MICROBICIDE PRECLINICAL DEVELOPMENT PROGRAM

Release Date:  November 7, 2000

RFA:  HD-00-018

National Institute of Child Health and Human Development
 (http://www.nichd.nih.gov)
National Institute of Allergy and Infectious Diseases
 (http://www.niaid.nih.gov)

Letter of Intent Receipt Date:  December 18, 2000
Application Receipt Date:       March 30, 2001

PURPOSE

The National Institute of Child Health and Human Development (NICHD) and the 
National Institute of Allergy and Infectious Diseases (NIAID) invite 
applications to conduct research on the discovery and preclinical development 
of novel microbicides, with or without contraceptive activity, for prevention 
of sexual transmission of HIV-1.  For the purpose of this RFA, all novel 
microbicides for prevention of sexual transmission of HIV-1 that are based on 
virus inactivation or prevention of viral infection of susceptible cells will 
be termed “microbicides.”  The preclinical activities supported through this 
RFA will target both new agents and products already identified as having 
potential for microbicide development. The program project grants funded 
through this initiative will be established to advance the development of 
novel microbicides with or without contraceptive activity.  Each program 
project will consist of:  (1) a Principal Investigator, who is responsible for 
the scientific and administrative aspects at his/her institution, including 
the Administrative Core, (2) three or more independent Research Projects, each 
directed by a Project Leader, and (3) Support Core(s) directed by Support Core 
Leader(s) that provide essential facilities or services to the Research 
Projects.  Since the majority of the women infected with HIV-1 in the United 
States are African-American or Hispanic, these studies will be relevant to the 
reduction of health disparities in minority populations. 
   
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 RFA is related to several priority 
areas.  Potential applicants may obtain "Healthy People 2010" at 
http://www.health.gov/healthypeople/.   

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic 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.  Foreign institutions are not eligible to apply for 
these grants, but components of a program project may be located at foreign 
sites.  Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal Investigators.

For further information regarding the application, contact the Program Staff 
listed under INQUIRIES.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) program project 
grant (P01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed projects will be solely that of the applicant.  The 
total project period for an application submitted in response to this RFA may 
not exceed four years.  The P01 supports broadly based multidisciplinary 
research programs that have a well-defined central research focus or 
objective. An important feature is that the interrelationships among the 
individual projects will result in a greater contribution to the overall 
program goals than if each project was pursued independently. The program 
project grant requires a minimum of three interrelated individual research 
projects that contribute to the overall program objective.  The application 
may request support for certain common core resources.  Complete guidelines 
for the NICHD Program Project Grant are available at:  
http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm.  These guidelines must be 
followed in preparing applications in response to this RFA.

FUNDS AVAILABLE

The NICHD and NIAID intend to commit approximately $3.0 million each in total 
costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2001 to 
fund six to eight new grants in response to this RFA.  An applicant may 
request a project period of up to four years.  Budgets for direct costs in 
excess of $750,000 in the first year, excluding F & A costs on consortium 
arrangements, will be accepted for review only with prior approval of the 
Program Staff listed under INQUIRIES, below.  Annual budgets for Years 02 to 
04 should not exceed the first year budget plus a three percent yearly 
increase.  

Because the nature and scope of the research proposed might vary, it is 
anticipated that the size of awards also will vary.  Although the financial 
plans of the NICHD and NIAID 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

Human immunodeficiency virus type-1 (HIV-1) infection is spreading most 
rapidly among women, especially among young women and women of color.  
Worldwide, the vast majority of new HIV infections in women now occur through 
heterosexual transmission.  There is a need to identify new and effective 
microbicides that, when administered vaginally or rectally, can prevent sexual 
infection with HIV and other sexually transmitted pathogens. 

This RFA encourages the discovery and preclinical development of novel or 
under-explored microbicides, with or without contraceptive activity, to 
prevent sexual transmission of HIV.  The active participation of industry is 
encouraged, which will allow that segment of the scientific community to 
contribute both intellectual and material resources.  The interaction of 
academic and non-profit research institutions with industry and the Government 
will facilitate subsequent development and marketing of the new products.

Objectives and Scope

The purpose of this RFA is to expand the range of novel microbicide candidates 
suitable for advancement into late stage preclinical development and clinical 
trials by encouraging the discovery and preclinical development of under-
explored or novel microbicidal products, with or without contraceptive 
activity, to prevent the sexual transmission/acquisition of HIV.  Applicants 
should utilize innovative approaches to prevention based on knowledge of HIV 
etiology and pathogenesis.  Specific approaches may target a wide range of 
topics.  Projects based on targeted interruption of HIV replication and 
attachment are encouraged.  Analogs or combinations of non-detergent products 
that have previously been entered into clinical trials may be considered 
responsive.  However, HIV therapeutic compounds, which have not been developed 
previously as microbicides, could be modified in accordance with section “b” 
below.

Each program project grant consists of three or more research projects (see 
SPECIAL REQUIREMENTS, below) and is centered on the discovery and preclinical 
development of a microbicide candidate.  Generic examples of some microbicides 
under development that could be the focus of research supported through this 
RFA are given below. This list is not meant to be all inclusive, but merely 
provides examples:

a.  products that interfere with binding, membrane fusion and/or entry of HIV 
such as small peptides or monoclonal antibodies,

b.  inhibitors of HIV replication previously developed as therapeutic 
products, such as non-nucleoside reverse transcriptase inhibitors, 
small peptides or organometallic complexes,

c.  naturally occurring antimicrobial inhibitors such as magainins, defensins, 
protegrins and secretory leukocyte protease inhibitor,

d.  adhesion and aggregation products that adhere to cell surfaces rendering 
them impervious to    infection or interact with receptors on multiple virus 
targets resulting in viral aggregates with resulting loss of infectivity,

e.  other novel approaches.

Any novel approach for which a strong scientific rationale is provided will be 
considered. 

A sound scientific rationale for selection of the lead microbicide candidate 
is strongly recommended.  Further, an experimental plan is required that 
describes the methods and decision-making process for evaluation of the 
candidate microbicide.  Since the intent of this RFA is the discovery and 
preclinical development of new microbicides, with or without contraceptive 
activity, with active involvement of industry and multiple collaborative 
partners, it will be imperative that applicants provide plans for patent 
coverage.

Analogs or combination products of marketed detergent-containing spermicides 
would not be considered responsive to this RFA.  Also excluded from this RFA 
is non-targeted random screening of potential microbicides.  Furthermore, 
advanced preclinical development activities, undertaken according to good 
laboratory/manufacturing processes (GLP/GMP), such as formulation, toxicology, 
or scale-up for production for clinical trials, as well as clinical trials 
themselves, are beyond the scope of this RFA.	

SPECIAL REQUIREMENTS

Applications submitted in response to this RFA should be prepared in 
accordance with the instructions presented in the NICHD Program Project (P01) 
Guidelines, available at http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm.

Required Application Components

The Program Project must contain three components:  An application must 
contain an Administrative Core unit, directed by the Principal Investigator, 
three or more independent Research Projects, directed by Research Project 
Leaders, and Support Cores as needed, directed by Support Core Leaders.  These 
components are described below.  Each application must include all components, 
however, one or more of the components may be located at collaborating 
institutions (see below).

o  Principal Investigator:  The scientist who is designated by the applicant 
institution to direct the Program Project.  The Principal Investigator (PI) 
will assume responsibility and accountability to the applicant institution and 
to the NICHD/NIAID for the performance and proper conduct of the Program 
Project in accordance with the requirements specified in this RFA.  The 
Principal Investigator is responsible for the Administrative Core unit.

o  Administrative Core:  A separately budgeted administrative unit that 
manages daily operations of the Program Project.  The Administrative Core 
unit, under the direction of the Principal Investigator, will coordinate all 
the operations of the Program Project.  The Administrative Core will ensure 
that the aims of the Research Projects are carried out by the Research Project 
Leaders and that Support Cores provide the necessary services to further the 
research aims. 

o  Research Projects:  Defined research aims for the discovery and development 
of novel microbicides, with or without contraceptive activity.  A minimum of 
three Research Projects must be described in the application. Some examples of 
individual research projects that might be one component of an application 
include:

1.  Characterization of the activity and toxicity of novel microbicides 
utilizing relevant in vitro, in vivo, and/or ex vivo laboratory models.  

2.  Design and development of genetically modified microbial organisms to 
deliver microbicides or augment the expression/activity of natural defense 
mechanisms of the vagina topically, such as single chain monoclonal 
antibodies produced by recombinant bacteria that naturally colonize the 
human vagina. 

3.  Development and use of animal models to evaluate in vivo efficacy and 
establish experimental proof-of-concept.

4.  Structure-activity relationship studies.  

An example of three inter-related research projects could be:  transgenic 
production of monoclonal antibodies, evaluation of the activity of the 
monoclonal antibodies, and distribution of labeled monoclonal antibody in the 
mouse vaginal model

o  Support Core(s):  Separately budgeted component(s) that provides support 
for the research programs, for example, crystallography, mass spectrometry, 
biological testing, or statistical support for the studies.  The most common 
support is likely to be in chemistry, however, pharmacokinetic support cores 
and animal support cores are other examples.

o  Research Project Leader:  The individual responsible for directing one or 
more of the Research Projects of the Program Project.  The Research Project 
Leader may or may not be the Principal Investigator.  

o  Support Core Leader(s):  The individual responsible for directing a support 
core facility. There may be one or more support cores.  These cores would 
provide services to achieve the research goals.

For the purposes of this RFA, each core must be utilized by at least two 
component projects at all times during the period of award.  This is an 
exception to the NICHD P01 Guidelines stating that each core should be 
utilized by three or more component projects.  If only one of the component 
projects requires proposed core support, then the required expertise, 
technology and/or infrastructure should be integrated within the relevant 
component project and the core as a separate entity eliminated.

Collaborative Arrangements

Two or more institutions that can demonstrate a credible plan for 
collaborative research may apply as a consortium.  Evidence of prior 
collaboration and/or a plan for proposed collaborations between the 
investigators should be cited.  A multi-institutional network application must 
be submitted by one applicant organization that will receive any resultant 
award.  The application must provide details of agreements regarding sub-
contracting arrangements, coordination, and support of activities at and among 
participating institutions, and must demonstrate the potential effectiveness 
of such a sub-network for the ongoing work of the program project.

Annual Meetings

Due to the anticipated proprietary nature of the products under development, 
each Program Project will act independently of the other.  The Program Project 
leadership will meet annually to exchange non-confidential information.  The 
Principal Investigator for the overall grant and the Project and Support Core 
Leaders for each component project should plan to attend an annual two-day 
meeting with NIH staff in Bethesda, MD. 

Applications should include a request for funds to support attendance of the 
Principal Investigator for the overall grant and the Project and Support Core 
Leaders for each component project and core at the annual meetings, as well as 
a statement of agreement to participate in these meetings. 

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, telephone 
number, and institution of the Principal Investigator, the identities of other 
key personnel and participating institutions, and the number and title of this 
RFA.  Although the letter of intent is not required, is not binding, and does 
not enter into the review of a subsequent application, the information it 
contains allows NICHD staff to estimate the potential review workload and plan 
the review.

The letter of intent is to be sent to Dr. Patricia Reichelderfer by December 
18, 2000 at the address listed under INQUIRIES, below.

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 are 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 the Inclusion of Children as Participants in 
Research Involving Human Subjects,” published in the NIH Guide for Grants and 
Contracts, March 6, 1998, and available on the Internet at:  
http://grants.nih.gov/grants/guide/notice-files/not98-024.html. 

Investigators may also obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.

Although this RFA will not support clinical trials, some applicants may 
propose research projects that involve the use of human tissue.  In these 
cases, guidelines on the protection and inclusion of human subjects in 
research apply.  

URLS IN NIH GRANT APLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained with 
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.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev.4/98) 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) 435-0714, E-mail:  GrantsInfo@nih.gov. 

Application Instructions

Applicants for P01 grants must follow special application guidelines in the 
NICHD PROGRAM PROJECT (P01) GUIDELINES (June 1998) that are available from 
NICHD program staff listed under INQUIRIES, below, and on the Internet at: 
http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm.  These guidelines contain 
important information on the suggested format of applications and on review 
criteria.

Submission Instructions

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
stapled to the bottom of the face page of the application and must display the 
number of this RFA, RFA-HD-00-018.  A sample RFA label is available at 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.  Please note that 
this is in 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 and five 
sets of all appendices should be sent to:

L.R. Stanford, Ph.D.
Director, Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Blvd., Room 5E03, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852 (for express/courier service)

Applications must be received by March 30, 2001.  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.

NIH policy permits a component research project of a multi-project grant 
application to be concurrently submitted as a traditional individual research 
project (R01) application.  If, following review, both the multi-project 
application and the R01 application are found to be in the fundable range, the 
investigator must relinquish the R01 and will not have the option to withdraw 
from the multi-project grant.  This policy is intended to preserve the 
scientific integrity of a multi-project grant, which may be seriously 
compromised if a strong component project(s) is removed from the program.  
Investigators wishing to participate in a multi-project grant must be aware of 
this policy before making a commitment to the Program Director and applicant 
institution.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR, and for 
responsiveness to this RFA by NICHD and NIAID staff.  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 
the 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 and/or the National Advisory Allergy and Infectious 
Diseases Council. 

Review Criteria

For program projects, peer review of scientific and technical merit focuses on 
three areas:  (1) review of the individual component projects, 2) review of 
the individual cores, and (3) review of the program as an integrated effort 
and the overall merit of the program.

The review criteria to be used to evaluate applications submitted in response 
to this RFA are presented in APPENDIX II, GUIDELINES FOR REVIEWERS COMMENTS, 
of the NICHD PROGRAM PROJECT (P01) GUIDELINES (June 1998), available at: 
http://www.nichd.nih.gov/funding/mechanism/p01_guide.cfm.

Schedule

Letter of Intent Receipt Date:    December 18, 2000
Application Receipt Date:         March 30, 2001
Peer Review Date:                 July 2001
Council Review:                   September 2001
Earliest Anticipated Start Date:  September 29, 2001
            
AWARD CRITERIA

Criteria that will be used to make award decisions include scientific and 
technical merit as determined by peer review, programmatic priorities and 
relevance, program balance, and the availability of funds.  

INQUIRIES

Potential applicants are strongly encouraged to contact program staff early in 
application development with any questions regarding the responsiveness of 
their proposal to the goals of this RFA.  Inquiries concerning this RFA are 
encouraged. The opportunity to clarify any issues or questions from potential 
applicants is welcome.

Direct inquiries regarding programmatic issues and microbicide candidates 
known or anticipated to have contraceptive activity to:

Patricia Reichelderfer, Ph.D.
Contraception and Reproductive Health Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B13G, MSC 7510
Bethesda, MD 20892-7510
Telephone:  (301) 496-1661
Fax:  (301) 480-1972
E-mail:  pr20f@nih.gov 

Direct inquiries regarding programmatic issues and microbicide candidates 
known to lack contraceptive activity to:

Roberta Black, Ph.D.
Vaccine and Prevention Research Program
Division of AIDS
National Institute of Allergy and Infectious Diseases
6700 B Rockledge Drive, Room 4110, MSC 7628
Bethesda, MD 20892-7628
Telephone: (301) 496-8199
Fax: (301) 402-3684
E-mail: rblack@niaid.nih.gov

Direct inquiries regarding fiscal matters to:

Mary Ellen Colvin
Grants Management Specialist
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17K, MSC 7510
Bethesda, MD 20892-7510 
Telephone:  (301) 496- 1304 
Fax:  (301) 402-7827  
E-mail:  mc113b@nih.gov 

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos. 
93.864 and 93.856. 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 inter-governmental 
review requirements of Executive Order 12372 or Health Systems Agency review.

The Public Health Service 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 case, 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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