[Federal Register Volume 67, Number 95 (Thursday, May 16, 2002)]
[Notices]
[Pages 34932-34936]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-12254]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

[Program Announcement 02074]


Interventional Epidemiologic Research Studies to Reduce Mother-
to-Child HIV-1 Transmission and Improve Infant Survival in Resource-
Limited Countries of High HIV-1 Seroprevalence; Notice of Availability 
of Funds

A. Purpose

    The Centers for Disease Control and Prevention (CDC), announces the 
availability of fiscal year (FY) 2002 funds for a cooperative agreement 
program to support interventional epidemiologic research studies to 
reduce the burden of HIV/AIDS by preventing mother-to-child HIV-1 
transmission peripartum and during breastfeeding in international 
settings of high HIV-1 seroprevalence. This cooperative agreement will 
receive cofunding by the National Institute of Child Health and Human 
Development (NICHD), National Institutes of Health (NIH) during FY 
2003. This program addresses the goals of CDC's HIV Prevention 
Strategic Plan through 2005.
    The purpose of this program is to conduct studies which include 
clinical trials in resource-limited countries that aim to reduce the 
risk of perinatal HIV-1 transmission near the time of delivery and 
during the breastfeeding period among HIV-1 infected women who reside 
in resource-limited settings and who choose to breastfeed. Also, within 
the context of these trials, nested research studies will assess 
mechanisms of transmission during lactation and/or issues related to 
the effectiveness of, or successful implementation of these 
interventions.

Background

    Worldwide over 600,000 infants each year become HIV-1 infected 
through mother-to-child transmission. Recent international perinatal 
trials demonstrated that short course antiretrovirals including 
zidovudine (AZT), zidovudine/lamivudine (AZT/3TC) and nevirapine (NVP) 
can reduce the risk of early HIV-1 transmission by about 40 percent in 
the first 6-14 weeks following delivery. The Joint United Nations 
Programme on HIV/AIDS (UNAIDS) has recommended that each of these drug 
regimens can now be considered as possible options for reducing the 
risk of mother-to-child transmission in resource-limited settings.
    However, the global health goal of maximally reducing mother-to-
child HIV-1 transmission in resource-limited settings to the low rates 
(i.e., 5 percent or less) achieved within the U.S. and Europe is yet to 
be accomplished. Ongoing breast milk transmission results in a near 
doubling of transmission by 24 months or about 9 percent absolute 
transmission attributed to breastfeeding between 2-24 months. Two 
recent studies, a randomized trial of breast milk versus formula in 
Nairobi and the South African Intrapartum Nevirapine Trial (SAINT) 
Trial in South Africa compared transmission rates between breastfed and 
non breastfed infants. Both studies suggest that the first 6-8 weeks 
may pose the highest risk period of breast milk transmission with about 
5-6 percent higher transmission risk for breastfed compared to formula 
fed infants in the first two months of life. After these first 6-8 
weeks, based on observational data from Malawi, ongoing transmission 
from exposure to breast milk is about 0.6 percent-0.7 percent per month 
in the first year; and about 0.2-0.3 percent per month in the second 
year of life.
    Currently most HIV-1 infected women in resource-limited settings 
breastfeed, often into the second year of life. This decision may be 
related to a number of factors: lack of awareness of their HIV-1 
status, cultural norms and strong social reinforcement of 
breastfeeding, fear or stigma, concerns regarding optimal infant 
nutrition and also water safety, or cost of breast milk substitutes. 
Given the high rates of breastfeeding among HIV-1 infected women in 
resource-limited areas, prevention of HIV-1 transmission during 
lactation remains a pressing perinatal research challenge.

Examples of Research Areas

I. Clinical Trials Addressing Prevention of HIV-1 Transmission During 
the Breastfeeding Period
    The primary aim of this Program Announcement is to support 
international clinical trials designed to reduce both peripartum and 
breastfeeding HIV-1 transmission in rural or urban settings in 
resource-limited countries.
    Critical research areas in preventing mother-to-child HIV-1 
transmission that applicants may address, include but are not limited 
to, clinical trials directed at one of the following areas:
    Trials of short course combination antiretrovirals in the last 
several weeks before delivery designed to reduce viral load to a 
nondetectable level, followed by maternal or infant antiretroviral 
prophylaxis during the first several months of lactation;
    Trials of short course antenatal or peripartum antiretrovirals 
paired with infant immune prophylaxis (e.g., HIV-1 vaccine) aimed at 
protecting the infant throughout the breastfeeding period;
    Trials assessing the efficacy of infant combination antiretroviral 
prophylaxis given to breastfed babies whose mothers were only 
identified as HIV-1 infected at labor and delivery; and/or
    Combinations of above.
II. Nested Research Studies Within Proposed Trials
    Investigators should also propose 1-2 nested research questions 
within the trials addressing mechanisms of transmission during 
lactation; and/or issues related to effectiveness of, or successful 
implementation of the intervention. Such studies might include but are 
not limited to: lab studies addressing mechanisms of transmission 
during lactation; lab studies assessing the development and waning of 
drug resistance for antiretrovirals used for perinatal HIV-1 
prevention; strategies that enhance uptake of voluntary counseling and 
testing using rapid HIV testing to support enrollment into the proposed 
trial; strategies to enhance adherence to antiretrovirals or immune 
trial interventions antenatally and during lactation; assessment of 
factors affecting mode of feeding or weaning decisions;

[[Page 34933]]

evaluation of toxicity and other complications of antiretrovirals 
interventions among HIV-1 infected women during pregnancy and post 
partum, and their infants; and testing of simplified tools for 
monitoring drug toxicities in community-based health care facilities.

B. Eligible Applicants

    Applications may be submitted by indigenous universities, colleges, 
research institutions, hospitals, other public and private nonprofit 
organizations, operating in settings with high antenatal HIV-1 
seroprevalence (i.e., 5 percent or greater) in resource-limited 
countries. For the purposes of this announcement, HIV-1 seroprevalence 
rates, circa 2000, as compiled by the U.S. Census will be used to 
determine eligibility. These rates can be accessed at: http://www.census.gov/ipc/www/hivtable.html.

C. Availability of Funds

    Approximately $1,000,000 million is available in FY 2002 and an 
additional $500,000 in FY 2003 to fund two awards to develop and carry 
out interventions aimed at maximally reducing perinatal HIV-1 
transmission near the time of delivery and during the breastfeeding 
period; and within the context of these trials, nested studies to 
assess mechanisms of transmission during lactation; and/or issues 
related to effectiveness of, or successful implementation of the 
intervention.
    It is expected that the average award will be $750,000 a year. All 
awards will begin on or about September 30, 2002 and will be made for a 
12-month budget period within a project period of up to five years. 
Funding estimates may change.
    Continuation awards within an approved project period will be made 
on the basis of satisfactory progress as evidenced by required reports 
and the availability of funds.
    All requests for funds, including the budget contained in the 
application, shall be stated in U.S. dollars. Once an award is made, 
the Department of Health and Human Services (DHHS) will not compensate 
foreign grantees for currency exchange fluctuations through the 
issuance of supplemental awards.
1. Use of Funds
    Applicants may contract with other organizations under this 
cooperative agreement; however, applicants must perform a substantial 
portion of the activities (including program management and operations) 
for which funds are requested.
    The costs that are generally allowable in grants to domestic 
organizations are likewise allowable to foreign institutions and 
international organizations, with the following exception:

    Indirect Costs: With the exception of the American University, 
Beirut, the Gorgas Memorial Institute, and the World Health 
Organization, indirect costs will not be paid (either directly or 
through a sub-award) to organizations located outside the 
territorial limits of the United States or to international 
organizations regardless of their location.
Needle Exchange
    No funds appropriated under this Act shall be used to carry out any 
program distributing sterile needles or syringes for the hypodermic 
injection of any illegal drug.
2. Funding Preference
    Preference will be given to achieve geographical diversity.

D. Program Requirements

    In conducting activities to achieve the purpose of these programs, 
the recipient will be responsible for the activities listed under 1. 
(Recipient Activities), and CDC/NIH will be responsible for conducting 
activities listed under 2. (CDC/NIH Activities).
1. Recipient Activities
    a. Develop research study protocols; and obtain local IRB approval.
    b. Develop and manage standardized data collection forms.
    c. Identify, recruit, obtain and carefully document informed 
consent; and enroll an adequate number of study participants as 
determined by the study protocol(s) and the program requirements 
described in the Program Announcement.
    d. Follow up and assume appropriate clinical care of study 
participants during the trial as described by the study protocol.
    e. Establish and monitor procedures to ensure the rights and 
confidentiality of all study participants.
    f. Perform laboratory tests (when appropriate) and data analysis as 
determined in the study protocol.
    g. Collaborate and share data and specimens (when appropriate) with 
other collaborators to answer specific cross cutting research 
questions.
    h. Contribute blood specimens (at least every 6-12 months depending 
on the protocol requirements) for shipment and storage at a centralized 
repository system.
    i. Conduct or help with coordination of data analysis; as well as 
present and publish research findings.
    j. Facilitate the establishment of, or engage an existing Community 
Advisory Board (CAB) to give ongoing community input related to the 
proposed research from the study inception through completion and 
eventual dissemination of study results to the community.
    k. Develop or enhance linkages and strong collaboration with CDC 
Global AIDS Program (GAP), ministries of health, nongovernmental 
organizations (NGO's) and other groups relevant to carrying out the 
research; and to implementing research findings following completion of 
the trial.

    Note: Recipients addressing the same or similar research 
issue(s) should state their willingness to participate in 
collaborative studies with other CDC- or NIH-sponsored researchers, 
including using common data collection instruments, specimen 
collection protocols, and data management procedures, as determined 
in post-award planning conferences.

2. CDC/NIH Activities
    a. Provide technical assistance in study design in order to 
facilitate the overall research project.
    b. Facilitate and assist in the development of research protocols 
for IRB (institutional review board) review by the cooperating 
institutions participating in the research project. The CDC IRB will 
review and approve the protocol initially and on at least an annual 
basis until the research project is completed.
    c. Assist in designing a data management system.
    d. Assist in performance of selected laboratory tests.
    e. Work collaboratively with investigators to help coordinate 
research activities across sites involved in similar research projects 
such as nested laboratory studies.
    f. Assist in the analyses of research information and the 
presentation and publication of research findings.

E. Application Content

    Use the information in the Program Requirements, Other 
Requirements, and Evaluation Criteria sections to develop the 
application content. Your application will be evaluated on the criteria 
listed, so it is important to address them in laying out the proposals 
for your application.

F. Submission and Deadline

    Submit the original and five copies of PHS-398 (OMB Number 0925-
0001) (adhere to the instructions on the Errata Instruction Sheet for 
PHS 398). Forms are available in the application kit and at the 
following Internet address: 
http://www.cdc.gov/od/pgo/forminfo.htm

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    Please obtain this program announcement and all attachments which 
are necessary for completing your application, at the Internet address 
referenced above. Program Announcements published on the Federal 
Register do not include attachments which are sometimes crucial to the 
development of your application.
    On or before July 15, 2002, submit the application to the Grants 
Management Specialist identified in the ``Where to Obtain Additional 
Information'' section of this announcement.
    Deadline: Applications shall be considered as meeting the deadline 
if hard copies of the applications are either:
    A. Received on or before the deadline date; or
    B. Sent on or before the deadline date and received in time for 
submission to the independent review group. (Applicants must request a 
legibly dated U.S. Postal Service postmark or obtain a legibly dated 
receipt from a commercial carrier or U.S. Postal Service. Private 
metered postmarks shall not be acceptable as proof of timely mailing.)
    Late Applications: Applications which do not meet the criteria in 
A. and B. above will be returned to the applicant.

G. Evaluation Criteria

    Each application will be evaluated individually against the 
following criteria by an independent review group appointed by CDC.
1. Demonstrated Access to Relevant Study Populations, and Demonstrated 
Capability To Recruit and Retain Study Participants Into a Clinical 
Trial (Total of 25 points)
    a. Evidence of ability to successfully recruit and follow mothers 
and their infants in longitudinal research studies. Applicants should 
include relevant information from previous studies documenting annual 
recruitment and retention rates including loss to follow up in these 
studies.
    b. For the proposal responding to research or program area, 
evidence of approximately 5 percent or greater HIV-1 seroprevalence 
among pregnant women in the catchment area described in the 
application; and/or ability to recruit and retain at least 500 HIV-1 
infected pregnant women and their HIV-1 exposed infants annually in 
settings where many HIV-1 infected women breastfeed.
    C. Demonstrated access to and laboratory capability to carry out 
HIV-1 serologic testing for mothers and PCR testing of infants, monitor 
responses to antiretroviral therapy including possible toxicities (e.g. 
hematology, blood chemistries).
2. Description and Justification of Research Plans (Total of 40 points)
    a. Understanding of the research objectives as evidenced by the 
high quality and scientific rigor of the proposed plans for research 
and a study design appropriate to answer research questions.
    b. Demonstration of a well designed innovative clinical trial which 
investigates and addresses:
    Maximal reduction of mother-to-child HIV-1 transmission during both 
the peripartum period and during lactation using antiretrovirals and/or 
immune-based interventions; nested studies within these trials which 
assess related research questions related to the trials such as 
mechanisms of transmission during lactation; development and waning of 
antiretroviral resistance; and/or issues related to effectiveness of, 
or successful implementation of the intervention strategies; strategies 
to enhance adherence to antiretrovirals or immune trial interventions 
antenatally and during the breastfeeding period; evaluation of 
potential toxicities of interventions; and testings of simplified tools 
for monitoring drug toxicities in community-based health care 
facilities.
    c. Originality and quality of the proposed clinical trial research, 
and direct relevance of the research to maximally reduce mother-to-
child transmission in high prevalence resource-limited settings with 
particular emphasis on reducing viral load in the last trimester and 
assessing prophylaxis strategies during lactation. The extent to which 
the proposal builds on current knowledge, extends or creates new 
knowledge and does not replicate past or present research efforts.
    d. Demonstrated willingness of the applicant to work with CDC/NIH 
staff on development of the research protocol and willingness to 
collaborate on related studies with other investigators funded under 
this Program Announcement.
    e. Feasibility of plans to recruit, follow and retain study 
participants in a longitudinal research protocol within the framework 
of the project period. This includes demonstration of the experience of 
the investigator in following mothers and infants in either 
longitudinal epidemiologic studies and/or in clinical trials, and the 
comprehensiveness of the plan to protect the rights and confidentiality 
of all participants.
    f. Adequacy of sample size to address research questions, and 
demonstration of available statistical expertise to carry out 
subsequent analyses of trial results. Thoroughness of plans for data 
management, data analysis, and laboratory analysis; reasonableness of 
data collected; and statistical rigor.
    g. Extent to which proposal demonstrates feasible plans for 
coordinating research activities of multiple local clinical sites, 
statement of potential willingness to work collaboratively with other 
grant recipients in other settings if similar or multi-site protocols 
were developed, and with CDC/NIH. Letters of support from cooperating 
organizations that demonstrate the nature and extent of such 
cooperation should be included, as well as GAP in-country directors and 
ministries of health.
    h. Extent to which proposal delineates plans for setting up or 
engaging an existing Community Advisory Board to give ongoing community 
input into the research study from its inception, through completion 
and eventual dissemination of study results to the community.
    i. The degree to which the applicant has met the CDC Policy 
requirements regarding the inclusion of women, ethnic and racial groups 
in the proposed research.
    This includes:
    (i) The proposed plan for the inclusion of racial and ethnic 
minority populations for appropriate representation;
    (ii) The proposed justification when representation is limited or 
absent;
    (iii) A statement as to whether the design of the study is adequate 
to measure differences when warranted.
    (iv) A statement as to whether the plans for recruitment and 
outreach for study participants include the process of establishing 
partnerships with communities and recognition of mutual benefits.
3. Research and Intervention Capability (Total of 25 points)
    a. Availability of qualified and experienced senior Principal 
Investigators (PI) and Co-PI's. Extent of familiarity and quality of 
Principal Investigator and other senior Co-Investigators' experience 
and expertise pertinent to proposed research or programmatic 
activities, including experience in perinatal and pediatric HIV-1 
infection epidemiologic or clinical trial research; or other 
epidemiologic and clinical trial research. Evidence of sufficient time 
dedicated to the proposed project.
    b. Applicant group's ability to carry out the proposed research as 
demonstrated by the training and

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experience of the proposed research team and organizational setting, 
including demonstration of ability to collect, manage, and analyze 
accurate data in a timely manner.
    c. Clarity of the described duties and responsibilities of project 
personnel.
    d. Demonstrated research infrastructure as evidenced by presence of 
current funding for ongoing research, program implementation and 
training (examples of other funding for infrastructure might include 
funding from National Institutes of Health, Medical Research Council, 
Agence Nationale de Recherche sur le SIDA (ANRS), Emory AIDS 
International Training Research Program (AITRP), Fogarty International 
Center (FIC), Wellcome Trust, Elizabeth Glaser Pediatric AIDS 
Foundation, and other private foundations, etc.
    e. Experience and evidence of ability to provide voluntary 
counseling and testing (VCT) in antenatal clinics, and to offer VCT at 
labor and delivery for women who are not tested antenatally.
    f. Adequacy of plans for project oversight to assure quality of 
data and specimen collection.
    (1) Evidence of ability to collect complete data including 
interviews of mothers in the immediate postpartum period, and to obtain 
blood samples from HIV-1 infected mothers enrolled around the time of 
delivery.
    (2) Evidence of ability to collect complete and accurate data, and 
to obtain regular blood samples from HIV-1 exposed infants, with at 
least one blood sample during the first 48 hours after birth, and at 
follow up pediatric health maintenance visits.
    (3) Ability to oversee specimen collection for the timely 
processing, storage, and retrieval of laboratory specimens as needed. 
This includes transfer of certain specimens to a central repository 
(e.g., at CDC) and transfer of other specimens to designated 
laboratories for specific laboratory studies.
    g. Evidence of capability to address informed consent issues, 
enhance social support and foster adherence to the antiretroviral 
prophylaxis regimen, with special attention directed at adherence to 
the neonatal component of the regimen.
    h. Documentation of appropriately constituted local IRB in place to 
review the protocol.
    i. Adequacy of facilities, equipment, data management resources, 
and systems for ensuring data security and patient confidentiality.
    j. Demonstration of working relationships with any proposed 
collaborators and extent to which services to be provided by external 
experts or consultants are documented by memoranda of agreement.
    k. Demonstration of research staff with epidemiologic, behavioral, 
clinical, administrative, laboratory, data management and statistical 
analysis expertise needed to conduct the proposed research.
    l. Adequacy of time line for completion of project activities.
4. Linkages and Planned Approaches to Translate Successful Research 
Findings Into Practice (10 points)
    a. Demonstration of linkages to the following groups are required: 
CDC Global AIDS Program (GAP) staff in currently funded CDC GAP 
countries or to relevant CDC staff in non GAP countries working on HIV-
1 related activities, Ministry of Public Health, Community Advocacy 
Groups; and linkages are strongly recommended with nongovernmental 
organizations (NGO's), international agencies such as UNICEF, UNAIDS, 
and WHO.
    b. Demonstration of a plan of action to translate and transition 
research findings to appropriate responsible groups that would result 
in upscaling and implementation in local or national communities. 
Linkages with other area hospitals, local ministry of health and a 
local Community Advisory Board are strongly encouraged.
5. Demonstration of Sound Fiscal Policies, and Fiscal Oversight by the 
Institution Which Would Receive the Funding Under this Application.
6. Budget (not scored)
    The extent to which it is reasonable, clearly justified, consistent 
with the intended use of funds, and allowable. All budget categories 
should be itemized.
7. Human Subjects (not scored)
    Does the application adequately address the requirements of Title 
45 CFR Part 46 for the protection of human subjects?

H. Other Requirements

Technical Reporting Requirements
    Provide CDC with original plus two copies of:
    1. annual progress report;
    2. financial status report, no more than 90 days after the end of 
the budget period; and
    3. final financial status and performance reports, no more than 90 
days after the end of the project period.
    4. Applicants are required to provide measures of effectiveness to 
evaluate the accomplishment of the various identified objectives of the 
cooperative agreement. These measures must be objective and 
quantitative and must measure the intended outcome. The submission of 
these measures shall be a data element to be submitted with, or 
incorporated into the annual progress reports.
    5. Awardee is required to obtain an annual audit of these CDC/NIH 
funds (program-specific audit) by a U.S.-based audit firm with 
international branches and current licensure/authority in-country, and 
in accordance with International Accounting Standards or equivalent 
standard(s) approved in writing by CDC.
    6. A fiscal Recipient Capability Assessment may be required with 
the potential awardee, pre or post award, in order to review their 
business management and fiscal capabilities regarding the handling of 
U.S. Federal funds.
    Send all reports to the Grants Management Specialist identified in 
the ``Where to Obtain Additional Information'' section of this 
announcement.
    The following additional requirements are applicable to this 
program. For a complete description of each, see attachment I of this 
announcement.
AR-1  Human Subjects Requirements
AR-2  Requirements for Inclusion of Women and Racial and Ethnic 
Minorities in Research
AR-4  HIV/AIDS Confidentiality Provisions
AR-6  Patient Care
AR-12  Lobbying Restrictions
AR-14  Accounting System Requirements
AR-22  Research Integrity

I. Authority and Catalog of Federal Domestic Assistance Number

    This program is authorized under sections 301(a) and 307 of the 
Public Health Service Act (42 U.S.C. sections 241(a) and 242l). The 
Catalog of Federal Domestic Assistance number is 93.943.

J. Where To Obtain Additional Information

    This and other CDC announcements can be found on the CDC home page 
Internet address--http://www.cdc.gov Click on ``Funding'' then ``Grants 
and Cooperative Agreements.'' NIH funding annoucements can be found on 
the NIH home page internet address--http://www.nih.gov Click on 
``Grants'' then ``NIH Guide for Grants and Contracts''.
    To obtain business management technical assistance, contact:

Dorimar Rosado, Grants Management Specialist, Grants Management

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Branch, Procurement and Grants Office, Centers for Disease Control and 
Prevention (CDC), Colgate Building, Room 3000, 2920 Brandywine Road, 
Mailstop K-69, Atlanta, GA 30341, Telephone: (770) 488-2738, Email 
address: [email protected]

    For program technical assistance, contact:

Mary Glen Fowler, MD, Chief, Mother-Child Transmission & Pediatric and 
Adolescent Studies Section, Epidemiology Branch, Division of HIV/AIDS 
Prevention Surveillance & Epidemiology, National Center for HIV, STD, 
TB Prevention, Centers for Disease Control and Prevention (CDC), 1600 
Clifton Road, NE., Mailstop E-45, Atlanta, Georgia 30333, Telephone: 
(404) 639-5190, E-mail: [email protected]

    Dated: April 30, 2002.
Sandra R. Manning,
Director, Procurement and Grants Office, Centers for Disease Control 
and Prevention (CDC).
[FR Doc. 02-12254 Filed 5-15-02; 8:45 am]
BILLING CODE 4163-18-P