Pediatric HIV/AIDS Cohort Study (PHACS)

RFA Number: RFA-HD-05-018

Part I Overview Information

Department of Health and Human Services

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

Components of Participating Organizations
National Institute of Child Health and Human Development (NICHD), (http://www.nichd.nih.gov/)
National Institute of Allergy and Infectious Diseases (NIAID), (http://www.niaid.nih.gov/)
National Institute on Drug Abuse (NIDA), (http://www.nida.nih.gov/)
National Institute of Mental Health (NIMH), (http://www.nimh.nih.gov/)

Announcement Type
New

Update: The following updates relating to this announcement have been issued:

Catalog of Federal Domestic Assistance Number(s)
93.865, 93.856, 93.279, 93.242

Key Dates

Release Date: December 3, 2004
Letters of Intent Receipt Date(s): February 10, 2005
Application Receipt Date(s): March 10, 2005
Peer Review Date(s): June/July 2005
Council Review Date(s): September 2005
Earliest Anticipated Start Date: September 2005
Additional Information To Be Available Date (URL Activation Date): not applicable
Expiration Date: March 11, 2005

Due Dates for E.O. 12372
Not Applicable

Executive Summary

The NICHD, NIAID, NIDA, and NIMH invite applications from investigators willing to participate with the Institutes under a cooperative agreement (U01) to address two critical pediatric HIV research questions: the long term safety of fetal and infant exposure to prophylactic antiretroviral chemotherapy, and the effects of perinatally acquired HIV infection in adolescents. This effort will include refocus of a currently ongoing NIH-funded project (the Women and Infants Transmission Study [WITS]) and may include merger with data from other U.S.-based pediatric HIV cohort studies. This joint effort will take the form of the Pediatric HIV/AIDS Cohort Study (PHACS).

The objective of this RFA is to create a body of data to understand more fully the effect of HIV on sexual maturation, pubertal development, and socialization of perinatally HIV-infected pre-adolescents and adolescents, and to acquire more definitive information regarding long-term safety of antiretroviral agents when used during pregnancy and in newborns.

The work of the RFA will be divided into two phases. First, with FY05 funding from NICHD, (a) a multi-disciplinary leadership group will be formed to collaborate with NICHD and its co-funding Institutes (NIAID, NIDA, and NIMH) in identifying the critical research questions and the best scientific methodology to address them, and (b) a data and operations center will determine common elements that may be shared between existing datasets, develop the database structure for the prospective base, and plan for the competitive subcontract applications from former WITS and other clinical sites that wish to compete to be part of this new initiative. In Phase Two, beginning after the first year, other Institutes will join NICHD in FY06 to fund implementation of the prospective protocol at the successfully competed sites.

The NICHD intends to commit approximately $2 million in FY05 for the one-year planning phase. In FY06, NICHD intends to commit approximately $4 million, NIAID intends to commit $4 million, NIDA intends to commit $3 million, and NIMH intends to commit $1 million in total costs [Direct plus Facilities and Administrative (F & A) costs] to support two new competing grants in response to this RFA. This RFA will use the NIH Cooperative Research Project Grant (U01) award mechanism.

Applications may be submitted if an institution has any of the following characteristics:

International institutions are not eligible to apply.

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research 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 programs. Institutions may submit an application for either or both structural components of the PACS: the PHACS Coordinating Center and the PHACS Data and Operations Center.

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. The PHS 398 is available at http://www.grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. Telecommunications for the hearing impaired is available at: TTY 301-451-5936.

Table of Contents

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
    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
      A. Receipt and Review and Anticipated Start Dates
        1. Letter of Intent
      B. Sending an Application to the NIH
      C. Application Processing
    4. Intergovernmental Review
    5. Funding Restrictions
    6. Other Submission Requirements

  Section V. Application Review Information
    1. Criteria
    2. Review and Selection Process
    3. Merit Review Criteria
      A. Additional Review Criteria
      B. Additional Review Considerations
      C. Sharing Research Data
      D. Sharing Research Resources

  Section VI. Award Administration Information
    1. Award Notices
    2. Administrative 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. Award Criteria
    4. 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
Section I. Funding Opportunity Description

1. Research Objectives

The NICHD, NIAID, NIDA, and NIMH invite applications from investigators willing to participate with NICHD and its co-sponsors under a cooperative agreement (U01) to address two critical pediatric HIV research questions: the long term safety of fetal and infant exposure to prophylactic antiretroviral chemotherapy, and the effects of perinatally acquired HIV infection in adolescents. This joint effort will take the form of the Pediatric HIV/AIDS Cohort Study (PHACS). This effort will include refocus of a currently ongoing NIH-funded project (the Women and Infants Transmission Study [WITS] and may include merger with data from other U.S.-based pediatric HIV cohort studies.

The objective of this RFA is to create a body of data to understand more fully the effect of HIV on sexual maturation, pubertal development, and cognitive, academic, vocational and social functioning of perinatally HIV-infected pre-adolescents and adolescents, and to acquire more definitive information regarding long-term safety of antiretroviral agents when used during pregnancy and in newborns.

The PHACS will achieve this objective by assembling an interdisciplinary leadership group whose subgroups have the capacity to collaborate with NIH program scientists to (1) establish a base protocol that will address the impact of HIV disease on sexual maturation, pubertal development, and socialization of perinatally HIV-infected preadolescents and adolescents; and (2) institute a drug toxicity surveillance system in children exposed to prophylactic antiretroviral chemotherapy. Both the base protocol and the surveillance system will be structured to accommodate focused sub-studies 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. The PHACS will bring expertise and resources to collaborative protocol development that will ensure feasible and acceptable study design for these focused sub-studies, as well as experience in recruiting and retaining these unique populations through competitive subcontracts to clinical sites with demonstrated high level performance in WITS or other U.S.-based pediatric HIV cohort studies. The objective of this RFA is to ensure that the follow-up of these populations continues and that a mechanism is in place to estimate the upper bounds of risk for children associated with the use of antiretrovirals in their HIV-infected pregnant mothers as recommended in PHS Guidelines to prevent perinatal HIV transmission. This network will bring the required numbers of subjects into rigorously designed common protocols and thus address pressing research questions more quickly than could individual centers acting alone.

Background

Several NIH-sponsored projects have focused on the prospective observation of U.S. children with HIV infection or exposure. Prominent among these is the Women and Infants Transmission Study (WITS), which began enrolling HIV-infected pregnant women and the children born to them in 1989, and is currently in its fourth funding cycle. Other ongoing U.S.-based observational pediatric HIV cohort studies began enrolling HIV-infected and uninfected HIV-exposed children during the 1990s.

Most other large U.S.-based prospective observational studies of pediatric HIV have ceased (e.g., NICHD's Mothers and Infants Cohort Study [MICS] and Hemophilia Growth and Development Study [HGDS], CDC's Pediatric AIDS Collaborative Transmission Study [PACTS], NHLBI's Pediatric Pulmonary and Cardiovascular Complications of HIV [P2C2] Study, etc.). The WITS RFA will not be reissued. CDC has recently solicited applications for its proposed LEGACY study, a medical record review-based data abstraction effort focused exclusively on HIV-infected adolescents, children, and youth.

The current NIAID-funded AIDS clinical trials effort is undergoing reorganization and recompetition, with a greater focus on international activities and trials. This reorganization, particularly its likely impact on the number of domestic pediatric clinical sites that will be funded and the increased emphasis on treatment studies internationally, will limit the capacity of the PACTG to sustain, in its current form, the PACTG domestic pediatric observational study, PACTG 219/219C (“Late Outcomes Protocol”).

NICHD's current Adolescent Medicine Trials Network (ATN) does focus on HIV-infected youth, but it is an interventional network and not intended to provide long-term, in-depth observational study. It targets a different group of subjects than WITS, and does not focus specifically on HIV-uninfected infants and children with intrauterine exposure to antiretroviral drugs, nor on adolescents born with HIV. Other domestic opportunities for systematic study of a representative sample of these two populations that would be provided best through a prospective cohort design appear, therefore, to be very limited.

This RFA thus is intended to refocus a currently ongoing NIH-funded project (the Women and Infants Transmission Study [WITS]) and potentially to include merger with data from other U.S.-based pediatric HIV cohort studies, to allow addressing two continuing critical research questions in pediatric HIV infection in the U.S. (long-term safety of fetal/infant exposure to antiretroviral drugs and the effects of perinatally acquired HIV infection in adolescent development).

Objective:

The purpose of this RFA is to address continuing critical research questions on the clinical course of perinatally acquired HIV infection in adolescents, and the consequences of fetal and neonatal exposure to antiretroviral chemotherapy, in a representative cohort of children from the United States. Although this initiative will be focused domestically, its findings will have relevance internationally as treatment becomes more available in resource-limited settings. Additionally, it is the expectation of NICHD, NIAID, NIMH, and NIDA that the research activities of the PHACS, particularly in the area of long-term follow-up for antiretroviral exposure, will be coordinated with future international efforts supported in the clinical trials networks funded through the Division of AIDS, NIAID.

The two major questions to be addressed regard (1) the long term safety of fetal and neonatal exposure to prophylactic antiretroviral chemotherapy, as recommended by current U.S. PHS guidelines, and (2) the effects of perinatally acquired HIV infection in adolescents.

There is substantial urgency in addressing both questions. 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 U.S. is such that children with perinatal HIV infection just now are reaching adolescence. At the same time ever increasing numbers of children worldwide sustain fetal or neonatal exposure to a growing variety of antiretroviral chemotherapeutic drugs with little information on long term safety, as it is but 10 years since the effectiveness of antiretroviral chemoprophylaxis for mother to child transmission first was demonstrated in the Pediatric AIDS Clinical Trials Group protocol 076. Thus study of an open cohort of HIV uninfected children with fetal and neonatal antiretroviral exposure to identify its potential consequences is a critical need.

The Women and Infants Transmission Study (WITS):

The WITS is the longest continuously enrolling prospective cohort study of HIV-infected pregnant women and their children, initiated in 1988 and currently in its fourth funding cycle. NIAID, NICHD, and NIDA currently sponsor WITS in a tri-Institute cooperative agreement. The WITS has enrolled 2,590 pediatric subjects at two NICHD, two NIAID, and two NIDA sites. These subjects include 181 known to be HIV infected and 2,162 known to be uninfected. Subjects no longer followed number 1,779, the majority due to randomization off study of uninfected subjects. A total of 818 continue in follow-up, 103 infected and 616 uninfected. Of those known to be infected 25 percent are over 10 years of age. Conversely, among those known to be uninfected, 92 percent are less than 11 years of age.

The WITS has produced to date nearly 150 scientific publications. Highlights of WITS original research published to date include:

In addition to collecting clinical and laboratory information on participants at regular intervals, WITS and other U.S.-based pediatric HIV cohort studies maintain valuable repositories of biological samples for current and future research.

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 and neonatal antiretroviral exposure have led to a U.S. 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 can inhibit mitochondrial DNA (mtDNA) synthesis, resulting in mitochondrial depletion and/or dysfunction.

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 risk of simple febrile seizures and effects on hematopoiesis among uninfected infants with antiretroviral exposure has been reported.

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.

Subsequent review of data from several large cohorts of children, with and without perinatal antiretroviral exposure, born to HIV-infected women has revealed to date no increased mortality attributable to mitochondrial disease, nor increase in clinically obvious mitochondrial disease. Similarly, echocardiography in ZDV-exposed uninfected infants from birth to five years of age did not find evidence of cardiac dysfunction. However, most of the infants with antiretroviral exposure studied have been exposed only to ZDV, with a relative few exposed to combination nucleoside chemoprophylaxis.

It is but 10 years since the effectiveness of antiretroviral chemoprophylaxis for mother to child transmission first was demonstrated in AIDS Clinical Trials Group protocol 076. As ever-increasing numbers of children sustain fetal or neonatal antiretroviral exposure and perinatal transmission rates have decreased to less than two percent in the U.S., research is needed on the potential effect of such exposure in uninfected children.

Understanding the prevalence and pathophysiologic mechanisms of antiretroviral-induced mitochondrial toxicity has been hampered by difficulties in obtaining definitive diagnosis. The diagnostic gold standard involves muscle or liver biopsy. Obviously, this is not a practical or acceptable method for screening and monitoring infants and children.

Although use of maternal antiretroviral prophylaxis to prevent mother to child HIV transmission is currently limited in resource-poor settings, with the influx of new funding and 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 should have global relevance.

Clinical Course of Perinatally Acquired HIV Infection in Preadolescents and Adolescents:

A number of effects on growth and development, 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 and, as observed in the WITS cohort, 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 is just now entering adolescence.

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 has not been studied.

Additionally, biological, psychological, and social development is highly interrelated. Problems with one may affect development of the others. Adherence issues become critically important when dealing with 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. Pregnancy in adolescent girls with perinatal HIV infection recently has been reported.

The existing research agendas for the WITS and other cohorts need to be focused and prioritized to address emerging scientific issues in the pediatric population. NICHD, NIAID, NIDA, and NIMH intend to work with PHACS investigators to further the HIV research agenda for American children in two major ways: (1) by developing a mechanism to identify long-term safety issues arising as a consequence of exposure to antiretroviral chemotherapy and (2) by developing research protocols that address specific questions regarding the effects of perinatal HIV infection in adolescents. To accomplish these goals, NICHD, NIAID, NIDA, and NIMH will coordinate the development of the PHACS research agenda and the use of available resources to address these pressing scientific questions.

Scope

This initiative is divided into two phases, Phase One (project year 01) and Phase Two (project years 02-05). In Phase One , with FY05 funding from NICHD, a multi-disciplinary leadership group will be formed to collaborate with NICHD, NIAID, NIDA, and NIMH in identifying the critical research questions and the best scientific methodology to address them. At the same time, a data and operations center will plan for the reconciliation of existing databases and for the solicitation and review of competitive subcontract applications from former WITS and other clinical sites conducting U.S.-based pediatric HIV cohort studies that choose to be part of this new initiative. Other Institutes will join NICHD in FY06 to fund the second phase that implements the new protocol at the successfully competed sites.

In Phase One, the leadership groups will establish a base protocol that will address the impact of HIV disease on sexual maturation, pubertal development, and socialization of perinatally HIV-infected preadolescents and adolescents; and (2) will institute a drug toxicity surveillance system in children exposed to antiretroviral chemotherapy. Both the base protocol and the surveillance system will be structured to accommodate focused sub-studies in future years. Phase One constitutes a planning period.

Focused sub-studies will not be designed in Phase One; however, areas of focus have been identified and the collection of basic information in these areas is expected to occur in both the base protocol and the drug toxicity surveillance system. These areas of focus include, but are not limited to, the following for the base protocol:

Areas of focus for the drug toxicity surveillance system will be identified during the planning phase by the leadership group, in collaboration with NIH and in consultation with experts in pharmacoepidemiology, mitochondrial disease, risk assessment, other relevant disciplines, and other federal agencies. It is expected that the PHACS effort will be fully coordinated with the Legacy Project sponsored by the Centers for Disease Control and Prevention (CDC) as well as other federally-funded cohorts in existence during the period of the study so that federal-wide resources can be best used. It is the expectation of NICHD, NIAID, NIMH, and NIDA that the research activities of the PHACS, particularly in the area of long-term follow-up for antiretroviral exposure, will focus initially on domestic activities but will be coordinated with similar international efforts supported in the clinical trials networks funded through the Division of AIDS, NIAID. It is anticipated that coordination of domestic and international drug toxicity surveillance may be a future PHACS activity once a research agenda has been fully defined and implemented.

In Phase Two, the base protocol and the drug toxicity surveillance system will be implemented at subcontracted sites, selected through a competitive process occurring at the end of Phase One. The Data and Operations Center shall be responsible for organizing, conducting, and documenting the solicitation, review, and selection, subject to NIH approval.

NICHD intends to pursue further application of efforts to identify potential longer-term consequences of early exposure to antiretroviral drugs beyond Phase Two subject to funding availability.

Organizational Components

The PHACS network will consist of the PHACS Coordinating Center (CC) and a Data and Operations Center (DOC). The CC is responsible for establishing a Leadership Group (LG) through performance-based subcontracts. The LG should have subgroups to reflect the different disciplines required to successfully implement the planning process in Phase One. 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 protocol and the drug toxicity surveillance system. Any organized ancillary groups that support the development or review of the proposed research should be described in the LG application. Ancillary groups must include a Clinical Investigator Group (CIG), and may include entities such as a Study Coordinator Group, a Community Advisory Board, Data and Safety Monitoring Board(s) (DSMB), an Ethics Advisory Panel, etc.

PHACS network governance and coordination will be provided by an Executive Committee, comprising 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 and Centers providing substantial support also will be represented as voting members of the Executive Committee at the request of NICHD. Other NIH scientists, representatives from ancillary clinical and community groups, will serve as non-voting ad hoc members. The Executive Committee will establish and enforce policies and procedures of the PHACS network.

The 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 the site solicitation, the review of all proposed subcontracts within PHACS, and determination of the need for (a) external review of the scope and content of the proposed base protocol at the end of the Phase One Planning stage prior to its implementation at the sites, (b) any study-specific DSMB oversight, and (c) external review of proposed sub-studies in Phase Two.

Network Responsibilities

The Principal Investigator (PI) of the PHACS Coordinating Center (CC) is 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 (grantee) institution to participate in the PHACS Leadership Group (LG) and to clearly outline the priority areas, plans, processes, and timelines for achieving the implementation of the planning process in Phase One. The proposed agenda should address the full spectrum of issues included in the purpose for establishing the PHACS. The LG will be responsible in Phase Two for the review and evaluation of focused sub-studies proposed for implementation within the PHACS, with additional review at the NIH program level. NICHD will specify when a study requires a DSMB to oversee the research activities. The LG establishes and maintains 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 sub-study calls, and semiannual network and ad hoc group meetings. Funds for travel should be requested within the proposed budget.

The PHACS Data and Operations Center (DOC) has 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 the existing WITS and other study databases in order that the new base protocol and drug toxicity surveillance system may build upon and continue follow-up of consenting individuals at successfully competing sites that participate in PHACS. The DOC will create and maintain a network of clinical sites through NICHD-approved performance-based subcontracts. It is expected that the first solicitation will be restricted to sites funded to participate in WITS or existing U.S.-based pediatric HIV cohort studies. Subsequent site solicitations may not be so restricted in order to give the drug toxicity surveillance system flexibility to follow the demographics of the epidemic. In Phase Two, the DOC is also 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 sub-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 to the CC and to the DOC will require prior approval from NICHD program and grants management staff after consultation with co-funding Institutes, and that subcontracts to subcontracts will be unallowable. The PHACS CC and DOC are responsible for the monitoring and distribution of these subcontract funds.

The subcontracted PHACS Clinical Units (CUs) will 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 CUs will enroll and monitor subjects in PHACS-supported studies, and provide guidance and counsel on the acceptability and feasibility of proposed network research. CUs will be 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 will be 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

1. Mechanism(s) of Support

This funding opportunity will use the NIH Cooperative Research Project Grant (U01) award mechanism(s). As an applicant, you will be responsible for planning, directing, and executing the proposed project.

This funding opportunity uses the just-in-time budget concepts. It also uses the non-modular budget format described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html). A detailed categorical budget for the "Initial Budget Period" and the "Entire Proposed Period of Support" is to be submitted with the application.

The NIH (U01) is a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Principal Investigator 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 and National Policy Requirements, "Cooperative Agreement Terms and Conditions of Award."

PHACS awards will be administered by NICHD, with co-funding from multiple NIH Institutes. Management oversight of the grants will be provided through an NIH PHACS Steering Committee.

2. Funds Available

The NICHD intends to commit approximately $2 million in FY 2005 for the one-year Planning Phase One. In FY 2006, NICHD intends to commit approximately $4 million, NIAID intends to commit approximately $4 million, NIDA intends to commit approximately $3 million , and NIMH intends to commit approximately $1 million in total costs [Direct plus Facilities and Administrative (F & A) costs] to fund two new competing grants in response to this RFA. An applicant for the PHACS Coordinating Center (CC) may request a project period of up to five years and budget for direct cost of up to $250,000 in Year 01 for Phase One activities. An applicant for the PHACS Data and Operations Center (DOC) may request a project period of up to five years and budget for direct cost of up to $750,000 for Phase One activities (project Year 01). Budgets for Phase Two (project Years 02-05) will be negotiated with NICHD after the scope of the initiative is defined through the planning process in Phase One and within the constraints of available funding. See Section IV. 6. below, for budget instructions for Phase Two. Although the financial plans of the NICHD, NIAID, NIDA, and NIMH provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. Fiscal and administrative costs on subcontracts are not included in the direct cost limitation (see NOT-OD-04-040).

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions

You may submit (an) application(s) if your organization has any of the following characteristics:

International institutions are not eligible to apply.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their 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 programs.

2. Cost Sharing

Cost sharing is not required.

The most current Grants Policy Statement can be found at: http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#matching_or cost_sharing.

3. Other-Special Eligibility Criteria

Individual institutions are eligible to submit an application for either or both the PHACS Coordinating Center and the PHACS Data and Operations Center.

Section IV. Application and Submission Information

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) 435-0714, Email: GrantsInfo@nih.gov.

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 Dun and Bradstreet (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 on line 2 of the face page of the application form and the YES box must be checked.

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

3.A. Receipt, Review and Anticipated Start Dates

Letter of Intent Receipt Date: February 10, 2004
Application Receipt Date(s): March 10, 2005
Peer Review Date: June/July 2005
Council Review Date: September 2005
Earliest Anticipated Start Date: September 2005

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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

The letter of intent is to be sent by the date listed at the beginning of this document.

The letter of intent should be sent to:

Jack Moye, Jr., M.D.
Pediatric, Adolescent and Maternal AIDS Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-7350
FAX: (301) 496-8678
Email: john.moye@nih.hhs.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the PHS 398 research grant application instructions and forms as described above. 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)

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
National Institute of Child Health and Human Development
6100 Executive Boulevard, 5B01, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)

Using the RFA Label: The RFA label available in the PHS 398 application instructions must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf. Personal deliveries of applications are no longer permitted.

3.C. Application Processing

Applications must be received on or before the application receipt date listed in the heading of this funding opportunity. If an application is received after that date, it will be returned to the applicant without review. Applications will be evaluated for completeness by CSR.

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NICHD . Incomplete and 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.

Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within eight (8) weeks.

4. Intergovernmental Review
This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All 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 http://grants.nih.gov/grants/policy/policy.htm (see also Section VI.3., Award Criteria).

6. Other Submission Requirements

Specific Application Requirements for PHACS Coordinating Center (CC)

An application for the CC is submitted by an institution on behalf of the Principal Investigator (PI) of the CC. In the application, the PI should clearly outline the priority areas in depth, discussing plans, processes, and timelines for achieving the implementation of the planning process in Phase One, 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 base protocol; and pharmacoepidemiologists, surveillance or registry and long-term cohort and international health study specialists, and risk assessment specialists for the drug toxicity surveillance system. The clarity of the planning process plan and the quality and expertise of the assembled leadership are the critical components of this application.

The budget for the CC in project year 01 should include, at a minimum, salary and administrative support for the Coordinating Center, LG and its operations, and travel to two three-day, Washington, DC-area meetings per year.

For Phase Two (project years 02-05), the CC PI should also request (in addition to recurring costs as requested in project year 01) a discretionary budget to be used for the funding of the focused sub-studies, for supporting collaboration or co-endorsement agreements with other research networks as indicated, and for accommodating central sub-study-mandated requirements (e.g., specimen shipping costs) on an as-needed basis. Requests for discretionary funds will be negotiated with NICHD in Phase Two. The application must describe the review procedures that will guide the Executive Committee in distributing discretionary funds. Recurring costs in budgets for project years 03-05 may be escalated at 3 percent. Any nonrecurring costs above 3 percent should be adequately justified in the application.

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 (PI) of the DOC who should propose activities for both Phase One (project year 01) and Phase Two (project years 02-05) in the application. For Phase One, 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. Phase One activities will also include the planning and execution of a solicitation for clinical sites to function at the inception of Phase Two (there should be no interruption of subject follow-up at sites selected to participate in PHACS). The DOC should include in their Phase Two budget under “Other Expenses” an amount of $9 million each year for subcontracts to clinical sites. 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 review and evaluation. 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 the existing WITS or other U.S.-based pediatric HIV cohort study research agenda; (4) relative number of eligible research subjects; and (5) quality of performance in conducting similar research. Related to this last requirement, it is the intention of NIH PHACS Steering Committee to work with the DOC to standardize the reporting of past performance in recruitment and retention of subjects to WITS or other studies. It is expected that the first site solicitation will be restricted to sites that have participated in WITS or other U.S.-based pediatric HIV cohort studies. Subsequent site solicitations may not be so restricted in order to give the drug toxicity surveillance system flexibility to follow the demographics of the epidemic.

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: (1) details of their proposed clinical site review and selection process; (2) the process for identification and selection of external reviewers for clinical site review and selection; (3) the process for addressing and managing potential conflicts of interest in clinical site review and selection; (4) the approach to solicitation of additional clinical site applicants after the initial solicitation and selection; and (5) that the DOC will provide full documentation of the review and selection process as required by NICHD.

For Phase Two, the applicant should 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 sub-study 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 staff after consultation with co-funding Institutes. The DOC will be 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.

In Phase Two, the DOC applicant should be able to respond flexibly to the changing needs of the PHACS as the project unfolds, adding and eliminating 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 the base protocol, drug toxicity surveillance system, and sub-studies; 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 of Phase One, as well as funds to support travel to two 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 Phase Two will be negotiated with NICHD and subsequent future year budgets may be escalated at 3 percent for recurring costs.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score.

In submitting a plan, all applicants for the CC component of the PHACS should describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Applicants for all other organizational components need only note their intention to adhere to PHACS policy; this will be considered responsive to providing a data-sharing plan.

Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (NIH Grants Policy Statement http://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131). Investigators responding to this funding opportunity should include a plan for sharing research resources addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590, http://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3., Award Criteria.

Investigators responding to this funding opportunity should include a statement of intention to adhere to the NICHD-approved policy for the storage and use of study specimens in the NICHD and other repositories.

Section V. Application Review Information

1. Criteria

Applications will be considered non-responsive to this solicitation if they fail to address all component-specific elements delineated in Section IV.6. (Other Submission Requirements).

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

2. Review and Selection Process

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NICHD . Incomplete and/or nonresponsive applications will not be reviewed.

Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NICHD in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

3. Merit Review Criteria

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific Review Criteria for the PHACS Coordinating Center (CC):

Specific Review Criteria for PHACS Data and Operations Center (DOC):

2. Approach. Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Specific Review Criteria for the PHACS Coordinating Center (CC):

Specific Review Criteria for PHACS Data and Operations Center (DOC):

3. Innovation. Is the project original and innovative? For example: Does the project challenge existing paradigms or clinical practice; address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

Specific Review Criteria for the PHACS Coordinating Center (CC):

Specific Review Criteria for PHACS Data and Operations Center (DOC)

4. Investigators. Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Does the investigative team bring complementary and integrated expertise to the project (if applicable)?

Specific Review Criteria for the PHACS Coordinating Center (CC):

Specific Review Criteria for PHACS Data and Operations Center (DOC):

5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

Specific Review Criteria for the PHACS Coordinating Center (CC):

Specific Review Criteria for PHACS Data and Operations Center (DOC):

3.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the priority score:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan, Section E on Human Subjects in the PHS Form 398).

3.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

3.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data will be assessed by the reviewers. However, reviewers will not factor the proposed data sharing plan into the determination of scientific merit or the priority score. The presence of a data sharing plan will be part of the terms and conditions of the award. The funding organization will be responsible for monitoring the data sharing policy.

3.D. Sharing Research Resources

NIH policy requires that grant awardee recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/archive/grants/policy/nihgps/part_ii_5.htm#availofrr and http://www.ott.nih.gov/policy/rt_guide_final.html). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan will be considered by Program staff of the funding organization when making recommendations about funding applications. Program staff may negotiate modifications of the data and resource sharing plans with the awardee before recommending funding of an application. The final version of the data and resource sharing plans negotiated by both will become a condition of the award of the grant. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report (PHS 2590). See Section VI.3., Award Criteria.

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

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 (http://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).

A formal notification in the form of a Notice of Grant Award (NGA) will be provided to the applicant organization. The NGA signed by the grants management officer is the authorizing document.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Once all administrative and programmatic issues have been resolved, the Notice of Grant Award will be generated via e-mail notification from the awarding component, NICHD, to the grantee business official (designated in Item 14 on the Application Face Page). If a grantee is not e-mail enabled, a hard copy of the Notice of Grant Award will be mailed to the business official.

2. Administrative Requirements

All awardees are required to submit annual progress reports to the co-sponsoring Institutes providing study and site performance information, as stipulated by the Institutes, and to respond to and address performance issues identified during the budget year.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the notice of grant award. 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/archive/grants/policy/nihgps_2003/index.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/archive/grants/policy/nihgps_2003/index.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. PHACS 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 (U 01 ), 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 Investigators 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 Leadership Group (LG). Specifically, the CC will:

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 Project Scientists. 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 RFA. 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:

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.

Specifically, the DOC will:

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:

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

An NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

An NIH Project Scientist will represent each of the Institutes co-sponsoring the RFA.

The NIH Project Scientists will:

An NIH PHACS Steering Committee (NPSC) will be 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 the site solicitation, the review of all proposed subcontracts within PHACS, and determination of the need for (a) external review of the scope and content of the proposed base protocol at the end of the Phase One Planning stage prior to its implementation at the sites, (b) any study-specific DSMB oversight, and (c) external review of proposed sub-studies in Phase Two.

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 Agency Program Official will:

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 the CC; the Principal Investigator and Project Director of the DOC; representation from the CIG; and the NICHD Project Scientist. NIH Institutes or Centers providing substantial support also will be represented as voting members of the Executive Committee at the request of NICHD. Other NIH scientists and representatives from ancillary clinical and community groups serve as non-voting ad hoc members. A quorum must exist for Executive Committee action; a quorum consists of five voting members. Voting members will have one vote each and motions will carry with a simple majority. The Chair of the 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 Project Scientists are eligible to serve as Chair or Vice Chair of the Executive Committee.

The Executive Committee will:

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 Executive 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. Award Criteria

The following will be considered in making funding decisions:

4. Reporting

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually (http://grants.nih.gov/grants/funding/2590/2590.htm) and financial statements as required in the NIH Grants Policy Statement.

Section VII. Agency Contacts

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:

Jack Moye, Jr., M.D.
Pediatric, Adolescent and Maternal AIDS Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 435-7350
FAX: (301) 496-8678
Email: john.moye@nih.hhs.gov

2. Peer Review Contacts:

Robert Stretch, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5B01, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 496-1485
FAX: (301) 402-4104
Email: stretchr@mail.nih.gov

3. Financial or Grants Management Contacts:

Lisa Moeller
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A01, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)
Telephone: (301) 435-6995
FAX: (301) 451-5510
Email: lisa.moeller@nih.hhs.gov

Section VIII. Other Information

Required Federal Citations

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.

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.

Public 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 public 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 PA 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.

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. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to 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 PA 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 or Health Systems Agency review. 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/.


Weekly TOC for this Announcement
NIH Funding Opportunities and Notices


H H S Department of Health
and Human Services

 
  N I H National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892