Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Allergy and Infectious Diseases (NIAID)
Funding Opportunity Title	Atopic Dermatitis Research Network (ADRN) (U19)
Activity Code	U19 Research Program Cooperative Agreements
Announcement Type	New
Related Notices	June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same.
Funding Opportunity Announcement (FOA) Number	RFA-AI-14-033
Companion Funding Opportunity	None
Number of Applications	Only one application per institution is allowed as defined in Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.855; 93.856
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) solicits applications from institutions to administer a multi-project, multi-institution program to conduct clinical research and provide the leadership and administrative responsibilities for the Atopic Dermatitis Research Network (ADRN). The ADRN conducts clinical research studies to better understand host defense mechanisms in the skin, by comparing responses to infections and vaccines, and underlying mechanisms, in healthy, non-atopic individuals vs. those with atopic dermatitis (AD). Such effects include skin barrier and adaptive and innate immune system responses to viral and bacterial infections, and genetic and epigenetic studies. The scope of research supported under this FOA will include the role of the microbiome in regulating host defense, and the development of clinical interventions to enhance host defense. The FOA will also support the conduct of longitudinal studies aiming at the identification of AD phenotypes pertaining to clinical presentation, skin and peripheral blood immunologic responses and patterns of cutaneous host defense.

Posted Date	March 20, 2014
Open Date (Earliest Submission Date)	June 8, 2014
Letter of Intent Due Date(s)	June 8, 2014
Application Due Date(s)	July 8, 2014, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	October 2014
Advisory Council Review	January 2015
Earliest Start Date	April 2015
Expiration Date	July 9, 2014
Due Dates for E.O. 12372	Not Applicable

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

Required Application Instructions

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

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

Atopic Dermatitis (AD) is a chronic inflammatory skin disease that affects many children and adults and has an estimated prevalence in the United States of 12% in children under age 18. AD is associated with reduced cutaneous immune responses, defective skin barrier function and increased susceptibility to cutaneous infections. In a subset of AD patients, defective skin barrier function is associated with genetic defects in the skin barrier proteins filaggrin and claudin. AD is also associated with several cutaneous immune abnormalities such as increased Th2 cytokine expression, decreased expression of antimicrobial peptides, and low numbers of plasmacytoid dendritic cells. The interrelationship between immune and skin barrier function in AD is complex. For example, patients with a deficiency of filaggrin have increased IgE sensitization to allergens. Th2 cytokines themselves can decrease cutaneous levels of filaggrin. Furthermore, the precise relationship of the skin barrier defects and immune abnormalities to increased susceptibility to infections is not known.

One potentially important problem with host defense in the skin of AD patients is increased risk of a serious complication to classical smallpox vaccination, a potentially life-threatening dissemination of vaccinia, called eczema vaccinatum (EV). In the 1960s and 1970s, EV occurred in approximately 10-40 per million vaccinees, and EV appeared to occur almost exclusively in patients with AD. Mortality in untreated EV has been reported to vary from 1% to 6%, and up to 30% in children under the age of 2 years. Between 50 and 66% of cases of EV, and almost all the deaths, were associated not with exposure by vaccination, but rather with exposure to vaccinated household contacts. Because of the limited use of standard smallpox vaccines, EV has been very rare in recent years. However, sporadic severe cases do occur: in 2007, an infant with a history of AD developed severe EV after his service member father received the smallpox vaccine and then had physical contact with his child. Thus, EV remains a risk, and protection against EV is an important element for our national biodefense program.

Patients with AD are susceptible not only to cutaneous viral infections, but also to Staphylococcus aureus (SA) skin colonization and infections. Such infections often result in exacerbations of AD. It has been suggested that certain components of SA, e.g., enterotoxin, can function as superantigens resulting in polyclonal T cell activation and an inflammatory cascade. The skin of SA colonized AD patients improves more after treatment with topical steroid and antibiotic therapy, than after topical steroid use alone; it is, therefore, likely that SA contributes to the pathophysiology of AD. SA colonization is estimated to occur in 76-100% of AD patients and 2-25% of healthy individuals. Because of the very high rate of SA colonization of AD patients, AD may be an important source of community acquired methicillin-resistant Staphylococcus aureus (MRSA), a significant health concern. However, the relative contribution of MRSA vs. methicillin-sensitive SA in the pathogenesis of AD is currently unknown.

It is postulated that host defense abnormalities in AD subjects are primarily defects in the skin, although systemic defects may also exist, and that the defects are due to dysfunction of the innate and adaptive immune system and of the skin barrier. Previous NIAID-sponsored atopic dermatitis related research activities include the Atopic Dermatitis Vaccinia Network (ADVN, 2004-2010) and the Atopic Dermatitis Network (ADRN, 2010-2015). The current ADRN consists of 8 clinical centers plus 3 additional sites, which support genetics and other mechanistic studies. It also includes 3 centers performing animal studies.

The ADRN is conducting, or has completed, the following human interventional clinical trials and clinical studies:

• Registry for Atopic Dermatitis Research Network (http://clinicaltrials.gov/ct2/show/NCT01494142)
• Interferon responses in AD patients with a history of eczema herpeticum (ADEH) (http://clinicaltrials.gov/ct2/show/NCT01429311)
• Pilot open label study of responses to intradermal and intramuscular influenza vaccine(http://clinicaltrials.gov/ct2/show/NCT01518478)
• Full study of responses to intradermal and intramuscular influenza vaccine (study completed; data are being analyzed) (http://clinicaltrials.gov/ct2/show/NCT01737710)
• Genetic studies on subjects from the ADRN registry protocol including:
  • Identification of rare variants in AD and ADEH by exome chip genotyping
  • Epigenetic studies in AD and ADEH
  • Targeted deep re-sequencing of ADEH candidate genes
  • Whole genome sequencing to identify variants in AD subjects with SA colonization
• ADRN barrier/immunoprofiling pilot study to be initiated by the end of 2013

The ADRN is conducting, or has completed, the following animal studies:

• Effects of FLG deficiency on cutaneous immune function and vaccinia immune responses in murine models of EV and eczema herpeticum (EH)
  • Vaccinia virus response in ft/ft mice
  • Role of IL-10 in the murine Vaccinia Virus model
• Susceptibility of atopic dermatitis model mice to vaccinia and herpes simplex virus
  • Mast cell requirement for allergen/SEB skin inflammation
  • Characterization of a murine model of EH
• Innate immunity: function of the microbiome
  • Skin surface microbiome in equilibrium with deep dermal compartments
  • Novel role for an immune receptor (MARCO) in mediating infection by HSV-1

Previous studies have evaluated immune responses in subsets of AD subjects, with these subsets being based mostly on clinical manifestations. These studies demonstrated that ADEH subjects have a more profound defect in innate immune response than AD subjects without EH, suggesting that the innate immune defect correlates with susceptibility to EH. In addition, compared to the total population of AD, subjects with ADEH have higher levels of serum total and specific IgE, suggesting that there are also adaptive immune system abnormalities in ADEH. Additional ADRN data show that AD subjects with SA colonization and/or infections also have elevated total and specific IgE. These clinical subsets (e.g., AD subjects with a history of EH or colonized with SA), may identify subjects whose genetic and epigenetic profiles differ from those of AD subjects who do not have a history of EH or SA colonization.

Other ADRN studies have focused on responses to vaccines that are administered by a cutaneous vs. a non-cutaneous route. In a trial of yellow fever vaccine (http://clinicaltrials.gov/ct2/show/NCT00723489), there were no differences in antibody or T cell responses between AD and non-atopic subjects following subcutaneous vaccination. However, in response to transcutaneous vaccine, AD subjects had a reduced T cell response compared to non-atopics. With the transcutaneous route, both T cell and antibody response correlated inversely with total serum IgE levels. In a trial of trivalent influenza vaccine (http://clinicaltrials.gov/ct2/show/NCT01737710), there were no differences in antibody or T cell responses between AD and non-atopic subjects following intramuscular vaccination. However, following intradermal vaccine, the antibody response was reduced in the subset of AD subjects whose skin was colonized with SA.

The ADRN organization will comprise multiple components to carry out the broad scope of research delineated below. These are:

Administrative Core The Administrative Core will be responsible for the overall scientific leadership and administrative functions as well as for establishing and maintaining the following committees/groups: ADRN Investigator Committee, ADRN Steering Committee and External Scientific Advisory Group

Clinical Projects In this FOA, clinical projects are divided into two categories: Interventional Clinical Trials with associated mechanistic studies and Clinical Studies with associated mechanistic studies. Applicants are required to propose 2 Interventional Clinical Trials Projects and 2 Clinical Studies Projects, and may propose up to 2 other, optional clinical projects, either interventional clinical trials or clinical studies, with no more than 6 total clinical projects proposed.

The two required Interventional Clinical Trials should be aimed at modulating viral or bacterial colonization/infection of the skin and/or the immune response to these infectious agents. Interventional Clinical Trials aiming at improving the clinical course of AD are acceptable as required Interventional Clinical Trials as long as improvement of the cutaneous host defense is included as a secondary objective.

In addition to the required Interventional Clinical Trials, optional Interventional Clinical Trials may also be proposed that either have the same focus as the required Interventional Clinical Trials, or have a broader focus: compare cutaneous and non-cutaneous vaccination approaches to examine the host defenses of the skin in various AD phenotypes.

Clinical Studies may include, but are not limited to, observational studies, genetic and/or epigenetic studies, studies of the skin microbiome or longitudinal studies to identify and characterize AD phenotypes pertaining to clinical presentation, skin and peripheral blood immunologic responses and patterns of cutaneous host defense. The objectives and scope of the Optional Clinical Studies are identical to those of the required Clinical Studies.

Both Interventional Clinical Trials and Clinical Studies projects should include mechanistic studies. Mechanistic studies should involve human subjects and are defined as aiming at 1) understanding the mechanisms of cutaneous host defense in AD, and/or 2) understanding the mechanisms of action of a treatment modality, and/or 3) identifying biomarkers that predict the ability of a treatment modality to affect host defense or safety. The mechanistic studies should take advantage of new mechanistic research developments and should introduce and integrate cutting edge technologies and state-of-the-art assays into the ADRN.

The majority of research to be conducted by the ADRN should involve human subjects.

Animal Projects - Animal studies are not required. They are optional and will be supported only if they provide information that cannot be obtained by human studies and only if they are directly linked to ongoing or planned human studies.

General areas of research interest that are responsive to this FOA include, but are not limited to, the following:

• Studying the microbiome in AD and its role in disease pathogenesis, including studies of alterations in the cutaneous or other microbiome in patients with AD compared to healthy controls, longitudinal studies of the skin microbiome, and evaluation of the effects of microbiome changes on cutaneous host defense.
• Blocking the effects of specific cytokines/chemokines.
• Cutaneous application of anti-microbial peptides and altering the skin microbiome.
• Evaluating the immunologic, genetic and epigenetic mechanisms underlying therapeutic interventions.
• Comparing new AD phenotypes to the subsets which have been explored to date by the ADRN, namely those with (1) a history of disseminated cutaneous viral infections (EV and EH), (2) cutaneous bacterial colonization/infections (SA including MRSA), (3) filaggrin deficiency, and (4) clinically severe AD.
• Understanding the susceptibility of subjects with AD to viral infections (EV and EH).
• Understanding the susceptibility of subjects with AD to bacterial infections (colonization and infection with SA including MRSA).
• Evaluating responses to vaccines of subjects with AD, with the focus on the difference between cutaneous and non-cutaneous routes of administration.
• Comparing the responses to cutaneous infections or vaccines of specific subsets of AD subjects such as ADEH; AD with SA colonization/infection; AD with filaggrin deficiency; clinically severe AD, to patients who do not have those characteristics.
• Investigating the genomic and epigenomic control of AD phenotype, by evaluating non-atopic controls versus AD patients with and without EH.
• Developing animal models to evaluate host defense in AD.
• Evaluating immunologic, genetic and epigenetic mechanisms underlying change in the skin microbiome in animal models and comparing to data from human AD subjects.

ADRN Resources

The ADRN maintains several resources. As of early November 2013, an ADRN registry included 2,132 subjects. The ADRN maintains the following repositories from registry subjects: (a) serum repository of 61,000 samples; (b) DNA sample repository of 15,000 samples; and (c) SA repository of 7,800 samples. The ADRN grantee is expected to maintain all current ADRN resources.

Areas of research not responsive to this FOA:

• Basic research using animal cells or models unless they provide information that cannot be obtained by human studies.
• Basic research that is not linked directly to ongoing or planned human studies.

Committees and Advisory Groups:

The Administrative Core will have responsibility for establishing and maintaining several committees/groups. Descriptions of the committees/groups include:

Network Investigator Committee: The investigator committee includes the Program Director/Principal Investigator (PD/PI) of the ADRN, the PD/PI of the Statistical and Clinical Coordinating Center (SACCC), both clinical and mechanistic investigators at all study sites, and NIAID staff.

Network Steering Committee: The voting members of the Steering Committee include the PD/PI of the ADRN, the PD/PI of the SACCC, three Clinical Project Investigators (either Clinical Site and/or Mechanistic Studies Site Project Leaders) appointed by the PD/PI, and up to two designated NIAID project scientists. The Steering Committee responsibilities include: (i) making decisions regarding overall scientific direction, recommending specific studies for NIAID approval, and coordinating and managing approved studies; (ii) developing and implementing policies to ensure the efficient operation and effective management of Network functions, including enforcement of Network Steering Committee decisions and resolution of disputes and differences of opinion within the Network Steering Committee and between the Network Steering Committee and the Network External Scientific Advisory Group; (iii) establishing and implementing policies and procedures for publications, presentations at scientific meetings, potential collaborations with external investigators, and other forms of information dissemination pertaining to Network-supported studies and study data; (iv) developing and implementing policies and procedures for the identification, disclosure, reporting and management of potential and actual conflicts of interest for members of the Network and the External Scientific Advisory Group; and (v) approving policies and procedures for the secure transfer of clinical and laboratory data to the central databases of the SACCC.

External Scientific Advisory Group (ESAG): The members of the ESAG should be selected from institutions that do not include members of the ADRN. The ESAG will be composed of no less than 3 and no more than 5 clinical and basic science investigators. The ESAG should include expertise in the areas: dermatology, skin pathophysiology, genetics and epigenetics, molecular biology, mucosal immunology, basic immunology, immunotherapeutics, human microbiome, interventional clinical trials, and mechanistic studies in human immunologic diseases. Applicants should not contact or name potential members. ESAG appointments should be for one year but may be renewed throughout the duration of the ADRN.

Responsibilities of the ESAG will include:

• Reviewing and recommending improvements/modifications to study protocols developed by Protocol Teams during protocol development.
• Reviewing and advising the Steering Committee on the results obtained from studies undertaken by the ADRN.
• Proposing specific studies and areas of research for Network consideration.

NIAID Resources: Certain resources for the ADRN will be provided by NIAID. These include:

The Atopic Dermatitis Research Network will be supported by a SACCC through an independent NIAID award. The SACCC will provide a broad range of clinical research support services, including support for the design and organization of each ADRN protocol, development of protocol-related materials, assistance in activities related to review and approval of final clinical study protocols, interim statistical analyses, progress reports, safety updates and final safety reports for the NIAID DSMB or SMC, data collection, data management and quality control, clinical site monitoring, safety monitoring and reporting, data analysis and manuscript development support.

NIAID will serve as the Sponsor for any ADRN interventional clinical trials conducted under Investigational New Drug (IND) Applications and Investigational Device Exemptions (IDEs) with full responsibility for carrying out sponsor regulatory requirements.

All clinical trial and mechanistic data produced by this Network will be made publicly available by NIAID, through the SACCC, within 18 months after database lock. NIAID will provide the resource for public access, either through ImmPort (https://immport.niaid.nih.gov/immportWeb/home/home.do?loginType=full) or through another NIAID resource.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIAID intends to commit $6 million total costs in FY 2015 to fund 1 award.
Award Budget	Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period	The scope of the proposed project should determine the project period. The maximum project period is 5 years.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

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

Applicant Organizations

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

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

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

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

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

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

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

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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

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

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

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

The letter of intent should be sent to:

Zhuqing (Charlie) Li, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
6700B Rockledge Drive Room 3136
Bethesda, MD 20817
Telephone: 301-402-9523
Fax: 301-480-2408
Email: liz@niaid.nih.gov

Component Types Available in ASSIST	Research Strategy/Program Plan Page Limits
Overall	30
Admin Core	12
Project (use for required and optional Interventional Clinical Trials, Clinical Studies, and Animal Studies Projects)	12

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

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

The application should consist of the following components:

• Overall: required
• Administrative Core: required
• Interventional Clinical Trials Projects: 2 required
• Clinical Studies Projects: 2 required

Optional Clinical Projects: up to 2; these may be either Interventional Clinical Trials Projects or Clinical Studies Projects

Note: no more than 6 total Clinical Projects (required and optional combined) may be proposed.

• Animal Studies Projects: optional; up to 3

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

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

SF424 (R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Research & Related Other Project Information (Overall)

Follow standard instructions.

Project/Performance Site Location(s) (Overall)

Enter primary site only.

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

Research & Related Senior/Key Person Profile (Overall)

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

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

Budget (Overall)

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

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

PHS 398 Research Plan (Overall)

Specific Aims: List the Specific Aims of the ADRN focusing on the overall research agenda and strategic plan.

Research Strategy: In this narrative section, the applicant should provide their overall Strategic Plan, Vision, and Research Agenda for the ADRN. The multi-component application should be viewed as a confederation of interrelated clinical projects, each capable of standing on its own scientific merit, but complementary to one another. This is an important section as it provides the group of investigators an opportunity to give conceptual wholeness to the overall program by giving a statement of the general problem area and by laying out a broad strategy and timeline for attacking the problems. The applicant’s Strategic Plan, Vision, and Research Agenda should identify gaps in current knowledge, address current challenges in human subjects research (e.g. include new approaches in the design of interventional clinical trials aiming at reducing trial duration), and discuss approaches to move the field in new directions. Include an overview of previous clinical trials and studies in AD pertinent to the proposed Research Agenda (these can include trials and studies performed by the applicant, including preliminary data, or those performed by other investigators, indicating what has been learned from previous studies). Applications responding to this FOA should explain how the proposed Clinical Projects (Interventional Clinical Projects, Clinical Studies Projects) and Mechanistic Studies are synergistic and fit under the overarching program theme and how the Research Agenda can evolve to incorporate new scientific discoveries in the field. Highlight accomplishments of the PD(s)/PI(s) and proposed key personnel and collaborators in the research areas proposed and describe the synergy and collaborations that will be possible within the framework of the ADRN.

In addition, applicants should provide a general overview of the processes that will be employed in the conduct of the Interventional Clinical Trials Projects, Clinical Studies Projects, and Mechanistic Studies proposed under the ADRN. Include a discussion of how clinical sites will be identified and established and how the protocol team will be formed. This description should include a Clinical Project Implementation and Management plan that establishes the policies and procedures for the Network. The overall section will also include a detailed summary of how the Network plans to conduct protocol-specific training for the participating investigators and the relevant clinical and technical Clinical Study Site and Mechanistic Study Site staff. Summarize any special features in the environment and/or resources that make this application strong or unique. Include a timeline for the milestones, timelines and performance guidelines for both the protocol development process and for study initiation, execution, completion and analysis of final data.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

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

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

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

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

SF424 (R&R) Cover (Administrative Core)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Administrative Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Administrative Core)

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

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

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

Project /Performance Site Location(s) (Administrative Core)

List all performance sites that apply to the specific component.

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

Research & Related Senior/Key Person Profile (Administrative Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The PD/PI of the ADRN must be Core lead of the Administrative Core.

Budget (Administrative Core)

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

The PDs/PIs (identified as the Core Lead in this component) will be required to commit a minimum of 3 person months effort per year to the project

Applicants are requested to budget for: (1) centralized operational, administrative and fiscal support of the ADRN; (2) maintenance of the ADRN Registry and the three ADRN Repositories (serum repository 61,000 samples, DNA repository 15,000 samples, SA repository 7,800) and (3) travel to ADRN Network meetings for ESAG members).

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

PHS 398 Research Plan (Administrative Core)

Specific Aims: List the Specific Aims of the Administrative Core.

Research Strategy: In this section describe the fiscal, administrative and management responsibilities of the Administrative Core

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

• Planning and directing the ADRN’s technical, operational, administrative, and fiscal requirements.
• Establishing plans for efficient and accelerated IRB review and approval of multi-site clinical trials. Alternatives to exclusively local IRB review, ranging from a simple reliance agreement with a single external and independent IRB entity, to a complex and tiered, federated IRB model, are preferred but not required.
• Establishing plans and procedures to reduce redundancy, start-up time, delays and excess due to duplicated infrastructure associated with a network of clinical and mechanistic sites.
• Establishing and maintaining the functions of committees responsible for Network governance and management.
• Providing a brief plan for leadership succession if the PD/PI is, for any reason, unable to continue as the leader of the program.
• In conjunction with the SACCC, providing plans for training or verification of training in accordance with Federal regulatory requirements, Good Clinical Practice (GCP) guidelines and International Conference on Harmonization (IHC) standards, including: local Institutional Review Board (IRB) policies/regulations; subject screening, recruitment, enrollment and retention; informed consent; assessment and reporting of Adverse Events and Serious Adverse Events; collection of protocol-specific biologic specimens; receipt, storage, packaging, labeling and management of study products; collection, quality control and management of study data; data entry, and creation, maintenance and storage of research records, including Case Report Forms (CRFs), standard operating procedures, manuals of operation, source documents, regulatory files, and subject identification information.
• Altering or modifying the research agenda based on new scientific developments.
• Establishing and implementing collaborations with other Federal and non-Federal organizations/institutions for the co-sponsorship of research in areas of mutual interest and collaborations with industry for the evaluation of specific products/approaches.

Within the governance and management structure, the Administrative Core will have responsibility for establishing and maintaining the following committees/groups:

Network Investigator Committee: Describe plans, processes or procedures for this committee to fulfill its role in reviewing the details of planned, ongoing or completed trials.

Network Steering Committee: Applicants should provide plans, processes and procedures for the following:

• Making decisions regarding overall scientific direction, recommending specific studies for NIAID project scientist/medical officer approval, and coordinating and managing approved studies.
• Developing and implementing policies to ensure the efficient operation and effective management of network functions, including enforcement of Steering Committee decisions and resolution of disputes and differences of opinion within the Steering Committee and between the Steering Committee and the External Scientific Advisory Group.
• Establishing and implementing policies and procedures for publications, presentations at scientific meetings and other forms of information dissemination pertaining to Network-supported studies and study data.
• Developing and implementing policies and procedures for the identification, disclosure, reporting and management of potential and actual conflicts of interest for members of the Network and the External Scientific Advisory Group.
• Approving of policies and procedures for the secure transfer of clinical and laboratory data to the central databases of the SACCC prior to implementation.

External Scientific Advisory Group: Applicants should describe plans, processes, and procedures for the following activities:

• Selecting members of the ESAG.

Note: Proposed ESAG members should not be named in the application or contacted prior to IRG review of the application.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

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

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

Planned Enrollment Report (Administrative Core)

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

PHS 398 Cumulative Inclusion Enrollment Report (Administrative Core)

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

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

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

SF424 (R&R) Cover (Interventional Clinical Trials Projects)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Interventional Clinical Trials Projects)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Interventional Clinical Trials Projects)

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

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

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

Facilities and Other Resources: Applicants should demonstrate:

• Ready access to patient populations, including the relevant subsets of AD patients, to ensure timely screening and enrollment of appropriate study participants.
• Clinical research facilities at the clinical sites such as outpatient clinical research facilities for human subject recruitment, screening, clinical testing, collection of clinical samples and treatment; clinical laboratory facilities for the conduct of protocol-specific laboratory tests, the storage of clinical samples, and the packaging, under appropriate conditions, and shipping of clinical samples to mechanistic sites; and research pharmacy facilities for the receipt, labeling, storage, distribution and inventory of investigational products.
• Capabilities to collect and process the biologic samples required for mechanistic protocols.
• Research pharmacy facilities at the clinical sites for the receipt, labeling, storage, monitoring, controlled access, inventory, packaging and distribution of investigational products, and for return or disposal of investigational products in accordance with protocol-specific requirements.
• General research facilities at the clinical sites, including: non-clinical space for contract/subcontract management, data management and study coordination; computers with broadband secure internet access; dedicated office space for clinical and technical staff; and areas for secure storage of confidential study documents with controlled access.
• Laboratory facilities capable of supporting the research proposed using human biologic specimens.

Project /Performance Site Location(s) (Interventional Clinical Trials Projects)

List all performance sites that apply to the specific component.

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

Research & Related Senior/Key Person Profile (Interventional Clinical Trials Projects)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Project Lead should be responsible for the overall conduct, management and oversight of all clinical research activities with experience in the diagnosis, treatment and management of AD and at least 5 years' experience in design and conduct of clinical research.
• Applicants should include site leaders with a strong history and experience in successfully designing and conducting clinical studies in AD (e.g. immunopathogenesis and immunotherapeutics and skin barrier in humans relevant to cutaneous host defense) and with appropriate GCP/ICH knowledge and experience; and a strong history and experience in conducting cutting-edge, technologically advanced human mechanistic studies.
• Applicants should include support and technical personnel with dermatology immunology, infectious diseases/microbiome, human genetics/epigenetics, molecular biology and systems biology laboratory experience for research using human biologic samples; with appropriate GCP/IHC training in handling human biologic samples; and personnel with experience in executing clinical and mechanistic study protocols.

Budget (Interventional Clinical Trials Projects)

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

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

The project must include a full budget for the entire proposed period of support. Budgets should be based on per patient costs and include the other costs of performing the study (clinical research tests, coordinator and Project Leader time, drug costs if applicable, pharmacy costs, etc.). The costs for mechanistic studies should be included. The costs for data collection and management, statistical support and monitoring and other costs associated with study management will be covered by the SACCC. Full development will begin soon after award, with the help of NIAID staff and the SACCC.

PHS 398 Research Plan (Interventional Clinical Trials Projects)

Specific Aims: List in priority order, the broad, long-range objectives and goals of the Project. Concisely describe the hypothesis or hypotheses to be tested.

Research Strategy: Use this section to describe how the proposed research will contribute to meeting the ADRN goals and explain the approach and rationale for selecting the methods to achieve the specific aims. In addition to stating the biological significance of the research, indicate the project's relevance to the primary theme of the application and its role in the overall research strategy of the ADRN.

Note that all clinical projects must have integrated mechanistic studies. The mechanistic studies must be described within the context of the interventional clinical trial or clinical studies project. More details about the mechanistic studies can be found below in the section on Mechanistic Investigations.

The clinical and mechanistic studies should not duplicate the applicants ongoing or previously completed studies, or ongoing or completed ADRN studies listed on clinicaltrials.govclinicaltrials.gov, and should provide new insights into atopic dermatitis. The number of Clinical Sites participating in a clinical or mechanistic study can range from 1 to all Clinical Sites that will participate in the ADRN. It is expected that multiple studies will be performed concurrently.

All interventional clinical trial projects must provide a single synopsis addressing the following aspects of the proposed trial. The synopsis should be presented in sufficient detail to allow reviewers to judge significance, approach, innovation and environment. Do not submit a detailed, final clinical protocol because the protocols from the application that is funded will be developed collaboratively as a result of initial peer review, external scientific advisory review, DAIT/NIAID CRC review, DSMB or SMC review, and NIAID priorities.

This Research Strategy section should include the following:

• A discussion of the significance of the problem being studied, the need for the trial, and the potential impact of the results of the trial, including improving cutaneous host defense in atopic dermatitis.
• A discussion of studies that led to the proposed clinical trial and information or data from preliminary studies which address the need for and the feasibility of the trial.
• A description of and rationale for the proposed study design, including how the associated mechanistic studies might inform the conduct of the trial.
• A concise description of the overall study design, its rationale, methodology and data analyses to be used to accomplish the goals and specific aims of the trial and discussion of how the trial will test the hypotheses proposed. This should include:
  • Study title
  • Hypothesis
  • Study objectives (primary, secondary; include mechanistic objectives)
  • Population
  • Study eligibility criteria
  • Intervention(s) and comparators
  • Descriptions of investigational study drugs, potential toxicities and experience in the proposed population. The discussion of toxicities should include known events as well as concerns unique for the population being studied.
  • Plan for provision of investigational drugs with letter(s) of commitment from suppliers, if needed (note additional requirements in appendix).
• Clinical study design
  • Description of the intervention to be tested and the protocol to be followed in each arm of the trial, including a discussion of potential biases or challenges in the protocol and how they will be addressed
  • Sample size (with justification)
  • Primary and secondary endpoints (include mechanistic endpoints)
  • Anticipated duration of recruitment and of the study as a whole
  • Preliminary study visit schedule and primary evaluations, including laboratory evaluations
  • Any anticipated Human Subjects issues and how those issues will be resolved
  • Summary of the statistical analysis plan for the proposed primary endpoint, including a description of the outcome measures and the statistical tests that will be used for data analysis. A more detailed and complete statistical analysis plan will be developed when studies are finalized post-award, with the assistance of the SACCC.
• Feasibility Assessment:
  • Discussion of the availability of the overall research population - to include the standard of care alternatives to trial participation, likelihood of acceptance by study populations of the proposed interventions (e.g. intravenous administration? required hospitalization? high risk to the subjects?).
  • Discussion of any competing interventional clinical trials underway at the sites or in the community and their potential influence on recruitment.
  • Discussion of interventions with similar mechanism of action currently under development and their potential influence on the proposed trial.
  • Description of collaborative clinical sites including the applicants site in detail.
  • Availability of special services needed to complete the trial (e.g. investigational pharmacy).
  • Availability and costs of the proposed study intervention relative to the total ADRN budget.
  • Description of source and quantity of samples to be obtained, and discussion of potential safety and ethical issues involved in obtaining the samples.
  • Description of the routine laboratory services required for the interventional clinical trials and studies to be performed by the ADRN.
  • Clinical trial timeline.

Mechanistic Investigations:

Each interventional clinical trial must include corresponding mechanistic components aiming at 1) understanding the mechanisms of cutaneous host defense in AD, and/or 2) understanding the mechanisms, including immunologic, genetic and epigenetic mechanisms, of action of a treatment modality, and/or 3) identifying biomarkers that predict the ability of a treatment modality to affect host defense or safety.

It is expected that state-of-the-art technologies that accommodate small blood volumes will be used wherever possible for the proposed studies. For interventional clinical trials involving multiple sites, it is expected that state-of-the-art laboratory assays (e.g., skin barrier function, assays of immune function, immune profiling, etc.) will be performed at a well-equipped central facility at one of the ADRN sites.

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

For each Project include the following:

• The need for the mechanistic study, and the potential impact of the results of the study.
• A discussion of studies that led to the proposed mechanistic study and information or data from preliminary studies which address the need for and the feasibility of the study.
• A concise description of the rationale, methodology and analyses to be used to accomplish the goals and specific aims of the study and a discussion of how the study will test the hypothesis(es) proposed.
• Feasibility Assessment:
  • Describe the participating mechanistic study sites
  • Investigators and their experience in the proposed study area
  • Availability of special services needed to complete the study (e.g. specialized equipment, high quality bioinformatics support)
  • A summary of the statistical analysis plan for the proposed primary endpoint, including a description of the outcome measures and the statistical tests that will be used for data analysis. A more detailed and complete statistical analysis plan will be developed when studies are finalized post-award, with the assistance of the SACCC.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

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

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

Planned Enrollment Report (Interventional Clinical Trials Projects)

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

PHS 398 Cumulative Inclusion Enrollment Report (Interventional Clinical Trials Projects)

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

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

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

SF424 (R&R) Cover (Clinical Studies Projects)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Clinical Studies Projects)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Clinical Studies Projects)

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

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

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

Facilities and Other Resources: Applicants should demonstrate:

• Ready access to patient populations, including the relevant subsets of AD patients, to ensure timely screening and enrollment of appropriate study participants.
• Clinical research facilities at the clinical sites such as outpatient clinical research facilities for human subject recruitment, screening, clinical testing, collection of clinical samples and treatment; clinical laboratory facilities for the conduct of protocol-specific laboratory tests, the storage of clinical samples, and the packaging, under appropriate conditions, and shipping of clinical samples to mechanistic sites; and research pharmacy facilities for the receipt, labeling, storage, distribution and inventory of investigational products.
• Capabilities to collect and process the biologic samples required for mechanistic protocols.
• Research pharmacy facilities at the clinical sites for the receipt, labeling, storage, monitoring, controlled access, inventory, packaging and distribution of investigational products, and for return or disposal of investigational products in accordance with protocol-specific requirements.
• General research facilities at the clinical sites, including: non-clinical space for contract/subcontract management, data management and study coordination; computers with broadband secure internet access; dedicated office space for clinical and technical staff; and areas for secure storage of confidential study documents with controlled access.
• Laboratory facilities capable of supporting the research proposed using human biologic specimens.

Project /Performance Site Location(s) (Clinical Studies Projects)

List all performance sites that apply to the specific component.

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

Research & Related Senior/Key Person Profile (Clinical Studies Projects)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• The Project Leader should be responsible for the overall conduct, management and oversight of all clinical research activities with clinical expertise in the diagnosis, treatment and management of AD and have at least 5 years experience in design and conduct of clinical research.
• Applicants should include site leaders with a strong history and experience in successfully designing and conducting clinical studies in AD and with appropriate GCP/ICH knowledge and experience; and a strong history and experience in conducting cutting-edge, technologically advanced human mechanistic studies.
• Applicants should include support and technical personnel with dermatology immunology, infectious diseases/microbiome, human genetics/epigenetics, molecular biology and systems biology laboratory experience for research using human biologic samples; with appropriate GCP/IHC training in handling human biologic samples; and personnel with experience in executing clinical and mechanistic study protocols.

Budget (Clinical Studies Projects)

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

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

The project must include a full budget for the entire proposed period of support. Budgets should be based on per patient costs and include the other costs of performing the study (clinical research tests, coordinator and Project Leader time, drug costs if applicable, pharmacy costs, etc.). The costs for mechanistic studies also should be included. The costs for data collection and management, statistical support and monitoring and other costs associated with study management will be covered by the SACCC. Full development of the protocols will begin soon after award, with the help of NIAID staff and the SACCC.

PHS 398 Research Plan (Clinical Studies Projects)

Specific Aims: List in priority order, the broad, long-range objectives and goals of the Project. Concisely describe the hypothesis or hypotheses to be tested.

Research Strategy: Use this section to describe how the proposed research will contribute to meeting the ADRN goals and explain the approach and rationale for selecting the methods to achieve the specific aims. In addition to stating the biological significance of the research, indicate the project's relevance to the primary theme of the application and its role in the overall research strategy of the ADRN.

Clinical Studies Projects may include: observational/natural history studies, genetics/epigenetic studies, studies focused on the skin microbiome or microbiome of other tissues, and/or vaccine administration where the focus is on the mechanisms underlying the response to the vaccine.

Note that all clinical projects must have integrated mechanistic studies. The mechanistic studies must be described within the context of the clinical studies project. More details about the mechanistic studies can be found below in the section on Mechanistic Investigations.

The clinical and mechanistic studies should not duplicate ongoing or previously completed studies, including ADRN studies, and should provide new insights into atopic dermatitis. The number of Clinical Sites participating in a clinical or mechanistic study can range from 1 to all Clinical Sites that will participate in the ADRN. It is expected that multiple studies will be performed concurrently.

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

Clinical Studies:

All clinical study projects must provide a clinical study synopsis addressing the following aspects of the proposed clinical study.

• Study title
• Hypothesis
• Study objectives (primary, secondary; include mechanistic objectives)
• Population
• Study eligibility criteria
• Key statistical design features, including primary and secondary endpoints, comparison/control groups, sample size calculation and rationale, statistical method employed, and relevance to the power of outcome measurement(s)
• Proposed state-of-the-art and experimental methodologies/assays to be used to measure clinical outcomes, and potential caveats/limitations of the methodologies/assays proposed and alternative approaches to overcome or mitigate such caveats/limitations. Please link to appropriate mechanistic project aims.
• Statistical analysis plan
• Key features of the safety monitoring plan
• Study duration, including duration of follow-up and contingency plans for any safety-related issues
• Identification of the proposed clinical sites; documentation of access to adequate numbers of the types of subjects required and target enrollment for each proposed clinical site
• Plans, anticipated problems, and proposed approaches to overcome or minimize such problems, for: subject screening, recruitment, enrollment and retention
• Clinical study timeline

Mechanistic Investigations:

Applicants should propose mechanistic studies involving human subjects for each clinical studies project in the description of the project. Potential areas for mechanistic studies research are described above in Part 2. Section I: Purpose.

It is expected that state-of-the-art technologies that accommodate small blood volumes will be used wherever possible for the proposed studies. For clinical studies involving multiple sites, it is expected that state-of-the-art laboratory assays (e.g., skin barrier function, assays of immune function, immune profiling, etc.) will be performed at a well-equipped central facility at one of the ADRN sites.

Study plans should be submitted with the understanding that the studies to be conducted by the ADRN may be different as a result of initial peer review, external scientific advisory review, and/or the priorities of NIAID.

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

For each Project include the following:

• The need for the mechanistic study, and the potential impact of the results of the study.
• A discussion of studies that led to the proposed mechanistic study and information or data from preliminary studies which address the need for and the feasibility of the study.
• A concise description of the rationale, methodology and analyses to be used to accomplish the goals and specific aims of the study and a discussion of how the study will test the hypothesis(es) proposed.
• Feasibility Assessment:
  • Describe the participating mechanistic study sites:
  • Investigators and their experience in the proposed study area
  • Availability of special services needed to complete the study (e.g. specialized equipment, high quality bioinformatics support)
  • A summary of the statistical analysis plan for the proposed primary endpoint, including a description of the outcome measures and the statistical tests that will be used for data analysis. A more detailed and complete statistical analysis plan will be developed when studies are finalized post-award, with the assistance of the SACCC.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

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

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

Planned Enrollment Report (Clinical Studies Projects)

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

PHS 398 Cumulative Inclusion Enrollment Report (Clinical Studies Projects)

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

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

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

SF424 (R&R) Cover (Animal Study Projects)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Animal Study Projects)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Animal Study Projects)

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

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

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

Project /Performance Site Location(s) (Animal Study Projects)

List all performance sites that apply to the specific component.

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

Research & Related Senior/Key Person Profile (Animal Study Projects)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Animal Study Projects)

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

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

PHS 398 Research Plan (Animal Study Projects)

Specific Aims: List in priority order, the broad, long-range objectives and goals of the Project. Concisely describe the hypothesis or hypotheses to be tested.

Research Strategy: Use this section to describe how the proposed research will contribute to meeting the ADRN goals and explain the approach and rationale for selecting the methods to achieve the specific aims. In addition to stating the biological significance of the research, indicate the project's relevance to the primary theme of the application and its role in the overall research strategy of the ADRN.

Animal Study Investigations:

• Must demonstrate a direct link to ongoing or planned human studies.
• Must include integrated mechanistic studies.
• Must provide information that cannot be obtained by human studies.
• Can provide critical validation for subsequent human research studies, or provide interventional clinical trials or clinical studies with background data for subsequent human laboratory methodologies.
• May develop animal models to evaluate host defense in AD
• May evaluate immunologic, genetic and epigenetic mechanisms underlying change in the skin microbiome in animal models and comparing to data from human AD subjects

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

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

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

Planned Enrollment Report (Animal Study Projects)

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

PHS 398 Cumulative Inclusion Enrollment Report (Animal Study Projects)

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

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

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

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

See more tips for avoiding common errors.

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

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Network 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 Network proposed).

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.

Does the proposed overall research strategic plan address important areas and will it advance knowledge and provide evidence for therapeutic approaches in cutaneous host defenses relevant to atopic dermatitis?

Is the ADRN as a whole scientifically compelling? Are there coordination and synergy of the individual research projects with the core towards the achievements of the central objectives of the ADRN? Will the integration of the individual projects into a single Network be more beneficial than pursuing each project independently?

Does the PD(s)/PI(s) have the leadership and scientific ability to develop an integrated and focused research network? Will the PD(s)/PI(s) devote adequate time and effort to the ADRN? Is there evidence of adequate institutional support in terms of space, equipment and other resources? Are plans adequate and appropriate to ensure sufficient communication and coordination among the investigators?

Is the administrative and organizational structure appropriate and adequate for the attainment of the objectives?

Are the clinical and mechanistic sites suitable to perform the proposed work?

Have the applicants assembled a team of investigators capable of conducting state-of-the-art clinical and mechanistic studies of the immunopathogenesis of atopic dermatitis, including severe systemic viral and bacterial reactions, and skin barrier function?

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? 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? Do the interventional clinical trials, clinical studies, animal studies and associated mechanistic studies conform to the overall strategic plan outlined in the Research Plan and Administrative Core?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project ? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI , do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Do the Clinical Project leaders, Clinical Site leaders and Mechanistic Study Site leaders have a strong history and experience in successfully designing and conducting interventional clinical trials, clinical studies and technologically advanced mechanistic studies in AD? Do key personnel involved in Clinical Projects have experience in executing clinical and mechanistic study protocols and appropriate experience and GCP/IHC training?

Innovation

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

Approach

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

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed? Are plans for development, review, implementation, execution and management of interventional clinical trials and clinical studies and associated mechanistic studies adequate including protocol development, selection and management of clinical and mechanistic study sites, and management of laboratory quality assurance and control? Are the applicants looking at the appropriate populations of interest? Are the proposed mechanistic studies feasible and would they contribute to the understanding the etiopathogenesis of AD or its treatment? Are state-of-the-art technologies and assays used in the mechanistic studies?

For any proposed animal studies: Do the animal studies propose work that cannot be obtained by human studies? Are the animal models used relevant to human disease? Do the proposed studies demonstrate a direct link to ongoing or planned human studies?

For each proposed interventional clinical trial, clinical study, mechanistic study and animal study, are adequate statistical analysis plans described, including sample size justification and power calculation? Are the proposed milestones and timelines appropriate? For multi-center trials, does the application adequately address standardization/quality control of, and adherence to, the clinical protocol and data collection or distribution guidelines?

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?

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Administrative Core 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 core proposed).

Reviewers will consider each of the review criteria below, as appropriate for the Administrative Core, in the determination of scientific merit and provide an overall impact score for the Core, but will not give separate scores for these items.

Are the plans for management (including fiscal) and planning, initiation, implementation, tracking, and monitoring adequate and timely for completion of planned activities?

Are plans for establishing and implementing collaborations with other Federal and non-Federal organizations/institutions for the co-sponsorship of research in areas of mutual interest and collaborations with industry for the evaluation of specific products/approaches adequate?

Are plans for reducing start-up time of multi-site studies by increasing the efficiency of IRB review and for reducing redundancy, delays and excess due to duplicated infrastructure associated with a Network of clinical sites adequate?

Are plans for establishing and maintaining the functions of committees responsible for governance and management adequate?

Are adequate plans in place for training of investigators and staff at interventional clinical trials, clinical studies and mechanistic studies sites?

Does the application adequately address Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and Good Manufacturing Practices (GMP) compliance as appropriate?

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.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

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

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Not Applicable

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by 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 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 l. The following will be considered in making funding decisions:

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

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

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

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

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

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

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

Awardee-selected projects that involve clinical trials or studies involving greater than minimal risk to human subjects require prior approval by NIH prior to initiation.

• The awardee institution will provide NIH with written study protocols that address risks and protections for human subjects in accordance with NIH s Instructions for Preparing the Human Subjects Section of the Research Plan.
• The awardee institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

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

• Establish and maintain subcontracts with the interventional clinical trials sites and the mechanistic sites.
• Develop, implement and manage a process for allocating ADRN resources for approved studies, including a plan to recommend reallocation of funds to achieve the scientific goals of the ADRN.
• Establish a Steering Committee to serve as the governing body of the ADRN.
• Establish, in consultation with the Steering Committee, an External Scientific Advisory Group (ESAG) composed of no less than 3 and no more than 5 clinical and basic science investigators.
• Establish a plan that will ensure that all IRB primary reviews of any multi-center trial or study are conducted within the timeframe negotiated by the NIAID Project Scientist. Alternatives to exclusively local IRB review, ranging from a simple reliance agreement with a single external and independent IRB entity, to a complex and tiered, federated IRB model, are preferred but not required.
• Participate with key staff personnel and the NIAID Program Officer and other NIAID personnel designated by the Program Officer to review overall progress and future plans and to discuss any matters relevant to the scientific and financial administration of the grant.

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

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

• Protocol Development, Review and Approval: NIAID Project Scientists and other NIAID staff will participate in the development, review, and approval of all interventional clinical trials, clinical study and mechanistic study protocols. All interventional clinical trials, clinical study and mechanistic study protocols will be reviewed by NIAID and, depending on their level of complexity and risk, will be further reviewed by the DAIT/NIAID Clinical Research Committee and by the DAIT/NIAID Asthma and Allergy Data and Safety Monitoring Board (DSMB), Safety Monitoring Committee (SMC), or another monitoring body. Prior to study initiation, all clinical study protocols must be approved by an assigned NIAID Project Scientist who will be the Medical Monitor of the study, as well as by an assigned NIAID Regulatory Officer.
• IND/IDE: NIAID will serve as the IND/IDE sponsor for all Network interventional clinical trials requiring an IND/IDE. As part of NIAID’s IND/IDE sponsor responsibilities, the NIAID Medical Monitor will obtain, through the SACCC, 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, will prepare and submit the final study reports to the FDA.
• Clinical Trial Monitoring: NIAID will be responsible for monitoring compliance with good clinical practices, regulatory compliance, accurate protocol implementation, internal quality assurance, and test agent accountability at the Clinical Study Sites. NIAID will convene an independent NIAID Data and Safety Monitoring Board (DSMB) or Safety Monitoring Committee (SMC) or another monitoring body to review and monitor any protocols deemed to possess more than minimal risks. At NIAID’s discretion, the NIAID Medical Monitor may request that the monitoring body convenes ad hoc to review a serious adverse event or a cluster of adverse events or serious adverse events. Furthermore, the NIAID Medical Monitor may request that the SACCC conducts for cause monitoring visits to a Clinical Study Site. Depending on the seriousness of the problem, such visits may be conducted by the NIAID Medical Monitor and/or NIAID project management staff.
• Access to Data: The NIAID Project Scientists or designee will have access to all data generated under this cooperative agreement, and may review the data as recorded on the case report forms or in a database. Data must be available for external checking against the original source documentation.
• Scientific and Programmatic Oversight: An NIAID program official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. This stewardship includes monitoring program progress, approving changes and concurring in proceeding into study implementation stage. The Government, via the NIAID program official, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. NIAID staff may use information obtained from the data for the preparation of internal reports on the activities of the study.
• Areas of Joint Responsibility between NIH and Awardees include: Research Plans. Implementing, monitoring, and updating the clinical research plan for the ADRN to ensure consistency and relevance with the NIAID scientific priorities
• Research Activities. Reviewing the ADRN's research activities and goals on an agreed upon schedule.

ADRN Investigator Committee

The investigator committee includes the PD/PI of the ADRN, the PD/PI of the SACCC, both clinical and mechanistic investigators at all study sites, and the NIAID staff.

ADRN Steering Committee

The voting members of the Steering Committee will include the PD/PI of the U19, the PD/PI of the SACCC, three investigators chosen by the PD/PI of the U19 who are either Clinical Site PD/PIs and/or Mechanistic study site leaders, and up to two NIAID-designated Project Scientists.

External Scientific Advisory Group (ESAG)

The members of the ESAG should be selected from institutions that do not include members of the ADRN. The ESAG shall be composed of no less than 3 and no more than 5 clinical and basic science investigators.

Responsibilities of the ESAG will include:

• During protocol development, reviewing and recommending improvements/modifications to study protocols developed by Protocol Teams
• Reviewing and advising the Steering Committee on the results obtained from studies undertaken by the ADRN.
• Proposing specific studies and areas of research for Network consideration
• The recommendations by the ESAG will be submitted to the Steering Committee Chairperson and the NIAID Project Scientist.
• The ESAG will meet face-to-face as determined by the NIAID, during one of the Steering Committee face-to-face meetings. At each of these meetings, ESAG sessions will be conducted to review study protocols at early stage of development, and major findings from Network-sponsored studies. The members of the ESAG may also participate in a joint session with the Network Steering Committee to convey and discuss the rationale for the Group s recommendations. The NIAID Project Scientist may request a meeting with the members of the ESAG in the absence of any Network members.
• All ESAG recommendations shall be considered advisory and shall not be binding on the decisions made by the Network Steering Committee

Publications and Communications Policy

After the grant award, the Steering Committee will develop and implement policies and procedures for planning, authorship, preparation, review and final approval of manuscripts resulting from Consortium-supported studies and for submission of manuscripts for publication in peer-reviewed journals. All final manuscripts must be submitted to the NIAID for review in advance of journal submission. The respective roles, rights and responsibilities of pharmaceutical and medical device companies providing investigational materials for Consortium-sponsored studies in the publication review process will be specified in Clinical Trial Agreements (CTAs) between NIAID and the company.

In addition, the Steering Committee will develop and implement policies and procedures for publicizing the accomplishments and the data resulting from Consortium sponsored studies to the scientific and lay communities and other relevant audiences. This includes policies for presentations at scientific meetings and for communications with the press. The PD/PI will ensure that the NIAID Project Scientist has received an advance copy of any press release related to the grant prior to the issuance of the press release.

Public Access to Data Generated by the ADRN

All clinical trial and mechanistic data produced by this Network will be made publicly available by NIAID, through the SACCC, within 18 months after database lock. NIAID will provide the resource for public access, either through ImmPort (https://immport.niaid.nih.gov/immportWeb/home/home.do?loginType=full) or through another NIAID resource.

Protocol-specific Training

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

Clinical Study Implementation and Management

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

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

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

Dispute Resolution:

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

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

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

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

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

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

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

TTY: 301-451-5939
Email: commons@od.nih.gov

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

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

Michael Minnicozzi, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3532
Email: minnicozzim@mail.nih.gov

Zhuqing (Charlie) Li, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-402-9523
Email: liz@niaid.nih.gov

Maggie Wells
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-594-9847
Email: wellsmaggie@niaid.nih.gov

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

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