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

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

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.

---------------------------------------------------------------------------

\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.

---------------------------------------------------------------------------

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: [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