[Federal Register Volume 61, Number 119 (Wednesday, June 19, 1996)]
[Notices]
[Pages 31121-31124]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-15558]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention
[Announcement Number 663]


Applied Research in Emerging Infections--Genetics of 
Antimicrobial Resistance and Novel Methods for Detection of Antiviral 
Resistance

Introduction

    The Centers for Disease Control and Prevention (CDC) is 
implementing a program for competitive cooperative agreement and/or 
research project grant applications to support applied research on 
emerging infections. CDC announces the availability of fiscal year (FY) 
1996 funds to provide assistance for a grant/cooperative agreement 
program to conduct research on the genetic analysis of antimicrobial 
resistance determinants.
    The CDC is committed to achieving the health promotion and disease 
prevention objectives of Healthy People 2000, a national activity to 
reduce morbidity and mortality and improve the quality of life. This 
announcement is related to the priority area of Immunization and 
Infectious Diseases. (For ordering a copy of Healthy People 2000, see 
the section WHERE TO OBTAIN ADDITIONAL INFORMATION.)

Authority

    This program is authorized under sections 301 and 317 of the Public 
Health Service Act, as amended (42 U.S.C. 241 and 247b).

Smoke-Free Workplace

    The CDC strongly encourages all grant recipients to provide a 
smoke-free workplace and to promote the nonuse of all tobacco products, 
and Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking 
in certain facilities that receive Federal funds in which education, 
library, day care, health care, and early childhood development 
services are provided to children.

Eligible Applicants

    Applications may be submitted by public and private, nonprofit and 
for-profit organizations and governments and their agencies. Thus, 
universities, colleges, research institutions, hospitals, other public 
and private organizations, including State and local governments or 
their bona fide agents, federally recognized Indian tribal governments, 
Indian tribes or Indian tribal organizations, and small, minority- and/
or women-owned businesses are eligible to apply.

Availability of Funds

    Approximately $250,000 is available in FY 1996 to fund up to three 
awards. It is expected that the average award will be $125,000, ranging 
from $80,000 to $250,000.
    It is expected that the awards will begin on or about September 30, 
1996, and will be made for a 12-month budget period within a project 
period of up to two years. Funding estimates may vary and are subject 
to change. Continuation awards within an approved project period will 
be made on the basis of satisfactory progress and availability of 
funds.

Purpose

    The purpose of the emerging infections extramural research program 
is to provide financial and technical assistance for applied research 
projects on emerging infections in the United States. As a component of 
the emerging infections extramural research program, the purpose of 
this grant/cooperative agreement announcement is to provide assistance 
for projects addressing the following two focus areas:
1. Mechanisms of Dissemination of Antimicrobial Resistance Genes
    The focus of the investigations should be the examination of the 
role of plasmids, transposons, and integrons in antimicrobial 
resistance gene dissemination, the natural variation of the nucleotide 
sequences of resistance genes, and the impact of those changes on the 
resistance phenotype mediated by the genes. This should include 
examination of the role of antimicrobial use in institutions and its 
effect on gene dissemination. Assistance under this focus area will be 
provided for projects specifically addressing either of the following:
    a. Improving understanding of the mechanisms by which vancomycin 
resistance genes in enterococci or genes encoding extended-spectrum 
- lactamases in Klebsiella pneumoniae are spread in hospitals 
or other healthcare institutions (including nursing homes and clinics) 
and become part of the endemic flora of the institution.
    b. Improving understanding of the mechanisms by which macrolide 
resistance genes (such as those encoding erythromycin resistance) are 
acquired and disseminated in Streptococcus pneumoniae in communities.
    2. Antiviral Susceptibility Determination Methods: Development of 
improved methods for measuring the susceptibility of herpes simplex 
virus (HSV) isolates to acyclovir. Current methods for measuring drug

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susceptibility of HSV isolates are labor-intensive, expensive, and have 
not been standardized. These shortcomings stand as impediments to 
surveillance for acyclovir-resistant HSV or resistance in other viral 
pathogens. Specifically, assistance will be provided for projects 
focusing on development of assays based on novel methods or approaches 
for measuring the susceptibility of HSV to acyclovir. Such assays 
should be capable of providing results comparable to current plaque 
reduction and dye-uptake assays.
    Applicants may submit separate applications for projects under one 
or both focus areas.

Program Requirements

    Recipients may separately apply and receive support for projects 
under one or both of the two focus areas. In conducting activities to 
achieve the purpose of this program, the recipient shall be responsible 
for the activities under A.1. or A.2. (depending upon which focus areas 
the recipient applies and receives support for) and CDC shall be 
responsible for conducting activities under B., below:

A. Recipient Activities

1. Mechanisms of Dissemination of Antimicrobial Resistance Genes
    a. Select study sites: Study sites may include (a) one or more 
hospitals or related health care institutions known to have endemic or 
emerging problems with antimicrobial-resistant organisms in which 
extensive monitoring of antimicrobial-resistant strains has been 
conducted or (b) communities with extensive active surveillance.
    b. Collect isolates with corresponding epidemiologic and clinical 
data: Assure that the isolates are well characterized with respect to 
phenotype, genotype, and mode of transmission from patient to patient. 
Collect bacterial strain typing information such as that derived by 
pulsed-field gel electrophoresis (PFGE), arbitrary primed polymerase 
chain reaction (PCR), restriction fragment length polymorphism (RFLP), 
plasmid fingerprinting, serotyping, or other highly discriminatory 
strain typing methods. Obtain antibiograms expressed as minimal 
inhibitory concentrations (MICs) of common antibiotics. One example of 
an appropriate approach to collection of isolates and data would be to 
assemble a series of isolates of vancomycin-resistant enterococci (VRE) 
from a single hospital with the corresponding PFGE data documenting the 
routes of transmission of the isolates among patients in the 
institution. The overall rates of infections over several years and the 
diversity of strains present in the institutions or communities would 
be determined. This would presumably involve microbiology laboratories, 
infection control practitioners (for health care institutions), public 
health officials, and epidemiologists. Additionally, collection of data 
regarding antimicrobial use (expressed as Defined Daily Doses per 1000 
patient-days) by area of the institution (e.g., intensive care unit or 
other inpatient ward) or in communities would be useful.
    c. Characterize the resistance determinants present by phenotypic 
and molecular methods: Obtain MICs to an extended array of 
antimicrobial agents to classify the phenotype (e.g., teicoplanin to 
distinguish VanA from VanB). Determine strain types (when appropriate), 
the presence of plasmids or other genetic elements, and the presence of 
resistance genes in the strains as identified by using DNA probes or 
specific PCR, LCR, or other genetic assays.
    d. Monitor transmission and evaluate data: Characterize the 
resistance genes present in the isolates, the modes of genetic exchange 
of the resistance determinants among isolates in the institutions or 
communities, and determine whether changes in the DNA or amino acid 
sequences of the genes are associated with broadening of the phenotype 
of the isolates carrying the genes. Consider the influence of 
antimicrobial use on frequency and mode of gene transmission and on 
changes in the phenotype of the isolates. Depending on the studies 
conducted, questions that could be addressed include: (1) Is an initial 
period of plasmid transfer among organisms followed by dissemination of 
a transposable element to multiple plasmids in strains of enterococci 
resulting in the vancomycin resistance phenotype being present in 
multiple strains of enterococci (as evidenced by widely divergent 
pulsed-field gel electrophoresis types)? (2) Do changes in the sequence 
of vanB correlate with increased resistance to teicoplanin? (3) Do the 
mode of transfer and the phenotype vary by antimicrobial use patterns 
in the institution or in certain wards of the institution?
    e. Disseminate research findings: Disseminate research results by 
appropriate methods such as publication in journals, presentation at 
meetings and conferences, etc.
2. Antiviral Susceptibility Determination Methods
    a. Study isolates: Identify a source of HSV isolates for study. 
Ideally, this should include isolates from fresh clinical specimens 
that can be tested in parallel with the plaque reduction or dye uptake 
methods and for which acyclovir resistance has previously been 
documented.
    b. Devise a novel assay for determining the level of acyclovir 
susceptibility of clinical HSV isolates: Establish a quality control 
system to insure the reproducibility of the assay. A quality control 
strain of HSV should be designated as part of the testing method and 
data showing its effectiveness should be established. A useful novel 
assay should be at least equivalent in performance and (ideally) 
substantially less expensive than current assays. The new method should 
be adaptable to a high-throughput, semi- automated format. Establish 
criteria for designating HSV isolates as ``susceptible'' or 
``resistant'' to acyclovir.
    c. Evaluate the performance of the new assay in comparison with the 
plaque reduction assay. To be useful for surveillance of resistance, 
any new assay should be substantially equivalent to those in current 
use (Am. J. Med. 73:380-382,1982).

B. CDC Activities

1. Research Project Grants
    A research project grant is one in which substantial programmatic 
involvement by CDC is not anticipated by the recipient during the 
project period. Applicants for grants must demonstrate an ability to 
conduct the proposed research with minimal assistance, other than 
financial support, from CDC. This would include possessing sufficient 
resources for clinical, laboratory, and data management services and a 
level of scientific expertise to achieve the objectives described in 
their research proposal without substantial technical assistance from 
CDC.
2. Cooperative Agreements
    In a cooperative agreement, CDC will assist recipients in 
conducting the proposed research. The application should be presented 
in a manner that demonstrates the applicant's ability to address the 
research problem in a collaborative manner with CDC. In addition to the 
financial support provided, CDC will collaborate by (1) providing 
technical assistance in the design and conduct of the research; (2) 
performing selected laboratory tests as appropriate; (3) participate in 
data management, the analysis of research data, and the interpretation 
and presentation of research findings; and

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(4) providing biological materials (e.g., strains) as necessary for 
studies, etc.

C. Determination of Which Instrument to Use

    Applicants must specify the type of award for which they are 
applying, either grant or cooperative agreement. CDC will review the 
applications in accordance with the Evaluation Criteria. Before issuing 
awards, CDC will inform the proposed grantee whether a grant or 
cooperative agreement is the appropriate instrument based upon the need 
for substantial CDC involvement in the project.

Notice of Intent To Apply

    In order to assist CDC in planning for and executing the evaluation 
of applications submitted under this Program Announcement, all parties 
intending to submit an application are requested to inform CDC of their 
intention to do so at their earliest convenience prior to the 
application due date. Notification should include 1) name and address 
of institution, 2) name, address, and phone number of contact person, 
and 3) under which focus area(s) application(s) will be submitted. 
Notification should be provided to Greg Jones, M.P.A., by facsimile 
(404) 639-4195, E-mail [email protected] or postal mail at 
National Center for Infectious Diseases, Centers for Disease Control 
and Prevention, 1600 Clifton Road, NE., Mailstop C-19, Atlanta, Georgia 
30333.

Application Process

    Applicants may apply for assistance for projects in one or both of 
the specific programmatic focus areas identified under Purpose and 
Program Requirements above. If applying for assistance for more than 
one of the two focus areas, a separate and complete application must be 
submitted for each project/focus area.

Evaluation Criteria

    The applications will be reviewed and evaluated according to the 
following criteria:
    1. Background and Need (20 points): Extent to which applicant's 
discussion of the background for the proposed project demonstrates a 
clear understanding of the purpose and objectives of this grant/
cooperative agreement program. Extent to which applicant illustrates 
and justifies the need for the proposed project that is consistent with 
the purpose and objectives of this grant/cooperative agreement program.
    2. Capacity (40 points total):
    a. Extent to which applicant describes adequate resources and 
facilities (both technical and administrative) for conducting the 
project. (10 points)
    b. Extent to which applicant documents that professional personnel 
involved in the project are qualified and have past experience and 
achievements in research related to that proposed as evidenced by 
curriculum vitae, publications, etc. (20 points)
    c. Extent to which applicant includes letters of support from non-
applicant organizations, individuals, etc. Extent to which the letters 
clearly indicate the author's commitment to participate as described in 
the operational plan. (10 points)
    3. Objectives and Technical Approach (40 points total):
    a. Extent to which applicant describes specific objectives of the 
proposed project which are consistent with the purpose and goals of 
this grant/cooperative agreement program and which are measurable and 
time-phased. (10 points)
    b. Extent to which applicant presents a detailed operational plan 
for initiating and conducting the project, which clearly and 
appropriately addresses all Recipient Activities. Extent to which 
applicant clearly identifies and describes appropriate study sites (per 
Recipient Activities 1.a.) or HSV isolates (per Recipient Activities 
2.a.). Extent to which applicant clearly identifies specific assigned 
responsibilities for all key professional personnel. Extent to which 
the plan clearly describes applicant's technical approach/methods for 
conducting the proposed studies and extent to which the plan is 
adequate to accomplish the objectives. Extent to which applicant 
describes specific study protocols or plans for the development of 
study protocols that are appropriate for achieving project objectives.
    If the proposed project involves human subjects, 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:
    (1) The proposed plan for the inclusion of both sexes and racial 
and ethnic minority populations for appropriate representation.
    (2) The proposed justification when representation is limited or 
absent.
    (3) A statement as to whether the design of the study is adequate 
to measure differences when warranted.
    (4) 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 
will be documented. (see Other Requirements for additional information 
regarding this requirement for research projects). (15 points)
    c. Extent to which applicant describes adequate and appropriate 
collaboration with CDC and/or others during various phases of the 
project. (10 points)
    d. Extent to which applicant provides a detailed and adequate plan 
for evaluating study results and for evaluating progress toward 
achieving project objectives. (5 points)
    4. Budget (not scored):
    Extent to which the proposed budget is reasonable, clearly 
justifiable, and consistent with the intended use of grant/cooperative 
agreement funds.
    5. Human Subjects (not scored):
    If the proposed project involves human subjects, whether or not 
exempt from the DHHS regulations, the extent to which adequate 
procedures are described for the protection of human subjects. Note: 
Objective Review Group (ORG) recommendations on the adequacy of 
protections include: (1) Protections appear adequate and there are no 
comments to make or concerns to raise, or (2) protections appear 
adequate, but there are comments regarding the protocol, or (3) 
protections appear inadequate and the ORG has concerns related to human 
subjects, or (4) disapproval of the application is recommended because 
the research risks are sufficiently serious.

Executive Order 12372 Review

    This program is not subject to Executive Order 12372, 
Intergovernmental Review of Federal Programs.

Public Health System Reporting Requirements

    This program is not subject to the Public Health System Reporting 
Requirements.

Catalog of Federal Domestic Assistance Number

The Catalog of Federal Domestic Assistance Number is 93.283.

Other Requirements

Paperwork Reduction Act

    Projects that involve the collection of information from ten or 
more individuals and funded by the grant/cooperative agreement will be 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act.

Human Subjects

    If the proposed project involves research on human subjects, the 
applicant must comply with the

[[Page 31124]]

Department of Health and Human Services Regulations (45 CFR Part 46) 
regarding the protection of human subjects. Assurance must be provided 
to demonstrate that the project will be subject to initial and 
continuing review by an appropriate institutional review committee. In 
addition to other applicable committees, Indian Health Service (IHS) 
institutional review committees also must review the project if any 
component of IHS will be involved or will support the research. If any 
American Indian community is involved, its tribal government must also 
approve that portion of the project applicable to it. The applicant 
will be responsible for providing evidence of this assurance in 
accordance with the appropriate guidelines and form provided in the 
application kit.

Women, Racial and Ethnic Minorities

    It is the policy of the Centers for Disease Control and Prevention 
(CDC) and Agency for Toxic Substances and Disease Registry (ATSDR) to 
ensure that individuals of both sexes and the various racial and ethnic 
groups will be included in CDC/ATSDR-supported research projects 
involving human subjects, whenever feasible and appropriate. Racial and 
ethnic groups are those defined in OMB Directive No. 15 and include 
American Indian, Alaskan Native, Asian, Pacific Islander, Black, and 
Hispanic. Applicants shall ensure that women, racial and ethnic 
minority populations are appropriately represented in applications for 
research involving human subjects. Where clear and compelling rationale 
exists that inclusion is inappropriate or not feasible, this situation 
must be explained as part of the application. This policy does not 
apply to research studies when the investigator cannot control the 
race, ethnicity and/or sex subjects. Further guidance to this policy is 
contained in the Federal Register, Vol. 60, No. 179, pages 47947-47951, 
dated Friday, September 15, 1995.

Application Submission and Deadline

    The original and two copies of each application Form PHS-5161-1 
(revised 7/92, OMB Control Number 0937-0189) must be submitted to 
Sharron P. Orum, Grants Management Officer, Grants Management Branch, 
Procurement and Grants Office, Centers for Disease Control and 
Prevention (CDC), 255 East Paces Ferry Road, NE., Room 300, Mailstop E-
18, Atlanta, Georgia 30305, Attention: Marsha Driggans, on or before 
August 5, 1996:
    1. Deadline: Applications shall be considered as meeting the 
deadline if they 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 objective 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.)
    2. Late Applications: Applications which do not meet the criteria 
in 1.a. or 1.b. above are considered late applications. Late 
applications will not be considered in the current competition and will 
be returned to the applicant.

Where To Obtain Additional Information

    A complete program description and information on application 
procedures are contained in the application package. An application 
package and business management and technical assistance may be 
obtained from Marsha Driggans, Grants Management Specialist, Grants 
Management Branch, Procurement and Grants Office, Centers for Disease 
Control and Prevention (CDC), 255 East Paces Ferry Road, NE., Mailstop 
E-18, Room 300, Atlanta, Georgia 30305, telephone (404) 842-6523, E-
mail [email protected], facsimile (404) 842-6513.
    Programmatic technical assistance may be obtained from Dr. Fred C. 
Tenover, Hospital Infections Program, National Center for Infectious 
Diseases, Centers for Disease Control and Prevention (CDC), 1600 
Clifton Road, NE., Mailstop G-08, Atlanta, Georgia 30333, E-mail 
[email protected], telephone (404) 639-3246.
    Please refer to Announcement Number 663 when requesting information 
regarding this program.
    Important Notice: Atlanta, Georgia, will be the host of the 1996 
Summer Olympics Games, July 19 through August 4, 1996. As a result of 
this event, it is likely that the Procurement and Grants Office (PGO), 
CDC, may experience delays in the receipt of both regular and overnight 
mail deliveries. Contacting PGO employees during this time frame may 
also be hindered due to the possible telephone disruptions. To the 
extent authorized, please consider the use of voice mail, E-mail, and 
facsimile transmission to the maximum extent practicable. However, do 
not fax lengthy documents or grant applications.
    You may obtain this announcement from one of two Internet sites on 
the actual publication date: CDC's homepage at http://www.cdc.gov or at 
the Government Printing Office homepage (including free on-line access 
to the Federal Register at http://www.access.gpo.gov).
    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) referenced in the Introduction 
through the Superintendent of Documents, Government Printing Office, 
Washington, DC 20402-9325, telephone (202) 512-1800.

    Dated: June 11, 1996.
Joseph R. Carter,
Acting Associate Director for Management And Operations, Centers for 
Disease Control and Prevention (CDC).
[FR Doc. 96-15558 Filed 6-18-96; 8:45 am]
BILLING CODE 4163-18-P