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). 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

The Purpose of this FOA is to support the Pediatric HIV/AIDS Cohort Study (PHACS) which addresses critical scientific questions on the clinical course of perinatally acquired HIV infection in adolescents and the oral and systemic health consequences of in utero and infant exposure to antiretroviral chemotherapy in representative cohorts of children in the United States. Since millions of HIV-infected children in resource-constrained settings receive treatment and survive into adolescence and adulthood and an increasing proportion of HIV-infected pregnant women have access to and use combination antiretroviral therapy to prevent infant HIV infection and preserve their own oral and systemic health, the findings from this domestically based initiative have great relevance internationally.

The continuing overall objectives of PHACS are:

• To investigate more fully the effect of HIV and its treatment on sexual maturation and function, growth, cardiovascular disease risk, bone and oral health, other organ systems, substance use, neurodevelopment, cognitive and mental health disorders, academic performance, and vocational and social functioning in perinatally-HIV infected youth and young adults; and

• To acquire more definitive information regarding long term safety of antiretroviral agents when used during pregnancy and in newborns.

• To achieve the goal of data sharing from large epidemiologic studies like PHACS in which data are collected over several discrete time periods or waves, it is reasonable to expect that these data would be released in waves as data become available or main findings from waves of the data are published.

Perinatally-infected youth now routinely survive to adulthood but face the developmental consequences of prolonged HIV infection, associated co-morbidities, and long-term antiretroviral therapy affecting multiple organs and systemic and oral health. The number of perinatally infected children born domestically (where a study of this intensity is feasible) has dropped sharply since 1998. Studying a closed cohort of these youth remains possible as the timing of the pediatric HIV epidemic in the United States is such that adolescents with perinatal HIV infection are now reaching young adulthood. However, at the same time that the ability to do this study of perinatally-infected children in the United States is drawing to a close, the worldwide need for information is growing as access to antiretroviral therapy expands. The increase in the number of available antiretroviral drugs in the face of limited clinical data on the long term safety of these agents in growing and developing youth continues to give this cohort study critical importance. To date over 380 children and adolescents with perinatal HIV infection and over 200 uninfected control subjects have been enrolled and are under intensive evaluation in PHACS. The transition to adulthood of this first wave of treated perinatally-infected youth will be a major focus of this continuation requiring careful study of biomedical outcomes, including reproduction, oral, as well as cognitive, neurodevelopmental, and mental health, HIV-risk behaviors, substance use, and behavioral, emotional, social, academic and vocational outcomes. More importantly, this cohort includes youth who received very early treatment and have had nearly lifelong HIV suppression, thus making them ideal candidates for preparatory studies of cure trials.

PHACS is the only ongoing domestic clinical research network that conducts studies to comprehensively assess the systemic and oral health status of a representative sample of two populations: perinatally-infected adolescents and young adults and HIV-exposed uninfected infants, children, and adolescents. The study of an open cohort of HIV-uninfected children exposed to antiretroviral drugs during pregnancy and early infancy to identify developmental consequences continues to be a critical need because new drugs and more complex antiretroviral regimens are increasingly being used by HIV-infected pregnant women to prevent mother to child transmission and/or for treatment for maternal health reasons. Timing of antiretroviral initiation continues to evolve as well with more women already on treatment at the time of conception or starting earlier in pregnancy. Continuation of this effort will support ongoing evaluations of in utero and postnatal exposures to new antiretroviral drugs in the HIV-uninfected cohort and further work to identify specific adverse events and potential etiologic factors. Over 3,000 HIV-exposed uninfected children have been enrolled in PHACS to date and are under active follow-up. Collaborations will continue to be encouraged with other cohorts in both resource-rich and resource-constrained settings.

The goal of this FOA is to allow for a continuation of PHACS to support continued study and follow up of three closed cohorts: 1) HIV-exposed, uninfected population already enrolled and/or with data available from pregnancy and birth; 2) HIV-infected adolescents and young adults already enrolled and/or with data available from the time of diagnosis; and 3) HIV-exposed, uninfected youth already enrolled to serve as a comparison group. In addition, enrollment in the fourth cohort - HIV-infected pregnant women and their newborns - should continue with the goal to focus on those participants with exposures to newer antiretroviral drugs or combinations of antiretrovirals. Given data available from site performance to date and populations available at sites, including information from other studies, minor changes in sites invited to participate will be allowed to maximize both retention and follow up of the three closed cohorts as well as to achieve target annual enrollment of HIV-infected pregnant women and their newborns in the fourth cohort.

Areas of focus have been identified and the collection of basic information in these areas is expected to continue in the base protocols and in other supported substudies.

The areas of focus include, but are not limited to:

• Neurodevelopmental, cognitive, academic, vocational, behavioral, and social outcomes

• Communication disorders or impairment of hearing and language

• Substance use and abuse and mental health and HIV disease outcomes

• Adherence to medication regimens and compliance with behavioral interventions, including the role of substance use

• Growth, endocrinologic, and bone development issues

• Sexual maturation, reproductive capacity, sexual health and HIV-risk behaviors

• Nutrition, body composition changes and tissue redistribution syndromes

• Oral health, including: impact of treatment on oral cells and tissues, oral bone mineral density, and tooth development; oral mucosal immunity; oral disease biomarkers; oral persistence, latency and reservoirs for HIV and pathogens causing oral diseases; and interaction of oral pathogens in disease exacerbation relative to virologic, immunologic, and therapeutic status.

• Cardiovascular complications and cardiovascular disease risk

• Genetic and epigenetic, including mitochondrial, effects of in utero and neonatal exposure to antiretroviral drugs and HIV, HIV infection itself, its complications, and its treatment

• Effects of maternal alcohol and drug exposures on outcomes in infants and children

• Central nervous system imaging correlates of neurodevelopmental, cognitive, behavioral, substance use and substance exposures, hearing, and language outcomes

• Peripheral nervous system complications

• Viral infections associated with malignancies

• Pulmonary complications

• Renal complications

• Studies of HIV persistence, latency, and reservoirs

The scientific objectives listed above will be easily achieved by continuing with a multi-disciplinary scientific leadership research group (SLG) and subgroups with the capacity to collaborate with NIH program scientists to continue with the three refocused ongoing protocols: (1) Surveillance Monitoring for Antiretroviral Treatment Toxicity (SMARTT), a drug toxicity surveillance system in children exposed to prophylactic antiretroviral chemotherapy; (2) The Adolescent Master Protocol (AMP) that addresses the impact of HIV disease and its treatment on sexual maturation, pubertal development, cardiovascular disease risk, bone and oral health, substance use, neurological and mental health outcomes, HIV-risk behaviors, cognitive, emotional, social, academic, and vocational functioning of perinatally-HIV infected preadolescents and adolescents; and (3) the AMP UP protocol that continues the follow up of perinatally HIV-infected youth as they become young adults. All three protocols will continue to be structured to accommodate focused substudies as scientific questions are identified by the leadership group itself, the NIH program scientists, the PHACS clinical sites, the HIV clinical research networks supported by NICHD and NIAID, or independent investigators conducting HIV related research funded by NIH Institutes and Centers or other entities. PHACS will bring expertise and resources to collaborative protocol development that will ensure feasible and acceptable study design for these focused substudies, as well as experience in recruiting and retaining these unique populations through competitive subcontracts to clinical sites with demonstrated high level performance in PHACS or other United States based pediatric HIV cohort studies. The network will continue to follow the required numbers of subjects in rigorously refocused protocols and thus will address pressing scientific questions more quickly than could individual centers acting alone.

The multi-disciplinary scientific leadership group will also continue to collaborate with the participating NIH Institutes to refocus the base protocols and develop substudies necessary for investigations on etiologic factors and impact of the observed complications. The data and operations center will continue to coordinate clinical site activities (including community advisory board participation and activities), to provide methodological and analytical support, and to manage the database, including reconciliation with collaborating databases. It is the expectation that the majority of clinical sites (subcontracted by the data & operations center) will continue to participate to allow for the seamless continued follow up of the closed cohorts described above. Importantly, though, flexibility to make changes with regards to a small number of sites will be allowed as long as the impact on the follow up of the closed cohorts is minimized and the potential to achieve target enrollment and retention in the open cohort is maximized. This process may include solicitation and review of competitive subcontract applications, subject to NIH approval.

The PHACS network will continue to consist of the PHACS Coordinating Center (CC) and the Data and Operations Center (DOC).

The CC is responsible for maintaining the Scientific Leadership Group (SLG) through performance-based subcontracts. The SLG should continue to have scientific specialty working groups to reflect the different disciplines required to successfully implement the protocols and substudies. It is expected that the scope of disciplines constituting the SLG will expand or contract as the scientific questions emerge during the project period.

The PHACS Coordinating Center will continue to be responsible for assembling, through NICHD-approved performance-based subcontracts, the necessary multidisciplinary teams of established investigators from within and outside of the home institution to participate in the PHACS Scientific Leadership Group (SLG). The Scientific Leadership Group will be responsible for the peer review of focused substudies proposed for implementation within PHACS with additional review at the NIH scientific program level. The SLG will continue to establish and maintain collaborative relationships with other research networks in order to accomplish the objectives of this initiative. Members of the SLG are expected to attend monthly group calls, scheduled specific substudy calls, and semiannual network meetings and ad hoc group meetings.

The DOC is responsible for statistical and data management support and for creating and maintaining the necessary clinical infrastructure through NICHD-approved performance-based subcontracts to implement the base protocols (and substudies). Ancillary groups must include a Clinical Investigator Group (CIG), Study Coordinator Group, and a Community Advisory Board. PHACS network governance and coordination will continue to be provided by an Executive Committee, comprised of the PD(s)/PI(s) of the CC and DOC, NICHD project scientist, other SLG members and representation from the clinical sites. NIH Institutes or Centers providing substantial support also will be represented as voting members of the Executive Committee at the request of NICHD. Other NIH scientists, representatives from ancillary clinical and community groups, will serve as non-voting ad hoc members. The Executive Committee will establish and enforce policies and procedures of the PHACS network.

NIH PHACS Steering Committee (NPSC) is composed of representatives from the co-funding NIH Institutes and Centers, and from the Office of AIDS Research (OAR).

This committee is responsible for the management oversight of this initiative,

the determination of the site eligibility criteria in collaboration with the DOC for any site solicitation,

the review of all proposed subcontracts within PHACS, and

for determining the need for (a) external review of the scope and content of revisions to the base protocols (b) any study-specific DSMB oversight, and (c) external review of proposed substudies.

It is important to note that the use of the funds to execute subcontracts in the Notice of Grant Award (NGA) to the CC and to the DOC for sites and multidisciplinary teams will require prior approval from NICHD program and grants management after consultation with co-funding Institutes. The PHACS CC and DOC are responsible for the monitoring and distribution of these subcontract funds.

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

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education

• Private Institutions of Higher Education

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

• Hispanic-serving Institutions

• Historically Black Colleges and Universities (HBCUs)

• Tribally Controlled Colleges and Universities (TCCUs)

• Alaska Native and Native Hawaiian Serving Institutions

• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)

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

For-Profit Organizations

• Small Businesses

• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments

• County Governments

• City or Township Governments

• Special District Governments

• Indian/Native American Tribal Governments (Federally Recognized)

• Indian/Native American Tribal Governments (Other than Federally Recognized)

• Eligible Agencies of the Federal Government

• U.S. Territory or Possession

Other

• Independent School Districts

• Public Housing Authorities/Indian Housing Authorities

• Native American Tribal Organizations (other than Federally recognized tribal governments)

• Faith-based or Community-based Organizations

• Regional Organizations

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the 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(s)/PI(s)) 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(s)/PI(s) 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.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

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

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.

• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept 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 must download 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.

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

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:

Sherry Dupere, PhD
Telephone: 301-496-3415
Fax: 301-402-4104
Email: duperes@mail.nih.gov

All page limitations 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 an application to this FOA.

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

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

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

All instructions in the SF424 (R&R) Application Guide must be followed. The applicant should assemble the necessary multidisciplinary team of established investigators from within and outside of the home institution. Disciplines should be included as required to support the purposes of this initiative, including, but not limited to: infectious and chronic disease epidemiologists, medical subspecialists, and specialists in mental health, substance abuse, neurodevelopment, mitochondrial disease, and behavior for the AMP protocol; and pharmacoepidemiologists, surveillance or registry and long term cohort and international health study specialists, and risk assessment specialists for the SMARTT protocol. The quality and expertise of the assembled leadership are one of the important elements of this application.

All instructions in the SF424 (R&R) Application Guide must be followed, in addition to the following instructions:

The CC PD(s)/PI(s) should request a discretionary budget to be used for funding of the focused substudies, for supporting collaboration or co-endorsement agreements with other research networks as indicated, and for accommodating central substudy-mandated requirements (e.g., specimen shipping costs) on an as-needed basis. Requests for discretionary funds will be negotiated with NICHD.

Funds for travel should be requested within the proposed budget

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

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

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

Research Strategy:

The PD(s)/PI(s) of the CC should clearly outline the scientific priority areas in depth, discussing plans, processes, and timelines for achieving them and assemble the necessary multidisciplinary team of established investigators from within and outside of the PD(s)/PI(s) home Institution. The application must also describe the review procedures used that will guide the Executive Committee in distributing discretionary funds for use by the multidisciplinary teams of researchers.

It is important to note that the use of the funds to execute subcontracts in the Notice of Grant Award (NGA) to the CC and to the DOC for sites and multidisciplinary teams will require prior approval from NICHD program and grants management after consultation with co-funding Institutes. The PHACS CC and DOC are responsible for the monitoring and distribution of these subcontract funds.

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 are expected to provide a Data Sharing Plan. When data from large epidemiologic studies like PHACS are collected over several discrete time periods or waves, it is reasonable to expect that the data would be released in waves as data become available or main findings from waves of the data are published.

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

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). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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) 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(s)/PI(s) Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness 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.

In order to expedite review, applicants are requested to notify the NICHD Referral Office by email at duperes@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD(s)/PI(s) name, and title of the application.

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 project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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?

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(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

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?

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?

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

For Renewals, the committee will consider the progress made in the last funding period.

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 NICHD, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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

• Will receive a written critique.

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

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

• Scientific and technical merit of the proposed project as determined by scientific peer review.

• Availability of funds.

• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD(s)/PI(s) 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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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:

PHACS Coordinating Center (CC)

The CC consists of the Principal Investigator, Project Director, and supporting staff of the institution receiving the award. The duties of the CC include but are not limited to:

• Provide for effective communication within the PHACS; disseminating information, coordinating conference calls, and collaboratively setting meeting and call agendas;

• Develop, review and maintain PHACS policies and procedures in a PHACS Manual of General Operations; any PHACS Executive Committee-approved and NICHD-acceptable revisions of the Manual during the project period of these awards will supersede the provisions of these specified terms of award;

• Execute all Memoranda of Understanding or Agreement with other entities to conduct PHACS developed research;

• Record and archive all EC-directed PHACS group meeting and conference call minutes and all PHACS study developmental documents;

• Maintain the PHACS discretionary fund and execute all necessary subcontracts or agreements to support PHACS function and research with Executive Committee and NICHD approval;

PHACS Scientific Leadership Group (SLG)

The SLG will consist of the Principal Investigator of the PHACS Coordinating Center (CC) and PHACS Data and Operations Center (DOC), the project directors of the CC and DOC, the collaborating investigators comprising the SLG subgroups, and the NIH staff science collaborators. The Principal Investigator of the CC will serve as chair of the group. A vice-chair will be elected by the members and from among the members of each leadership subgroup. The CC project director will coordinate the activities of the SLG at the direction of its officers. The SLG, in collaboration with NIH project scientists, will have the primary responsibility for defining the research agenda and its implementation in the network, and initiating and maintaining collaboration with other NIH-funded HIV-related research networks within the guidelines of this FOA. The SLG will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. Specifically, the SLG will:

• Develop and adopt policies and procedures for elected terms of office and voting procedures, protocol development and review, authorship and publication, collaboration, site and, where indicated, laboratory monitoring, repository requirements, and related issues and submit to the Executive Committee for approval;

• In collaboration with NIH project scientists, retain the primary responsibility for defining and prioritizing the research agenda and submitting the agenda to the Executive Committee for approval;

• Identify the most efficient and scientifically sound mechanisms for developing the research agenda, deciding if the specific agenda items are best pursued independently in the PHACS, given resources, or in collaboration with existing research networks funded by NIH or other agencies, such as CDC;

• Commit to the development of focused substudies that take into account the needs and capacities of this special population through active consultation with the PHACS Principal Investigators, addressing their scientific and medical interests and the capacity of their sites;

• Coordinate PHACS collaboration with investigators with funding from sources other than NIH-funded networks. These investigators may include but are not limited to individuals with RO1 funding;

• Interact, coordinate, and, where indicated, contract with immunology and virology laboratories participating or willing to participate in NIH-supported quality assurance programs in order to provide the PHACS with necessary laboratory support for independent PHACS studies;

• Develop in collaboration with the leadership of NIH-supported or other prevention and clinical trials networks or other agencies, such as CDC, formal liaison mechanisms to facilitate interaction and communication on an ongoing basis for the purpose of identifying emerging scientific questions that can be addressed by the PHACS network;

• Consult and interact with NIH-supported or other prevention and clinical trials networks or other agencies, such as CDC, in the design or adaptation of existing trials consistent with PHACS objectives to meet the needs and characteristics of relevant populations in order to implement these studies in subjects available in the PHACS;

• Assume responsibility for communication and liaison with existing networks and their scientific working group chairs to inform substudy development within PHACS; negotiate shared study costs, and define and resolve key logistical issues (e.g. data collection and transfer, repository and regulatory requirements) where relevant if substudies become collaboratively developed research protocols;

• Recommend the implementation of independent or collaborative research to the Executive Committee when two-thirds of the SLG subgroup members approve the research concept and the remaining SLG members confirm;

• Identify, with the assistance of the NIH staff, resources within the PHACS to support subject recruitment, enrollment, retention, data collection, specimen shipping, and negotiated protocol monitoring costs for PHACS-approved protocols and recommend to NICHD the use of funds for such support;

• Negotiate any PHACS rights to data and authorship with executive bodies of collaborating networks;

• Participate in regular conference calls and attend SLG meetings to be held at least semi-annually.

Data and Operations Center

The Data and Operations Center (DOC) will consist of the Principal Investigator, DOC project director, and staff deemed necessary to carry out the mission of the DOC. The DOC project director will coordinate the activities of the DOC at the direction of the principal investigator. The DOC will:

• Execute the solicitation for clinical sites and maintain the subcontracts, executing all necessary agreements with CUs to support study and subject accrual costs, and reconciling reimbursement to site performance with NICHD approval;

• Provide a mechanism for the timely and full input of clinical investigators and staff to the SLG and Executive Committee to guide the implementation of the base protocol and the drug toxicity surveillance system as well as the feasibility and acceptability of proposed substudies;

• Collaboratively plan and conduct all SLG and full PHACS Network meetings;

• Provide methodologic and analytic support to the development of all PHACS research projects, design the corresponding data collection forms and database(s), maintain the database(s) and supply the required analytic capacity;

• Supervise all data collection procedures by the clinical sites, arranging for combined efforts when indicated by regulatory demands of collaborative research;

• Provide for the most efficient transfer of study data generated by collaborative research either by maintenance of all necessary study-associated database(s) with their electronic transfer or arranging for on-site data entry at the clinical sites;

• Conduct protocol and site registration and other regulatory duties as delegated from NICHD, including executing data use agreements to protect PHACS data and subject rights;

• Establish and support Data and Safety Monitoring Boards (DSMB) when instructed by NIH PHACS Steering Committee;

• Provide training, including the development and updating of study manuals of operation, to all site personnel related to acceptable quality control and quality assurance procedures at the sites as well as protocol-training where indicated;

• Provide on-site monitoring to the clinical sites for those studies being performed at a particular site on a schedule dictated by the EC or its authorized subcommittee;

• Recruit and support the Community Advisory Board (CAB) staff person who will act as a liaison between the CAB members and the PHACS, and provide logistical support to any CAB-associated meetings;

• Participate in regular conference calls and attend SLG meetings to be held at least semi-annually.

The PHACS Clinical Investigators Group (CIG)

The CIG will consist of the Clinical Investigators of the subcontracted sites. The CIG will have a chair and vice chair elected from among and by the Clinical Investigators. Specifically, the CIG will:

• Have primary responsibility for the implementation of PHACS-approved study protocols, the recruitment and monitoring of study participants, associated data collection, and study-associated quality control measures at the clinical site including but not limited to identifying local CLIA-certified laboratory support in facilities participating in NIAID-supported quality assurance programs when indicated; these activities may be coordinated by the site study coordinator at the direction of the Clinical Investigator;

• Obtain Institutional Review Board (IRB) approval of all PHACS study protocols implemented locally and comply with both IRB and PHACS policies and procedures;

• Provide counsel and advice to the PHACS Executive Committee through its elected representatives on the feasibility of proposed research, implementation strategies, and subsequent data collection as well as information on their own perceptions of needed evaluations;

• Recruit at least one representative per site to serve as a community representative to participate in the PHACS Community Advisory Board;

• Have the opportunity to generate clinical research substudy proposals for submission to the LG for review;

• Participate in conference calls and attend PHACS meetings to be held at least semi-annually.

• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

NIH Project Scientists will represent each of the Institutes co-sponsoring the FOA. The NIH Project Scientists will:

• Facilitate the exchange of information between the SLG and other existing research networks to support collaborative efforts;

• Participate in the Executive Committee that oversees the establishment and maintenance of the PHACS and its progress in achieving program goals;

• Assist the Executive Committee in monitoring the progress of ongoing studies, including field data collection, standardization of methods across study sites, and adherence to protocol and quality control measures;

• Assist the SLG in the selection of research topics, and the development or review of protocols for specific studies;

• Arrange program review of all PHACS protocols and, when necessary, the external peer review of the protocols, clearing these studies for implementation;

• Assist the SLG in identifying PHACS resources required for the successful implementation of collaboratively developed research protocols;

• Assist in data analyses, interpretation, and publication of study results;

• Assist in identifying the need to terminate or curtail the study (or an individual subcontract or award) in the event of nonparticipation in the committee/group activities, substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of protocol, or substantive protocol changes without prior approval from program or the PHACS Executive Committee.

• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The duties of the IC Program Official include:

• Carry out continuous review of all activities to ensure that the objectives are being met and that all regulatory, fiscal, and administrative matters are handled according to NIH guidelines.

• Have the option to withhold support to a participating institution if technical performance requirements are not met.

• Perform other duties required for normal program stewardship of grants.

• These duties will be performed in consultation with the NIH PHACS Steering Committee.

Areas of Joint Responsibility include:

Executive Committee

The Executive Committee is the main governing body of the PHACS. The Committee is composed of the Principal Investigator and Project Director of the CC; the Principal Investigator and Project Director of the DOC; representation from the CIG; and the NICHD Project Scientist. NIH Institutes or Centers providing substantial support also will be represented as voting members of the Executive Committee at the request of NICHD. Other NIH scientists and representatives from ancillary clinical and community groups, serve as non-voting ad hoc members. A quorum must exist for Executive Committee action; a quorum consists of five voting members. Voting members will have one vote each, and motions will carry with a simple majority. The Chair of the SLG will also chair the Executive Committee. The Vice Chair of the Executive Committee will be elected by the entire committee from among the committee members; none of the NIH science collaborators are eligible to serve as Chair or Vice Chair of the Executive Committee. The Executive Committee will:

• Assist the SLG in the identification of research issues;

• Approve the direction of the research effort including any reconfiguration of the research subgroups to better address the direction of the scientific agenda, and oversee the conduct and monitoring of the studies;

• Approve policies and procedures adopted and developed by the SLG;

• Implement and enforce either directly or through delegation to other PHACS-supported personnel a Conflict of Interest (COI) Policy acceptable to the NICHD, that addresses any COI that may occur or may be perceived to occur through financial interest or other associations between members of the PHACS and the private sector to ensure compliance with all Federal regulations and NIH policies applying to the conduct of research involving human subjects (these include, but are not limited to, Title 42 CFR 50 and Title 45 CFR 46). NICHD notes that the primary regulatory authority for enforcement of COI belongs to the grantee institution and NICHD does not intend by this term of award to abrogate that responsibility. Rather, NICHD is imposing on the PHACS an additional responsibility to protect the integrity of the research produced by the PHACS. Therefore, if either the EC or the grantee institution identifies a real or perceived COI, both the EC and the grantee institution must address the COI and inform NICHD of the resulting action. This provision extends to subcontracted investigators;

• Approve any proposed substudy specific to its feasibility, clinical relevance, and implications as well as advise on the development of implementation strategies;

• Approve use of discretionary funds as recommended by the SLG;

• Establish timelines for the completion of tasks and monitor progress;

• Oversee site participation and performance, informing the appropriate program managers.

• Each full member will have one vote. Awardee members of the Executive Committee will be required to accept and implement policies approved by the Executive Committee.

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 annual Non-Competing Progress Report (PHS 2590 or RPPR) 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.

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Denise Russo, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6871
Email: drusso1@mail.nih.gov

Sherry Dupere, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-3415
Email: duperes@mail.nih.gov

Bryan Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: clarkb1@mail.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.