[Federal Register Volume 63, Number 131 (Thursday, July 9, 1998)]
[Notices]
[Pages 37117-37121]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-18199]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention
[Program Announcement 98094]


Measuring the Risk for Transmission and Sequelae From Chlamydial 
Disease in the Era of Amplification Testing; Notice of Availability of 
Funds for Fiscal Year 1998

A. Purpose

    The Centers for Disease Control and Prevention (CDC) announces the 
availability of fiscal year (FY) 1998 funds for a cooperative agreement 
program on Chlamydia trachomatis (Ct) infection in order to enhance 
strategies for prevention of STD-related infertility. Please reference 
the Attachment for background information relevant to this program 
announcement. This program addresses the ``Healthy People 2000'' 
priority area 19, Sexually Transmitted Diseases.
    The purpose of this research program is to gain a better 
understanding of the risk for Ct disease transmission and sequelae in 
the context of new, highly sensitive diagnostic technologies. When 
patient specimens are subjected to both standard non-amplification 
tests (culture, enzyme immunoassay [EIA], direct fluorescent-antibody 
[DFA], DNA hybridization) and highly sensitive nucleic acid 
amplification tests such as the polymerase chain reaction [PCR], ligase 
chain reaction [LCR], or transcription mediated amplification [TMA], 
some proportion of patient specimens will test positive by one 
diagnostic measure, and negative by another. Rarely, a specimen will 
test positive by standard non-amplification tests and negative by more 
sensitive tests (+/-). Much more commonly, a specimen which is negative 
by standard diagnostic testing will test positive by highly sensitive 
nucleic acid amplification tests (-/+). Such discordant specimens have 
usually been classified as true positives, or false positives on the 
basis of a highly sensitive third confirmatory test targeting a 
different portion of the Ct

[[Page 37118]]

genome [(-/+/+) or (-/+/-) respectively].
    It is not clear to what extent (-/+) discordant specimens (positive 
by amplification test only) reflect collection of low quality specimens 
from infected individuals, a phase in the natural disease course of Ct 
infection, a subgroup of true positive tests (i.e., specimens from some 
infected persons will always be discordant), or false positive test 
results. If poor quality specimen collection is the dominant 
explanation, it is possible that discordant tests result from a small 
organism load detectible only by highly sensitive tests. If infectious 
stage, immunity, or menstrual cycle play a role, discordant specimens 
may be due to such factors as early infection, previous infection, 
partially treated infection, non-viable organisms, or spontaneously 
resolving infection. It is not known if persons with discordant 
specimens have the same risk for disease transmission and development 
of sequelae as those with concordant specimens. With limited resources 
for screening it will be important to define criteria to determine the 
adequacy of collected specimens, and to be able to measure both the 
risk of disease transmission and the risk for sequelae among persons 
whose specimens test positive by nucleic acid amplification tests in 
order to weigh the potential benefit against the added cost and 
technical demands of screening with amplification tests.
    In addition to standard methods of observational data analysis, CDC 
envisions that data from this study will be used to generate parameter 
estimates to supplement later work with mathematical models to estimate 
(a) changes in disease transmissibility over the course of infection, 
(b) estimates of the critical interval between disease acquisition and 
development of irreversible sequelae, and (c) the optimal screening 
intervals to most efficiently interrupt disease transmission and 
prevent the development of sequelae in diverse epidemiologic 
situations.

B. Eligible Applicants

    Applications may be submitted by public and private non-profit 
organizations and by governments and their agencies; that is, 
universities, colleges, research institutions, hospitals, State and 
local governments or their bona fide agents, and federally recognized 
Indian tribal governments, Indian tribes, or Indian tribal 
organizations.

    Note: Public Law 104-65 states that an organization described in 
section 501(c)(4) of the Internal Revenue Code of 1986 that engages 
in lobbying activities is not eligible to receive Federal funds 
constituting an award, grant, cooperative agreement, contract, loan, 
or any other form.

C. Availability of Funds

    Approximately $700,000 is available in FY 1998 to fund 
approximately two awards. It is expected that the average award will be 
$350,000, ranging from $300,000 to $400,000. It is expected that the 
awards will begin on or about September 30, 1998 and will be made for a 
12-month budget period within a project period of up to 3 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.

Funding Preferences

    Funding preferences may be given to (1) applications from 
particular geographic locations in order to achieve geographic 
balance or (2) applications from sites which differ from others in 
the prevalence of Ct (to select study sites diverse in stage of 
prevention program and phase in the Ct epidemic).

D. Program Requirements

    In conducting activities to achieve this program, the recipient 
shall be responsible for the activities listed under 1. (Recipient 
Activities), and CDC shall be responsible for conducting activities 
listed under 2. (CDC Activities).

1. Recipient Activities

    During the first 3-6 months of the study period, funded recipients 
will work as a group to develop a protocol that synthesizes ideas 
submitted by each funded site. Recipients will implement the protocol 
during the remaining months of the study period.
    a. Collaborate on Study Design: Recipients will meet together to 
collectively develop a study protocol to be adopted across 
collaborating recipient sites. Collaborative activities will include 
(but may not be restricted to) the development of common data 
collection instruments, common specimen collection protocols, and 
common data management procedures.
    b. Collaborate During Implementation of the Study: Collaboration 
will include: (1) communication regarding study progress; and (2) 
participation in across-site quality control procedures, and in 
regularly scheduled meetings and conference calls.
    c. Conduct Productive and Scientifically Sound Studies: Recipients 
will identify, recruit, obtain informed consent forms, and enroll and 
follow to completion a minimum number of participants as specified by 
the study design and sample size requirements. Recipients will perform 
laboratory tests as determined by the study protocol, and will follow 
study participants over time as determined by the protocol.
    d. Carry Out Site-Specific Analyses: Recipients may conduct 
analyses and publish manuscripts using data collected at their own 
site.
    e. Share Data and Specimens: Recipients will take responsibility 
for cleaning and/or editing locally collected data, and sharing data 
and (when appropriate) specimens to allow for analysis of specific 
research questions.
    f. Collaborate on Publication of Results: Researchers will develop 
at least one publication recording results from both study sites for a 
peer-reviewed journal.
    g. Meet the requirements for approval of the study protocol 
specified by the recipients' local institutional human investigation 
review board (IRB).

2. CDC Activities

    a. Provide Technical Assistance and Coordination: CDC staff will 
provide current scientific and programmatic information relevant to the 
project, and may provide technical guidance in the design and conduct 
of the research (including study design, operations and evaluation, and 
development and dissemination of study protocols, consent forms, and 
questionnaires). CDC will provide coordination of the project and will 
assist in designing a data management system.
    b. Analyze Study Data and Coordinate Publication: CDC staff may 
assist in cross-site analyses of data gathered over the course of the 
study and may collaborate with recipients in developing at least one 
overall publication describing the multi-site project results.
    c. Share Data and Specimens: CDC staff may coordinate the 
dissemination of data and specimens (when appropriate) to participating 
sites.
    d. Monitor and Evaluate Scientific and Operational Accomplishments 
of the Project: This will be accomplished through periodic site visits, 
telephone calls, and review of technical reports and interim data 
analysis.
    e. Meet the requirements for approval of the study protocol 
specified by the CDC's human investigation review board (IRB).

E. Application Content

    Applicants should use the following study questions, as well as 
information in the Program Requirements, Other Requirements, and 
Evaluation Criteria

[[Page 37119]]

sections of this announcement to develop the application content. 
Applications will be evaluated on the criteria listed, so it is 
important to follow them in laying out your program plan. The narrative 
should be no more than 25 double-spaced pages, printed on one side, 
with one inch margins, and unreduced font. Please include a table of 
contents.
    Applicants should develop a research proposal outlining a single 
integrated study to address as many of the following study questions as 
they deem feasible, and consider study designs which would permit 
consideration of how patient gender, specimen type, and Ct ``epidemic 
phase'' (as evidenced by Ct prevalence, and trends in disease) affect 
the interpretation of the results. Site-specific differences in the Ct 
epidemic and local prevention program development may affect the 
proportion of collected specimens which come from prevalent versus 
incident cases, or symptomatic versus asymptomatic cases; these factors 
may influence the likelihood that a specimen tests positive by nucleic 
acid amplification test (NAAT) only, as well as modifying the risk for 
transmission and sequelae among infected persons. Because of this 
potential confounding, applicants for each site must demonstrate a 
sample size adequate to allow the chief research questions to be 
addressed conclusively at their (single) site (i.e. without relying on 
an aggregate data analysis).
    Applicants must give evidence (in the form of a letter of 
agreement) that they will conduct their proposed study in collaboration 
with a State or local health department. Applications from State and 
local health departments must include evidence (in the form of a letter 
of agreement) that they will collaborate with a research institution.
    Applicants should include a summary abstract at the front of the 
application listing their name and the proposed participating 
institutions, and outlining (in 300 words or less) the key, 
distinguishing methodologic and technical aspects of the proposed 
study.
    The applicant should provide a line-item annualized budget with a 
budget narrative that justifies each line item and which anticipates 
the salaries of appropriate staff, travel for principal investigator(s) 
and project supervisor(s) to meet with CDC three times during the first 
year and two times per year thereafter, as well as costs related to the 
diagnosis and management of Ct and other concurrently diagnosed STDs. 
This could include the cost of anticipated partner tracing activities, 
longitudinal participation, and other needs.

Study Questions

    (1) Is there a differential risk for disease transmission and 
development of the sequelae from Ct disease in persons with 
discordant compared to concordant test results? Are there laboratory 
correlates, such as quantification of bacterial load or a test for 
viability, which could be used to identify those at most risk for 
transmission or sequelae?
    (2) What factors influence detection of Chlamydial antigen and 
the reproducibility of results, and how does detection of Ct disease 
by non-amplification and amplification methods vary over the course 
of infection? Factors which could be explored include the quality of 
the biologic specimen obtained, phase in the menstrual cycle or 
other characteristics of the infected person such as immune status, 
relative timing within the natural history of untreated Ct 
infection, co infection with other sexually transmitted disease(s), 
or the order in which specimens are collected when multiple 
specimens are obtained from the same person? To what extent are 
these factors influenced by the type of specimen collected 
(cervical, vaginal, urine)?
    (3) What are the defining characteristics of false positive 
specimens (that subset of discordant patient specimens which test 
negative when subjected to a third, confirmatory test)? Are there 
any laboratory or clinical factors which could be used to predict 
those specimens likely to be false positives (proximity in testing 
wells, identical genotypes, low amplicon count)? Does the frequency 
of measurable clinical outcomes--such as evidence of transmission 
within a sexual partnership, or development of sequelae--concur with 
the ``negative'' classification such specimens would be accorded by 
a third confirmatory test?

    Applicants are also encouraged to develop secondary study 
hypotheses which may be addressed at their own or all collaborating 
sites, depending on the level of interest among the collaborating 
investigators.

F. Submission and Deadline

1. Applications

    Applicants should use Form PHS 398 (OMB Number 0925-0001) and 
adhere to the ERRATA Instruction sheet for form PHS-398 contained in 
the application kit. Please submit an original and five copies on or 
before August 14, 1998 to: Kathy Raible, Grants Management Specialist, 
Procurement and Grants Office, Centers for Disease Control and 
Prevention (CDC), 255 East Paces Ferry Road, NE, Room 300, M/S E-15, 
Atlanta, Georgia 30305.

2. Deadlines

    A. Applications will meet the deadline if they are either:
    1. Received on or before the deadline date; or
    2. Sent on or before the deadline date and received in time for 
submission to the objective review committee. (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 accepted as proof of timely mailing.)
    B. Applications that do not meet the criteria in A.1. or A.2. above 
are considered late applications. Late applications will not be 
considered in current competition and will be returned to the 
applicant.

G. Evaluation Criteria

    Each application will be evaluated individually against the 
following criteria by an independent reviewer group appointed by CDC:

1. Background and Objectives (10 points)

    Depth of knowledge regarding Ct transmission, including 
demonstrated understanding of the strengths and limitations of previous 
studies examining the issue. Demonstrated understanding of how 
introduction of new diagnostic tests may affect the scientific 
communities' understanding of transmissibility and could shape public 
health recommendations for screening, partner notification and patient 
follow up.
    The extent to which the applicant provides a set of research 
objectives that are realistic, specific, and measurable, and reflect an 
optimal integration of the study questions outlined earlier in this 
announcement. Points will be awarded for attention to each of the 
possible modifying variables: (a) gender; (b) specimen type; and (c) 
epidemic phase of Ct in the study population.

2. Site Selection/Study Population (10 points)

    The extent to which the selected study site and study population 
(including the choice of whether or not to include symptomatic persons) 
will enable the results from this research to be generalizeable to 
other settings or populations likely to be screened for Ct. 
Applications will be scored on the likely feasibility of completing the 
research in the proposed population. Highest points will be given to 
applications demonstrating the capacity to enroll persons at risk for 
Ct infection in numbers adequate to address a maximal number of 
research questions at a single site, and to undertake longitudinal 
follow-up of these persons as required by the study design.
    The feasibility of utilizing the proposed study population will be 
evaluated on the basis of the applicant's:

[[Page 37120]]

(a) outline of STD services available in their jurisdiction; (b) 
specification of the type of setting in which the proposed study would 
be conducted (e.g., family planning clinic, sexually transmitted 
diseases clinic, primary care clinic), and health care delivery system 
within which this setting exists (managed care, federally funded 
facility, University affiliated); (c) description of the population 
accessible at the proposed study site, including the number of people 
seen per month and per annum, with a tabulation by gender, age group 
<20, 20-24, 25-29, 30-34, 35-44 and ethnicity; and (d) description of 
the prevalence of Ct in population attending the proposed study site 
stratified by these same variables, with specification of whether study 
subjects will be limited to asymptomatic persons, or will include 
symptomatic individuals. The applicant's decision to include or exclude 
symptomatic individuals will be judged on the basis of the rationale 
provided, and demonstrated understanding of how such inclusion or 
exclusion might be expected to influence sample size requirements, and 
generalizeability of the study findings.

3. Methods (25 points)

    Applications will be evaluated with regard to the appropriateness, 
efficiency, and adequacy of the research design and proposed 
methodology to answer the research questions. This evaluation will be 
based on the extent to which the application: (a) Describes a well 
conceived study design in clear terms; (b) describes the likely range 
of explanatory and outcome variables in each component of the study; 
(c) specifies appropriate comparison groups for analysis within each 
study component; (d) provides explicit outlines of sampling schemes, 
sample size calculations (including all assumptions made for the 
purposes of the calculations), and plans for handling sampling 
biases;1 (e) gives evidence of access to the relevant data 
sources and the plan for data collection; and (f) clearly describes the 
specific quantitative and qualitative analytic techniques to be used to 
address the research questions.
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    \1\ Although applicants may describe a study which includes 
specimen collection and testing for the presence of other STDs (such 
as Neisseria gonorrhea), sample size estimates should be made with 
reference only to Chlamydia trachomatis prevalence and detection.
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4. Public Health Applicability (10 points)

    Points will be awarded to study proposals which will utilize 
laboratory methods which could be easily applied to practice in public 
health clinical or laboratory settings with a minimum of additional 
training, resources, and infrastructure. For example, applications 
describing fast, practical means of assessing specimen adequacy and 
quantifying bacterial load would be awarded points because of the 
potential application of these techniques if these parameters are found 
to be key factors influencing the interpretation of discordant 
specimens and the risk for transmission and sequelae.

5. Quality Assurance (10 points)

    The extent to which the applications present a sound plan (with 
specific procedures) to monitor the quality and consistency of clinical 
and laboratory specimens and data collection.

6. Research Capacity (25 points)

    Applicants will be judged on their overall ability to perform the 
technical aspects of the project which include: (a) The availability 
and identification of study personnel with the needed experience and 
competence in research design, conduct, data collection (observational, 
clinical, and laboratory), analysis, and dissemination; (b) assurance 
that staff can be hired within 3 months of award of monies; (c) the 
availability of adequate laboratory, clinical, and administrative 
facilities and resources for the conduct of the proposed research, 
including a letter of agreement from the director of the laboratory 
services which will be conducting related laboratory studies; (d) 
documentation of access to the necessary study population including a 
letter of agreement from the administrators of proposed enrollment 
site; (e) plans for the administration of the project(s), including a 
detailed and realistic time line for the specified activities; (f) 
details of proposed collaboration between academia, federally funded 
clinics, laboratories, state and local health departments, etc., 
including letters of agreement between institutions; (g) demonstration 
of the applicant's ability, and willingness to collaborate in study 
design and analysis, including use of common study protocols and data 
collection instruments, and sharing data and (when appropriate) 
specimens; and (h) access to cost-efficient, locally available staff to 
complete data entry and data management.

7. Budget (not scored)

    Budgets will be evaluated on the appropriateness of budget 
estimates in relation to the proposed research, and the extent to which 
the budget is reasonable, clearly justified, and consistent with the 
intended use of funds.

8. Human Subjects (not scored)

    Does the application adequately address the requirements of 45 CFR 
Part 46 for the protection of human subjects?
____ Yes ____ No    Comments: ________

9. Inclusion of Women, Ethnic, and Racial Groups (10 points)

    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: (a) The proposed plan 
for the inclusion of both sexes and racial and ethnic minority 
populations for appropriate representation; (b) The proposed 
justification when representation is limited or absent; (c) A statement 
as to whether the design of the study is adequate to measure 
differences when warranted; and (d) A statement as to whether the plans 
for recruitment and outreach for study participants include the process 
of establishing partnerships with community(ies) and recognition of 
mutual benefits.

H. Other Requirements

1. Technical Reporting Requirements

    An original and two copies of annual progress reports must be 
submitted no later than 30 days after the end of each budget period. An 
original and two copies of a financial status report (FSR) are required 
no later than 90 days after the end of each budget period. A final 
progress report and FSR are due no later than 90 days after the end of 
the project period. All reports are submitted to the Grants Management 
Branch, Procurement and Grants Office, CDC.

2. For Other Requirements, see the following enclosures

AR98-1  Human Subjects Requirements
AR98-2  Requirements for Inclusion of Women and Racial and Ethnic 
Minorities in Research
AR98-4  HIV/AIDS Confidentiality Provisions
AR98-5  HIV Program Review Panel Requirements
AR98-9  Paperwork Reduction Act Requirements
AR98-10  Smoke-Free Workplace Requirements
AR98-11  Healthy People 2000
AR98-12  Lobbying Restrictions
AR98-14  Accounting System Requirements

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I. Authority and Catalog of Federal Domestic Assistance Number

    This program is authorized under sections 318 and 318A of the 
Public Health Service Act, 42 U.S.C. sections 247c and 247c-1, as 
amended. The Catalog of Federal Domestic Assistance number is 93.941.

J. Where To Obtain Additional Information

    A complete program description, information on application 
procedures, an application package, and business management technical 
assistance may be obtained from Kathy Raible, Grants Management 
Specialist, Grants Management Branch, Procurement and Grants Office, 
Centers for Disease Control and Prevention (CDC), 255 East Paces Ferry 
Road, NE, Room 300, Mail Stop E-15, Atlanta, Georgia 30305, telephone 
(404) 842-6649, or via email at: <[email protected]>.
    Programmatic technical assistance may be obtained from Julie 
Schillinger, MD, MSc, Division of STD Prevention, NCHSTP, CDC, 1600 
Clifton Road; Mailstop E-02, Atlanta, Georgia 30333, telephone (404) 
639-8368, or via email at: <[email protected]>.
    This and other CDC announcements can be found on the CDC homepage 
(http://www.cdc.gov) under the ``Funding'' section. For your 
convenience, you may be able to retrieve a copy of the PHS Form 398 
from (http://www.nih.gov/grants/funding/phs398/phs398.html).

Please Refer to Announcement Number 98094 When Requesting Information 
and Submitting an Application.

    CDC will not send application kits by facsimile or express mail.
    Potential applicants may obtain a copy of ``Healthy People 2000'' 
(Full Report, Stock No. 017-001-00474-0) or ``Healthy People 2000'' 
(Summary Report, Stock No. 017-001-00473-1) through the Superintendent 
of Documents, Government Printing Office, Washington, DC 20402-9325, 
telephone (202) 512-1800.

    Dated: July 2, 1998.
John L. Williams,
Director, Procurement and Grants Office.
[FR Doc. 98-18199 Filed 7-8-98; 8:45 am]
BILLING CODE 4163-18-P