Part I Overview Information

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Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov/)

Components of Participating Organizations

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), (http://www.nichd.nih.gov/)
National Institute on Drug Abuse (NIDA), (http://www.nida.nih.gov/)
National Institute of Allergies and Infectious Diseases (NIAID), (http://www.niaid.nih.gov/)
National Institute of Mental Health (NIMH), (http://www.nimh.nih.gov/)
National Institute of Neurological Disorders and Stroke (NINDS), (http://www.ninds.nih.gov/)
National Institute on Deafness and Other Communication Disorders (NIDCD), (http://www.nidcd.nih.gov)
National Heart, Lung and Blood Institute (NHLBI), (http://www.nhlbi.nih.gov)
National Institute on Alcohol Abuse and Alcoholism (NIAAA), (http://www.niaaa.nih.gov/)

Title: Limited Competition for the Pediatric HIV/AIDS Cohort Study (U01)

Announcement Type

Update: The following update relating to this announcement has been issued:

• October 23, 2014 - This RFA has been reissued as RFA-HD-15-027.

This is a reissue of RFA-HD-05-018.

Request for Applications (RFA) Number: RFA-HD-09-006

Catalog of Federal Domestic Assistance Number(s)
93.865, 93.279, 93.273, 93.242, 93.173, 93.838, 93.856, 93.846

Key Dates
Release Date: September 1, 2009
Application Receipt Date: October 28, 2009
Peer Review Date(s): February/March 2010
Council Review Date: May 2010
Earliest Anticipated Start Date: July 1, 2010
Additional Information to Be Available Date (Url Activation Date): Not Applicable
Expiration Date: October 29, 2009

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

• Purpose. This Funding Opportunity Announcement (FOA), issued by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the NIDA, NIAID, NIMH, NINDS, NIDCD, NHLBI, and NIAAA solicits competing renewal applications to provide support for the Pediatric HIV/AIDS Cohort Study (PHACS) to continue the observational cohorts developed during the first competitive funding cycle. These cohorts address two critical issues in HIV research: the long-term safety of in utero exposure to multiple antiretroviral drugs in HIV-exposed but uninfected children, and the interactive effects of HIV and its treatments on perinatally infected children and adolescents.
• Mechanism of Support. This FOA will utilize the NIH Cooperative Research Project Grant (U01) grant mechanism.
• Funds Available and Anticipated Number of Awards. The NICHD intends to commit approximately $5,400,000, NIDA intends to commit approximately $3,400,000, NIAID intends to commit approximately $2,000,000, NIMH intends to commit approximately $1,200,000, NINDS intends to commit approximately $750,000, NIDCD intends to commit approximately $650,000, NHLBI intends to commit approximately $600,000, and NIAAA intends to commit approximately $250,000 in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2010 to support 2 competing grants in response to this FOA, one as the PHACS Coordinating Center (CC) and the other as the PHACS Data and Operations Center (DOC).
• Budget and Project Period. An applicant for the PHACS CC may request a project period of up to 5 years and an expected first-year budget for direct costs of up to $760,000 per year. An applicant for the PHACS DOC may request a project period of up to 5 years and an expected first-year budget for direct costs of up to $12,400,000 per year (note: clinical site consortium indirect costs are included in direct cost line under subcontracts in DOC budget). Additional funds may become available from current co-sponsors or other NIH institutes.
• Eligible Institutions/Organizations. This is a limited solicitation made available to the grantees funded under the first PHACS RFA (HD-05-018) as a recompetition for an additional award of up to five years.
• Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/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.
• Number of Applications. Applicants may not submit more than one application.
• Resubmissions. Resubmission applications are not permitted in response to this FOA.
• Renewals. Renewal applications are permitted in response to this FOA.
• Application Materials. See Section IV.1 for application materials.
• Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY: (301) 451-5936.

Table of Contents

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Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
A. Eligible Institutions
B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
A. Receipt, Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
D. Application Assignment
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
A. Additional Review Criteria
B. Additional Review Considerations
C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
A. Cooperative Agreement Terms and Conditions of Award
1. Principal Investigator Rights and Responsibilities
2. NIH Responsibilities
3. Collaborative Responsibilities
4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

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Section I. Funding Opportunity Description

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1. Research Objectives

Purpose

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute on Drug Abuse (NIDA), National Institute of Allergies and Infectious Diseases (NIAID), National Institute of Mental Health (NIMH),National Institute of Neurological Disorders and Stroke (NINDS), National Institute on Deafness and Other Communication Disorders (NIDCD), National Heart, Lung and Blood Institute (NHLBI), and National Institute on Alcohol Abuse and Alcoholism (NIAAA) invite applications from investigators for a limited competition to participate under a cooperative agreement (U01) to address two critical pediatric HIV research questions: what is the long term safety of fetal and infant exposure to prophylactic antiretroviral chemotherapy, and what are the effects of perinatally acquired HIV infection in adolescents and young adults. This joint effort will take the form of a continuation and refocus of a currently ongoing NIH funded project - the Pediatric HIV/AIDS Cohort Study (PHACS) and may include merger with data from other United States-based and international pediatric HIV cohort studies.

The purpose of PHACS is to continue to address two critical research questions on the clinical course of perinatally acquired HIV infection in adolescents and the consequences of fetal and infant exposure to antiretroviral chemotherapy in a representative cohort of children from the United States. Although this initiative is focused domestically, its findings will have tremendous relevance internationally as 1) treatment becomes more available in resource-constrained settings and millions of HIV-infected children receive treatment and survive into adolescence and adulthood and 2) an increasing proportion of HIV-infected pregnant women have access to combination antiretroviral therapy for prophylaxis or their own health.

The objectives of PHACS are to create a body of data to help us understand more fully the effect of HIV and its treatment on sexual maturation, growth, cardiovascular disease risk, bone health, other organ systems; substance abuse, neurodevelopment and mental health disorders; and cognitive, academic, vocational, sexual and social functioning of 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.

Background

PHACS includes 2 distinct cohorts 1) HIV-exposed but uninfected infants and children and 2) HIV-infected 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. 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 1,700 HIV-exposed uninfected children have been enrolled in PHACS to date and are under active follow-up.

Perinatally-infected youth now routinely survive to adulthood but face the developmental consequences of prolonged HIV infection and long-term antiretroviral therapy on multiple organs and systems in the body. The great increase in the number of available antiretroviral drugs in the face of the limited 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 170 uninfected control subjects have been enrolled and are under intensive evaluation in PHACS to date. While a high prevalence of abnormalities has already been detected (for example, 47% of the children in the HIV-infected cohort have been found to have hyperlipidemia), there is a continued need to determine etiologic factors (HIV, complications of treatment, and/or other risk factors). The transition to adulthood of this first wave of treated perinatally-infected youth will be a major focus requiring careful study of biomedical outcomes as well as cognitive, neurodevelopmental, mental health, HIV-risk behaviors, substance use, behavioral, emotional, social, academic and vocational outcomes.

PHACS is the only ongoing domestic effort to study systematically a representative sample of these two populations: perinatally-infected adolescents and young adults and HIV-exposed uninfected infants, children, and adolescents. The Adolescent Medicine Trials Network (ATN) funded by NICHD, NIMH and NIDA focuses on HIV infected youth but in contrast to PHACS it is an interventional network and not intended to provide long-term, in-depth observational data. In addition, the ATN targets primarily adolescents with behaviorally-acquired HIV, and does not include studies of HIV uninfected infants and children with in utero exposure to antiretroviral drugs. While PHACS is a domestic cohort the findings are increasingly important to resource-constrained countries as access to antiretroviral drugs expands among HIV-infected pregnant women and HIV-infected infants, children, and youth in these settings. Collaborations will be encouraged to access datasets in the United States as well as other cohorts in both resource-rich and resource-constrained settings.

This FOA is intended to continue and refocus PHACS and to encourage merger of data with other pediatric HIV cohort studies, to address two critical research questions in pediatric HIV infection in the United States: 1) what is the long-term safety of fetal/infant exposure to antiretroviral drugs and 2) what are the effects of perinatally-acquired HIV infection on adolescent development and transition to adulthood. There is substantial urgency in addressing both questions. Increasing numbers of children worldwide sustain fetal and/or infant exposure to a growing variety of antiretroviral chemotherapeutic drugs with little information on long term safety. Thus study of an open cohort of HIV uninfected children with fetal and infant antiretroviral exposure to identify its potential consequences continues to be a critical need. 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 children remains possible as the timing of the pediatric HIV epidemic in the United States is such that children with perinatal HIV infection are now reaching adolescence and in some cases young adulthood. However, at the same time that the ability to do this study of perinatally-infected children in the U.S. is drawing to a close, the worldwide need for the information is growing as access to antiretroviral therapy expands.

Scope

Areas of focus have been identified and the collection of basic information in these areas is expected to continue to occur in both base protocols as well as in substudies either funded by PHACS or by other mechanisms, such as other NIH grants.

These areas of focus include, but are not limited to, the following:

• Neurodevelopmental, cognitive, academic, vocational, behavioral, and social outcomes
• Communication disorders or impairment of hearing and language
• Substance use and abuse and mental health outcomes
• Adherence to medication regimens and compliance with behavioral interventions, including the role of substance abuse
• Growth, endocrinologic, and bone development issues
• Sexual maturation, reproductive capacity, sexual health and HIV-risk behaviors
• Nutrition, body composition changes and tissue redistribution syndromes
• Cardiovascular complications and cardiovascular disease risk

  - Use of novel biomarkers to evaluate cardiovascular risk, metabolic abnormalities, and vascular dysfunction
  - Noninvasive imaging to assess risk of premature atherosclerosis and vascular dysfunction in adolescents with HIV/AIDS

• Genetic and epigenetic, including mitochondrial, effects of exposure to antiretroviral drugs
• Effects of maternal alcohol and drug use 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
• Genetics and epigenetics related to HIV, its complications, and its treatment

The goals of the PHACS network are to:

• Acquire more definitive information regarding long-term safety of antiretroviral drugs used during pregnancy and in infancy on HIV-exposed but uninfected children, and to estimate the upper bounds of risk to children associated with in utero exposure to antiretroviral drugs.
• Understand the effect of HIV infection and its treatment on various domains including cardiovascular risk, bone health, sexual maturation and sexual health, pubertal development, substance use, mental health and cognitive, emotional, social functioning in perinatally HIV-infected children and adolescents.

Types of research and experimental approaches that are being sought to achieve the objectives

PHACS will achieve these objectives by continuing an interdisciplinary leadership group and subgroups with the capacity to collaborate with NIH program scientists to continue and refocus 2 ongoing protocols (1) Surveillance Monitoring for Antiretroviral Treatment Toxicity (SMARTT), a drug toxicity surveillance system in children exposed to prophylactic antiretroviral chemotherapy, and (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 health, substance use, mental health outcomes, HIV-risk behaviors, cognitive, emotional, social, academic, and vocational functioning of perinatally-HIV infected preadolescents and adolescents. Both protocols will continue to be structured to accommodate focused substudies as 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 U.S. based pediatric HIV cohort studies. This network will continue to follow the required numbers of subjects in rigorously refocused protocols and thus will address pressing research questions more quickly than could individual centers acting alone.

The goal of this FOA is to allow for a seamless continuation of PHACS to enable continued study and follow up of 3 closed cohorts [1) HIV-exposed, uninfected population already enrolled and/or with data available from pregnancy and birth, 2) HIV-infected children and youth already enrolled and/or with data available from the time of diagnosis, and 3) HIV-exposed, uninfected children and youth already enrolled to serve as a comparison group]. In addition, enrollment to the 4^th cohort - HIV-infected pregnant women and their newborns - should continue with the goal to target those with exposures to newer agents or combinations of agents. 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 3 closed cohorts as well as to achieve target annual enrollment of HIV-infected pregnant women and their newborns.

The multi-disciplinary leadership group will continue to collaborate with NICHD, NIDA, NIAID, NIMH, NINDS, NIDCD, NHLBI, and NIAAA 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 cohort 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.

Consequences of Exposure to Antiretroviral Chemotherapy

Prevention of mother to child HIV transmission through antiretroviral chemoprophylaxis may be the most significant advance yet in control of the global HIV epidemic. However, concerns for potential adverse effects of fetal/infant antiretroviral exposure have led to a United States Public Health Service recommendation for long-term follow-up of exposed children.

Nucleoside-analogue reverse transcriptase inhibitors (NRTIs) constitute the backbone of all current antiretroviral therapeutic regimens. These agents can inhibit DNA polymerase gamma, which in turn inhibits mitochondrial DNA (mtDNA) synthesis, resulting in mitochondrial dysfunction and/or DNA depletion. Such mitochondrial toxicity can have potentially far-reaching consequences for development in multiple organ systems.

In 1999, Blanche and other investigators in France reported evidence of mitochondrial dysfunction in eight HIV-negative children who had intrauterine and neonatal exposure to zidovudine (ZDV) or ZDV and lamivudine (3TC). Five of these children had neurologic involvement, and two died at approximately one year of age. Further epidemiologic surveillance and evaluation identified mitochondrial dysfunction in four more children and possible dysfunction in 14 others. Risk was higher among infants exposed to combination antiretroviral drugs (primarily ZDV/3TC) than ZDV alone. These reports are of serious concern, as the findings were consistent with mitochondrial effects observed in vitro and in certain tissues of fetal Erythrocebus patas monkeys exposed to ZDV. Additionally, increased risks of simple febrile seizures and effects on hematopoiesis among uninfected infants with antiretroviral exposure have been reported.

Review of data from several large United States cohorts of children with and without perinatal ZDV exposure and born to HIV-infected women did not identify increased mortality attributable to mitochondrial disease. However, these cohorts were primarily exposed to ZDV with relatively few exposed to combination antiretroviral drugs.

Several small laboratory studies have shown potentially deleterious effects of perinatal antiretroviral exposure including mitochondrial DNA depletion in peripheral blood mononuclear cells and placenta, and transient hyperlactatemia. While the clinical significance of these laboratory findings is unclear, the need for further investigation is not.

Although use of maternal antiretroviral prophylaxis to prevent mother to child HIV transmission is currently limited in resource-constrained settings, with the influx of new funding and growing efforts to provide antiretroviral therapy for HIV-infected individuals in such countries, it is anticipated that an increasing number of children will be exposed to antiretroviral drugs globally. The intensive studies conducted as part of PHACS will provide important information about potential outcomes of such exposures that will have global relevance.

As of June 2009, PHACS has enrolled over 1700 HIV-uninfected infants and children born to HIV-infected women and has followed these participants with annual evaluations including medical, neurologic, neurodevelopmental, behavioral including when appropriate substance use, HIV-risk behaviors and mental health, language, growth, metabolic, cardiac, hearing, and laboratory studies. There is ongoing enrollment into an open cohort of approximately 400 newborns per year to allow for studies on exposures to new combinations of antiretroviral drugs. For example, data from PHACS demonstrates that the use of tenofovir disoproxil fumarate (TDF) in pregnant women in the U.S. has increased to 30% despite minimal data on the effects on exposed offspring. Such information will be particularly important as regards to bone and kidney health. Data from PHACS also shows that the choice of protease inhibitor therapy in pregnant women is changing over time. In addition, a small but growing number of pregnant women will be exposed to newer classes of agents, such as integrase inhibitors and CCR5 antagonists (the first class of antiretroviral drugs that targets a human protein), and follow up of children exposed to these agents in utero will be a major focus of PHACS.

Biological and self-report data collected from PHACS thus far indicate that almost 30% of HIV-infected pregnant women engaged in substance use during pregnancy including tobacco, alcohol, marijuana, cocaine and/or other drugs of abuse. Exposure to such substances can impact growth and development and may increase vulnerability to substance abuse later on in life. PHACS will continue to measure in utero substance use exposure since these exposures may be associated with similar outcomes related to exposure to antiretroviral drugs and need to be taken into consideration. Furthermore, exposure to alcohol, tobacco, and drugs of abuse may have additive or interactive effects which are important to understand. PHACS will also monitor postnatal exposure to substance use in the environment and its impact on development.

The rates of protocol-defined abnormalities to date in PHACS are noted below and require further study to assess etiologic factors and impact. They include impairments in the following:

• Growth (1%)
• Hearing/Language (11%)
• Laboratory (<1%)
• Metabolic/adiposity (29%)
• Neurology (2%)
• Neurodevelopment (3%)

We encourage the recruitment and assessment of age and race/ethnicity matched control infants and children (born to non-HIV infected mothers) as part of the SMARTT protocol. Collecting comparable developmental information on control children will enhance understanding and improve our ability to assess and evaluate the protocol-defined abnormalities found to date in the SMARTT protocol of PHACS.

Clinical Course of Perinatally Acquired HIV Infection in Preadolescents and Adolescents

Effects on growth and development, lipid profiles, immunologic status, bone health, sexual maturation, and other aspects of human health have been demonstrated in adolescents who have acquired HIV infection by transfusion or sexual transmission, but this remains to be investigated in adolescent populations with HIV infection acquired perinatally. With advances in treatment in the U.S., perinatal HIV infection has now become a chronic illness. The time course of the HIV epidemic has been such that the majority of the oldest wave of HIV infected children in the U.S. who acquired HIV infection through perinatal exposure are just now entering young adulthood.

In adolescents with chronic disease, it is known that chronic illness can affect adolescent development and that adolescent development can have an effect on the illness. Delayed growth and puberty are common to most chronic illnesses. HIV infection may affect metabolic and endocrine function and alter hormonal systems involved in the control of growth and pubertal development. With increased survival due to treatment, the long-term effects of antiretroviral therapy, including metabolic complications and effects on bone, have become evident. The effect of superimposing such drug-related adverse effects on the rapidly changing hormonal, metabolic, and endocrinologic milieu of adolescence needs to be studied.

Additionally, biological, psychological and social development is highly interrelated. Problems with one may affect development of the others. High levels of adherence are critically important to the success of antiretroviral therapy. Because of cognitive and behavioral characteristics unique to adolescence, HIV-infected adolescents may have greater difficulty adhering to complex treatment regimens. The impact of chronic illness on school and education is also important. Recurrent illness and demands of treatment regimens may significantly influence school attendance and educational achievement. The development of peer relationships and self-image issues is a critical component of adolescent development. Adolescence is a time of risk-taking and initiation of sexual activity, and may be particularly difficult for adolescents with HIV infection and carry risk of HIV transmission. Pregnancy in adolescent girls with perinatal HIV infection recently has become increasingly common. Adolescence is also the time for drug use initiation including tobacco, alcohol, marijuana, and other drugs of abuse as well as abuse of prescription medication. HIV-infected adolescents, especially those with in utero exposure to drugs of abuse, may be particularly at risk for substance use disorders beginning in adolescence.

As of June 2009, PHACS has enrolled over 380 HIV-infected children and adolescents between the ages of 7 and 16 years and over 170 uninfected control subjects and has followed these participants with semi-annual medical, neurologic, neurodevelopmental, behavioral, substance use and mental health, sexual health, language, growth, metabolic, bone, cardiac, and hearing evaluations. The rates of protocol-defined abnormalities to date in PHACS are noted below and require further study to assess etiologic factors and impact. They include impairments in the following:

• Sexual maturation (<1%)
• Growth (7%)
• Insulin resistance (18%)
• Bone mineral density (20%)
• Lipids (47%)
• Hearing/Language (31%)

Organizational Components

The PHACS network will continue to consist of the PHACS CC and a DOC. The CC is responsible for maintaining the Leadership Group (LG) through performance-based subcontracts. The LG should have subgroups to reflect the different disciplines required to successfully implement the protocols and substudies. It is expected that the scope of disciplines constituting the LG will expand or contract as the scientific questions emerge during the project period. 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 Principal Investigator and Project Director of the CC, the Vice Chair(s) for any LG subgroup, the Principal Investigator and Project Director of the DOC, the NICHD project scientist, 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, 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.

Network Responsibilities

The Principal Investigator (PI) of the PHACS CC 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 PI's home institution to participate in the PHACS Leadership Group (LG). The LG will be responsible for the peer review of focused substudies proposed for implementation within PHACS with additional review at the NIH program level. The LG will continue to establish and maintain collaborative relationships with other research networks in order to accomplish the purposes of this initiative. Members of the LG are expected to attend monthly group calls, scheduled specific substudy calls, and semiannual network and ad hoc group meetings.

The PHACS DOC will continue to have the responsibility to provide clinical infrastructure, and statistical, data management, and organizational support. The DOC is responsible for identification of common elements to be shared within other study databases in order that PHACS will build upon and continue follow-up of the PHACS cohorts. The DOC will continue to maintain a network of clinical sites through NICHD-approved performance-based subcontracts. It is expected that the majority of current PHACS sites will have their subcontracts renewed to allow continued follow up of the 3 closed cohorts. A site solicitation may be necessary to maximize the annual enrollment and retention targets in the open cohort of HIV-infected pregnant women and their newborns. This decision will be made by the PHACS leadership and NIH. The DOC will continue to be responsible for staff and site training, quality assurance procedures including site monitoring, PHACS study development and support, the operation and integrity of the study databases including the support of remote data capture, analytic capacity, and regulatory compliance assurance as required. Members of the DOC are expected to attend monthly group calls, scheduled specific study calls, and semi-annual network and ad hoc group meetings. Funds for travel should be requested within the proposed budget.

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 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.

The subcontracted PHACS Clinical Sites have the responsibility of PHACS subject recruitment, retention, and safety through their capacity to provide a wide array of patient-specific services by multidisciplinary clinical staffs in well-established pediatric and adolescent medicine clinical sites with experience in HIV care. The clinical sites will continue to enroll and monitor subjects in PHACS supported studies, and provide guidance and counsel on the acceptability and feasibility of proposed network research. Clinical sites are required to cooperate with site monitoring teams, to discharge remote data capture responsibilities and adhere to PHACS policies and procedures. Clinical investigators and study coordinators are expected to attend monthly group calls, scheduled specific study calls, and semi-annual network and ad hoc group meetings.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

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1. Mechanism of Support

This funding opportunity will use the NIH Cooperative Research Project Grant (U01) award mechanism. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses Just-in-Time information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

This funding opportunity will use a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".

PHACS awards will be administered by NICHD. However, awards will consist of funds from multiple NIH Institutes. Management oversight of the grants will be provided through an NIH PHACS Steering Committee.

2. Funds Available

The estimated amount of funds available for support of 2 projects awarded as a result of this announcement is $14.25 million in total costs (expected up to $1,000,000 total costs for the Coordinating Center and expected up to $13,250,000 total costs for the Data and Operations Center [note: clinical site consortium indirect costs are included in direct cost line under subcontracts in DOC budget]) for fiscal year 2010. Future year amounts will depend on annual appropriations.

Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation see NOT-OD-05-004.

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.

Section III. Eligibility Information

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1. Eligible Applicants

1.A. Eligible Institutions

This is a limited solicitation made available to the grantees funded under the first PHACS FOA (RFA-HD-05-018) as a recompetition for an additional award of up to five years.

1.B. Eligible Individuals

This is a limited solicitation made available to the grantees funded under the first PHACS FOA (RFA-HD-05-018) as a recompetition for an additional award of up to five years. Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her institution 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.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Number of Applications. Applicants may not submit more than one application.

Resubmissions. Resubmission applications are not permitted in response to this FOA.

Renewals. Renewal applications are permitted in response to this FOA.

Section IV. Application and Submission Information

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1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: [email protected].

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of the application form and the YES box must be checked.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates

Application Receipt Date: October 28, 2009
Peer Review Date(s): February/March 2010
Council Review Date: May 2010
Earliest Anticipated Start Date: July 1, 2010

3.A.1. Letter of Intent

A letter of intent is not required for the funding opportunity.

3.B. Sending an Application to the NIH

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

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

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Robert Stretch, Ph.D.
Director, Division of Scientific Review
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institutes of Health (NIH)
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: (301) 496-1485
FAX: (301) 402-4104
Email: [email protected]

3.C. Application Processing

Applications must be received on or before the application receipt date) described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed. Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute Incomplete and/or non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or renewal award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or renewal award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project (see NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.)

6. Other Submission Requirements

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2.A "Award Administration Information".

Specific Application Requirements for PHACS Coordinating Center (CC)

An application for the CC is submitted by an institution on behalf of the Principal Investigator of the CC who, in the application, should clearly outline the priority areas in depth, discussing plans, processes, and timelines for achieving them and should assemble the necessary multidisciplinary team of established investigators from within and outside of the PI's 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 the critical components of this application.

The CC PI should request a discretionary budget to be used for the funding of the focused substudies, for supporting collaboration or coendorsement 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. The application must describe the review procedures that will guide the Executive Committee in distributing discretionary funds. Recurring costs in budgets for project years 06-10 may be escalated at 3% depending on the availability of funds.

Specific Application Requirements for PHACS Data and Operations Center (DOC)

An application for the DOC is submitted by an institution on behalf of the Principal Investigator of the DOC. The applicant should clearly outline a detailed plan for the reconciliation of the WITS and other study databases as dictated by the common elements identified by the LG. This plan should be accompanied by timelines. The applicant should also identify the statisticians, data management specialists, and epidemiologists who will be responsible for this effort, delineating their credentials and experience. The DOC should include in their budget under Other Expenses category an amount each year for subcontracts to clinical sites. The DOC will continue to maintain a network of clinical sites through NICHD-approved performance-based subcontracts. It is expected that the majority of current PHACS sites will have their subcontracts renewed to allow continued follow up of the 3 closed cohorts. A site solicitation may be necessary to maximize the annual enrollment and retention targets in the open cohort of HIV-infected pregnant women and their newborns. This decision will be made by the PHACS leadership and NIH. Site selection criteria will be developed in collaboration with the NIH PHACS Steering Committee. This committee will conduct final review and recommend to NICHD approval of the sites proposed as a result of a DOC supported external peer review. It is expected that the selection criteria will include but may not be limited to (1) the capacity of the site through a brief description of the site's interdisciplinary health team providing care and the array of pediatric and adolescent-specific clinical services on site; (2) documentation of local CLIA-certified laboratory support; (3) the experience of the site in implementing existing U.S. based pediatric HIV studies; (4) relative number of eligible research subjects; and (5) quality of performance in conducting similar research. The DOC applicant should propose administrative and management functions that assure continuing attention to cost-efficiency and productivity; including mechanisms for resource allocation during the conduct of the study based on site performance. The DOC applicant should specify (a) details of their proposed clinical site review and selection process, (b) the process for identification and selection of external reviewers for clinical site review and selection if necessary, (c) the process for addressing and managing potential conflicts of interest in clinical site review and selection, (d) the approach to solicitation of additional clinical site applicants if necessary, and (e) that the DOC will provide full documentation of the review and selection process as required by NICHD.

The applicant should also provide a plan that clearly outlines the mechanisms proposed for negotiating the performance-based subcontracts to the clinical sites including site-specific subject accrual reimbursement, staff and site training, quality assurance procedures, the operation and integrity of the PHACS study databases including remote data capture capacity, PHACS substudy development and support, and analytic capacity. These responsibilities should be presented with plans, processes, and timelines. The use of the funds for the clinical subcontracts will require prior approval from NICHD program and grants management after consultation with co-funding Institutes. The DOC is responsible for the monitoring and distribution of protocol funds. The DOC should propose administrative and management functions that would assure continuing attention to cost-efficiency and productivity. This should include adjustment of resource allocation during protocol performance.

The DOC applicant should be able to respond flexibly to the changing needs of the PHACS as the project unfolds, adding and deleting staff as the requirements dictate. The application should reflect an understanding of these processes. An application for the DOC must provide evidence of data management capabilities by describing standard operating procedures that address: (1) plans for database design and administration; (2) plans for data collection (remote data capture (RDC)), management, analysis, and data quality control for both main protocols and substudies; and (3) plans for providing an electronic communication system to participants of the PHACS.

The budget for the DOC should include, at a minimum, salary and administrative support for the PI, Project Director, and staff required to achieve the activities, including travel to two to three-day Washington, DC area meetings per year. The DOC budget should also include a funding request for Community Advisory Board (CAB) staff support and travel of CAB representatives (one from each CU) to one annual meeting. Funding for years 2-5 will be negotiated with NICHD and subsequent future year budgets may be escalated at 3% for recurring costs depending on the availability of funds.

Research Plan Page Limitations

Twenty-five (25) pages.

Appendix Materials

All paper PHS 398 applications submitted must provide appendix material on CDs only. Include five identical CDs in the same package with the application. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the required page limitations may be delayed in the review process.

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(a) Data Sharing Plan: Investigators seeking $500,000 or more in direct costs in any year are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact. See Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight) or the presence or absence of a disease or condition. For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

Section V. Application Review Information

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1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NICHD and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

• 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 impact/priority score.
• Receive a written critique.
• Receive a second level of review by the appropriate national advisory council or board..

The following will be considered in making funding decisions:

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

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability. As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact. Reviewers will provide an overall impact/priority 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 five core review criteria, and additional review criteria (as applicable for the project proposed).

Core Review Criteria. Reviewers will consider each of the five review criteria below in the determination of scientific and technical 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?

Specific review criteria for the PHACS Coordinating Center (CC):

• Potential significance of the proposed protocols to address the purpose of PHACS;
• Evidence of significant breadth of understanding of the purpose of the PHACS initiative.

Specific review criteria for the PHAC Data and Operations Center (DOC):

• Evidence of significant scientific and statistical contribution to the PHACS initiatives;
• Significance of the operational contribution to the PHACS initiatives.

Investigator(s). Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific review criteria for the PHACS Coordinating Center (CC):

• Assessment of the qualifications, research experience, and time commitment of the Leadership Group PI;
• Assessment of the adequacy, appropriateness, and scope of the qualifications and research experience of the proposed scientific leadership, including contributions to PHACS, previous experience or working knowledge of relevant recent HIV research findings;
• Assessment of the quality of the proposed resources and personnel for administering PHACS.

Specific review criteria for the PHACS Data and Operations Center (DOC):

• Quality of the qualifications and research experience of the management and analytic team;
• Quality of previous experience with design, administration, management and coordination of PHACS and multi-center clinical studies or trials;
• Quality of the proposed resources and personnel for supporting the PHACS.

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?

Specific review criteria for the PHACS Coordinating Center (CC):

• Assessment of innovativeness of the proposed PHACS base protocols.

Specific review criteria for the PHACS Data and Operations Center (DOC):

• Demonstration of innovative analytic approaches to evaluating clinical research data.

Approach. Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Specific review criteria for the PHACS Coordinating Center (CC):

• Quality of the PHACS base protocols and conduct;
• Strength and quality of the overall management plans, including plans for effective communication among PHACS components and collaborators;
• Quality of the plans for PHACS policy enforcement and necessary policy revisions;
• Quality of plans to assure appropriate protection of the rights and safety of subjects involved in clinical investigations;
• Quality of the review plans and procedures that will guide the Executive committee in distributing discretionary funds.

Specific review criteria for the PHACS Data and Operations Center (DOC):

• Quality of database reconciliation with databases from the Women and Infants Transmission Study and PACTG 219/219C;
• Quality of plans for sites implementation, site operations, staffing, and monitoring of site performance;
• Flexibility of plans to respond to the changing analytic needs of the PHACS;
• Quality of the plans to guarantee the quality and integrity of collected data;
• Quality of plans to maintain accurate and timely information on the progress of studies and site performance;
• Quality of plans for collaboration and data-sharing with other research networks when necessary (e.g., CDC-funded LEGACY project; IMPAACT Network studies P1074).

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?

Specific review criteria for the PHACS Coordinating Center (CC):

• Quality of the institutional support and probability that the scientific environment in which the work will be done will contribute to the success of the PHAC CC.

Specific review critieria for the PHAC Data and Operations Center (DOC):

• Quality of the institutional support and probability that the scientific environment in which the work will be done will contribute to the success of the PHACS.

Additional Review Criteria. As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, 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.

Inclusion of Women, Minorities, and Children. When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

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.

Renewals. Renewal applications are permitted in response to this FOA.

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.

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

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

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 (http://grants.nih/gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

3. Anticipated Announcement and Award Dates

Not Applicable

Section VI. Award Administration Information

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1. Award Notices

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.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official.

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. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS 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.

2. A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator 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 for the LG. 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 Leadership Group (LG)

The LG 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 LG 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 LG at the direction of its officers. The LG, 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 LG 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 LG 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 LG subgroup members approve the research concept and the remaining LG 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 LG 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 LG 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 LG 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 CUs, 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 CUs;
  
  
• 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 CU 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 CUs 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 LG 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 HHS, PHS, and NIH policies.

2. A.2. NIH Responsibilities

NIH Project Scientists will 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 LG 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 LG 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 LG 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.

2.A.3. Collaborative Responsibilities

The Executive Committee

The Executive Committee is the main governing body of the PHACS. The Committee is composed of the Chair of the LG, the Vice Chair(s) of the LG subgroups, and Project Director of 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 LG 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 LG 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 LG;
  
  
• Implement and enforce either directly or through delegation to other PHACS-supported personnel a Conflict of Interest (COI) Policy acceptable to the Pediatric, Adolescent, and Maternal AIDS Branch, 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 LG;
  
  
• 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.

2.A.4. Arbitration Process

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 arbitration. An Arbitration 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 arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts

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We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Rohan Hazra, MD
Pediatric Adolescent and Maternal AIDS Branch
Center for Research for Mothers and Children
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institutes of Health
6100 Executive Boulevard, Room 4B11, MSC 7510
Bethesda, MD 20892
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: 301-435-6868
FAX: 301-496-8678
Email: [email protected]

Nicolette Borek, Ph.D.
Division of Clinical Neuroscience and Behavioral Research
National Institute on Drug Abuse (NIDA)
National Institutes of Health/DHHS
6001 Executive Blvd MSC 9593
Telephone: 301-402-0866
Fax: 301-443-0107
E-mail: [email protected]

Melanie C. Bacon, RN, MPH, MA
Basic Science Program, Division of AIDS
National Institutes of Allergy and Infectious Diseases (NIAID)
National Institutes of Health (NIH)
Department of Health and Human Services (DHHS)
6700B Rockledge Drive
Room 4216, MSC-7626
Telephone: 301-451-2747
Fax: 301-402-3210
Email: [email protected]

Pim Brouwers, Ph.D.
Division of AIDS & Health and Behavior Research
National Institute of Mental Health (NIMH)
6001 Executive Boulevard, Room 6216, MSC 9619
Bethesda, MD 20892-9619
Rockville, MD 20852 (for express/courier service)
Telephone: 301-443-4526
FAX: 301-443-6000
Email: [email protected]

May Wong, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke (NINDS)
6001 Executive Boulevard, NSC 2113.
Bethesda, MD 20892-9521
Telephone: 301-496-1431
FAX: 301-402-2060
E-mail: [email protected]

Howard Hoffman, M.A.
Division of Scientific Programs
National Institute on Deafness and Other Communication Disorders (NIDCD)
6120 Executive Blvd., Room 400B
Bethesda, MD 20892-7180
Telephone: (301) 435-6881
FAX: (301) 402-6251
Email: [email protected]

Jonathan Kaltman, M.D.
Medical Officer
Heart Development and Structural Diseases Branch
Division of Cardiovascular Diseases
National Heart, Lung, and Blood Institute (NHLBI)
6701 Rockledge Drive, Room 8222
Bethesda, MD 20892
Phone: 301-435-0528
Email: [email protected]

Kendall J. Bryant, PhD
AIDS Coordinator
Division of Epidemiology and Prevention Research
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Room 2069
5635 Fishers Lane
Bethesda, MD 20892
Telephone: (301) 403-9289
Fax: 301-443-8614
Email: [email protected]

2. Peer Review Contacts:

Robert Stretch, Ph.D.
Director, Division of Scientific Review
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institutes of Health (NIH)
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service; non-USPS service)
Telephone: 301-496-1485
FAX: 301-402-4104
Email: [email protected]

3. Financial or Grants Management Contacts:

Bryan S. Clark, M.B.A.
Chief Grants Management Officer
Grants Management Branch
Eunice Kennedy Shriver National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A01A, MSC 7510
Rockville, MD 20852 (for express/courier service; non-USPS service)
Phone: 301-435-6975
E-Fax: 301-451-5510
E-mail: [email protected]

Section VIII. Other Information

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Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award. For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372. 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 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.