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 
https://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 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a 
complete copy of the updated Guidelines is available at  
https://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: 
https://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:  
https://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:
https://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 
https://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 https://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: 
https://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 
https://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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