[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="">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
[[Page 37121]]
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: kcr8@cdc.gov>.
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: jus8@cdc.gov>.
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
