[Federal Register Volume 67, Number 90 (Thursday, May 9, 2002)]
[Notices]
[Pages 31312-31315]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-11558]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

[Program Announcement 02167]


``Phase I Study To Assess The Safety, Tolerability, 
Immunogenicity, And Shedding Of Attenuated Measles Vaccine Administered 
As A Single Intranasal Dose To Healthy Adults''; Notice of Availability 
of Funds

A. Purpose

    The Centers for Disease Control and Prevention (CDC) announces the 
availability of fiscal year (FY) 2002 funds for a cooperative agreement 
program for ``Phase I Study to Assess the Safety, Tolerability, 
Immunogenicity, and Shedding of Attenuated Measles Vaccine Administered 
as a Single Intranasal Dose to Healthy Adults.'' This program addresses 
the ``Healthy People 2010'' focus area ``Immunization and Infectious 
Diseases'' and ``Medical Product Safety''.
    The purpose of the program is to conduct a double blinded, 
randomized, placebo controlled, 2-step, single-center study of 
intranasal administration of attenuated measles vaccine in healthy 
adults to assess safety and immunogenicity of vaccine, tolerability of 
vaccination, and shedding of vaccine virus.
Research Objectives
Primary
    1. To determine the safety and tolerability of live attenuated 
measles vaccine administered intranasally (IN) to healthy adults.
    2. To compare the serum antibody responses elicited following IN 
versus subcutaneous (SC) administration of live attenuated measles 
vaccine, using standard methods (plaque-reduction neutralization titers 
and ELISAs).
Secondary
    1. To measure the incidence of measles vaccine viral shedding 
following vaccination.
    2. To explore the utility of mucosal antibody measurements in 
evaluating responses to measles immunization.

Background

    Measles continues to be a major source of morbidity and mortality 
in developing countries despite the availability of an effective 
vaccine. Expanded immunization programs are hampered by the fact that 
until now there has only been a parenteral vaccine available. 
Inappropriate vaccination procedures can lead to injection site 
infections, nerve damage or transmission of blood-borne pathogens.
    Mucosal immunization has proven to be an effective and non-invasive 
manner by which to induce a local and systemic immune response. Measles 
immunization via aerosol has been studied extensively and has been 
found to be safe and effective. Previous studies of IN measles 
vaccination have yielded variable results attributable to varied doses 
and methods of administration plus interference by concomitant upper 
respiratory infections, making it difficult to determine if this is an 
effective vaccination route. No serious adverse events have been 
reported. Currently, the only Food and Drug

[[Page 31313]]

Administration (FDA) approved method for giving Measles-Mumps-Rubella 
(MMR) vaccination is by subcutaneous injection.
Research Plan
    This is a request for proposals to conduct a phase 1, double 
blinded, randomly assigned, study comparing the safety, tolerability 
and immunogenicity of IN vs. SC administration of measles vaccine. The 
study must be done under an Investigational New Drug application from 
the FDA, as the goal is to eventually obtain FDA approval for IN 
vaccination with MMR vaccine. In order to maximize participant safety 
this request is for proposals to study only measles vaccination, and to 
begin with immune and semi-immune adults. The first step should include 
healthy measles-immune adults, the second, partially immune adults. 
Immune adults are those having a plaque-reduction neutralization titer 
of 1:120 or higher; partially immune adults are those with detectable 
titers that fall under 1:120. An Independent Safety Monitor (ISM) 
should review safety data from step 1 and determine that it is safe to 
continue before additional work begins with step 2. Before actually 
doing so, however, the grantee and researchers from the CDC should 
discuss the report of the ISM and the data, and agree whether or not to 
proceed with step 2.
    Measurable outcomes of the program will be in alignment with the 
``Government Performance Results Act'' (GPRA) performance goals for the 
National Immunization Program (NIP):
    1. Reduce the number of indigenous cases of vaccine-preventable 
diseases.
    2. Ensure that 2 year-olds are appropriately vaccinated.
    3. Work with global partners to reduce the cumulative global 
measles related mortality rate.

B. Eligible Applicants

    Applications may be submitted by public and private nonprofit and 
for-profit organizations and by governments and their agencies; that 
is, universities, colleges, research institutions, hospitals, other 
public and private nonprofit and for-profit organizations, faith-based 
organizations, State and local governments or their bona fide agents, 
including the District of Columbia, the Commonwealth of Puerto Rico, 
the Virgin Islands, the Commonwealth of the Northern Mariana Islands, 
American Samoa, Guam, the Federated States of Micronesia, the Republic 
of the Marshall Islands, and the Republic of Palau, federally 
recognized Indian tribal governments, Indian tribes, or Indian tribal 
organizations, and small, minority, women-owned businesses.

    Note: Title 2 of the United States Code Section 1611 states that 
an organization described in section 501(c)(4) of the Internal 
Revenue Code that engages in lobbying activities is not eligible to 
receive Federal funds constituting an award, grant, or loan.

C. Availability of Funds

    Approximately $192,000 is available in FY 2002 to fund one (1) 
award. It is expected that the award will be begin on or about 
September 30, 2002 and will be made for a 12-month budget period within 
a project period of up to two 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.

Use of Funds

    Funds cannot be used for construction or renovation, to purchase or 
lease vehicles or vans, to purchase a facility to house project staff 
or carry out project activities, or to supplant existing support.

D. Program Requirements

    In conducting activities to achieve the purpose of this program, 
the recipient will be responsible for the activities under 1. 
(Recipient Activities), and CDC will be responsible for the activities 
listed under 2. (CDC Activities). The intention is for the Recipient 
and the CDC to work jointly and in collaboration in developing, 
executing and reporting on this project.
1. Recipient Activities
    The following section describes the expected activities of the 
recipient:
    a. Develop the study protocol, determining the approaches to take 
in addressing the specific aims in the program announcement.
    b. Plan the analytic approach to be taken to understand and 
interpret the principal findings from the study.
    c. Obtain IRB approval for the protocol.
    d. Develop, submit and obtain an Investigational New Drug 
Application from the FDA for intranasal administration of measles 
vaccine.
    e. With assistance from and in collaboration with CDC staff, 
develop a plan of studies for phase I/II trials of intranasal rubella 
and mumps vaccines, as well as further studies of intranasal measles 
vaccine and phase I/II trials of combined MMR vaccine.
    f. Provide research pharmacist and facilities for filling nasal 
spray device with reconstituted measles vaccine.
    g. Hire, manage and train research staff to provide clinical 
assessments, administer vaccine, collect samples and perform laboratory 
tests in compliance with Good Clinical Practice.
    h. Implement the study protocol, conducting the study according to 
the protocol and resolving problems in study implementation as they 
arise.
    i. Arrange for an Independent Safety Monitor to review the progress 
of the study and to determine if it is safe to proceed from step 1 to 
step 2. Before actually doing so, however, the grantee and researchers 
from the CDC should discuss the report of the ISM and the data, and 
agree whether or not to proceed with step 2.
    j. Report serious and unexpected adverse events to CDC and FDA in a 
timely manner.
    k. Perform standard measles immunogenicity assays, including ELISAs 
and plaque-reduction neutralization titers.
    l. Perform tests of mucosal immunity.
    m. Participate as authors in the preparation of manuscripts 
describing the results of the research.
    n. Prepare reports for regulatory agencies and grantee 
Institutional Review Board (IRB), as necessary.
    o. Applicants are required to provide Measures of Effectiveness 
that will demonstrate the accomplishment of the various identified 
objectives of the grant. Measures must be objective/quantitative and 
must measure the intended outcome. These Measures of Effectiveness 
shall be submitted with the application and shall be an element of the 
evaluation.
2. CDC Activities
    CDC staff will participate as a partner in the activities of the 
study, providing technical and laboratory assistance, where needed, as 
well as scientific collaboration.
    a. Provide technical assistance and programmatic information 
relevant to the project.
    b. Assist in the development of a research protocol for IRB review 
by all cooperating institutions participating in the research project. 
The CDC IRB will review and approve the protocol initially and on an 
annual basis until the research project is completed.
    c. Assist in the performance of the study and participate, with 
recipient staff members, in the progression from step 1 to step 2 of 
the research plan (as per ``i.'' of Recipient's Activities).
    d. Participate in the development of the plan for future studies 
(as per ``e.'' of Recipient's Activities).
    e. Perform nucleic acid detection (RT-PCR methods) and/or viral 
cultures to

[[Page 31314]]

detect measles vaccine virus in clinical samples.
    f. Participate in the analysis and interpretation of data from the 
study and in presentation and publication of the findings of the 
research.

E. Content

    The Program Announcement title and number must appear in the 
applications. Use the information in the Program Requirements, Other 
Requirements, and Evaluation Criteria sections to develop the 
application content. Applications will be evaluated on the criteria 
listed, so it is important to address them when describing the program 
plan. The narrative should be no more than 20 single-spaced pages and 
be printed on one side, with one-inch margins and a 12-point unreduced 
font.
    The narrative should consist of, at a minimum, a Plan, Objectives, 
Methods, Evaluation and Budget.

F. Submission and Deadline

    Submit the original application and five copies of PHS 398 (OMB 
Number 0925-0001) (adhere to the instructions on the Errata Instruction 
Sheet for PHS 398). Forms are available in the application kit and at 
the following Internet address: www.cdc.gov/od/pgo/forminfo.htm 
Application forms must be submitted in the following order:
Cover Letter
Table of Contents
Application
Budget Information Form
Budget Justification
Checklist
Assurances
Certifications
Disclosure Form
Human Subjects Certification (if applicable)
Indirect Cost Rate Agreement (if applicable)
Narrative
    On or before 5 p.m. Eastern Time July 15, 2002, submit the 
application to the Technical Information Management Section, PA# 02167, 
Procurement and Grants Office, Centers for Disease Control and 
Prevention (CDC), 2920 Brandywine Road, Room 3000, Atlanta, GA 30341-
4146.
    Deadline: Applications shall be considered as meeting the deadline 
if they are received before 5 p.m. Eastern Time on the deadline date. 
Applicants sending applications by the United States Postal Service or 
commercial delivery services must ensure that the carrier will be able 
to guarantee delivery of the application by the closing date and time. 
If an application is received after closing due to (1) carrier error, 
when the carrier accepted the package with a guarantee for delivery by 
the closing date and time, or (2) significant weather delays or natural 
disasters, CDC will upon receipt of proper documentation, consider the 
application as having been received by the deadline.
    Applications which do not meet the above criteria will not be 
eligible for competition and will be discarded. Applicants will be 
notified of their failure to meet the submission requirements.

G. Evaluation Criteria

    Applicants are required to provide Measures of Effectiveness that 
will demonstrate the accomplishment of the various identified 
objectives of the grant or cooperative agreement. Measures of 
Effectiveness must relate to the performance goal (or goals) as stated 
in section ``A. Purpose'' of this announcement. Measures must be 
objective and quantitative and must measure the intended outcome. These 
Measures of Effectiveness shall be submitted with the application and 
shall be an element of evaluation.
    Applications will be evaluated against the following criteria by an 
independent review group appointed by CDC:
1. Understanding the Project Objectives (10 points)
    The extent to which the applicant possesses an understanding of the 
needs and purpose of the project as demonstrated through knowledge and 
understanding of current research and activities being performed in 
this area, past studies, existing literature and the clarity and 
practicality of the proposed project plan.
2. Research Objectives (10 points)
    The extent to which the research proposal addresses the research 
objectives provided in this announcement, provides a clear description 
of the methods to be used, and demonstrates adherence to accepted 
research practices as well as Good Clinical Practice. The applicant 
should also demonstrate that the applicant's research proposal is 
clear, feasible and practical.
3. Research Methods (30 points)
    The adequacy of the proposed research design, approaches and 
methodology to carry out the research, including quality assurance 
procedures and plans for data management and statistical analyses:
    a. Recruitment procedures, screening tests and eligibility/
exclusion criteria.
    b. Method for allocation of subjects to IN vs. SC immunization.
    c. Method for masking investigators and participants as to 
vaccination group.
    d. Quality assurance procedures, plans for data analysis, 
statistical analysis methods and study endpoints.
    e. Safety assessments and reporting of adverse events.
    f. Methods for testing immunogenicity of vaccine, both in serum and 
mucosal fluids; these should be consistent with any methods described 
in the research objectives of this announcement.
    g. Criteria for suspending the trial or for moving from step 1 to 
step 2.
    h. A statistical analysis plan appropriate to the primary and 
secondary objectives.
    i. The project time line.
    j. Informed consent procedures.
    k. Measures of Effectiveness. The Peer Review Panel shall assure 
that measures set forth in the application are in accordance with CDC's 
performance plans. (See CDC's Performance plans at website www.cdc.gov/od/perfplan/2001perfplan.pdf).
4. Research Population (5 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.
    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.
5. Management Plan (20 points)
    The soundness and feasibility of the applicant's proposed 
management plan for accomplishing the work expectations outlined in 
section D to include identification of applicant's key personnel to be 
assigned to the study and clear identification of their respective 
roles in the management and operations of the program.
6. Experience and Capabilities (25 points)
    The experience, qualifications, and technical abilities of the 
applicant and the proposed project staff relevant to:
    a. The content areas of immunizations and mucosal immunology.
    b. Conducting clinical research and publishing in peer-reviewed 
journals.

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    c. Ability to recruit suitable participants.
    d. Demonstrable performance of measles serologies using ELISA and 
plaque-reduction neutralization methods.
    e. Transmission of information in a timely, efficient, secure, and 
accurate manner.
    f. Obtaining Investigational New Drug Applications from the FDA.
    g. Receiving, storing and shipping biological specimens related to 
this project.
7. Human Subjects (not scored)
    The application should also adequately address the requirements of 
45 CFR part 46 for the protection of human subjects. This should 
include the provision of the FWA number from the Office of Human 
Research Projection (OHRP).
8. Budget (not scored)
    The applicant shall describe their proposed plan for managing the 
resources necessary to comply with the requirements specified in 
Section D. This shall include a description of the proposed person 
hours for each key individual.
9. GPRA Goals (not scored)
    The applicant shall describe how their research plan meets the GPRA 
goals listed in Section A.

H. Other Requirements

Technical Reporting Requirements

    The grantee will provide CDC with the original plus two copies of:
    1. Quarterly progress reports (the results of the Measures of 
Effectiveness shall be a data requirement to be submitted with or 
incorporated into the progress report);
    2. Adverse event reports (within 24 hours of discovery of adverse 
event);
    3. Financial status report, no more than 90 days after the end of 
the budget period;
    4. Final financial report and performance report, no more than 90 
days after the end of the project period.
    Send all reports to the Grants Management Specialist identified in 
the ``Where to Obtain Additional Information'' section of this 
announcement.
    The following additional requirements are applicable to this 
program. For a complete description of each, see Attachment 1 of the 
announcement.

AR-1  Human Subjects Requirements
AR-2  Requirements for Inclusion of Women and Racial and Ethnic 
Minorities in Research
AR-10  Smoke-Free Workplace Requirements
AR-11  Healthy People 2010
AR-12  Lobbying Restrictions
AR-14  Accounting System Requirements
AR-21  Small, Minority, and Women-Owned Business
AR-22  Research Integrity

I. Authority and Catalog of Federal Domestic Assistance Number

    This program is authorized under section 301, 317 and 2102 of the 
Public Health Service Act, 42 U.S.C. 241, 247 and 30099-2(9), as 
amended. The Catalog of Federal Domestic Assistance number is 93.185.

J. Where To Obtain Additional Information

    This and other CDC announcements, the necessary applications, and 
associated forms can be found on the CDC home page Internet address--
http://www.cdc.gov Click on ``Funding'' then ``Grants and Cooperative 
Agreements.''
    For business management assistance contact: Peaches Brown, Grants 
Management Specialist, Grants Management Branch, Procurement and Grants 
Office, Centers for Disease Control and Prevention, 2920 Brandywine 
Road, Room 3000, Atlanta, GA 30341-4146. Telephone number: (770) 488-
2738. Email address: [email protected].
    For program technical assistance, contact: Robert Perry, M.D., 
M.P.H., Epidemiology and Surveillance Division, National Immunization 
Program, Centers for Disease Control and Prevention, 1600 Clifton Road, 
NE, Mailstop E-61, Atlanta, GA 30333. Telephone number: (404) 639-8224. 
Email address: [email protected].

    Dated: May 4, 2002.
Sandra R. Manning,
Director, Procurement and Grants Office, Centers for Disease Control 
and Prevention (CDC).
[FR Doc. 02-11558 Filed 5-8-02; 8:45 am]
BILLING CODE 4163-18-P