[Federal Register: May 14, 2004 (Volume 69, Number 94)]
[Notices]
[Page 26836-26841]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr14my04-47]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Centers for Disease Control and Prevention
Request for Applications to Determine the Pharmacokinetics of
Clostridium Botulinum Neurotoxins A, B, C, E, and F
Announcement Type: New.
Funding Opportunity Number: 04099.
Catalog of Federal Domestic Assistance Number: 93.283.
Key Dates:
Letter of Intent Deadline: June 1, 2004.
Application Deadline: June 28, 2004.
Executive Summary: The Centers for Disease Control and Prevention
(CDC) invites investigator-directed research grant applications that
will lead to an understanding of the relationship between oral exposure
to Clostridium botulinum neurotoxin, morbidity, and lethality. Research
should include, but is not limited to, the establishment and
implementation of methods and procedures in non-human primates for
determination of the pharmacokinetics of both the di-chain and
progenitor forms of C. botulinum neurotoxins A, B, C, E, and F. The
information gathered by this study will help guide policy development
and most importantly
[[Page 26837]]
enable informed treatment recommendations. Applications should define
the proposed project goal, interim objectives (development milestone),
potential ultimate product, and provide a timeline for milestone and
goal attainment. This grant seeks researchers that can collaborate with
relevant ongoing small animal studies or that have established small
animal models and the ability to transfer these studies to non-human
primates. Preference will be given to otherwise equivalent proposals
that take measures to minimize suffering and preserve the life of
animals utilized in this study to the extent possible. All applicants
must comply with CDC guidelines on the care and use of laboratory
animals.
I. Funding Opportunity Description
Authority: This program is authorized under the Public Health
Service Act Sections 301(a) [42 U.S.C.241(a)], as amended.
Purpose: The purpose of this research grant is to support the
development and utilization of a non-human primate model system to
gather data on the adsorption, distribution, localization, metabolism
and clearance of botulinum neurotoxins. The data obtained from this
study will aid the development of methods and procedures to rapidly
identify and more effectively treat a human population exposed to
botulinum neurotoxin via natural or intentional mechanisms.
The botulinal neurotoxins pose a significant threat to the public
as bioterrorist weapons because of their potency, ease of production
and transport, and the potential burden that affected individuals would
place on the public health care system. These neurotoxins, which are
produced by the ubiquitous pathogen Clostridium botulinum and some
strains of Clostridium baratii and Clostridium butyricum, are among the
most toxic substances known to man. The botulinum neurotoxins (BoNTs)
are produced in seven antigenically distinct forms that are identified
as types A, B, C, D, E, F, and G. The toxins are naturally found
complexed to neuroassociated proteins (progenitor toxin), but can be
purified to a fully active di-chain neurotoxin molecule. The BoNTs
block the release of the neurotransmitter, acetylcholine, which
uncouples the neuromuscular junction and results in paralysis and death
if left untreated. Estimates suggest that as little as 1 ng/kg and 3
ng/kg of neurotoxin type A is enough to kill 50 percent of a human
population exposed by oral and inhalation routes, respectively.
In the United States, less than 150 cases of laboratory confirmed
botulism are reported each year and there are no preventative therapies
for the general public at this time as natural cases of botulism are
relatively rare. Most cases of botulism traditionally result from
exposure to the BoNTs through ingestion of preformed toxin in foods or
through secondary means in which a toxin producing organism is
introduced and becomes established in the body. Inhalational botulism
is not a common form of exposure. Most of the information on botulinum
intoxication and treatment in humans is derived from cases of naturally
occurring foodborne botulism. Neurological signs of botulism in humans
include: symmetric, descending flaccid paralysis with bulbar palsies,
ptosis, diplopia, blurred vision, enlarged pupils, dysarthria,
dysphonia, and dysphagia. The lag time between exposure and rapidity of
symptom onset is difficult to establish in naturally occurring
foodborne cases as it is dependent on the rate and amount of toxin
ingested by each affected individual among other variables. At this
time, clinical presentation consistent with botulism, which may occur
12-72 hours after toxin ingestion, is the only basis for implementation
of antitoxin therapy, which will stop the progression of neuronal
damage but not reverse it. Although clinical specimens such as
aspirates, serum and stool can be analyzed for the presence of BoNT,
the absence of toxin in such specimens does not rule out intoxication.
Thus, although it is crucial that BoNT exposed individuals are
identified and appropriately treated in a timely manner, insufficient
data are available to establish a defined time line between exposure to
botulinum toxin, adsorption by mucosal tissues, toxin stability in
vivo, toxin serum levels over time, and clearance.
Currently, the treatment of botulism patients requires extensive
supportive care and passive immunization with equine antitoxin. Data
from outbreaks resulting from ingestion of naturally contaminated foods
suggest that up to 95 percent of exposed individuals require
hospitalization and up to 62 percent require long-term ventilation.
This suggests that with our current capabilities, a large outbreak
would place an enormous strain on the existing health care
infrastructure, possibly limiting treatment capacity. Although modern
antitoxin therapy treatments are highly effective in reducing mortality
in humans, existing supplies need to be used in an effective and timely
manner.
The determination of the pharmacokinetics of the BoNTs resulting
from oral exposure will provide critical information that will aid
early identification of exposed individuals and enable the development
of informed guidelines that will maximize effective delivery of
therapeutic antitoxin in a large scale outbreak.
This program addresses the ``Healthy People 2010'' focus area of
Immunization and Infectious Disease.
Measurable outcomes of the program will be in alignment with the
following performance goal for the National Center for Infectious
Diseases (NCID): Protect Americans from infectious diseases.
Research Objectives: Develop and utilize a non-human primate model
system to determine the pharmacokinetics of both di-chain and
progenitor forms of C. botulinum neurotoxins A, B, C, E, and F
resulting from low to high level toxin exposure. The product of this
research should establish a timeline of events and a relationship among
the following: C. botulinum toxin exposure level, neurotoxin type (A,
B, C, E, and F), toxin form (di-chain and progenitor toxin), rate of
toxin adsorption into serum, distribution and quantity of toxin in body
fluids and products (serum, and stool), toxin stability/duration of
action, time of botulism symptom onset (as related to time of exposure,
and toxin serum levels), biotransformation of toxin in body fluids/
products (i.e. presence of progenitor, di-chain, or another form of the
toxin), rate of toxin clearance, variability in exposed population, and
recovery.
Activities: Awardee activities for this program but are not limited
to the following:
Establish a relevant small animal model (examples include
guinea pigs or mice) to conduct pharmacokinetic studies on botulinum
toxins that can be transferred to non-human primate studies.
Alternatively, it is acceptable to establish collaboration with
researcher(s) conducting ongoing small animal studies and to propose
how those studies would be transferred to non-human primates.
Develop protocols and procedures for testing, maintenance,
and recovery of non-human primates.
Describe a timeframe for development of a proof-of-concept
small animal model, establishment of a non-human primate model,
attainment of necessary materials to perform the study, collection and
analysis of clinical specimens, and completion of the study.
[[Page 26838]]
Develop and implement protocols to address the research
objectives in a non-human primate model system, including but not
limited to methods for oral toxin exposure, collection and testing of
appropriate tissues and or body fluids/products, evaluation of botulism
symptom onset, and evaluation of intra-study variation among test
subjects.
II. Award Information
Type of Award: Grant.
Award Mechanism: R01.
Fiscal Year Funds: 2004.
Approximate Total Funding: $2,000,000.00.
Approximate Number of Awards: 1-2.
Approximate Average Award: $900,000.00.
Floor of Award Range: None.
Ceiling of Award Range: None.
Anticipated Award Date: September 1, 2004.
Budget Period Length: 12 months.
Project Period Length: 3 years.
Throughout the project period, CDC's commitment to continuation of
awards will be conditioned on the availability of funds, evidence of
satisfactory progress by the recipient (as documented in required
reports), and the determination that continued funding is in the best
interest of the Federal Government.
III. Eligibility Information
III.1. Eligible Applicants
Applications may be submitted by public and private organizations
and by governments and their agencies, such as:
Public nonprofit organizations.
Private organizations.
Universities.
Colleges.
Research institutions.
Hospitals.
Community-based organizations.
Faith-based organizations.
Federally recognized Indian tribal governments.
Indian tribal organizations.
State and local governments or their Bona Fide Agents
(this includes the District of Columbia, the Commonwealth of Puerto
Rico, the Virgin Islands, the Commonwealth of the Northern Marianna
Islands, American Samoa, Guam, the Federated States of Micronesia, the
Republic of the Marshall Islands, and the Republic of Palau).
Political subdivisions of States (in consultation with
States).
A Bona Fide Agent is an agency/organization identified by the state
as eligible to submit an application under the state eligibility in
lieu of a state application. If you are applying as a bona fide agent
of a state or local government, you must provide a letter from the
state or local government as documentation of your status. Place this
documentation behind the first page of your application form.
III.2. Cost Sharing or Matching
Matching funds are not required for this program.
III.3. Other
If your application is incomplete or non-responsive to the
requirements listed in this section, it will not be entered into the
review process. You will be notified that your application did not meet
submission requirements.
Individuals Eligible to Become Principal Investigators: Any
individual with the skills, knowledge, and resources necessary to carry
out the proposed research is invited to work with their institution to
develop an application for support. Individuals from underrepresented
racial and ethnic groups as well as individuals with disabilities are
always encouraged to apply for CDC programs.
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.
IV. Application and Submission Information
IV.1. Address to Request Application Package
To apply for this funding opportunity, use application form PHS 398
(OMB number 0925-0001 rev. 5/2001). Forms and instructions are
available in an interactive format on the CDC Web site, at the
following Internet address: http://www.cdc.gov/od/pgo/forminfo.htm.
Forms and instructions are also available in an interactive format on
the National Institutes of Health (NIH) Web site at the following
Internet address: http://grants.nih.gov/grants/funding/phs398/phs398.html
.
If you do not have access to the Internet, or if you have
difficulty accessing the forms on-line, you may contact the CDC
Procurement and Grants Office Technical Information Management Section
(PGO-TIM) staff at: 770-488-2700. Application forms can be mailed to
you.
IV.2. Content and Form of Application Submission
Letter of Intent (LOI): Your LOI must be written in the following
format:
Maximum number of pages: 3.
Font size: 12-point unreduced.
Single spaced.
Paper size: 8.5 by 11 inches.
Page margin size: One inch.
Printed only on one side of page.
Written in plain language, avoid jargon.
Your LOI must contain the following information:
Descriptive title of the proposed research.
Name, address, E-mail address, and telephone number of the
Principal Investigator.
Names of other key personnel.
Participating institutions.
Number and title of this Program Announcement.
Application: Follow the PHS 398 application instructions for
content and formatting of your application. For further assistance with
the PHS 398 application form, contact PGO-TIM staff at 770-488-2700, or
contact GrantsInfo, Telephone (301) 435-0714, E-mail:
GrantsInfo@nih.gov.
Your research plan should address activities to be conducted over
the entire project period.
You are required to have a Dun and Bradstreet Data Universal
Numbering System (DUNS) number to apply for a grant or cooperative
agreement from the Federal government. Your DUNS number must be entered
on line 11 of the face page of the PHS 398 application form. The DUNS
number is a nine-digit identification number, which uniquely identifies
business entities. Obtaining a DUNS number is easy and there is no
charge. To obtain a DUNS number, access http://www.dunandbradstreet.com
or call 1-866-705-5711. For more information, see the CDC Web site at:
http://www.cdc.gov/od/pgo/funding/pubcommt.htm.
This PA uses just-in-time concepts. It also uses the modular
budgeting as well as non-modular budgeting formats. See: http://grants.nih.gov/grants/funding/modular/modular.htm
for additional
guidance on modular budgets. Specifically, if you are submitting an
application with direct costs in each year of $250,000 or less, use the
modular budget format. Otherwise, follow the instructions for non-
modular budget research grant applications.
Additional requirements that may require you to submit additional
documentation with your application are listed in section ``VI.2.
Administrative and National Policy Requirements.''
IV.3. Submission Dates and Times
LOI Deadline Date: June 1, 2004. CDC requests that you send a LOI
if you
[[Page 26839]]
intend to apply for this program. Although the LOI is not required, not
binding, and does not enter into the review of your subsequent
application, the LOI will be used to gauge the level of interest in
this program, and to allow CDC to plan the application review.
Application Deadline Date: June 28, 2004.
Explanation of Deadlines: Applications must be received in the CDC
Procurement and Grants Office by 4 p.m. eastern time on the deadline
date. If you send your application by the United States Postal Service
or commercial delivery service, you must ensure that the carrier will
be able to guarantee delivery of the application by the closing date
and time. If CDC receives your application 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, you will be given the opportunity to
submit documentation of the carriers guarantee. If the documentation
verifies a carrier problem, CDC will consider the application as having
been received by the deadline.
This announcement is the definitive guide on application submission
address and deadline. It supersedes information provided in the
application instructions. If your application does not meet the
deadline above, it will not be eligible for review, and will be
discarded. You will be notified that your application did not meet the
submission requirements.
CDC will not notify you upon receipt of your application. If you
have a question about the receipt of your application, first contact
your courier. If you still have a question, contact the PGO-TIM staff
at: 770-488-2700. Before calling, please wait two to three days after
the application deadline. This will allow time for applications to be
processed and logged.
IV.4. Intergovernmental Review of Applications
Your application is subject to Intergovernmental Review of Federal
Programs, as governed by Executive Order (EO) 12372. This order sets up
a system for state and local governmental review of proposed federal
assistance applications. You should contact your state single point of
contact (SPOC) as early as possible to alert the SPOC to prospective
applications, and to receive instructions on your state's process.
Click on the following link to get the current SPOC list: http://www.whitehouse.gov/omb/grants/spoc.html
.
IV.5. Funding restrictions
Restrictions, which must be taken into account while writing your
budget, are as follows:
None.
If you are requesting indirect costs in your budget, you must
include a copy of your indirect cost rate agreement. If your indirect
cost rate is a provisional rate, the agreement should be less than 12
months of age.
Awards will not allow reimbursement of pre-award costs.
IV.6. Other Submission Requirements
LOI Submission Address: Submit your LOI by express mail, delivery
service, fax, or E-mail to: Barbara Stewart, Centers for Disease
Control and Prevention, National Center for Infectious Diseases, 1600
Clifton Road, NE., Mail Stop C-19, Atlanta, GA 30333, Phone: 404-639-
0044, Fax: 404-639-2469, E-mail Address: bsg2@cdc.gov.
Application Submission Address: Submit the original and five hard
copies of your application by mail or express delivery service to:
Technical Information Management-PA 04099, CDC Procurement and
Grants Office, 2920 Brandywine Road, Atlanta, GA 30341.
Applications may not be submitted electronically at this time.
V. Application Review Information
V.1. Criteria
You are required to provide measures of effectiveness that will
demonstrate the accomplishment of the various identified objectives of
the grant. Measures of effectiveness must relate to the performance
goals stated in the ``Purpose'' section of this announcement. Measures
must be objective and quantitative, and must measure the intended
outcome. These measures of effectiveness must be submitted with the
application and will be an element of evaluation.
The goals of CDC-supported research are to advance the
understanding of biological systems, improve the control and prevention
of disease and injury, and enhance health. In the written comments,
reviewers will be asked to evaluate the application in order to judge
the likelihood that the proposed research will have a substantial
impact on the pursuit of these goals.
The scientific review group will address and consider each of the
following criteria in assigning the application's overall score,
weighting them as appropriate for each application. The application
does not need to be strong in all categories to be judged likely to
have major scientific impact and thus deserve a high priority score.
For example, an investigator may propose to carry out important work
that by its nature is not innovative, but is essential to move a field
forward.
The criteria are as follows:
Significance: Does this study address an important problem? If the
aims of the application are achieved, how will scientific knowledge be
advanced? What will be the effect of these studies on the concepts or
methods that drive this field? Will this study make significant
contributions to the existing knowledge base regarding effective
antitoxin treatment of botulinum toxin exposed individuals?
Approach: Are the conceptual framework, design, methods, and
analyses adequately developed, well-integrated, and appropriate to the
aims of the project? Does the applicant acknowledge potential problem
areas and consider alternative tactics? Has the applicant outlined a
reasonable plan for attaining the objectives of this project within the
indicated time frame? Are standardized operating procedures and
documentation practices described?
Innovation: Does the project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies?
Investigator: Is the investigator appropriately trained and well
suited to carry out this work? Is the work proposed appropriate to the
experience level of the principal investigator and other researchers
(if any)?
Environment: Does the scientific environment in which the work will
be done contribute to the probability of success? Do the proposed
experiments take advantage of unique features of the scientific
environment or employ useful collaborative arrangements? Is there
evidence of institutional support? Is the entity or facility conducting
the experiments approved to work with botulinum toxin by the Select
Agent Program?
Additional Review Criteria: In addition to the above criteria, the
following items will be considered in the determination of scientific
merit and priority score:
Study Animal Model(s): Are the animal models described appropriate
for attainment of study objectives? Has the applicant described a
reasonable timeline and approach for development and implementation of
a non-human primate model system? Has the applicant described an
approach that will enable satisfactory attainment of the study
objectives? Are adequate treatment/therapy methods described
[[Page 26840]]
for non-human primates used in this study?
Laboratory Analysis and Clinical Evaluation: Has the applicant
described satisfactory methods for collection of clinical specimens? Is
a method described for analysis of clinical specimens and is this
method adequately sensitive to detect relevant levels of toxin? Does
the applicant recognize potential problems regarding sensitive
detection of toxin in clinical specimens and considered alternative
strategies? Has the applicant provided background and experience for
the entity conducting laboratory testing, if applicable? Has the
applicant described a reasonable method for evaluation of botulism
symptom presentation in small animals and non-human primates?
Study Timeline and Protocol: Has the applicant described a
reasonable timeframe for completion of the proof-of-concept small
animal study, initiation and completion of the non-human primate study,
collection and analysis of clinical specimens, reporting, and
successful completion of the program?
Protection of Human Subjects from Research Risks: Does the
application adequately address the requirements of Title 45 CFR Part 46
for the protection of human subjects? This will not be scored; however,
an application can be disapproved if the research risks are
sufficiently serious and protection against risks is so inadequate as
to make the entire application unacceptable.
Inclusion of Women and Minorities in Research: Does the application
adequately address 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; and (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.
Care and Use of Vertebrate Animals in Research: If vertebrate
animals are to be used in the project, the five items described under
Section f of the PHS 398 research grant application instructions will
be assessed.
Budget: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
V.2. Review and Selection Process
Applications will be reviewed for completeness by the Procurement
and Grants Office (PGO) and for responsiveness by NCID. Incomplete
applications and applications that are non-responsive to the
eligibility criteria will not advance through the review process.
Applicants will be notified that their application did not meet
submission requirements.
Applications that are complete and responsive to the PA will be
evaluated for scientific and technical merit by an appropriate peer
review group or charter study section convened by NCID in accordance
with the review criteria listed above. As part of the initial merit
review, all applications may:
Undergo a process in which only those applications deemed
to have the highest scientific merit, generally the top half of the
applications under review, will be discussed and assigned a priority
score.
Receive a written critique.
Receive a second level review by CDC senior staff.
Award Criteria: Criteria that will be used to make award decisions
include:
Scientific merit (as determined by peer review).
Ability of proposal to attain research objectives.
Availability of funds.
Programmatic priorities.
V.3. Anticipated Announcement and Award Dates
Anticipated Award Date: September 1, 2004.
VI. Award Administration Information
VI.1. Award Notices
Successful applicants will receive a Notice of Grant Award (NGA)
from the CDC Procurement and Grants Office. The NGA shall be the only
binding, authorizing document between the recipient and CDC. The NGA
will be signed by an authorized Grants Management Officer, and mailed
to the recipient fiscal officer identified in the application.
Unsuccessful applicants will receive notification of the results of
the application review by mail.
VI.2. Administrative and National Policy Requirements
45 CFR Parts 74 and 92
For more information on the Code of Federal Regulations, see the
National Archives and Records Administration at the following Internet
address: http://www.access.gpo.gov/nara/cfr/cfr-table-search.html.
The following additional requirements apply to this project:
AR-1 Human Subjects Requirements.
AR-2 Requirements for Inclusion of Women and Racial and
Ethnic Minorities in Research.
AR-3 Animal Subjects Requirements.
AR-7 Executive Order 12372.
AR-10 Smoke-Free Workplace Requirements.
AR-11 Healthy People 2010.
AR-12 Lobbying Restrictions.
AR-15 Proof of Non-Profit Status.
AR-22 Research Integrity.
AR-23 States and Faith-Based Organizations.
AR-25 Release and Sharing of Data.
Additional information on these requirements can be found on the
CDC Web site at the following Internet address: http://www.cdc.gov/od/pgo/funding/ARs.htm
.
VI.3. Reporting
You must provide CDC with an original, plus two hard copies of the
following reports:
1. Interim progress report, (use form PHS 2590, OMB Number 0925-
0001, rev. 5/2001 as posted on the CDC Web site) no less than 90 days
before the end of the budget period. The progress report will serve as
your non-competing continuation application, and must contain the
following elements:
a. Current Budget Period Activities Objectives.
b. Current Budget Period Financial Progress.
c. New Budget Period Program Proposed Activity Objectives.
d. Budget.
e. Additional Requested Information.
f. Measures of Effectiveness.
2. Financial status report and annual progress report, no more than
90 days after the end of the budget period.
3. Final financial and performance reports, no more than 90 days
after the end of the project period.
These reports must be mailed to the Grants Management Specialist
listed in the ``Agency Contacts'' section of this announcement.
VII. Agency Contacts
For general questions about this announcement, contact: Technical
Information Management Section, CDC Procurement and Grants Office, 2920
Brandywine Road, Atlanta, GA 30341, Telephone: 770-488-2700.
For scientific/research issues, contact: Dr. Mary Lerchen, Acting
Director, Office of Extramural Research, CDC, National Center for
Infectious Diseases,
[[Page 26841]]
1600 Clifton Road, NE., Mailstop: C-19, Atlanta, GA 30333, Telephone:
404-639-0043, E-mail: mll0@cdc.gov.
For questions about peer review, contact: Barbara Stewart, Public
Health Analyst, CDC, National Center for Infectious Diseases, 1600
Clifton Road, NE., Mailstop: C-19, Atlanta, GA 30333, Telephone: 404-
639-0044, E-mail: bsg2@cdc.gov.
For financial, grants management, or budget assistance, contact:
Jeff Napier, Contract Specialist, CDC Procurement and Grants Office,
2920 Brandywine Road, Atlanta, GA 30341, Telephone: 770-488-2628, E-
mail: JNapier@cdc.gov.
VIII. Other Information
None.
Dated: May 10, 2004.
Bill Nichols,
Acting Director, Procurement and Grants Office, Centers for Disease
Control and Prevention.
[FR Doc. 04-10947 Filed 5-13-04; 8:45 am]
BILLING CODE 4163-18-P