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 Allergy and Infectious Diseases (NIAID), (http://www.niaid.nih.gov)
National Institute of Alcohol Abuse and Alcoholism (NIAAA), (http://www.niaaa.nih.gov)
National Cancer Institute (NCI), (http://www.nci.nih.gov)
National Institute of Dental and Craniofacial Research (NIDCR), (http://www.nidcr.nih.gov/)
National Institute on Drug Abuse (NIDA), (http://www.nida.nih.gov/)
National Institute of Mental Health (NIMH), (http://www.nimh.nih.gov/)
John E. Fogarty International Center (FIC), (http://www.fic.nih.gov/)

Title: Units for HIV/AIDS Clinical Trials Networks

Announcement Type
New

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

Request For Applications (RFA) Number: RFA-AI-05-002

Catalog of Federal Domestic Assistance Number(s)
93.855, 93.856, 93.395, 93.865, 93.121, 93.279, 93.242, 93.989, 93.273

Key Dates
Release Date: February 10, 2005
Letters of Intent Receipt Date(s): June 10, 2005
Application Receipt Dates(s): July 11, 2005
Peer Review Date(s): November, 2005
Council Review Date(s): January, 2006
Earliest Anticipated Start Date: April, 2006
Additional Information To Be Available Date (Url Activation Date): http://www.niaid.nih.gov/ncn/budget/QA/rfa-05-002.htm
Expiration Date: July 12, 2005

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

The objective of this RFA is to solicit applications for Clinical Trials Units (CTUs) to implement the clinical research plans of one or more of the HIV/AIDS Clinical Trials Networks. Each CTU will be led by a Principal Investigator, comprised of an Administrative Component and one or more Clinical Research Sites, and optimally configured to conduct clinical research by recruiting, screening, enrolling and following research participants from the populations most affected and/or endangered by the HIV/AIDS epidemic. The other Clinical Trials Network components are being solicited in a companion solicitation, RFA AI-05-001 “Leadership for HIV/AIDS Clinical Trials Networks” (See http://www.niaid.nih.gov/daids/rfa/network06) through which Leadership applicants will propose clinical research plans in the following areas: (1) Vaccine Research and Development; (2) Translational Research/Drug Development; (3) Optimization of Clinical Management, Including Co-Morbidities; (4) Microbicides; (5) Prevention of Mother-to-Child Transmission (MTCT) of HIV; and (6) Prevention of HIV Infection.

The NIAID strongly encourages the establishment of CTUs that reach populations most affected or threatened by the HIV/AIDS epidemic in the U.S. and abroad, participate in more than one Clinical Trials Network, and demonstrate appropriate sharing of resources. A CTU may also contribute scientific and clinical research expertise to the development of the Network clinical research plans. Public or private institutions and organizations, domestic or foreign, for-profit or non-profit, such as universities, colleges, hospitals, private and group medical practices, units of State and local governments, and eligible agencies of the U.S. Federal government may submit an application.

Applicants may apply under this RFA in one of three ways:

(1) Affiliate with one or more Clinical Trials Networks by prior agreement with the Network Leadership applicant(s).

(2) Indicate interest and describe scientific expertise and clinical research capacity in one or more of the research priority areas defined in RFA AI 05-001 “Leadership for HIV/AIDS Clinical Trials Networks” without prior agreement with Network Leadership applicant(s). The Division of AIDS (DAIDS), NIAID will affiliate such applicants, if successful, with appropriate Network(s) at the time of award.

(3) A combination of (1) and (2) i.e. affiliating with one or more Clinical Trials Network(s) by prior agreement with Network Leadership applicants and also indicating an interest in a high priority research area not addressed by the affiliated Network applicants.

In FY 2006, NIAID anticipates providing $60 million to $130 million to fund approximately 75-150 CTUs as Cooperative Agreements (U01s). CTUs are expected to vary substantially in size, scope of activities, and number of Clinical Trials Network affiliations. For this reason, direct costs for first year awards are expected to be approximately $200,000 for a CTU that has one Clinical Research Site participating in one HIV/AIDS Clinical Trials Network and will increase for a CTU supporting several Clinical Research Sites and/or participating in multiple Clinical Trials Networks.

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html. Additional information and application materials are available for this and the companion RFA AI 05-001 at http://www.niaid.nih.gov/daids/rfa/network06.

Public Briefing

NIAID will hold informational sessions for groups considering submission of applications in response to this RFA. Dates, locations, and other details of the meetings will be announced on the NIAID website (http://www.niaid.nih.gov), at the application website http://www.niaid.nih.gov/daids/rfa/network06, and in the NIH Guide to Grants and Contracts. Representatives from the NIAID Division of AIDS (DAIDS) and from the NIAID Division of Extramural Activities (DEA) will provide information and answer questions pertinent to preparing applications in response to this RFA.

A Clinical Trials Unit, led by a PI (applicant), may submit only one application. Institutions are encouraged to submit a single application, although multiple applications from an institution are allowed with justification. A Clinical Research Site (a component of an application) may participate in up to two CTU applications (e.g. as a consortium arrangement) as long as there is no scientific overlap.

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 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 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
      A. Additional Review Criteria
      B. Additional Review Considerations
      C. Sharing Research Data
      D. Sharing Research Resources
    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
Section I. Funding Opportunity Description

The National Institute of Allergy and Infectious Diseases (NIAID) and collaborating Institutes and Centers (ICs) solicits applications from domestic and foreign institutions to serve as Clinical Trials Units (CTUs) for HIV/AIDS Clinical Trials Networks focused on vaccines, prevention and therapeutics. Each CTU will implement the clinical research plans of one or more of the Clinical Trials Networks by conducting the clinical research and also may contribute scientific and clinical research expertise to the development of the Network clinical research plans. The Leadership of three to six HIV/AIDS Clinical Trials Networks will be established through a companion RFA, AI 05-001 “Leadership for HIV/AIDS Clinical Trials Networks” (http://www.niaid.nih.gov/daids/rfa/network06). Each Network Leadership will be responsible for establishing the Network clinical research plan, ensuring that the Network is capable of carrying out its responsibilities, and ensuring well-coordinated operations. Each Network Leadership will consist of: (1) a Coordinating and Operations Center (CORE) to provide scientific and administrative leadership, central operations, and communications; (2) a Statistical and Data Management Center (SDMC) to provide biostatistical leadership and central data management; and (3) a Network Laboratory Structure to provide the laboratory services necessary to conduct the clinical research. The resulting combination of a Network Leadership and affiliated Clinical Trials Units will constitute an HIV/AIDS Clinical Trials Network.

1. Research Objectives

Nature of the research opportunity

Each HIV/AIDS Clinical Trials Network will implement research plans responsive to one or more of the following high priority research areas: (1) Vaccine Research and Development; (2) Translational Research/Drug Development; (3) Optimization of Clinical Management, Including Co-Morbidities; (4) Microbicides; (5) Prevention of Mother-to-Child Transmission (MTCT) of HIV; and (6) Prevention of HIV Infection. The Networks will work cooperatively with DAIDS, NIAID to implement a research agenda focused on the most important clinical research questions as defined by NIAID and the collaborating NIH Institutes and Centers (ICs). The Networks will give high priority to collaborations with the other DAIDS-sponsored Networks funded through these solicitations (AI 05-001 and AI 05-002), other NIH HIV/AIDS clinical research programs, and other HIV research entities in order to effectively develop and implement a clinically relevant, scientifically sound, interdisciplinary and cost-efficient clinical research program.

Clinical Trials Units (CTUs) contribute to the Network clinical research plan by conducting the clinical research (that is, executing clinical protocols). CTUs also may contribute scientific and clinical research expertise to the development of the Network clinical research plan. CTUs are responsible for developing and maintaining effective community relationships; enabling community participation in Clinical Research Sites, CTU, and Network activities; and ensuring that all clinical research is conducted in compliance with Network bylaws, policies and procedures, DAIDS policy and procedures, Federal regulations, and any applicable local requirements.

Each Clinical Trials Unit must have the following components:

a. CTU Administrative Component located at the awardee organization/institution to provide oversight, coordination and administrative support for the Clinical Research Site(s) and its required Community Advisory Board.

b. One or more Clinical Research Sites where qualified professionals contribute to the clinical research plan of one or more Networks through the conduct of clinical research activities (i.e. protocol execution).

Additional information about CTU structure and function is located in this section under the heading Clinical Trials Unit (CTUs).

Background

The mission of DAIDS is to help ensure an end to the HIV/AIDS epidemic by supporting research to increase basic knowledge of the pathogenesis and transmission of HIV, the development of therapies for HIV infection and its complications, and the development of vaccines and other preventive strategies. Despite the many advances in understanding the pathogenesis, control and treatment of HIV/AIDS, the HIV pandemic continues virtually unabated, particularly in resource-limited nations and in minority and impoverished communities in developed nations. Current estimates are that 38 million people were living with HIV infection at the end of 2003 and that the epidemic continues to expand in almost every region of the world, with approximately 4.8 million new infections in 2003 (UNAIDS 2004 Report on the Global AIDS Epidemic). The burden of disease in this pandemic is disproportionately high among women and those who live in poverty. The proportion of infected persons who are women has increased steadily during the epidemic so that now more than 50% of those living with HIV worldwide are female. Adolescents and young adults aged 15-24 years account for half of all new infections worldwide: girls and young women are particularly vulnerable. In Sub-Saharan Africa, women account for 57% of infected adults and 75% of the infections in young adults.

Though a large proportion of HIV-infected adults in the U.S. are men, the proportion of HIV-infected women is growing and women now account for 25% of all HIV infections in North America. Some minority groups within the U.S. also are disproportionately affected. For example, approximately 50% of those living with HIV/AIDS are African-American and 10% are Hispanic (HIV/AIDS Surveillance Report 2002). The geographic distribution of people living with AIDS in the U.S. also has changed as the epidemic has become more generalized. By the end of 2002, 39% of persons living with AIDS in the U.S. resided in the South, 29% in the Northeast, 19% in the West, 10% in the Midwest, and 3% in the U.S. territories.

Women, adolescent and young adults, and minorities continue to be underrepresented in clinical research because of social, cultural, and geographic barriers. This lack of involvement in clinical research slows widespread adoption of available care and preventive approaches, limits safe and effective management of HIV treatment and associated complications, and jeopardizes the ability of researchers to generalize findings to those most in need. The scientific research plans of the DAIDS Networks must reflect current realities in capitalized and resource-limited settings and develop innovative approaches for the prevention and treatment of HIV infection that recognize the role of family, household and community as participants in a successful clinical research process. Approaches also should have worldwide applicability wherever possible.

Achieving the mission of ending the HIV epidemic requires a carefully coordinated clinical research strategy aimed at preventing new infections and reducing HIV morbidity and mortality in those already infected in the U.S. and internationally. Though substantial progress in the development of strategies to prevent and manage HIV infection has occurred, less than 20% of individuals worldwide who need prevention services have access to them and only 7% of HIV-infected persons in low and middle-income countries can access antiretroviral medications (UNAIDS 2004 Report on the Global AIDS Epidemic). Development of safe and effective vaccines, microbicides and other protection methods, improvement of regimens to safely prevent the transmission of HIV from mother to child, and continued development of new therapeutic agents, especially those that cure the infection or those that prevent or interrupt transmission, are essential to halt the spread of HIV and to treat the infected. Significant questions remain, especially in resource-limited settings, regarding the most effective use of currently available anti-HIV agents to maintain good health, prevent the development of drug resistance, preserve immune function, manage co-infections and complications of HIV and HIV therapy, and prevent the acquisition and spread of HIV. Though these areas of inquiry have been advanced significantly through the existing Clinical Trials Networks supported by DAIDS, rapidly evolving research priorities demand a more integrated research strategy to use available resources efficiently and effectively in order to achieve the mission of DAIDS.

Current NIAID-sponsored HIV/AIDS Clinical Trials Networks

The Division of AIDS, NIAID has designed, developed and sponsored extramural Clinical Trials Networks since its inception that conduct research to develop and optimize therapies, vaccines and prevention modalities for HIV/AIDS. These Clinical Trials Networks have played a vital role in HIV and AIDS research, providing the critical mass and infrastructure for both quality and continuity in collaborative, protocol-driven clinical research. The contributions and progress made by these Networks have been unparalleled and have advanced the state of the art of HIV clinical science around the world. The current NIAID-sponsored HIV/AIDS Clinical Trials Networks are identified below:

DAIDS supports contracts with several organizations to provide clinical research support to sites conducting DAIDS-sponsored research. Activities conducted by these contractors include clinical site monitoring, drug distribution, laboratory quality assurance, training, regulatory assistance and specimen repository management. Additional information about the current and planned contracts, DAIDS-supported HIV/AIDS Clinical Trials Networks and their accomplishments to date, their organizational components and current clinical trials sites, and ongoing and planned clinical trials is located at the application web site http://www.niaid.nih.gov/daids/rfa/network06.

Other NIH HIV/AIDS Clinical Trials Programs and Collaborations

DAIDS and the DAIDS-sponsored Clinical Trials Networks also collaborate with other HIV/AIDS Clinical Trials Programs sponsored by the NIH, the Centers for Disease Control and Prevention (CDC), and the Department of Defense (DoD). Affiliation and collaboration with these other NIH Networks is not being solicited through this RFA. These programs are identified in this solicitation because coordination with the HIV/AIDS Clinical Trials Networks is expected and include:

Research Objectives

The objective of this RFA is to solicit applications for Clinical Trials Units (CTUs) that will implement the clinical research plans of one or more of the HIV/AIDS Clinical Trials Networks by conducting the clinical research. The CTUs must be optimally configured to recruit, screen, enroll and follow research participants from the populations most affected and/or endangered by the HIV/AIDS epidemic. Flexibility in structure and resource allocation is necessary to ensure that the proportion of research efforts expended in the U.S. and abroad are appropriate based on current scientific priorities and research opportunities.

Organization of HIV/AIDS Clinical Trials Networks

A. Structure of HIV/AIDS Clinical Trials Networks

DAIDS anticipates establishing three to six HIV/AIDS Clinical Trials Networks through Cooperative Agreement awards to be made under the companion solicitation, RFA AI-05-001, titled “Leadership for HIV/AIDS Clinical Trials Networks”. Each HIV/AIDS Clinical Trials Network will consist of (1) the Leadership, which will include the Coordinating and Operations Center (CORE), the Statistical and Data Management Center, and the Network Laboratories, and (2) the Clinical Trials Units. An Executive Committee, as well as scientific and resource committees for each Network, will be established by the Leadership to provide governance, to oversee implementation of the clinical research plan, to evaluate performance, and to manage functional issues within each Network.

Applicants for RFA AI-05-001, “Leadership of the HIV/AIDS Clinical Trials Networks," will propose specific research plans within one or more of the six high priority clinical research areas identified by DAIDS: (1) Vaccine Research and Development; (2) Translational Research/Drug Development; (3) Optimization of Clinical Management, including Co-Morbidities; (4) Microbicides; (5) Prevention of Mother-to-Child Transmission (MTCT) of HIV; and (6) Prevention of HIV Infection. A description of these high priority research areas as well as the HIV/AIDS clinical research priorities of other collaborating NIH ICs can be found in the companion RFA AI-05-001 at http://www.niaid.nih.gov/daids/rfa/network06.

Collaboration and coordination among the DAIDS-sponsored HIV/AIDS Clinical Trials Networks are strongly encouraged and two groups, the Managing Partners and the Community Partners, will be established to facilitate these efforts.

B. Clinical Trials Units (CTUs)

The number, size and location of required Clinical Trials Units will be based upon characteristics of the clinical research plans of the funded Networks, including the developmental stage and availability of clinical study products (e.g. therapeutics, vaccine, microbicides, etc.), the target populations for proposed interventions and strategies, and the size, duration and anticipated start dates for the proposed clinical trials. Each applicant responding to the companion Network Leadership RFA-AI-05-001 is required to identify criteria for the selection of Clinical Research Sites for their Network and to propose specific CTU/Clinical Research Site affiliations. Identification of CTUs and Clinical Research Sites by successful Network Leadership applicants does not imply CTU or Clinical Research Site funding, nor does it restrict the CTU's participation in other Networks.

Overall, DAIDS will ensure that the clinical research plans of the Networks address the highest clinical research priorities as defined by DAIDS. DAIDS also will ensure that the resulting Networks are configured with sufficient flexibility and linkages to enable efficient response to new scientific opportunities and outreach to communities in which key questions around HIV/AIDS prevention and treatment research must be addressed to safeguard the public health. Priority, therefore, will be placed on reaching underrepresented populations severely impacted by the epidemic, including women, adolescents, and minorities in the U.S. as well as populations in resource-limited settings worldwide. Clinical Trials Units with the flexibility and capability to conduct multiple clinical research projects, the ability to respond rapidly to evolving research opportunities, and/or the capacity to participate in implementing the clinical research plans of more than one Network are particularly sought. Requirements for minimum clinical research capacity, described below, have been established for all Clinical Research Sites.

Each Clinical Trials Unit must include a CTU Administrative Component and one or more Clinical Research Sites as defined and described below. Each CTU is also required to establish a productive partnership in the community in which they propose to conduct research, including the development and ongoing support of a Community Advisory Board (CAB). A Clinical Trials Unit may be comprised of U.S.-based organizations only, non-U.S. organizations only or a combination of both. Each CTU should be organized to promote optimal and efficient conduct of clinical research.

CTU Administrative Component. An Administrative Component is located at the awardee institution and provides oversight, coordination, and financial and administrative support for the Clinical Research Sites and required Community Advisory Board(s). The Principal Investigator is responsible for all CTU activities and CTU performance, and also provides CTU scientific and administrative representation to the Network(s). The CTU Administrative Component must be adequately staffed to provide essential oversight, financial and administrative support, and coordinate research activities at the Clinical Research Sites. Staff at the CTU Administrative Component may also contribute to the Network clinical research plan and priorities through activities such as scientific and resource committee membership.

Centralized Clinical Research Functions. CTUs are encouraged to centralize clinical research functions within the CTU Administrative Component if the resulting organizational configuration promotes efficiency and coordination or contributes to participant safety. Examples of functions that may be centralized include, but are not limited to, specimen processing, quality management, data management, staff training, and regulatory compliance coordination. The practicality of centralizing functions will depend on CTU characteristics, such as number of institutions involved and geographic location. NIAID will provide support for the Clinical Research Site related activities and needs either through the CTU Administrative Core or through the individual Clinical Research Sites – but not both.

Community Advisory Board (CAB). A CAB is an active group representing the local population(s) impacted by HIV/AIDS. CAB members work in partnership with CTU investigators and staff to provide a local perspective in the implementation of the HIV/AIDS clinical research plan. CTUs with multiple Clinical Research Sites, or geographically or culturally diverse populations, may require more than one CAB to enable effective representation of the populations involved.

Clinical Research Sites. Clinical Research Sites are discrete locations (e.g. hospitals, outpatient clinics, health maintenance organizations, community health centers, private practices, clinics, etc.) with identified and characterized potential cohorts (e.g. demographics, incidence and prevalence of HIV/AIDS) that meet the requirements for conducting Network clinical trials and where qualified professionals conduct clinical research for one or more Networks in accordance with Good Clinical Practices.

Required Clinical Research Site Activities. Each Clinical Research Site must carry out the following activities: recruit, screen, and enroll participants; perform protocol required assessments; manage study products; dispense investigational agents (if applicable); monitor for, assess and report adverse events; collect, process, store and ship specimens; collect, manage and submit clinical research data, that meets all data reporting requirements of the Network(s) and DAIDS; conduct internal quality assurance, and create, maintain and store research records including participant files, source documents, regulatory files, subject identification information, clinical reports, and case report forms.

Required Clinical Research Site Staffing. Each Clinical Research Site must be staffed with sufficient, adequately trained and experienced personnel to ensure a culturally appropriate environment and timely execution of all required clinical research activities. An appropriate staffing plan should include physicians, behavioral scientists for prevention research components, and nursing, pharmacy, data management and outreach personnel.

Optional Clinical Research Site Activities and Staffing. Clinical Research Sites may support the establishment, education, and activities of a local Community Advisory Board (in addition to the CTU CAB) where necessary to adequately represent the community. Clinical Research Sites may also support staff to carry out research activities not feasibly performed within the CTU Administrative Component, including provision or coordination of medical/clinical procedures and/or social services, quality management program components, coordination of regulatory activities, and provision of local secretarial and administrative support. Clinical Research Site staff may also contribute to the development of the Network research plans through activities such as membership on protocol teams, scientific and resource committees, and scientific review of proposed concepts and protocols.

Other Clinical Research Site Requirements. All Clinical Research Sites, regardless of location, must have the infrastructure, including clinical, laboratory and pharmacy facilities, necessary for the conduct of the proposed research, an identified and characterized (demographics, incidence and prevalence) participant cohort, and must be ready to initiate participant recruitment within the first six (6) months of award. Evidence of institutional support for the conduct of clinical research under U.S. regulations is also required. NIAID will not make awards to, or include, institutions or organizations in awards that have not identified an active Institutional Review Board/Ethics Committee registered at the DHHS Office of Human Research Protections (OHRP) for ethical oversight of clinical research and a Federal Wide Assurance (See http://www.hhs.gov/ohrp for additional information.).

Core Clinical Research Site Capacity. Each Clinical Research Site must maintain an average monthly census of 20 study participants over a 12-month period for each Network. That is, each Clinical Research Site within a CTU must recruit, screen, enroll and follow sufficient participants so that the average number of participants per month ‘on study' is no less than 20 over a 12- month period. The minimum of 20 participants applies to each Network with which the Clinical Research Site is affiliated.

Expanded Clinical Research Site Capacity. HIV/AIDS Clinical Trials Networks proposing large Phase III and Phase IV studies, such as treatment optimization, MTCT, and prevention research studies, may have clinical research needs that exceed the sum of the core clinical research capacity requirements for affiliated Clinical Research CTUs and Sites. Clinical Research Sites affiliated with these Networks, therefore will be expected to recruit, screen, enroll and follow sufficient participants so that the average number of participants per month ‘on study' is no less than 100 over a 12-month period. Funds for these activities beyond core requirements will be provided as needed.

Addition or Relocation of CTU Clinical Research Sites. NIAID will fund CTUs based on the Clinical Research Sites proposed and approved in the CTU application. Post award, NIAID prior approval will be required for deleting, adding, or changing approved and funded Clinical Research Sites. NIAID approval will be required for the addition of any domestic or foreign Clinical Research Site not included in a funded application. In addition, notification to DAIDS will be required prior to the physical relocation of any existing Clinical Research Site and DAIDS reserves the right to inspect the new premises and make a determination of acceptability. These requirements for prior notification and NIAID approval for the addition or relocation of any Clinical Research Site will be incorporated into the Terms and Conditions of Award in the Notice of Grant Award.

C. CTU Network Affiliation

A CTU with one or more Clinical Research Sites can affiliate with a single Network or with multiple Networks. Affiliation with multiple Networks is encouraged for U.S. and foreign Clinical Research Sites with sufficient resources, experience and expertise in the conduct of clinical research, and access to the appropriate target populations for the clinical research. Multiple Network affiliation should result in sharing of required resources and key personnel (e.g. administrative, regulatory coordination, data management, specimen processing, and pharmacy) and enhance the flexibility of a Clinical Research Site and its parent CTU.

The PI is scientifically and administratively responsible for the entire CTU research effort. The PI of a multi-Network CTU may delegate responsibilities related to a specific Network to a Co-Investigator. These delegated responsibilities must be clearly defined and may include CTU representation to the Network, administration, and performance oversight for the Clinical Research Site(s) implementing the Network's clinical research plan.

D. Flexible Resource Allocation

Rapid responses to unanticipated high priority research opportunities require the timely reordering of priorities accompanied by the reallocation of resources to accommodate the changing priorities. A system of ongoing performance evaluation that ensures maximal efficiency and effectiveness of all Network components, coupled with the allocation of reserve funds by DAIDS and of Protocol Implementation Funds by the Network Leadership, will be adopted to meet the challenge of responding to unanticipated high priority research opportunities. Each CTU will receive Core Funding at a level sufficient to maintain minimum Clinical Research Site capacity requirements described above (i.e. monthly average of 20 participants ‘on study' over a 12-month period). Additional funds allowing for participation above this level will be based on satisfactory performance measures and research priorities, and will be allocated to CTUs through the Networks' Protocol Implementation Fund and the DAIDS Reserve Fund.

CTU Core Funding. The CTU Core Funding will include funds required to maintain the CTU Administrative Component, including Community Advisory Board support, and ‘Core Costs' for each Clinical Research Site. The “Core Costs” for a Clinical Research Site will include the funds for site administration as well as funds required to maintain the site and recruit, screen, enroll and follow sufficient participants in representative studies for each Network affiliation. “Sufficient participants” means the number of participants required so that the average number of participants per month ‘on study' is no less than 20 over a 12- month period. Additional funds to continue ongoing clinical research will be included in each budget period award to currently funded DAIDS-sponsored clinical trials units (e.g. HVTUs, HPTUs, Adult and Pediatric ACTUs, CPCRA units, etc) that are successful in this competition.

To ensure that the available funds are used for the highest priority clinical research, annual unobligated balances for the grants awarded under this RFA will be allocated at the discretion of the NIAID.

Additional Funds Available Based on Performance

Performance Evaluation. Each Network Leadership will be required to implement processes and procedures for ongoing evaluation of all Network components, including each Clinical Research Site and each CTU as a whole. The Managing Partners will be expected to oversee the establishment of common parameters and methods used for evaluations based on Network-specific processes and on best practices for clinical trials conduct in the private and public sector.

DAIDS Reserve Fund. Contingent upon availability, a portion of the total funds committed to the awards resulting from this solicitation will be set aside by NIAID as the DAIDS Reserve Fund, for the purpose of pursuing high priority, high impact or high cost clinical research. NIAID will develop procedures for informing the Network Leadership, soliciting ideas, requesting and receiving recommendations as necessary, and allocating these funds to the HIV/AIDS Clinical Trials Networks. NIAID anticipates the establishment of the DAIDS Reserve Fund in the second budget period of the Network Leadership and CTU awards.

Protocol Implementation Fund. To allow for managerial flexibility and to address unexpected scientific opportunities, a portion of the available funds will be set aside for each Network Leadership in a Protocol Implementation Fund. The Network Leadership will develop procedures for allocating these funds to CTUs and other Network components as needed to support high priority clinical research projects and expand the capabilities of highly successful CTUs when necessary. This will be accomplished through a formally defined process, and the results will be made available to the Network membership.

E. Clinical Trials Units in Communities Severely Impacted or Threatened by HIV/AIDS

A priority of DAIDS is to reach underrepresented populations severely impacted by the epidemic, including women, adolescents, and minorities in the U.S. as well as populations in resource-limited settings worldwide. DAIDS recognizes that the needs of the communities most affected or threatened by HIV/AIDS will be represented most successfully in the Network scientific goals and priorities when their local investigators are fully established and autonomous within the Network structures. The requirements of this RFA, therefore, have been designed to encourage independence where appropriate and scientific and technical linkages where useful.

Institutions in resource-limited settings abroad and with access to underrepresented populations in the U.S. are encouraged to evaluate their current capabilities in HIV/AIDS clinical research and their potential for growth. These assessments should inform organizational decisions about whether to seek independent CTU funding or to align as a Clinical Research Site with a more experienced CTU.

Through contract resources and in coordination with the Managing Partners, DAIDS intends to make available additional resources to facilitate the continued development of Clinical Research Sites and CTUs funded through this RFA and located in communities especially affected by the HIV/AIDS epidemic. These additional resources are likely to include short-term training opportunities as well as ongoing assistance to meet the many scientific, technical, administrative and financial requirements of Clinical Research Sites. These training and assistance opportunities will be targeted to meet site-specific needs identified after award. Awardees will be encouraged to utilize other NIH training and capacity building opportunities, such as the Fogarty International Center programs including the AIDS International Training and Research Program (http://www.fic.nih.gov/) and the Institutional Development programs of the National Center for Research Resources (http://www.ncrr.nih.gov/). Utilization of these multiple approaches should enable sites in settings with limited resources and disadvantaged populations to gain scientific and administrative independence as soon as possible.

U.S. organizations with access to underrepresented populations appropriate for HIV/AIDS clinical research and foreign organizations/institutions in resource-limited settings with access to appropriately identified and characterized populations for HIV/AIDS clinical research that meet the requirements for Clinical Trials Units and Clinical Research Sites stated in section B above are strongly encouraged to propose Clinical Trials Units that link clinical research resources under local leadership. Participation in more than one HIV/AIDS Clinical Trials Network is encouraged but not required. In addition, CTUs located in resource-limited settings abroad and serving underrepresented population in the U.S. may be eligible to request additional funding to establish Mentoring Partnerships as described below.

Mentoring Partnership

Funds to establish and maintain a Mentoring Partnership (a formal arrangement for consultation and assistance from established HIV/AIDS CTUs), are available to less experienced CTUs. The purpose of a Mentoring Partnership is to facilitate independent functioning of the less experienced CTU while developing (or continuing) effective mentoring relationships with more experienced CTUs. An assessment of needs, program goals and objectives, a mentoring plan, and an evaluation plan for the Mentoring Partnership should be developed jointly by the less experienced (Mentee) CTU and more experienced (Mentor) CTU. However, the Mentee institution will be responsible for initiating the request, receiving funds, and monitoring and reporting progress.

Scope of a Mentoring Partnership. The scope of a Mentoring Partnership can include, but is not limited to, advice and assistance regarding administration, financial management, clinical research execution and management, project selection, scientific concept development and Network interactions and processes. Examples of possible activities include: the selection, orientation, and training of new study staff including study coordinators, research nurses, laboratory personnel, and research pharmacists; report preparation; development of standard operating procedures as required; scientific concept development; and consultations regarding the impact of new Network policies, procedures and decisions on CTU operations. Identification of the goals, objectives, and timeline for completion of the proposed activities is the responsibility of the CTU seeking mentoring, as is identification of the Mentoring Partner or Partners. It is anticipated that the Mentoring Partnerships will be of one to three consecutive years duration, beginning in the first budget period. DAIDS Program staff will monitor progress through interactions with awardees and annual review of progress.

Eligibility for a Mentoring Partnership. CTU applicants that can demonstrate the ability and intent to recruit, screen, enroll and follow a substantial proportion of their clinical research participants from health disparities groups that are underrepresented in health-related research may submit a request for support of a Mentoring Partner. Such institutions may be foreign institutions in resource-limited settings or U.S. institutions/organizations serving minorities with health disparities or other health disparities groups as defined by the applicant institution. Mentee candidates for a Mentoring Partnership include, but are not limited to, CTU applicants that currently function as clinical research sites, subsites, or subunits in one or more current DAIDS-sponsored Clinical Trials Networks that have acquired experience in the execution of clinical research protocols, and that can identify a Mentoring Partner CTU. Such clinical research groups, particularly those in international settings, may be able to conduct independent clinical research, but would benefit from additional guidance.

Funds Available for Mentoring Partnership. Direct costs not to exceed $50,000 (U.S. dollars) each year for one to three years may be requested by eligible institutions for Mentoring Partnership activities.

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 U01 award mechanism(s). As an applicant, you will be solely 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 Requirements, "Cooperative Agreement Terms and Conditions of Award".

The U01 sets up an assistance relationship between NIH and the award recipient for projects similar to grants in which NIH acts as a partner in the research effort.

This RFA is a one time only solicitation with a single receipt date. NIAID may issue a subsequent solicitation with annual receipt dates to solicit additional HIV/AIDS Clinical Trials Network capacity through the addition of new CTUs, reorganization of existing CTUs, or expansion of existing CTUs by adding Clinical Research Sites. NIAID may identify specific programmatic needs through Notices in advance of each receipt date.

2. Funds Available

The participating ICs intend to commit approximately $60 Million - $130 Million dollars in FY 2006 to fund 75-150 new and/or competitive continuation grants in response to this RFA. An applicant may request a project period of up to seven years. 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 ICs 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.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-05-004.html.

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:

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 or Matching

Cost sharing is not required.

The most current Grants Policy Statement can be found at: http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing.

3. Other-Special Eligibility Criteria

1. Organizations located in foreign countries are eligible to apply as applicant organizations, contractual organizations, or as part of a consortium. NIH provides limited facilities and administration (F&A) costs (8 percent of total direct costs less equipment) to foreign institutions and international organizations to support the costs of compliance with NIH requirements including, but not limited to, protection of human subjects, animal welfare, and research misconduct. Organizations in foreign countries with a per capita annual gross national income (GNI) equal to or less than U.S. $5,000 may request direct costs for facility and administrative expenditures such as security, transportation and equipment to ensure uninterrupted power supply (e.g. generators). Direct cost funding available to foreign organizations in countries with per capita annual gross national income (GNI) greater than U.S. $5,000 will be limited to reimbursable clinical research costs based on protocol requirements. Reimbursable clinical research costs will include: recruitment, screening, enrollment and participant care costs (laboratory, clinical procedures, and study staff labor costs per hour); essential Administrative component personnel costs (e.g. PI, data management, coordinators); essential equipment and supplies; specimen storage and shipment; communications including postage, telephone and internet; and essential travel for Network activities (e.g. Network meetings, DSMB. [For additional information about GNI, refer to the World Bank at www.worldbank.org]).

2. An applicant organization is defined as the one organization that will be legally and financially responsible for the conduct of the activities supported by the award. Applicant organizations are encouraged to submit a single application proposing a Clinical Trials Unit. The CTU may propose to affiliate with one or more HIV/AIDS Clinical Trials Networks by prior agreement with the Network applicant(s), propose to conduct clinical research in one or more DAIDS scientific research priority areas without prior agreement for Network affiliation, or a combination of both. A CTU may submit only one application in response to this RFA.

3. Large applicant organizations are strongly discouraged from submitting more than one application unless there are compelling geographic, organizational or other barriers that prevent effective sharing of resources. An organization that submits more than one application should explain those barriers, how the applicant organization will ensure that the proposed CTUs do not duplicate infrastructure or staff resources, and how the applicant organization will maximize collaborative activities.

4. The CTU applicant organization may include Clinical Research Sites located at its own institution or at other performance sites through a consortium or contractual arrangement. Clinical Research Site affiliation with more than one CTU will be funded only when such a multiple affiliation enables the Clinical Research Site to participate in HIV/AIDS Networks that have no scientific overlap. Should applications with overlap occur, DAIDS will determine which Network affiliation will be supported. A Clinical Research Site cannot be included in more than two Clinical Trials Unit awards.

Note: The NIH does not accept similar grant applications with essentially the same research focus from the same applicant organization. Clinical Research Sites may not propose substantially the same research efforts under different applications (for example participation as a Clinical Research Site in two different CTU applications focusing on the same clinical research areas). Likewise, identical or essentially identical grant applications submitted by different applicant organizations will not be accepted. Applicant organizations should be careful to assure that the materials they are submitting on behalf of the Principal Investigator are the original work of the Principal Investigator and have not been used elsewhere in the preparation and submission of a similar grant application. Essentially identical applications and applications that include essentially identical components will not be accepted and will be returned to the applicant without review.

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 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 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

Letter of Intent Receipt Date: June 10, 2005
Application Receipt Date(s): July 11, 2005
Peer Review Date: November, 2005
Council Review Date: January, 2006
Earliest Anticipated Start Date: April, 2006

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:

Edward W. Schroder, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3136, MSC-7616
6700B Rockledge Drive
Bethesda, MD 20892-7616 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
Telephone: 301-435-8537
FAX: 301-480-2310
Email: eschroder@niaid.nih.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:

Edward W. Schroder, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3136, MSC-7616
6700B Rockledge Drive
Bethesda, MD 20892-7616 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
Telephone: 301-435-8537
FAX: 301-480-2310
Email: eschroder@niaid.nih.gov

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(s) described above (Section IV.3.A.). If an application is received after that date, it will be returned to the applicant without review. Upon receipt, applications will be evaluated for completeness by the CSR and responsiveness by the NIAID. 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 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 http://grants.nih.gov/grants/policy/policy.htm (see also Section VI.3. Reporting).

Direct funds to organizations located in foreign countries with a per capita annual gross national income (GNI) greater than U.S. $5,000 will be limited to reimbursable clinical research costs based on protocol requirements. (For additional information about GNI, refer to the World Bank at http://www.worldbank.org).

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 competing continuation award if such costs: are necessary to conduct the project, and 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 competing continuation 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

I. Web Site for Application Information

NIAID has established a web site (URL http://www.niaid.nih.gov/daids/rfa/network06) containing application instructions, suggested forms and templates to assist in completing applications in response to this RFA, as well as useful background materials. Applicants are strongly encouraged to consult this website and to develop their applications through the use of these templates.

In addition, NIAID will make available a website for the voluntary sharing of information among applicants to the "Leadership for HIV/AIDS Clinical Trials Networks" and "Units for HIV/AIDS Clinical Trials Networks." Applicants may, at their choosing, use this website to share information about applicant Network clinical research plans and Network capacity needs, as well as the interests and availability of Clinical Trials Units and Clinical Research Sites. NIAID will accept and post information, statements of interest, and contact information. Instructions for submitting information for posting is available at http://www.niaid.nih.gov/daids/rfa/network06. All postings will remain on the website until the final receipt date for applications.

II. Principal Investigator

A Principal Investigator who proposes to form a Clinical Trials Unit is responsible for coordinating the preparation of the application.

III. Submission and Award Options

A. A CTU may be proposed in only one application.

B. Institutions/organizations are strongly discouraged from submitting more than one CTU application. An organization that submits more than one application should explain the geographic, organizational or other compelling barriers that prevent effective sharing of resources, how the applicant organization will ensure that the proposed CTUs do not duplicate infrastructure or staff resources, and how the applicant organization will maximize collaborative activities.

C. Organizations are strongly discouraged from including a Clinical Research Site in more than one CTU application. The rationale for proposing a Clinical Research Site in more than one CTU application must be justified in each application. A Clinical Research Site can not be included in more than two Clinical Trial Unit awards and in no more than one CTU application for a particular high priority research area. CTU applicants should be aware of this when discussing prospective alignments with Clinical Research Sites.

D. Participation in Multiple Networks. CTU applicants are encouraged to collaborate with more than one Network. Clinical Research Sites within the CTU may implement the clinical research plan of one or more of the affiliated Network(s). Care should be taken to ensure that there is no overlap in the proposed contribution to research plans of separate Networks and that both scientific and resource capacity is sufficient to ensure optimal performance in each proposed Network.

IV. Supplementary instructions

Applicants should follow the most current PHS 398 instructions. Additionally, applicants should include the additional items identified below and assemble applications in the following order.

1. PHS 398 Face page.

2. PHS 398 Form Page 2. Describe the CTU and its overall structure, including the Administrative Component. Identify each HIV/AIDS Clinical Trials Network with which the CTU is proposing affiliation by prior agreement and link this affiliation to the appropriate Clinical Research Site(s). Letters of commitment from the Principal Investigator of each applicant Network Leadership should be included in the section titled “Consortium and Contractual arrangements”. Identify each HIV/AIDS Clinical Trials Network or high priority research area in which the CTU is proposing to participate but without prior Network applicant agreement and link this affiliation to the appropriate Clinical Research Site(s). Include the countries in which foreign Clinical Research Sites are located. Include Mentoring Partners in the section titled ‘Other Significant Contributors'.

3. Table of Contents. If multiple Clinical Research Sites are included, do not use form page 3 of the PHS 398; a more comprehensive table of contents is needed. Prepare a detailed table of contents that will enable reviewers to locate information pertinent to the CTU Administrative Component, to individual Network and/or high priority research area affiliation, and to each proposed Clinical Research Site. Identify each Clinical Research Site by title and Clinical Research Site Leader and provide a page reference for each component's budget.

The budget should include the following components presented in the order below:

(i) Administrative Component, including required funds to establish effective community relations, community outreach and education, and Community Advisory Board support.

(ii) For each Clinical Research Site: ‘Core Costs' – Core costs should identify the financial resources required to maintain the Clinical Research Site and meet the following Clinical Research Site capacity requirement: each Clinical Research Site must maintain an average monthly census of 20 study participants over a 12-month period for each proposed Network affiliation. That is, each Clinical Research Site within a CTU must recruit, screen, enroll and follow sufficient participants so that the average number of participants per month ‘on study' is no less than 20 over a 12-month period. The minimum of 20 participants applies to each Network with which the Clinical Research Site is affiliated (For example, if a Clinical Research Site is proposing affiliation with two Networks, the ‘Core Costs' would include the costs to maintain an average of 20 participants per month over a 12-month period in a representative study for Network A and 20 participants over a 12-month period in a representative study for Network B.). Representative studies for the purposes of estimating costs will be available on the NIAID application web site. Clinical Research Sites proposing affiliation with more than one Network and/or high priority research area must identify the expenditures for each Network/high priority research area in the budget justification.

(iii) Transition Costs (Ongoing Costs at the Time of Award). For each applicable Clinical Research Site, ongoing costs should identify the financial resources required to continue protocol-required follow-up of participants enrolled through an existing DAIDS-sponsored Clinical Trials Network. CTU applicants should contact Network Leadership applicants for Information on studies identified by Network Leadership applicants as anticipated to be continued into the first budget period of awards made through this RFA.

(iv) Mentoring Partnership (optional). See instructions below for costs that can be requested.

All Clinical Research Sites not part of the CTU grantee institution are considered consortium organizations and must submit separate PHS 398 Forms Page 4 and Page 5 for support in any of the above CTU categories. Budgets for the consortiums must be arranged as indicated below. Totals of all consortium sites must be cumulatively added to the budget of the CTU grantee institution.

Note: Organizations located in foreign countries with a per capita annual gross national income (GNI) less than U.S. $5,000 may budget for additional administrative and facilities expenditures such as transportation, security and maintenance of power supply (e.g. back up generators).

Note: Funds available to organizations located in foreign countries with a per capita annual gross national income (GNI) greater than U.S. $5,000 will be limited to reimbursable clinical research costs based on protocol requirements and allowable Facilities and Administrative costs for foreign institutions. Reimbursable clinical research costs will include: recruitment, screening, enrollment and participant care costs (laboratory, clinical procedures, and study staff labor costs per hour); essential Administrative Component personnel costs (e.g. PI, data management, coordinators); essential equipment and supplies; specimen storage and shipment; communications including postage, telephone and internet; and essential travel for Network activities (e.g. Network meetings).

5. PHS 398 Form Page 5: Budget for Entire Proposed Period of Support. Provide a Composite Budget covering all component budgets, followed by individual budgets for each component indicated below. Applicants proposing affiliation with more than one Network and/or high priority research area must identify the percentage of overall expenditures for each Network/high priority research area in the budget justification. If requesting 7 years of support, applicants will need to include two (2) page 5's. A breakdown by major budget category for the first 5 years on the first page 5 and the 6th and 7th on the second page 5.

The budgets should include the following components presented in the order below:

(i) Administrative Component

(ii) Core Costs for each Clinical Research Site

(iii) Transition Costs (Ongoing Costs at the Time of Award) for applicable Clinical Research Sites for year 1 only. NIAID will request budgets for transition costs in subsequent years during year 1 of these awards.

(iv) Mentoring Partnership (optional). See instructions below for costs that can be requested.

If requesting support for more than one Network and/or high priority research areas, the budget justification must include the percentage breakdown of costs by Network and/or priority area.

6. CTU Resources

7. Research Plan (a-d). Limit to a total of 10 pages for the following three sections: (i) the Overall Clinical Trials Unit and Administrative Component, (ii) Contribution to Network Clinical Research Plans, and (iii) Community Interactions and 10 additional pages for each Clinical Research Site proposed. Use the topics identified below and items in Section 2.A. Cooperative Agreement Terms and Conditions of Award as a guide for writing the research plan in lieu of items a-d listed on pages 17-18 of the PHS 398 application brochure. NIAID will host a website for the voluntary sharing of information among applicants for this and the companion RFA "Leadership for HIV/AIDS Clinical Trials Networks." Applicants may, at their choosing, use this website to share information about applicant Network clinical research plans and Network capacity needs, as well as the interests and availability of Clinical Trials Units and Clinical Research Sites. Details regarding this website are available at http://www.niaid.nih.gov/daids/rfa/network06/.

(i) Overall Clinical Trials Unit and Administrative Component. The following topics should be covered.

(ii) Contribution to Network Clinical Research Plans. Reviewers will independently assess the contributions to specific HIV/AIDS Clinical Trials Networks and/or priority clinical research areas to which the CTU is proposing affiliation. Each proposed Network and/or priority clinical research area should be identified, briefly described, and linked to the specific Clinical Research Sites that will be conducting the research.

(iii) Community Interactions. Applicants must describe plans to achieve meaningful community partnership in CTU clinical research activities, including outreach and community education activities. Plans should include the establishment and maintenance of one or more Community Advisory Boards (CAB) to represent the local population(s) impacted or threatened by HIV/AIDS at the Clinical Research Site(s) and present the research to be conducted to the community. Community Advisory Board plans may be more appropriately described for individual Clinical Research Sites, but the overall CTU CAB structure and support should be described and the application should identify the CAB(s) that will advise each Clinical Research Site.

(iv) Clinical Research Site(s). Limit to 10 pages for each Clinical Research Site. Include the following.

Note: Each of the current DAIDS-sponsored Clinical Trials Networks has developed and implemented a unique system for routine evaluation of site performance. Reviewers will have access to performance evaluations of applicant Clinical Research Sites performed by these systems. The types of parameters measured in these systems will be summarized by DAIDS and made available to all applicants at http://www.niaid.nih.gov/daids/rfa/network06.

8. Mentoring Partnerships (Optional).

9. PHS 398 Section f. Vertebrate animals (not applicable)

10. PHS 398 Section g. Literature Cited

11. PHS 398 Section h. Consortium and Contractual Agreements. This section must include:

a. a description of the programmatic, fiscal, and administrative arrangements to be made between the applicant organization and the consortium organization(s).

b. Letters of commitment from Leadership for HIV/AIDS Clinical Trials Network applicants with whom there is a prior agreement for Network affiliation.

12. PHS 398 Section i. Resource Sharing. Successful CTU applicants will be subject to the policies and procedures for sharing research resources developed by their affiliated HIV/AIDS Clinical Trials Network(s). Rather than develop an individual approach, applicants should indicate that they plan to adhere to the policies and procedures for resource sharing developed by the affiliated Network(s).

13. PHS 398 Section j. Consultants. Include Mentoring Partnerships or other consultants.

14. All Biographical Sketches should be positioned at the end of the application with the application's Principal Investigator first, followed by other key personnel in alphabetical order.

Do not submit Other Support pages; if needed, these will be requested by NIAID “just-in-time” for an award.

15. Application Checklist.

16. Appendices. Appendices are limited to 30 pages. Note: Key information submitted in the Appendix should be clearly referenced in the Research Plan Section. Information submitted as appendices should be limited to essential materials in support of the application; summaries or examples of information are encouraged. Applicants should understand that appendices will be used for supplemental information and may not be made available to all reviewers. Letters of support that do not formally commit to contributions to the program should not be included.

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.

Applicants requesting more than $500,000 in direct costs in any year of the proposed research must include a plan for sharing research data in their application. The funding organization will be responsible for monitoring the data sharing policy (http://grants.nih.gov/grants/policy/data_sharing).

The reasonableness of the data sharing plan or the rationale for not sharing research data may 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.

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.

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/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.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. Reporting.

Section V. Application Review Information

1. Criteria

The following will be considered in making funding decisions:

NIAID reserves the right to make awards based upon the maximum potential benefit offered by a Clinical Trials Unit in terms of the research priorities that it proposes to address, composition of the resulting HIV/AIDS Clinical Trials Networks, ability to reach populations most impacted or threatened by the HIV/AIDS pandemic, the merit of each of the Clinical Research Sites with respect to each of the scientific priorities as well as the CTU taken as a whole, and the funds available.

In addition to the NIAID Clinical Terms of Award (http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf), special terms and conditions may apply and be included in the Notice of Grant Award.

2. Review and Selection Process

Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIAID. Incomplete and/or non-responsive applications will not be reviewed.

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

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?

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?

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?

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)?

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?

Overlaid upon the standard review criteria listed above, the following criteria will be considered in the determination of scientific merit and a priority score. These review criteria address a broad range of Clinical Research Site and Clinical Trials Unit features required by the Networks. Individual Clinical Research Sites and Clinical Trials Units will bring unique strengths and characteristics to the Networks. Accordingly, the final funding decision will be made after review of the priority scores for each CTU application and a qualitative assessment of the strength of each Clinical Research Site's contribution to each proposed Network and/or research priority area.

Clinical Trials Unit (Administrative Component)

1. Adequacy of the Principal Investigator's qualifications, time commitment, experience and vision in the design, coordination, and conduct of HIV clinical research.

2. Strength and merit of proposed contributions to overall success of each Network and/or high priority research area with which the CTU seeks alignment.

3. Strength and merit of organizational, management, and communication plans within the CTU.

4. Strength, merit and feasibility of the plans to involve the local community(ies) affected by HIV/AIDS in CTU and Clinical Research Site activities, including support of the Community Advisory Board(s), community outreach and community education. Demonstrated ability of CTU personnel to interact with the community in linguistic and culturally appropriate ways.

5. Appropriateness of plans to foster participation of new investigators and clinical research staff, especially women and racial/ethnic minorities in the full spectrum of CTU activities.

Clinical Research Sites

1. Strength of the documentation of, and the availability and appropriateness of the potential participant cohorts of each Network, based on demographic characteristics and the incidence and prevalence of HIV/AIDS, to address the proposed clinical research.

2. Strength of plans and demonstrated (documented) ability to recruit and retain research participants drawn from population(s) required for the proposed clinical research, including as appropriate underrepresented populations such as ethnic/racial minorities, children, women, and intravenous drug users.

3. Strength and adequacy of plans and mechanisms to protect clinical trial participants drawn from vulnerable populations including pregnant women, neonates and fetuses, children, and prisoners if applicable.

4. Adequacy of the availability, qualifications and experience of staff to recruit, screen, enroll, follow, and retain, as well as adequately manage required clinical care (e.g., toxicity management) of sufficient numbers of participants required for optimal conduct of clinical studies within the proposed research area(s).

5. Adequacy, availability and appropriateness of facilities to recruit, screen, enroll, follow, and retain as well as to adequately manage required clinical care (e.g., toxicity management) of sufficient numbers of participants required for the conduct of clinical studies.

6. Adequacy of the demonstrated ability to develop an effective partnership with the community, and to incorporate community support and involvement in site activities, or adequacy and appropriateness of the documented plans for developing such partnerships and support.

7. Strength and merit of the site management plans for conducting clinical research including personnel, data management, compliance with regulatory requirements and adherence to Network policies and procedures.

8. Strength and evidence of organizational support of clinical research activities (e.g. financial management, frequency of IRB or Ethics Committee meetings).

9. Demonstrated ability to adhere to timelines for submission of data, and regulatory requirements such as Institutional Review Board submissions and reporting of required adverse events.

Additional Criteria for CTUs with Foreign Components

1. Appropriateness of arrangements and plans for clearances (drug importation, specimen shipping, local regulatory) with local and national authorities.

Mentoring Partnership

1. Strength and merit of stated goals and objectives for Mentoring Partnership.

2. Quality and feasibility of plans to provide mentoring, training, and the exchange of scientific expertise and experience.

3. Likelihood that plans will contribute to the CTU capability to conduct clinical research within timeframe specified.

4. Strength, merit and appropriateness of Mentor(s) qualifications to meet Mentoring Partnership goals and objectives. Quality of Mentor(s) role and stated commitment to meeting Partnership goals and objectives.

2.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).

2.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.

2.C. Sharing Research Data

Data Sharing Plan: The reasonableness of the data sharing plan or the rationale for not sharing research data may 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 funding organization will be responsible for monitoring the data sharing policy. http://grants.nih.gov/grants/policy/data_sharing.

Awardees will be subject to the policies and procedures for sharing research data developed by their affiliated HIV/AIDS Clinical Trials Network(s) and approved by NIAID.

2.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/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.

Awardees will be subject to the policies and procedures for sharing research resources developed by their affiliated HIV/AIDS Clinical Trials Network(s) and approved by NIAID.

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. Reporting.

3. Anticipated Announcement and Award Dates
Not Applicable.

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/grants/policy/nihgps_2003/NIHGPS_part4.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. See Also Section IV.5. Funding Restrictions.

NIAID will transmit the NGA via U.S. mail for a hard copy and/or via email for an electronic copy.

2. Administrative and National Policy Requirements

All clinical research activities performed under this award must be in compliance with all U.S. Federal regulations, guidance and NIH policies applying to the conduct of research involving human subjects and regulatory application for new drug or biological licenses when applicable. These include, but are not limited to, U.S. Code of Federal Regulations (CFR) Title 21, Parts 11, 50, 54, 56, 312, 314, 601 and Title 45, Part 46; ICH guidance for Good Clinical Practice (GCP); and NIH grants policy (refer to http://grants1.nih.gov/grants/policy/nihgps_2003/index.htm). In addition, the Awardee must assure that all sites in the U.S. and outside the U.S. comply with the following:

a. Each institution engaged in human subjects research has a current, approved Assurance Number on file with the DHHS Office for Human Research Protections (OHRP).

b. Each protocol and informed consent document is approved by the responsible Institutional Review Board (IRB)/Ethics Committee (EC) prior to subject entry.

c. For Investigational New Drug (IND) studies, each local Investigator of Record has supplied a completed FDA Form 1572 to DAIDS for each protocol conducted at each site.

d. For non-IND studies, each local principal investigator provides written documentation according to DAIDS guidelines.

e. Each study investigator and sub-investigator has provided current curriculum vitae to DAIDS.

f. Each study participant (or legal representative) will sign an IRB/EC-approved protocol consent prior to entry on study as part of the Informed Consent Process.

All clinical research activities performed outside of the U.S. must, in addition to U.S. Federal regulations, comply with the host country regulations for human subjects and AIDS research.

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/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 U01 , 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 above.

2.A.1. Principal Investigator Rights and Responsibilities

The Principal Investigator will have the primary responsibility for:

1. Knowledge, acceptance and compliance by all CTU components with the policies, procedures and bylaws of the DAIDS-sponsored HIV/AIDS Clinical Trials Networks, including: Network policies and procedures for the sharing of research data and research resources, the research priorities of the DAIDS and the affiliated Networks; and acceptance of the performance standards established by DAIDS and the affiliated Networks.

2. Ensuring that the CTU has investigators or mentors with demonstrated expertise in HIV/AIDS multi-center clinical trials, and implementing clearly defined organizational and communications plans and standard operating procedures that ensure close mentoring, supervision and oversight of the day to day activities of the Clinical Research Sites.

3. The receipt and appropriate administration of Core funding to establish and maintain a base of clinical research activities, and the receipt and appropriate administration of additional funding based on studies to be conducted and the adequacy of past performance.

4. Ensuring that each Clinical Research Site within the CTU meets the minimum enrollment goals established by DAIDS to be eligible for continued funding. Those criteria are:

a. Each Clinical Research Site must maintain an average monthly census of 20 study participants over a 12-month period for each Network. That is, each Clinical Research Site within a CTU must recruit, screen, enroll and follow sufficient participants so that the average number of participants per month ‘on study' is no less than 20 over a 12-month period. The minimum of 20 participants applies to each Network with which the Clinical Research Site is affiliated.

b. Clinical Research Sites that contribute to large Phase III and Phase IV studies, such as therapeutics, treatment optimization, MTCT studies, and prevention research studies, must demonstrate a greater capacity for efficient participation. These Clinical Research Sites must be able to recruit, screen, enroll and follow sufficient participants so that the average number of participants per month ‘on study' is no less than 100 over a 12-month period. Funds for these activities beyond core requirements will be provided as needed and administered by the CTU Principal Investigator.

c. HIV/AIDS Clinical Trials Networks may, with prior DAIDS approval, establish performance standards regarding enrollment expectations that exceed and supercede a.

5. Ensuring compliance with all Federal regulations for human subjects and investigational agents, NIH policies, DAIDS policies and procedures, and DAIDS Pharmacy Guidelines and Procedures. DAIDS-sponsored clinical research cannot be initiated at any Clinical Research Site until a Site Establishment Plan and the clinical protocol are approved by DAIDS.

6. Laboratory - Clinical site laboratory needs will be determined by the Network. The responsibilities of local Clinical Research Site laboratories will be defined by the Network and may include: (i) processing clinical specimens; (ii) shipping of specimens to designated laboratories or repositories; (iii) performance of routine laboratory tests and other protocol-mandated testing as designated by the Network; (iv) participating in QA programs required by the Network and DAIDS. The awardee shall follow the standards set forth by the Network and DAIDS for quality assurance, certification and specifications.

7. Developing and implementing strategies at each Clinical Research Site for the recruitment, screening, enrollment, retention and long-term follow-up of study participants appropriate to the conduct of the proposed research. The awardee must make every effort to recruit participants who are representative of the populations most impacted by HIV/AIDS within their geographical region, paying particular attention to gender and members of minority groups.

8. Ensuring compliance with the policies and procedures of each affiliated Network regarding the collection, recording, storage and reporting of clinical trial data.

9. Quality Management

a. Internal Quality Management. The awardee must establish and maintain an effective internal quality management plan that continually assesses the quality of the research records and activities to assure compliance with all federal regulations, International Conference on Harmonization Good Clinical Practice (ICH GCP) guidelines, and NIH policies regarding patient safety, data completeness, accuracy, and quality assurance. These plans are subject to approval by all affiliated Network(s) Leadership and DAIDS or designee, and apply to all Clinical Research Sites.

b. External Quality Management/Independent Clinical Site Monitoring. The awardee shall cooperate with the DAIDS Clinical Site Monitoring Group, and any other site monitoring groups authorized by DAIDS. The purpose will include but not be limited to the review of research records and activities to verify compliance with all federal regulations and ICH GCP guidelines, and NIH policies on patient safety, data completeness and accuracy, and quality control. All performance problems identified through clinical monitoring must be evaluated in a timely manner and a plan for resolution developed, implemented, and documented.

10. Participation of New Investigators, Women and Minorities. The awardee will establish procedures, and opportunities to ensure the participation of junior investigators, especially women and racial/ethnic minorities, in all aspects of the research effort.

11. The CTU must establish and implement a plan to achieve meaningful community partnership in CTU activities. This must include one or more Community Advisory Boards (CAB) to represent the local population(s) impacted by HIV/AIDS at the Clinical Research Site(s) and present the research to be conducted to the community. The CTU must have procedures to ensure the community is a partner in the research process; provide financial and technical assistance from appropriately trained, culturally sensitive and experienced staff to support CAB activities and training; foster a partnership between researchers and the community, including the sharing of research results with the community, and develop ways to assess these efforts.

12. The awardee must comply with all adverse event reporting requirements designated by DAIDS, including but not limited to the established policies and procedures delineated in the "Expedited Adverse Experience Reporting Manual”.

13. The awardee must ensure that all information required by DAIDS or affiliated Network policy and procedures is provided in a timely fashion. In addition to clinical trial data, routine and ad hoc reports may be required. These reports may include, but not be limited to, participant recruitment and retention rates, summary demographic profiles of study participants, timeliness and completeness of all data, completeness and quality of laboratory data, and administrative and financial reports.

14. The awardee must comply with the policies and procedures set forth by the Network Leadership and DAIDS regarding presentation and publication in the scientific literature of major findings. Every publication or oral presentation of work performed under this cooperative agreement will require acknowledgment of NIAID/NIH support. Prior to the submission of manuscripts for publication, a copy must be provided to DAIDS for review no later than 14 working days prior to the submission date. The awardee retains the rights to the data consistent with current HHS, PHS, and NIH policies; however, DAIDS will have access to all data generated under this cooperative agreement and may periodically review it.

15. The CTU will participate in the affiliated Network(s) resource allocation evaluation activities. This includes, but will not be limited to, sharing of the components of the original grant application, annual renewal reports, budgets, and justifications. This allows for fair comparison of all sites from a resource perspective and may influence decisions for continued funding.

For CTUs involved in vaccine and prevention research

18. The awardee will provide long-term follow-up for participants who become infected during the conduct of the vaccine or prevention trial. The awardee will refer such infected participants to a qualified physician or clinic for medical care after HIV infection is determined and provide information on the availability and locality of clinical trials with potentially beneficial treatments for HIV-1 infection and disease to the infected participants.

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.

NIAID and other NIH co-sponsors will have substantial scientific and programmatic involvement during the conduct of this activity, through establishing the research agenda, and providing technical assistance, advice, and coordination. The role of the NIH staff, as described throughout these terms of cooperation, is to assist and facilitate and not to direct the specific research activities necessary to execute the research agenda. NIH staff will interact directly with the CTU PI, as well as the Network CORE PI, Principal Investigators of the SDMC, Central Laboratory, scientific leadership and any other collaborating institutions as needed.

A. Sponsor and Regulatory Responsibilities

The DAIDS will serve as a liaison between pharmaceutical companies, the FDA, and Network investigators. In accordance with NIH policy, NIAID will ensure that all clinical trials performed through the HIV/AIDS Clinical Trials Networks are conducted in accordance with ICH Good Clinical Practices and applicable Federal regulations.

1. Clinical Research Site Oversight. DAIDS will review and approve a Site Establishment Plan, which identifies the responsible individuals and contact information in key areas at the institution and Clinical Research Site, for each Clinical Research Site prior to the initiation of any clinical research at the site. All Clinical Research Sites are also required to complete Protocol Registration for all clinical protocols in accordance with current DAIDS policy and procedures prior to study initiation. DAIDS staff may conduct site visits at the Administrative Component and the Clinical Research Sites for the purposes of assessing site readiness, or to evaluate ongoing operations, clinical research processes and recordkeeping, or to investigate significant findings on monitoring or other reports.

2. Clinical Trials Agreements (CTA). A CTA, describing the responsibilities and rights of each party, will be negotiated when a pharmaceutical or other collaborator provides an investigational agent for a clinical study. The agreement will include, but is not limited to, IND sponsorship, safety and data monitoring, and access to data. The Core PI or designee generally will be consulted on the terms prior to the execution of the CTA. Pharmaceutical collaborators generally request that patentable inventions discovered in the studies be brought to their attention, and that the company has right of first refusal provided that the collaborator has rights to the background patent. In general, terms in the CTA covering data access and sharing will conform to policies developed jointly by the Network Leadership and DAIDS.

3. Investigational New Drug Applications. DAIDS will have the option to cross file or independently file an IND on investigational agents evaluated in DAIDS-sponsored clinical studies. Appropriate DAIDS staff will advise the investigators on the specific regulatory requirements for IND sponsorship. In situations where DAIDS is the IND sponsor, DAIDS will also assemble, review, and submit the required regulatory documents to the FDA.

4. Site and Laboratory Monitoring. DAIDS has an external Clinical Site Monitoring Contract to evaluate good clinical research practice, regulatory compliance, accurate protocol implementation, internal quality assurance, and test agent accountability. The monitoring contractor will visit performance sites and laboratories periodically to review selected protocols, provide training on general protocol conduct, review internal quality management plans, and audit pharmacies. DAIDS staff in coordination with the site monitoring contractor will periodically conduct a review of the sites for the reliability of and compliance with clinical and regulatory systems, and will advise the site and the Network CORE of findings. In collaboration with the Network CORE, DAIDS may take action to temporarily or permanently halt enrollment and/or follow-up at a Clinical Research Site or CTU in response to significant findings during a monitoring visit.

5. Study Product. For studies in which DAIDS is the IND or IDE sponsor, the DAIDS staff and/or contractors will provide consultation on study agent-related issues including manufacturing, preparation, administration and availability of active dosage forms and placebo. Pharmacy Establishment Plans, identifying the Pharmacist of Record, describing the policies and procedures for the safe and proper use of investigational agents, and the investigational agent control system, including technical procedures for agent ordering, control, dispensing, and accountability are required for sites conducting research using investigational agents. The DAIDS staff and/or contractors may also:

6. Training. DAIDS will provide a variety of training activities to help ensure that consistent standards for protection of human subjects, conduct of clinical trials, and documentation is achieved across the DAIDS-sponsored HIV/AIDS Clinical Trials Networks. This training may be developed in conjunction with Network and cross-Network staff and the Managing Partners and be provided directly by DAIDS staff or through contractors. Training areas will include, but not be limited to, regulatory requirements, GCP, adverse event reporting, human subject protections, and DAIDS policies and procedures. Some training or retraining may require mandatory attendance. Some trainers may be on site for an extended period of weeks or months.

7. Safety Reports. As the IND holder, DAIDS will assume responsibility for the reporting of safety information in accordance with FDA requirements and preferences. In order to provide for consistent reporting of serious adverse experiences across clinical trials groups, DAIDS shall provide current policies and procedures that govern the reporting of adverse events in DAIDS-sponsored trials. DAIDS staff and/or contractors will provide training in the specific procedures and requirements for adverse event reporting for clinical trials conducted under this award.

B. Protocol Development, Implementation and Oversight

1. Protocol Development. DAIDS staff who will participate in the development of selected clinical research protocols include:

2. Review. All clinical research protocols must be approved by the DAIDS Project Scientist or designee prior to study initiation. The Clinical Trials Networks will submit the protocols to the NIAID Prevention Sciences Research Committee (PSRC) or the NIAID Clinical Sciences Review Committee (CSRC). The Committee will evaluate the proposal relative to: (i) the NIAID and other collaborating Institutes' research agenda and other NIH clinical studies; (ii) subject safety; (iii) compliance with Federal regulations; (iv) study oversight and monitoring; (v) feasibility of timely completion; and when appropriate, (vi) plans for interim monitoring and analysis. The Project Scientist or designee will return comments and recommendations to the group within 30 days after review. The Network must address in writing all safety, regulatory, ethical, and conflict of interest concerns raised by NIAID staff to the satisfaction of the NIAID before patient accrual or participant enrollment can begin. If a protocol is disapproved, NIAID will not provide investigational products or permit expenditure of NIH funds for the proposed investigation.

3. Independent Safety Monitoring. Independent Safety Monitoring is strongly recommended for all clinical trials involving investigational drugs, devices, or biologics and other clinical research perceived to involve more than a minimal risk. NIAID program staff will participate in the development of appropriate safety monitoring plans for all planned clinical trials. The frequency and intensity of safety monitoring will be based on individual study characteristics and may require review by an Independent Safety Monitor, Independent Monitoring Committee (IMC) or Safety Monitoring Committee (SMC) or Data and Safety Monitoring Board (DSMB). Approval of the final monitoring plan, including the composition of the review committee, by DAIDS must occur prior to study initiation.

4. Study Termination. NIAID reserves the right to terminate or curtail a clinical study or the participation of a Clinical Research Site in a clinical study for any of the following reasons: (i) risk to subject safety; (ii) the scientific question is no longer relevant or the objectives will not be met; (iii) failure to comply with Good Clinical Practices, federal regulations, or Terms of Award; (iv) occurrence of unforeseen drug safety issues or data from preclinical studies indicate a presence of unanticipated toxicity; (v) risks that cannot be adequately quantitated; (vi) ethical concerns raised by the local community or local medical care/health care authorities; (vii) failure to remedy deficiencies identified by site monitoring teams; (viii) substandard data; (ix) inadequate progress in fulfilling the research agenda; (x) slow accrual; or (xi) reaching a major study endpoint with persuasive statistical significance substantially before schedule.

5. Access to Data. The Project Scientist or designee will have access to all data generated under this cooperative agreement, and may review the data as recorded on the case report forms or in the central database. Data must be available for external checking against the original source documentation as required by federal regulation and DAIDS as the IND sponsor.

C. Study Conduct

A DAIDS Medical or Program Officer will monitor the safety and, when appropriate based on study design, the efficacy of the intervention(s) for ongoing studies, and will be provided with appropriate reports. DAIDS supports independent Data and Safety Monitoring Boards (DSMB) that oversee Phase III and other select clinical trials.

D. Performance Review

The performance of the CTU and each Clinical Research Site will be monitored and assessed on a routine basis. It is anticipated that the Managing Partners will develop a standard system for Clinical Research Site evaluation that will be applied across all of the HIV/AIDS Clinical Trials Networks. Network progress and performance also will be assessed in an ongoing manner by DAIDS and DAIDS-appointed external ad hoc working groups, in the context of an evaluation plan with defined goals and measurable objectives linked to specific performance metrics as appropriate to the research area(s).

Each Network will use a Protocol Reserve Fund to adjust and allocate resources to Network components, including CTUs, based on performance and to support high priority research projects as appropriate. A DAIDS Reserve Fund will be used to adjust and allocate resources to the Networks to support high priority research projects.

CTUs or Clinical Research Sites that fail to meet performance standards may be subject to withdrawal of funding.

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.

2.A.3. Collaborative Responsibilities

Execution of this program will require collaboration among the CTU PI, the DAIDS Project Scientist(s), Program Officer and DAIDS staff, the Leadership of the HIV/AIDS Clinical Trials Networks with which the CTU is affiliated, and NIAID and other co-sponsoring NIH Institutes and Centers. Specific tasks and responsibilities in carrying out the activity will be shared among the awardee, DAIDS staff, Network staff, and DAIDS' contractors as described above.

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

The awardee must ensure that all information required by DAIDS or affiliated Network policy and procedures is provided in a timely fashion. In addition to clinical trial data, routine and ad hoc reports may be required. These reports may include, but not be limited to, participant recruitment and retention rates, summary demographic profiles of study participants, timeliness and completeness of all data, completeness and quality of laboratory data, and administrative and financial reports.

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:

Office of the Director
Division of AIDS
National Institute of Allergy and Infectious Diseases
Room 4142, MSC-7620
6700-B Rockledge Drive
Bethesda, MD 20892-7620
Bethesda, MD 20817 (for express/courier service; non-USPS service)
Telephone: 301-451-2729
FAX: 301-402-1505
Email: FY06UNITRFA@niaid.nih.gov

2. Peer Review Contacts:

Edward W. Schroder, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3136, MSC-7616
6700B Rockledge Drive
Bethesda, MD 20892-7616 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
Telephone: 301-435-8537
FAX: 301-480-2310
Email: eschroder@niaid.nih.gov

3. Financial or Grants Management Contacts:

Ms. Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2128, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
Telephone: 301-402-6824
FAX: 301-480-3780
Email: junsworth@niaid.nih.gov

Section VIII. Other Information

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.

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. Applications that do not provide this information will be returned without review.

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.healthypeople.gov/.

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/.


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