PROGESTIN CONTRACEPTION AND ENDOMETRIAL BLEEDING
Release Date: July 2, 2001
RFA: RFA-HD-01-016
National Institute of Child Health and Human Development
(http://www.nichd.nih.gov)
Letter of Intent Receipt Date: December 17, 2001
Application Receipt Date: February 13, 2002
THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA.
PURPOSE
The purpose of this initiative is to identify effective agents for the
prevention and treatment of endometrial breakthrough bleeding in women using
progestin-only contraception. The availability of agents to prevent or
effectively treat such breakthrough bleeding would markedly improve the
acceptability of progestin-only contraceptives.
HEALTHY PEOPLE 2010
The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2010," a PHS-led national
activity for setting priority areas. This Request for Applications (RFA) is
related to one or more of the priority areas. Potential applicants may obtain
"Healthy People 2010" at http://www.health.gov/healthypeople/.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal government. Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as Principal
Investigators.
MECHANISM OF SUPPORT
This RFA will use the National Institutes of Health (NIH) research project
grant (R01) award mechanism. Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant. The
total project period for an application submitted in response to this RFA may
not exceed five years. This RFA is a one-time solicitation. Future
unsolicited competing continuation applications will compete with all
investigator-initiated applications and be reviewed according to the customary
peer review procedures.
Specific application instructions have been modified to reflect MODULAR
GRANT and JUST-IN-TIME streamlining efforts being examined by the NIH.
Complete and detailed instructions and information on Modular Grant
applications can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm.
FUNDS AVAILABLE
The NICHD intends to commit approximately $1 million in total costs [Direct
plus Facilities and Administrative (F&A) costs] in FY 2002 to fund three to
five new grants in response to this RFA. An applicant may request a project
period of up to five years and a budget for direct costs of up to $250,000 per
year. Because the nature and scope of the research proposed may vary, it is
anticipated that the size of each award will also vary. Although the
financial plans of the NICHD provide support for this program, awards pursuant
to this RFA are contingent upon the availability of funds and the receipt of a
sufficient number of meritorious applications.
RESEARCH OBJECTIVES
Background
Several long-term, progestin-only contraceptives, including Norplant, depot
medroxyprogesterone acetate, and norethindrone enanthate, are widely used in
both developed and developing countries. These methods are highly effective,
convenient to use, and generally well-tolerated. However, unpredictable,
irregular endometrial bleeding is a common side effect with all of the
progestin-only methods. Irregular bleeding limits the acceptability of these
methods and it is the single most common reason for early discontinuation.
The identification of agents that could effectively prevent or treat this
irregular bleeding would markedly enhance the initial acceptability of these
methods, as well as reduce the likelihood of premature discontinuation.
Up to the present, no consistently effective preventive measures or treatments
have been identified. Estrogens, combined oral contraceptives, nonsteroidal
anti-inflammatory drugs, vitamins, and other agents have been used to treat
irregular bleeding associated with these methods. However, none of these
agents consistently provide long-term resolution of irregular bleeding and,
for many women, the use of estrogen-containing compounds negates the value of
using progestin-only methods of contraception. It is clear that new, more
effective approaches to this irregular bleeding are needed.
During the past two decades, considerable progress has been made in the
understanding of the underlying mechanisms of irregular bleeding associated
with progestin-only contraceptives. Recent findings suggest that the final
common pathway for progestin-related irregular endometrial bleeding may be the
fragility of superficial endometrial capillaries. Irregular bleeding from
these vessels may be related to abnormal vascular structure and increased
vascular density caused by progestin-induced aberrant angiogenesis. Decreased
vascular perfusion and resulting hypoxia-induced expression of vascular
endothelial growth factor (VEGF) may also play a role. A number of other
factors have also been implicated in irregular bleeding associated with these
abnormal vessels including transforming growth factor, matrix
metalloproteinases, insulin-like growth factors, and others.
Objectives and Scope
This RFA is soliciting applications for the support of human or animal studies
of therapeutic agents that have potential for the prevention or treatment of
irregular bleeding associated with progestin-only methods of contraception,
with the objective of identifying clinically useful agents. Supported
research may include both clinical trials and other human or animal research
to elucidate the mechanism of action of specific agents. Research focused
only on mechanisms of irregular bleeding, without investigation of a potential
therapeutic agent, is not included and will not be considered responsive to
this RFA.
Agents that may be of value in treating irregular bleeding include, but are
not limited to, COX-2 inhibitors, antioxidants, antiprogestins, selective
progestin receptor modulators, selective estrogen receptor modulators, and
tissue inhibitors of matrix metalloproteinase.
Research supported under this RFA could include pilot clinical trials of the
efficacy of one or more of the potential therapeutic agents. Other approaches
include, but are not limited to, studies of the endometrial effects of
particular agents in animal models or longitudinal studies of endometrial
effects in women with serial endometrial biopsies.
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of the NIH that women and members of minority groups and
their sub-populations must be included in all NIH-supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification are provided indicating that inclusion
is inappropriate with respect to the health of the subjects or the purpose of
the research. This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).
All investigators proposing research involving human subjects should read the
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," published in the NIH Guide for Grants and Contracts on
August 2, 2000
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a
complete copy of the updated Guidelines is available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The
revisions relate to NIH-defined Phase III clinical trials and require: a) all
applications or proposals and/or protocols to provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable, and b) all
investigators to report accrual, and to conduct and report analyses, as
appropriate, by sex/gender and/or racial/ethnic group differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.
All investigators proposing research involving human subjects should read the
NIH Policy and Guidelines on Inclusion of Children as Participants in
Research Involving Human Subjects, published in the NIH Guide for Grants and
Contracts, March 6, 1998, and available at:
http://grants.nih.gov/grants/guide/notice-files/not98-024.html.
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS
All investigators proposing research involving human subjects should read the
policy that was published in the NIH Guide for Grants an Contracts, June 5,
2000 (Revised August 25, 2000), available at:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
URLS IN NIH GRANT APPLICATIONS OR APPENDICES
All applications and proposals for NIH funding must be self-contained within
specified page limitations. Unless otherwise specified in an NIH
solicitation, Internet addresses (URLs) should not be used to provide
information necessary to the review because reviewers are under no obligation
to view the Internet sites. Reviewers are cautioned that their anonymity may
be compromised when they directly access an Internet site.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT
The Office of Management and Budget (OMB) Circular A-110 has been revised to
provide public access to research data through the Freedom of Information Act
(FOIA) under some circumstances. Data that are (1) first produced in a
project that is supported in whole or in part with Federal funds and (2) cited
publicly and officially by a Federal agency in support of an action that has
the force and effect of law (i.e., a regulation) may be accessed through FOIA.
It is important for applicants to understand the basic scope of this
amendment. NIH has provided guidance at:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm
Applicants may wish to place data collected under this RFA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that includes a
descriptive title of the proposed research, the name, address, and telephone
number of the Principal Investigator, the identities of other key personnel
and participating institutions, and the number and title of this RFA.
Although a letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application, the information that it
contains allows NICHD staff to estimate the potential review workload and plan
the review.
The letter of intent is to be sent to H. Trent MacKay, M.D., M.P.H., at the
address listed under INQUIRIES, below, by December 17, 2001.
APPLICATION PROCEDURES
The most recent version of research grant application form PHS 398 is to be
used in applying for these grants. These forms are available at most
institutional offices of sponsored research, on the Internet at
http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the Division
of Extramural Outreach and Information Resources, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301-710-0267, E-mail: grantsinfo@nih.gov.
Application Instructions
The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there
is the possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicants, reviewers, and Institute
staff. The most recent version of research grant application form PHS 398 is
to be used in applying for these grants, with the modifications noted below.
Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $250,000 per year. The total direct costs must
be requested in accordance with the program guidelines and the modifications
made to the standard PHS 398 application instructions described below:
o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period. Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.
o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the
application.
o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required
and will not be accepted with the application.
o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for
sample pages.) At the top of the page, enter the total direct costs requested
for each year. This is not a Form Page.
o Under Personnel, list all project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided. However, the applicant should use the NIH appropriation language
salary cap and the NIH policy for graduate student compensation in developing
the budget request.
For Consortium/Contractual costs, provide an estimate of total costs (direct
plus F&A costs) for each year, each rounded to the nearest $1,000. List the
individuals/organizations with whom consortium or contractual arrangements
have been made, the percent effort of personnel, and the role on the project.
Indicate whether the collaborating institution is foreign or domestic. The
total cost for a consortium/contractual arrangement is included in the overall
requested modular direct cost amount. Include the Letter of Intent to
establish a consortium.
Provide an additional narrative budget justification for any variation in the
number of modules requested.
BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by
reviewers in the assessment of each individual"s qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for
all personnel, following the instructions below. No more than three pages may
be used for each person. A sample biographical sketch may be viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm.
- Complete the educational block at the top of the Form Page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years,
- List selected peer-reviewed publications, with full citations.
o CHECKLIST: This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the
type of agreement and the date. All appropriate exclusions must be applied in
the calculation of the F&A costs for the initial budget period and all future
budget years.
o The applicant should provide the name and telephone number of the individual
to contact concerning fiscal and administrative issues if additional
information is necessary following the initial review.
Submission Instructions
The RFA label available in the PHS 398 application form must be stapled to the
bottom of the face page of the application and must display the RFA number HD-
01-016. A sample RFA label is available at
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this
is in the pdf format. Failure to use this label could result in delayed
processing of the application such that it may not reach the review committee
in time for review. In addition, the RFA title and number must be typed on
line 2 of the face page of the application form and the YES box must be
marked.
Submit a signed, typewritten original of the application, including the
Checklist, and three signed photocopies, in one package to:
CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application should be
sent to:
Director
Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E03, MSC 7510
Bethesda, MD 20892-7510
Bethesda, MD 20852 (for express/courier service)
Applications must be received by February 13, 2002. If an application is
received after that date, it will be returned to the applicant without review.
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application. The
CSR will not accept any application that is essentially the same as one
already reviewed. This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications must include
an introduction addressing the previous critique.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the CSR and
for responsiveness to this RFA by NICHD. Incomplete and/or non-responsive
applications will be returned to the applicant without further consideration.
Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group
convened by NICHD in accordance with the review criteria stated below. As
part of the initial merit review, all applications will receive a written
critique and may undergo a process in which only those applications deemed to
have the highest scientific merit will be discussed, assigned a priority
score, and receive a second level review by the National Advisory Child Health
and Human Development Council.
Review Criteria
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In
the written comments, reviewers will be asked to discuss the following aspects
of the application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals. Each of these
criteria will be addressed and considered in assigning the overall score,
weighting them as appropriate for each application. Note that 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.
(1) 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?
(2) 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?
(3) 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?
(4) 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)?
(5) 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?
In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:
o The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will also be
evaluated.
o The reasonableness of the proposed budget and duration in relation to the
proposed research.
o The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.
SCHEDULE
Letter of Intent Receipt Date: December 17, 2001
Application Receipt Date: February 13, 2002
Peer Review Date: June 2002
Council Review: September 2002
Earliest Anticipated Start Date: September 30, 2002
AWARD CRITERIA
Criteria that will be used to make award decisions include:
o scientific merit (as determined by peer review)
o availability of funds
o programmatic priorities.
INQUIRIES
Inquiries concerning this RFA are encouraged. The opportunity to clarify any
issues or answer questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
H. Trent MacKay, M.D., M.P.H.
Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Blvd., Suite 8B13, MSC 7510
Bethesda, MD 20892-7510
Bethesda, MD 20852 (for express/courier service)
Telephone: (301) 435-6988
FAX: (301) 480-1972
Email: mackayt@mail.nih.gov
Direct inquiries regarding fiscal matters to:
Kathy Hancock
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Blvd., Suite 8A17, MSC 7510
Bethesda, MD 20892-7510
Bethesda, MD 20852 (for express/courier service)
Telephone: (301) 496-5482
FAX: (301) 402-0195
Email: Kathy.hancock@nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.864, Population Research. Awards are made under authorization of Sections
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)
and administered under NIH grants policies and Federal Regulations 42 CFR 52
and 45 CFR Parts 74 and 92. This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.
The PHS strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products. In addition,
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain
facilities (or in some cases, any portion of a facility) in which regular or
routine education, library, day care, health care, or early childhood
development services are provided to children. This is consistent with the
PHS mission to protect and advance the physical and mental health of the
American people.
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