supply of study materials for study initiation and conduct, and monitor supplies throughout the duration of the study.
• Establish and implement policies and procedures for the secure transfer of clinical and laboratory data to the central databases of the ICAC-SACCC. Training for site personnel in the use of these databases will be provided by the ICAC-SACCC.

All policies and procedures delineated above will be approved by the Steering Committee prior to implementation.

Dispute Resolution

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

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

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

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

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

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)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
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]

Peter Gergen, M.D., M.P.H
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-451-3233
Email: [email protected]

Priti Mehrotra, M. Sc., Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-435-9369, 301-496-2550
Email: [email protected]

Mollie Shea
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-402-6576
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.