Part 1. Overview Information

Key Dates

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

NIAID has a long-standing interest in understanding and reducing the disproportionate burden of asthma among children living in low-income urban communities and has funded research initiatives towards this goal over the previous 3 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 urban residents with 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; 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, the use of omalizumab therapy for inner-city children with asthma and established URECA, a birth cohort; d) the Inner City Asthma Consortium II (ICAC II, 2008-2014), which conducted a large asthma phenotyping study, a clinical trial evaluating the use of omalizumab for fall exacerbations, and conducted safety and biomarker trials of cockroach immunotherapy. The current Inner-City Asthma Consortium III (ICAC III, 2014-2021) consists of 10 clinical sites and 6 mechanistic sites. The ongoing ICAC III has completed a clinical study determining the transcriptomic signature of asthma exacerbations and is conducting a clinical trial evaluating the effectiveness of mepolizumab among exacerbation prone children with asthma and a trial of cockroach subcutaneous immunotherapy for asthma.

Objectives and Scope

The CAUSE Clinical Research Network will conduct observational studies and clinical trials to further improve our understanding of asthma and to develop effective interventions and asthma prevention approaches tailored to children of low-income families living in urban communities.

Research supported by this FOA will involve a) children of families living in census tracts within US Office of Management and Budget-defined Metropolitan Statistical Areas (MSAs) where =10% of families have income below the poverty level and b) children of families who have publicly-funded health insurance, but live in MSA census tracts where <10% of families have income below the poverty level.

Specifically, research areas to be pursued in center-specific projects by the CAUSE-CRC investigators may include, but are not limited to:

• Mechanisms of immune tolerance to allergens
• Understanding the role of early environmental exposures in the pathogenesis of asthma
• The role of the respiratory epithelium in asthma
• Investigations into the pathogenesis and mechanisms of non-atopic asthma
• Development or early-stage evaluation of allergen immunotherapy or other immunomodulatory modalities to mitigate and/or prevent the effects of relevant allergens on asthma

Other areas of interest include studies that fall under the general objective of elucidating the pathogenesis of asthma or improving the management of asthma in children living in low-income, urban communities and focus on the immune system.

Overall Structure of the CAUSE Clinical Research Network

The CAUSE Clinical Research Network will consist of distinct entities that will operate as a single network: multiple CAUSE Clinical Research Centers (CAUSE-CRCs) and a single CAUSE Leadership Center (CAUSE-LC). The CAUSE-LC will provide overall strategy, leadership and support for the network-wide clinical research projects.

CAUSE-CRCs

The CAUSE-CRCs will implement network-wide, multi-site research projects under the direction of the CAUSE-LC. In addition, the CAUSE-CRCs will conduct 1-2 small, center-specific, single-site projects. These projects can be pilot, non-therapeutic clinical trials or observational studies, clinical mechanistic studies, or laboratory studies utilizing new or existing human biosamples, and should involve junior faculty investigators in key roles. These projects need to address mechanisms of disease or the management of asthma in children living in low-income urban communities.

The CAUSE-CRCs will contribute to the overall CAUSE strategic goals by participating in the CAUSE Steering Committee and other network functions.

Note: It is anticipated that at least three network-wide CAUSE clinical projects will be implemented during the course of the awards. At least one project will be a clinical trial, while the other projects may be either clinical trials or observational clinical studies. The clinical projects to be implemented will be chosen by the CAUSE-LC PD(s)/PI(s) from projects proposed by the CAUSE-LC or by the CAUSE Steering Committee based on recent scientific advances.

Applications proposing the following topics will be deemed non-responsive and will not be reviewed.

• Animal Research
• Research on HIV/AIDS
• Phase III, IV or V clinical trials
• Clinical studies or clinical trials performed at a foreign site
• Studies using only transformed human cell lines

Note: Foreign Components may only provide services in support of Clinical Study or Clinical Trial activities (e.g. conduct of laboratory assays). Foreign Components must not conduct Clinical Trials or Clinical Studies.

Resources provided by NIAID to the CAUSE network

The following resources will be provided by NIAID to the CAUSE-CRCs:

NIAID-DAIT Data, Clinical Safety, and Statistical Center(s) (NIAID-DAIT data management center(s)): The DAIT data management center(s) may provide support for some CAUSE-CRC center-specific clinical trials, if NIAID chooses to be the sponsor, particularly if they are conducted under Investigational New Drug (IND) applications. In those studies, the NIAID-DAIT data management center(s) will provide support for the design and organization of the protocol, development of protocol-related materials, data management and quality control, clinical site monitoring, safety monitoring and reporting, data analysis and manuscript development. The determination whether the CAUSE NIAID-DAIT data management center(s) will provide resources to a CAUSE center-specific research project will be made by NIAID. For projects that will not be supported by the NIAID-DAIT data management center(s), the NIAID-DAIT data management center(s) will validate the biostatistical work conducted by the CAUSE-CRC prior to final manuscript submission.

NIAID-appointed Asthma and Allergy Data and Safety Monitoring Board (DSMB): All center-specific clinical trials (and some clinical studies if necessary) and all CAUSE network-wide clinical trials will be reviewed by a DSMB provided by NIAID. After study initiation, the DSMB will conduct periodic safety reviews.

Public Access: For CAUSE-CRC center-specific research projects that will be supported by the NIAID-DAIT data management center(s), NIAID will provide for public access through the DAIT data management center(s), which will have the responsibility to upload all clinical, biomarker and mechanistic data produced by the CAUSE-CRC either to ImmPort or to another NIAID-approved resource. This service will not be provided for center-specific projects that are not supported by the NIAID-DAIT data management center(s) and the PD(s)/PI(s) of each CAUSE-CRC will be responsible for directly uploading the data deriving from those projects. The timetable for public availability of all CAUSE studies data (network-wide and center-specific) will be determined by the CAUSE Steering Committee and NIAID.

CAUSE Clinical Research Network Steering Committee

The CAUSE Clinical Research Network Steering Committee will be the forum for CAUSE to discuss network-wide studies and to advise the CAUSE-LC PD(s)/PI(s) on scientific and organizational aspects of the network's activities. The Steering Committee will also receive information and discuss the progress of individual CAUSE-CRC center-specific research projects, but it will not be involved in the development or implementation of these projects.

Structure of the CAUSE Clinical Research Centers

The CAUSE-CRCs will conduct network-wide and center-specific research. To accomplish this the CAUSE-CRC should provide:

Clinical Research Functions: This will involve personnel and facilities capable of conducting network-wide and CAUSE-CRC center-specific research, including trained clinical staff, capabilities of recruiting children and adolescents with asthma who live in low-income urban communities, clinical research facilities, investigational pharmacy services, and laboratory facility capable of processing, storing and shipping human biosamples. For center-specific research, additional requirements include local biostatistical support, an active, IRB-approved protocol for recruitment and clinical characterization of children with asthma, a data management facility with established data management, quality assurance and control plans, and capability to upload data into the NIAID designated repositories.

CRC Specific Research Projects: Each CAUSE-CRC application should propose one or two center-specific clinical research projects organized around a common theme which could include protocols that test a hypothesis associated with a specific asthma phenotype or endotype with immunologic, epithelial function, allergen exposure, microbiome or other focus of pathophysiologic importance in asthma. These projects may range from a small non-therapeutic, mechanistic trial to an observational study, or in vitro or ex vivo testing of human biosamples. Studies using only transformed human cell lines will not be considered in scope. Only one small, center-specific clinical trial will be allowed.

CAUSE Protocol Funds

Center-specific research funds are provided in the CAUSE-CRC grant. Additional protocol funds will be disbursed by the CAUSE-LC to the CAUSE-CRCs participating for the network-wide clinical research projects.

For more information see the NIAID Research Funding site Questions and Answers for RFA-AI-19-073 found at the following:

https://www.niaid.nih.gov/grants-contracts/questions-answers-RFA-AI-19-073

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

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

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

Applicant organizations

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

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) 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 to register in eRA Commons.Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

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

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

Only one application per institution (normally identified by having a unique DUNS number or NIH IPF number) is allowed

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

Applicants may submit to both the CAUSE-CRC (RFA-AI-19-073) and the CAUSE-LC (RFA-AI-19-074) funding opportunities. However, different clinical projects must be proposed in each of the two applications.

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guideexcept where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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

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

• 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:

Konrad Krzewski, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-747-7526
Email: konrad.krzewski@nih.gov

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed

For this specific FOA, the Research Strategy is limited to 30 pages.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed.

Facilities & Other Resources:

• Clinical Sites: Describe the clinical research facilities available to conduct single-center and multi-site clinical trials and clinical studies under the CAUSE umbrella.
• Laboratory Facilities: Describe the laboratory facilities capable of processing, storing and shipping human biosamples including peripheral blood, respiratory samples, stool samples, and microbial samples.
• Pharmacy: Describe the investigational pharmacy services available and their capabilities to store, mask, dispense and maintain product accountability in multi-site clinical trials and for randomization and blinding for center-specific non-therapeutic mechanistic clinical trials, if applicable.
• Data Management: Describe the data management facility available to conduct center-specific clinical research projects including the capacity to carry out randomization and blinding, data management and quality control with reference to Federal regulations and ICH E6 (R2) guidelines.

All instructions in the SF424 (R&R) Application Guide must be followed.

• The PD(s)/PI(s) and key personnel should include in their biosketches their experience in conducting large single-center and multi-site clinical trials and clinical studies.
• The bio sketches should also include cGCP training status, and experience in preparing IND/IDE applications and, if applicable, reference relevant recent clinical studies conducted, highlighting recruitment target and recruitment and retention success.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

• For single PD/PI applications, the PD/PI must commit an overall minimum of 2 person-months for CAUSE-CRC activities. For multi-PD/PI applications, one of the PD(s)/PI(s) must commit a minimum of 2 person-months for CAUSE-CRC activities.
• Include costs for at least 12 person-months of clinical coordinator effort.
• Include funds for travel and other expenses for CAUSE-CRC Senior/Key Personnel to attend two (2) one and a half (1.5) day CAUSE Steering Committee meetings per year in the Rockville, Maryland area.
• For the CAUSE-CRC center-specific research projects, include the costs for the proposed center-specific project, all support for additional personnel, materials and equipment, participant recruitment, retention and compensation, statistical design, data collection, monitoring, analysis and management, data deposition into ImmPort or other public portals designated by NIAID, and ClinicalTrials.gov if required, as well as costs for project management, adverse event collection, safety reporting, and quality assurance.
• Do not include costs for DSMB expenses. NIAID will provide DSMB for all clinical trials.
• Do not include additional costs for CAUSE network-wide projects. Protocol funds for those studies will be disbursed by the CAUSE-LC to the CAUSE-CRCs participating in each network-wide clinical research projects and will not be determined until after all CAUSE awards are issued.

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

Specific Aims: List the Specific Aims of the application.

Research Strategy:

The Research Strategy must include 2 clearly marked Subsections: A) CRC-Clinical Research Functions and B) CRC-Specific Research Projects.

Subsection A: CRC-Clinical Research Functions

• Discuss the capacity and readiness of the CAUSE-CRC to conduct center-specific and network-wide CAUSE clinical research projects under the direction of the CAUSE-LC, including the processes and flexibilities in place to expeditiously expand efforts, including staffing, to accommodate the needs of network-wide CAUSE clinical research projects.
• Discuss any unique characteristics that the CAUSE-CRC will contribute to the CAUSE network.
• Describe recruitment capabilities and approaches for pediatric patients of low-income families, as defined in this FOA, for participation in the CAUSE network-wide and center-specific research studies. Indicate the number of pediatric patients with asthma seen per year in clinics within the applicant's institution.
• Provide a summarized description of the required site's local IRB-approved recruitment and clinical characterization protocol for children with asthma.
• Describe the plans, process and communication strategies required to work with the CAUSE-LC single IRB.
• Describe and discuss approaches to improve incorporation of difficult-to-enroll groups such as minorities and infants.
• Describe the professional development in clinical research that the staff of the CRC will be receiving and how this ensures in-depth knowledge of cGCP, Federal regulatory requirements, and ICH guidelines.

Subsection B: CRC-Specific Research Projects

To improve clarity, applicants are encouraged to organize this subsection using headings to distinguish between the different research projects.

• Propose 1 or 2 small CAUSE-CRC-specific clinical research projects organized around a common theme; only one of these projects may be a clinical trial. The research proposed should involve individuals with asthma from low-income urban communities or clinical specimens from such individuals. The clinical trial, if proposed, should be limited to a non-therapeutic, mechanistic trial (e.g., allergen provocation studies, studies involving an intervention that aims at investigating the role of a specific biologic pathway or an environmental factor). Observational studies may be proposed to address clinically important questions or for mechanistic research. Studies using human specimens obtained from relevant ongoing or completed clinical studies or clinical trials (therapeutic trials included) may also be proposed for mechanistic research. For each proposed project, describe the background and earlier relevant studies and provide the rationale and pertinent information and/or data from preliminary studies which address the need for the project. Outline the hypothesis, objective and how the proposed outcomes will adequately address the hypothesis. Concisely describe the design of the proposed center-specific project, include the rationale and process for the selection of the participant population, choice of intervention (if applicable), duration and schedule of events. Discuss each project's feasibility, limitations, difficulties that may be encountered, and offer alternative approaches to be implemented, if needed. Include general concepts for sample size determinations and statistical methodologies, but, particularly for a clinical trial, provide study-specific details in the PHS Human Subjects and Clinical Trial Information Forms. Note: Specific details for trials and studies will be captured using the PHS Human Subjects and Clinical Trials Information Form. Do not duplicate information requested under the PHS Human Subjects and Clinical Trials Information.
• Emphasize innovative elements included in the proposed project(s), both in terms of novel hypotheses, as well as in terms of novel study designs.
• Provide a management plan for the CAUSE-CRC-specific project(s) that includes description of personnel involved in conducting the research, personnel involved in data entry and management, and, if applicable, pharmacy personnel involved in handling investigational products and personnel involved in processing and handling of biosamples.
• Describe the biostatistical and monitoring support available for CAUSE center-specific projects.
• For the CAUSE-CRC-specific project(s), discuss planned laboratory methodologies and provide evidence to demonstrate proof-of-principle and/or support feasibility of the planned methodologies.
• For proposed mechanistic studies associated with a CAUSE-CRC-specific clinical research project, describe the rationale, biosample selection, assay selection, methodology and analytic approach. Discuss each study's feasibility, difficulties that may be encountered, and offer alternative approaches that will be implemented, if needed. Include sample size calculations and statistical methodology.

Letters of Support: Provide a letter of commitment from manufacturers if investigational drug(s) or device(s) are to be provided at no cost. Provide letter(s) of commitment from the principal investigator(s) of any study that will provide samples from a previously conducted or ongoing clinical trial or study. Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. The awardee is expected to make the biological samples, diagnostic products, and other research tools, methods, data, and materials that they develop under the CAUSE-CRC award, available to the research community per policies established by the CAUSE-Steering Committee. Therefore, the Data Sharing plan should include a summary of how the applicant will achieve this.

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. When involving human subjects research, clinical research, and/or NIH-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

• All applicants must upload a study record for existing IRB-approved, active protocol that allows recruitment and clinical characterization of pediatric patients with asthma, as well as healthy volunteers in addition to the proposed new CRC-specific clinical trial and/or study(ies).

Section 2 - Study Population Characteristics

2.7 Study Timeline

Provide a table or graphic representation of a timeline of the proposed center-specific clinical projects.

Section 3 - Protection and Monitoring Plans

3.1 Protection of Human Subjects

3.1.1 Risks to Human Subjects

3.1.1.a. Human Subjects Involvement, Characteristics, and Design

Additional Instructions

For studies involving the use of identifiable human biospecimens collected from independently funded clinical research, applicants should include both historical and current study information that is clearly distinguishable within the same study record when providing the information requested.

3.1.1.b. Study Procedures, Materials and Potential Risks

Additional Instructions

For applications proposing to use samples from ongoing or completed clinical research, provide a timeline for the request, transportation and arrival of the biological samples, and the timeline associated with the preparation and use of the biological samples.

Section 4 - Protocol Synopsis

4.2 Study Design

4.2.a Narrative Study Description

For multi-visit studies, provide a description of the study design including the procedures and activities that can occur at each visit (schedule of events).

Section 5.1 - Other Clinical Trial-related Attachments

Describe the plan to obtain required investigational agent(s). Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

• Awards issued under this FOA will be incrementally funded awards for project periods of seven years.
• Grants awarded under this FOA will be excluded from automatic carryover all carryover requests must be approved.
• Grants awarded under this FOA will not be provided the authority to automatically extend the final budget period one time for up to 12 months beyond the original expiration date shown in the Notice of Award all extensions, including the first extension, will require approval.
• Progress and financial reporting will be required and reviewed annually.
• All funds must be expended within the approved project period.

7. Other Submission Requirements and Information

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

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

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

In addition, for applications involving clinical trials:

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation. Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project 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 project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project 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?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, and/or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Specific for this FOA

Does the application provide overall convincing evidence that the proposed CAUSE-CRC will be a valuable component of the CAUSE clinical research network by providing a strong clinical research site for the conduct of the CAUSE network-wide clinical trials and studies and through its own proposed center-specific studies?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Specific for this FOA

Do the PD(s)/PI(s) have documented experience of working collaboratively in multi-center clinical trials and/or studies? Do the PD(s)/PI(s) have experience conducting clinical research that involves children with asthma from low-income, urban communities?

Are junior faculty members included in key roles in the proposed research projects?

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?

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable?

Study Design

Is the design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the l trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the clinical trial/study protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific for this FOA:

CRC Clinical Research Functions

• Do the staff have appropriate and adequate qualifications, training and expertise in the field of asthma research?
• Does the application present adequate plans for professional development for CAUSE-CRC investigators and staff in accordance with Federal regulatory requirements, Good Clinical Practice (GCP) guidelines and International Conference on Harmonization (IHC) standards?
• Does the application describe a cohesive structure and range of services to support asthma clinical research projects under the CAUSE clinical research network?
• Does the application indicate capacity and readiness to conduct CAUSE network-wide clinical research projects in an expeditious manner?
• Does the proposed CRC offer unique characteristics that will contribute to the CAUSE, such as unique recruitment capabilities and approaches for pediatric patients?
• Is the number of low-income, urban pediatric patients with asthma seen per year in clinics within the applicant's institution adequate to support the CRC's role in conducting the CAUSE network-wide and the center-specific projects?
• Does the application offer satisfactory approaches to recruitment of difficult-to-enroll groups, such as minorities and infants, if required?
• Is there an IRB-approved, active protocol that allows recruitment and clinical characterization of pediatric patients with asthma, as well as healthy volunteers?

CRC-Specific Research Projects

• Are the center-specific research project plans realistic and capable of completion within the period of the award?
• Is each of the proposed center-specific projects adequately justified and supported by preliminary data and/or previously published research?
• Is the experimental design of each center-specific project appropriate in terms of outcomes, study population and eligibility criteria, study arms (appropriate controls), study visit schedule and primary evaluations, study duration and study timeline?
• For proposed center-specific mechanistic studies, has a clear rationale justifying the need for each study been presented and has adequate evidence been provided demonstrating the robustness and feasibility of proposed laboratory tests/capabilities?
• Does each center-specific project include an appropriate management plan describing the personnel involved in conducting the research, data entry and management, processing and handling of biosamples, and, if applicable, in handling investigational products?
• For proposed biosamples in each center-specific project, is there a description of the source and quantity to be obtained, and have potential safety and ethical issues in obtaining such samples (for example, blood drawing volume limitations) been addressed?
• If the use of an investigational drug is proposed in one or more of the center-specific projects, has the applicant included clear evidence of commitment by the manufacturer?

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

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?

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Specific for this FOA

CRC-Specific Research Projects

• Does the application include acceptable evidence for the capabilities of the research laboratories to be used in center-specific projects?
• If applicable, does the application include suitable evidence for the availability and capabilities of investigational pharmacy services?

As applicable for the project 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.

Study Timeline

Specific to applications involving clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

For research that involves human subjects but does not involve one of thecategories 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 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 Individuals Across the Lifespan

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

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. 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) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

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

As part of the scientific peer review, all applications:

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

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

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

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

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.htmlor call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 75 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:

• Implementing and managing the CAUSE network-wide clinical research projects assigned to the CAUSE-CRC by the CAUSE-LC.
• Participating in the CAUSE Steering Committee meetings and teleconferences and in its subcommittees, as applicable.
• Implementing CAUSE policies and procedures, as established by the CAUSE Steering Committee and the CAUSE-LC.
• Executing and coordinating the scientific activities of the CAUSE-CRC center-specific projects; setting project goals and timelines.
• Reporting progress, presenting data and discussing obstacles related to the CAUSE-CRC center-specific projects with the CAUSE Steering Committee.

Protocol Review and Approval

• The CAUSE-CRC PD(s)/PI(s) will provide all center-specific clinical research protocols to NIAID for review and will not implement a protocol until all NIAID approvals are obtained and a NIAID DAIT study initiation notification has been provided.

Investigational New Drug Applications (IND)

• For any CAUSE-CRC center-specific clinical trial for which NIAID decides not to have IND/IDE (Investigational Device Exemptions) Sponsor responsibilities, it is the responsibility of the CAUSE-CRC PD(s)/PI(s) to contact the US FDA and obtain guidance as to the need for an IND or IDE for interventions planned to be employed, if these interventions are not approved for the specific indication (including medical condition, age range, dose range) for which they will be used in the trial. If an IND/IDE is required, the CAUSE-CRC investigator will act as the IND/IDE Sponsor. The Sponsor of an IND/IDE is responsible for the development, assembly, and submission of all required regulatory documents. The IND/IDE Sponsor will provide NIAID all required information following NIH clinical research guidance. This includes but is not limited to all communications with the FDA (or other regulatory authority) and the IRB. If NIAID decides to be the IND/IDE Sponsor, NIAID will be responsible for the development, assembly, and submission of all required regulatory documents, unless this responsibility is otherwise delegated by the NIAID. If NIAID is the Sponsor, the PD(s)/PI(s) of the CAUSE-CRC is responsible for providing all information to NIAID that is needed for compliance with FDA regulations.

Data Sharing Responsibilities

• Awardees are expected to make the biological samples, diagnostic products, and other research tools, methods, data, and materials that they develop under CAUSE-CRC award available to the research community, per policies established by the CAUSE-Steering Committee and consistent with achieving the goals of the program. Informed consent/assent forms utilized in CAUSE-CRC supported clinical trials or studies should reflect this commitment.
• To promote rapid public access to CAUSE-supported data, all CAUSE-CRC investigators are expected to share their CAUSE-supported data publicly through ImmPort or other public portals designated by NIAID. The privacy of participants will be safeguarded, and confidential and proprietary information will be protected. The PDs/PIs are responsible for developing data sharing plans to be presented to the NIAID Program Official assigned to the grant for approval. Sharing plans represent a commitment by the awardee to support and abide by the plan. The PD(s)/PI(s) will establish procedures to ensure that all members of CAUSE-CRC and associated scientists conform to the data-sharing plan.

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

NIAID Project Scientists will provide guidance and support in the design and implementation of research activities including protocol design and development, study implementation, will advise in the selection of sources or resources, and in management and technical performance. In CAUSE-CRCs that include a center-specific clinical trial and, in some cases, clinical studies, the NIAID-assigned Project Scientist may also have Medical Monitor responsibilities. In addition, an NIAID Program Official will be responsible for the normal programmatic stewardship of the award and will be named in the award notice.

Protocol, Review and Approval

All clinical research protocols will be reviewed by NIAID and, depending on their level of complexity and risk, will be further reviewed by the NIAID DAIT Clinical Research Committee and by the NIAID DAIT Data and Safety Monitoring Board (DSMB) or other monitoring body.

IND/IDE

NIAID will serve as the IND/IDE sponsor for all CAUSE network-wide clinical trials and, at its discretion, for some CAUSE-CRC site-specific clinical trials requiring an IND/IDE. As part of NIAID’s IND/IDE sponsor responsibilities, the NIAID Medical Monitor will obtain regular reports on adverse events and protocol deviations from the NIAID-DAIT data management center(s) or the CAUSE-CRC 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 NIAID-DAIT data management center(s) and the CAUSE-CRC PD(s)/PI(s), will prepare and submit the final study reports to the FDA. This role may be delegated by NIAID to another entity (e.g., a collaborating pharmaceutical company).

Clinical Trial Monitoring

NIAID will monitor compliance with good clinical practices, regulatory compliance, accurate protocol implementation, internal quality assurance, and test agent accountability at the CAUSE-CRCs. At NIAID’s discretion, the NIAID Medical Monitor may request that the DSMB convenes ad hoc to review a serious adverse event or a cluster of adverse events or serious adverse events. The NIAID Medical Monitor may request that the NIAID-DAIT data management center(s) conduct for-cause monitoring visits to a CAUSE-CRC. Depending on the nature of the problem, such visits may be conducted by the NIAID Medical Monitor and/or NIAID staff. The PD/PI of the CAUSE-LC may be asked to participate in those visits.

Study Termination

NIAID reserves the right to terminate or curtail a clinical study for any of the following reasons:

• Risk to subject safety
• Occurrence of unforeseen safety issues or emerging data indicating a presence of unanticipated toxicity
• Risks that cannot be adequately quantified
• The scientific question is no longer relevant, or the objectives will not be met
• Failure to comply with cGCP, federal regulations, or Terms and Conditions of Award
• Failure to remedy deficiencies identified through site monitoring
• Substandard data
• Inadequate progress in fulfilling the research agenda
• Slow accrual
• Reaching a major study endpoint substantially before schedule with persuasive statistical significance

Access to Data

The NIAID Project Scientist 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. NIAID staff may use information obtained from the data for the preparation of internal reports on the activities of the study.

Coordination with Outside Entities

In the occasion a company provides investigational materials for an CAUSE study, NIAID will be responsible for entering into Clinical Trial Agreements with that company.

External Scientific Advisory Group (ESAG)

NIAID will establish an ESAG composed of clinical and basic science investigators. Members of the ESAG will review and offer input on CAUSE network-wide clinical projects and, at NIAID's discretion, some CAUSE-CRC center-specific projects, both during protocol development and during the analysis of results. ESAG members may be invited to attend some CAUSE Steering Committee meetings. The ESAG will submit its recommendations to the NIAID Project Scientists, who will then inform the CAUSE-LC or CAUSE-CRC PD(s)/PI(s).

Areas of Joint Responsibility include:

Protocol Development

The CAUSE-CRC PD(s)/PI(s) will fully develop the center-specific clinical research protocols for the projects supported by this FOA with the participation of NIAID Division of Allergy, Immunology, and Transplantation (DAIT) program staff. CAUSE-CRC center-specific protocols will utilize the protocol templates provided by NIAID.

Research Activities

Reviewing the CAUSE-CRC's research activities and goals on an agreed upon schedule (but no less than once every year). Promoting, evaluating and executing opportunities to collaborate with other federal or non-federal research sponsors.

CAUSE Steering Committee

The purpose of this committee is to advise the CAUSE-LC PD(s)/PI(s) on the network-wide clinical projects to be conducted, approve the final clinical trial and study protocols and modify or add protocols as scientifically indicated. The overall CAUSE scientific plan will be reviewed and updated yearly. In addition, the Steering Committee will regularly review and advise on the progress of center-specific CAUSE-CRC research projects and will develop and implement policies and procedures for publicizing the accomplishments and the data resulting from CAUSE studies to the scientific and lay communities and other relevant audiences. The CAUSE Steering Committee will include the PD(s)/PI(s) of the CAUSE-LC (who will serve as the Chairperson), a PD/PI from each of the CAUSE-CRCs, the designated Project Leader of the NIAID-DAIT data management center(s), and 2 NIAID Project Scientists. All members of the Steering Committee are voting members with the exception of the NIAID Project Scientists. If one individual is the same PD/PI for both a CAUSE-CRC and the CAUSE-LC, s/he will have only one vote.

Network-wide Clinical Study Implementation and Management

The PD(s)/PI(s) of the CAUSE-LC will work in coordination with the NIAID-DAIT data management center(s), through NIAID, to execute the following tasks related to network-wide CAUSE clinical research projects:

• 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. This will include compliance with clinical site and study monitoring functions carried out by the NIAID-DAIT data management center(s) for: (i) site initiation visits; (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(s)/PI(s) 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 preparation and submission of AE and SAE Reports to the NIAID-DAIT data management center(s) for initial review and assessment, followed by final assessment and classification by the NIAID-designated Medical Monitor.

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.

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement. A final RPPR, 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 agreementsare 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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM)about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings.Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threatensubmission by the due date, and post-submission issues)

Finding Help Online:http://grants.nih.gov/support/(preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email:GrantsInfo@nih.gov(preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support(Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email:support@grants.gov

Gang Dong, M.D., Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3508
Email: gdong@niaid.nih.gov

Konrad Krzewski, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-747-7526
Email: konrad.krzewski@nih.gov

Shaun Gratton
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3594
Email Address: shaun.gratton@nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. 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 Part 75.