It is critical that applicants follow 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 the 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 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Atopic Dermatitis (AD) is a chronic inflammatory pruritic skin disease that affects 12% of children under 18 years of age in the United States. AD is associated with defective skin barrier function as well as with several cutaneous immune abnormalities including type 2 inflammation, decreased expression of antimicrobial peptides, and low numbers of plasmacytoid dendritic cells. These abnormalities, several of which have been previously identified by the Atopic Dermatitis Research Network (ADRN), appear to translate into cutaneous defense defects as patients with AD are more susceptible to certain viral (e.g., Herpes simplex) and bacterial (e.g., Staphylococcus aureus) infections. A major viral complication in patients with AD is eczema vaccinatum, which is associated with the administration of smallpox vaccine.

The extent of and the mechanisms responsible for the apparent defects in cutaneous host defense, seen in AD patients, are not fully defined and therefore, effective therapies to reverse these defects are absent. Beyond its effects on cutaneous defenses, AD is associated with systemic inflammation and appears to be the first step in the development of other atopic conditions including food allergy and asthma.

AD is recognized as a research need by the NIAID Strategic Plan for Biodefense Research. In its 3 iterations, the ADRN has carefully examined various aspects of the cutaneous immune system in patients with atopic dermatitis and healthy individuals and has identified at least 3 instances where a specific AD patient group has diminished host defense compared to another: (a) patients with severe versus moderate or mild atopic dermatitis; (b) patients with atopic dermatitis and a history of eczema herpeticum versus patients with no history of this condition; and (c) individuals with genetic filaggrin-deficiency versus no deficiency in filaggrin. In addition to identifying these groups of atopic dermatitis patients who are at risk for complications from various infectious processes, the ADRN has generated pivotal knowledge on the structure and function of the skin including abnormalities of the skin barrier, the generation of anti-microbial peptides, the skin’s lipidomic profile and its susceptibility to Staphylococcus aureus (S. aureus) colonization.

The ADRN aims at further improving our understanding of the defense mechanisms of the skin by focusing on differences in skin structure/function and immune responses between patients with AD and healthy individuals, or disease controls. Specifically, research areas to be pursued by the ADRN-CRC investigators may include, but are not limited to:

• Evaluating the immune and skin barrier impairments leading to cutaneous viral (e.g., Herpes simplex) and bacterial (e.g., S. aureus) infections.
• Evaluating the role of the skin microbiome in host defense, including the effects of microbiome perturbations on cutaneous immunity, and the effects of targeted biologic treatments on the skin microbiome.
• Evaluating the role of proteins in both the stratum corneum and the tight junctions, as well as the role of cutaneous lipids in host defense and in the chronic inflammatory aspects of AD.
• Studying the genetic and epigenetic basis of the cutaneous host defense abnormalities and the chronic inflammatory aspects of AD in children and adults.
• Comparing immune responses to cutaneous pathogens in AD versus other chronic or inflammatory skin conditions, such as psoriasis or ichthyosis.
• Developing and validating sample-sparing assays and non-invasive methods to study cutaneous immunity in infancy.
• Characterizing the cutaneous microbiome in infancy.
• Designing and conducting small, mechanistic clinical trials or small observational clinical studies aiming at better understanding the pathophysiology of AD in adults or children.

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

ADRN-CRC:

The objectives of the ADRN-CRCs are to a) conduct the network-wide ADRN clinical research projects under the leadership of the ADRN-LC, b) conduct center-specific, clinical or laboratory, human-sample based research within the scope of ADRN and c) contribute to the overall ADRN strategic goals by participating in the ADRN Steering Committee and other network functions.

ADRN-CRC will propose only center-specific research projects. These projects can be small, mechanistic clinical trials, small, human observational/mechanistic studies or laboratory studies utilizing new or existing human biologic samples.

Note: It is anticipated that at least two network-wide clinical research projects will be implemented during the course of the awards. At least one project will be a clinical trial, while the second project may be either a clinical trial or a clinical study. The network-wide clinical research projects to be implemented will be chosen by the ADRN-LC PD(s)/PI(s) from projects proposed by the ADRN-LC or the ADRN Steering Committee, based on scientific advancements in field during the grant period.

The ADRN will participate in the Systems Biology of Early Atopy Birth Cohort study that is under development by the Consortium for Food Allergy Research (CoFAR). NIAID will inform the ADRN-CRCs after award if they will participate as clinical sites in the cohort study. The ADRN-LC PD(s)/PI(s) will participate in the cohort's steering committee.

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

• Research on HIV/AIDS.
• Phase III, IV or V clinical trials.
• Clinical trials testing clinical efficacy of therapeutic interventions.
• Clinical studies or clinical trials performed at a Foreign site.

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.

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

NIAID-DAIT Statistical and Clinical Coordinating Center (SACCC): The NIAID DAIT SACCC may provide statistical support for some ADRN-CRC center-specific clinical trials, if NIAID choses to be the sponsor, particularly if they are conducted under Investigational New Drug (IND) applications. The SACCC will provide 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. NIAID will determine whether the ADRN SACCC will provide resources to the ADRN center-specific research projects.

NIAID-appointed Asthma and Allergy Data and Safety Monitoring Board (DSMB): All center-specific clinical trials (and clinical studies if necessary) and all ADRN 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 ADRN-CRC center-specific research projects that will be supported by the NIAID-DAIT SACCC, NIAID will provide for public access, either through ImmPort or through another NIAID-approved resource and all clinical trial, clinical study, biomarker and mechanistic data produced by the ADRN-CRC will be made publicly available. This resource will not be provided for center-specific projects that are not supported by the SACCC and the PD(s)/PI(s) of each ADRN-CRC will be responsible for directly uploading these data.

The ADRN Steering Committee will be the forum for the ADRN to discuss network-wide ADRN studies and to advise the ADRN-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 ADRN-CRC center-specific research projects, but it will not be involved in the development or implementation of these projects.

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

A. Clinical Research Functions: This will involve personnel and facilities capable of conducting network-wide and ADRN-CRC center-specific research, including trained clinical staff, capabilities of recruiting adult and pediatric atopic dermatitis populations, clinical research facilities, investigational pharmacy services, and laboratory facility capable of processing, storing and shipping human biosamples. For center-specific research, additional requirements include an active, IRB-approved protocol for recruitment and clinical characterization of AD patients, a data management facility with established data management, quality control plans, and capability to upload data into the NIAID designated repositories and biostatistical support.

B. CRC Specific Research Projects: At least two, center-specific clinical research projects organized around a common theme or hypothesis. These could include one or more protocols that test a hypothesis associated with a specific AD phenotype or endotype with immunologic, skin barrier, skin microbiome or other focus of pathophysiologic importance in AD. These projects may range from a small mechanistic clinical trial to an observational study and to in vitro or ex vivo testing of human biosamples. Studies using only transformed human cell lines will not count toward this requirement. Limited animal research may be included for experimentation that is not possible in humans or with human materials. The animal studies must be necessary and must be fully integrated into a plan that will translate animal findings in human disease.

Additional protocol funds will be disbursed by the ADRN-LC to the ADRN-CRCs participating in network-wide clinical research projects. Protocol funds include (but are not limited to) the following protocol-specific expenses:

• Salary for additional staff or expanded commitment of core staff.
• Protocol-specific participant screening and recruitment.
• Study participant retention.
• Protocol required tests and evaluations.
• Study participant reimbursement.
• Equipment and supplies necessary to conduct the clinical trials and clinical studies.
• Shipping costs for biosamples from the ADRN-CRC sites to the ADRN biorepository and from the biorepository to mechanistic laboratories.
• Funds for mechanistic research associated with every network-wide clinical research project.

For more information see the NIAID Research Funding site Questions and Answers for RFA-AI-19-015 found at the following:

https://www.niaid.nih.gov/grants-contracts/questions-answers-rfa-ai-19-015

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

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

Applicant Organizations

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

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) 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.

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

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 ADRN-CRC (RFA-AI-19-015) and the ADRN-LC (RFA-AI-19-014) funding opportunities. However, different clinical projects must be proposed in each of the two applications.

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.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) 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:

Louis Rosenthal, Ph.D.
Telephone: ( 240-669-5070
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed with the following additional instructions:

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, with the following additional instructions:

Facilities & Other Resources:

• Clinical Sites: Describe the unique clinical research facilities available to conduct single-center and multi-site clinical trials and clinical studies under the ADRN umbrella.
• Laboratory Facilities: Describe the unique laboratory facilities capable of processing, storing and shipping human biosamples including peripheral blood, skin samples, stool samples and microbial samples.
• Pharmacy: Describe the unique investigational pharmacy services available and their capabilities for multi-site clinical trials and for randomization and blinding for center-specific trials, if applicable.
• Data Management: Describe the unique data management facility available to conduct center-specific clinical research projects including the capacity to carry out 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. With the following additional instructions:

• 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.

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

• For single PD/PI applications, the PD/PI must commit an overall minimum of 2 person-months for ADRN-CRC activities. For multi-PD/PI applications, one of the PD(s)/PI(s) must commit a minimum of 2 person-months for ADRN-CRC activities.
• Include funds for travel and other expenses for ADRN-CRC Senior/Key Personnel to attend two (2) one and a half (1.5) day ADRN Steering Committee meetings per year in the Rockville, Maryland area.
• For the ADRN-CRC center-specific research projects, include the costs of all support for statistical design, data collection 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 and safety reporting, and quality assurance.
• Do not include costs for DSMB expenses. NIAID will provide DSMB for all clinical trials.
• Do not include costs for ADRN network-wide projects. Protocol funds for those studies will be disbursed by the ADRN-LC to the ADRN-CRCs participating in each network-wide clinical research projects and will not be determined until after all ADRN 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) Clinical Research Functions and B) CRC-Specific Research Projects.

Subsection A: Clinical Research Functions

• Discuss the capacity and readiness of the ADRN-CRC to conduct network-wide ADRN clinical research projects under the direction of the ADRN-LC, including the processes and flexibilities in place to expeditiously expand efforts, including staffing, to accommodate the needs of network-wide ADRN clinical research projects.
• Discuss any unique characteristics that the ADRN-CRC will contribute to the ADRN. Describe unique recruitment capabilities and approaches for both adult and pediatric patients for participation in the ADRN network-wide and center-specific research studies. Indicate the number of adult and pediatric patients with AD seen per year in clinics within the applicant's institution.
• Discuss capacity to contribute to the Systems Biology of Early Atopy Birth Cohort study including approaches for recruitment of women in mid-pregnancy.
• Describe and discuss approaches to improve incorporation of other difficult-to-enroll groups such as minorities and infants.
• Describe the professional development in clinical research that staff receives and how this ensures in-depth knowledge of cGCP, Federal regulatory requirements, and ICH guidelines.
• Describe the plans, process and communication strategies required to work with the ADRN-LC sIRB.

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 a minimum of two small clinical research projects organized around a common theme or hypothesis; one of these projects may be a clinical trial. The research proposed should involve individuals with AD, or clinical specimens from such individuals. Healthy volunteers and persons with other skin diseases may be included in proposed studies as controls. Clinical trials, if proposed, should be limited to non-therapeutic, mechanistic trials. 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 may also be proposed for mechanistic research. As applicable for research studies include approaches to statistical methodology. Note: Specific details for trials and studies will be captured using the PHS Human Subjects and Clinical Trials Information. Do not duplicate information requested under the PHS Human Subjects and Clinical Trials Information Form.
• Discuss the most important scientific questions facing ADRN research and provide the rationale and approach to the common theme behind the topic areas proposed for study within the ADRN-CRC center-specific research.
• Describe and discuss the scientific rationale behind the proposed trial(s) and studies(s) including the significance of the research proposed, pertinent preliminary or literature-based data, and describe how the proposed projects relate to each other and the objectives of this FOA.
• Outline the hypothesis, objective and how the proposed outcomes will adequately address the hypothesis. Concisely describe the design of the proposed project, include rationale for the selection of the patient population, choice of intervention (if applicable), and study duration. As applicable, provide a schematic of the study design and a schedule of events for proposed projects using samples from observational studies or trial(s) funded through other means. Note if the proposed research includes clinical studies or clinical trials, specific information for that study will be entered using the PHS Human Subjects and Clinical Trials Information and should not be duplicated un the Research Strategy.
• Emphasize innovative elements included in the proposed projects, both in terms of novel hypotheses, as well as in terms of novel study designs.
• Provide a management plan 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 support available for ADRN center-specific projects.
• Discuss potential difficulties and limitations of the proposed procedures and alternative approaches to achieve the scientific objective.
• Discuss general approaches behind identification and selection of research laboratories to be used in these projects and their qualifications. In addition, 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 the Clinical Research Projects describe the rationale and overall thought process for laboratory and biosample selection.
• In the case where animal models are to be used, provide justification for the necessity of the model in the context of the proposed clinical research and describe how the findings will be translated into human research.

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, with the following modification:

• 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 ADRN-CRC award, available to the research community per policies established by the ADRN-Steering Committee. Therefore, the Data Sharing plan should include a summary of how the applicant will achieve this.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving NIH-defined human subjects research, clinical research, and/or clinical 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 with the following additional instructions:

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

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

1 Risks to Human Subjects

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.

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.

For all research projects provide information on:

• Describe the type(s) of biosamples to be used
• Describe the handling and processing of biosamples at the collection site (collection, processing, storage, transportation and quality control measures to ensure sample integrity)
• List the research laboratory(ies) to be used and describe the selection rationale and qualifications
• Describe the laboratory methodology(ies) to be used for each proposed assay/test and provide evidence of assay feasibility

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.

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

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.

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.

• Awards issued under this FOA will be incrementally funded awards for project periods of up to seven years. Multi-year funded grants will not be awarded.
• 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.

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.

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.

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?

Specific for this FOA

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

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, or information in the literature or knowledge of biological mechanisms? For trials or studies focusing on clinical or public health endpoints, is this clinical trial or study 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 clinical trials or studies focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, are these trials or studies needed to advance scientific understanding?

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?

Specific for this FOA:

Do the PD(s)/PI(s) have documented experience of working collaboratively in multi-center clinical trials and/or studies?

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?

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?

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?

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?

Specific for this FOA:

If animal studies are proposed, does the use of animals constitute a clear and specific need to support the project because equivalent experiments cannot be performed with human specimens?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable?

Study Design

Is the study 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 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 trial 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?

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?

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.

Clinical Research Functions

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

CRC-Specific Research Projects

• Does each proposed center-specific project address significant problems in AD research and does it have a high likelihood to achieve significant advances in AD?
• Are the center-specific research project plans realistic to allow for completion within the period of the award?
• Is each of the proposed projects adequately justified and supported by preliminary data 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?
• Does each project include an appropriate management plan describing the 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?
• Does each project include an appropriate summary of the statistical analysis plan and of sample size calculations with description of statistical power?
• For each center-specific project, is there sufficient discussion of anticipated problems and approaches to overcome or minimize such problems?
• For proposed laboratory studies, has a clear rationale justifying the need for each study been presented?
• Does the application include evidence for the qualifications of the research laboratories to be used in center-specific projects?
• For proposed laboratory methodologies, has evidence been provided demonstrating their robustness and feasibility?
• 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?

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 and milestones 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)?

For research that involves human subjects but does not involve one of the 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 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.

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.

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.

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.

Not Applicable

Not Applicable

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.

Not Applicable

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).

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).

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.

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the 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 to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Allergy and Infectious Diseases Council. The following will be considered in making funding decisions:

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

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

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 of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/.

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).

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.

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.html; and https://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.html or 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.

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.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 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 ADRN network-wide clinical research projects assigned to the ADRN-CRC by the ADRN-LC.
• Participating in the ADRN Steering Committee meetings and teleconferences and in its subcommittees, as applicable.
• Implementing ADRN policies and procedures, as established by the ADRN Steering Committee and the ADRN-LC.
• Executing and coordinating the scientific and administrative activities of the approved ADRN-CRC center-specific projects; setting project goals and timelines.
• Reporting progress, presenting data and discussing obstacles related to the ADRN-CRC center-specific projects with the ADRN Steering Committee.

Protocol Review and Approval

• The ADRN-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 the ADRN-CRC center-specific clinical trials or studies for which NIAID decides not to have IND/IDE Sponsor responsibilities, it is the responsibility of the ADRN-CRC PD(s)/PI(s) to contact the US FDA and obtain guidance as to the need for an IND or IDE (Investigational Device Exemptions) for interventions planned to be employed in any clinical study or trial, 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 research project. If an IND/IDE is required, the ADRN-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 ADRN-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 ADRN-CRC award available to the research community, per policies established by the ADRN-Steering Committee and consistent with achieving the goals of the program. Informed consent/assent forms utilized in ADRN-CRC supported clinical trials or studies should reflect this commitment.
• To promote rapid public access to ADRN-supported data, all ADRN-CRC investigators are expected to share their ADRN-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 ADRN-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 will advise in management and technical performance. In ADRN-CRCs that include center-specific clinical trials and, in some cases, clinical studies, the NIAID-assigned Project Scientist may also have Medical Monitor responsibilities.

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 another monitoring body.

IND/IDE

NIAID will serve as the IND/IDE sponsor for all ADRN network-wide clinical trials and, at its discretion, for some ADRN-CRC site-specific clinical trials requiring an IND/IDE. As part of NIAID’s IND/IDE sponsor responsibilities, the NIAID Medical Monitor will obtain through the SACCC or directly from the ADRN-CRC 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 SACCC and the ADRN-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 ADRN-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 SACCC conduct for-cause monitoring visits to an ADRN-CRC. Depending on the seriousness of the problem, such visits may be conducted by the NIAID Medical Monitor and/or NIAID staff. The PD/PI of the ADRN-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 ADRN 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 ADRN network-wide clinical projects and, at NIAID's discretion, some ADRN-CRC center-specific projects, both during protocol development and during the analysis of results. ESAG members may be invited to attend some ADRN Steering Committee meetings. The ESAG will submit its recommendations to the NIAID Project Scientists, who will then inform the ADRN-LC or ADRN-CRC PD(s)/PI(s). Recommendations by the ESAG are advisory.

Areas of Joint Responsibility include:

Protocol Development

The ADRN-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 the ADRN Steering Committee, SACC and the NIAID Division of Allergy, Immunology, and Transplantation (DAIT) staff. ADRN-CRC center-specific protocols will utilize the protocol templates provided by NIAID.

Research Activities

Reviewing the ADRN-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.

ADRN Steering Committee

The purpose of this committee is to advise the ADRN-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 ADRN scientific plan will be reviewed and updated yearly. In addition, the Steering Committee will regularly review and advise on the progress of center-specific ADRN-CRC research projects and will develop and implement policies and procedures for publicizing the accomplishments and the data resulting from ADRN studies to the scientific and lay communities and other relevant audiences. The ADRN Steering Committee will include the PD(s)/PI(s) of the ADRN-LC (who will serve as the Chairperson), a PD/PI from each of the ADRN-CRCs, the designated Project Leader of the SACCC, 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 an ADRN-CRC and the ADRN-LC, s/he will have only one vote.

Network-wide Clinical Study Implementation and Management

The PD(s)/PI(s) of the ADRN-LC will work in coordination with the SACCC, through NIAID, to execute the following tasks related to network-wide ADRN 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 SACCC 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 SACCC 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.

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 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.

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.

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 threaten submission 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: [email protected] (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: [email protected]

Michael Minnicozzi, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3532
Email: [email protected]

Louis Rosenthal, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5070
Email: [email protected]

Jordan A. Kindbom
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2983
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 Part 75.