PARTNERSHIPS FOR TOPICAL MICROBICIDES

RELEASE DATE:  August 13, 2004 (see addendum NOT-AI-05-003)

RFA Number:  RFA-AI-04-047  

EXPIRATION DATE:  December 21, 2004

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH) 
 (http://www.nih.gov/)

COMPONENT OF PARTICIPATING ORGANIZATION:
National Institute of Allergy and Infectious Diseases (NIAID) 
 (http://www.niaid.nih.gov)

CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:
No. 93.855, Immunology, Allergy, and Transplantation Research
No. 93.856, Microbiology and Infectious Diseases Research

LETTER OF INTENT RECEIPT DATE: November 19, 2004
APPLICATION RECEIPT DATE: December 20, 2004  

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Cooperative Agreement Terms and Conditions of Award 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

Research of the National Institute of Allergy and Infectious Diseases 
(NIAID), National Institutes of Health, strives to understand, treat and 
ultimately prevent the myriad infectious, immunologic, and allergic diseases 
that threaten millions of human lives.  The NIAID supports extramural 
research to control and prevent diseases caused by virtually all infectious 
organisms. Studies to evaluate these organisms involve basic biomedical 
research in areas of microbial physiology and antigenic structure; applied 
research, including the development of diagnostic tests; and clinical trials 
to evaluate experimental drugs and vaccines.

This Partnership Program will support the development and testing of topical 
microbicides that target multiple organisms for the control and prevention of 
Sexually Transmitted Infections (STIs), including co-infections of the Human 
Immunodeficiency Virus (HIV) and other STIs. 

PARTNERSHIPS

A key component of this initiative is the development of appropriate 
partnerships between the government and industry.  For the purpose of this 
RFA, "industry" is defined as large and small, domestic or foreign, 
pharmaceutical, biotechnology, bioengineering, and chemical companies.  Since 
academic organizations are often the source of new candidate products, this 
RFA can also support a partnership between industry and a collaborator(s) as 
necessary from academic and/or non-profit research organizations.  The 
involvement of an academic and/or non-profit research organization is NOT a 
requirement; therefore, industry does not need a collaborator to submit an 
application to this program.  

All projects must demonstrate substantive involvement by the industry 
partner.  For the purpose of this RFA, "substantive involvement" is defined 
as the commitment of one or more of the following resources: funds; 
personnel; or in-kind contributions of materials and/or reagents, including, 
but not limited to, chemical libraries, GMP chemical synthesis or recombinant 
or other high capacity method of protein production, provision of animal or 
other laboratory models, and assays, subcontracts, data management resources 
and regulatory support. The Principal Investigator of the project may be 
affiliated with either industry or academic organizations (if academia is 
part of a partnership with industry).  See information under Eligible 
Institutions below.

The Partnership Program is intended to support a variety of phases of 
development of a candidate product. For this RFA, the Partnership Program 
will support the develop of a candidate product that has moved from early 
discovery to preclinical evaluation including, but not limited to, pre-
clinical evaluation studies, formulation optimization, IND enabling studies, 
and pilot lot production. Clinical evaluation of products will not be 
supported under this RFA. NIAID recognizes that the inherent nature and 
demands of the product development process may require funding large, complex 
grants with interdependent specific aims. Furthermore, some aspects of the 
product development process (e.g., production of GLP and cGMP product) are 
inherently not innovative.  Recognizing that product development is often an 
iterative and sequential process, and that steps early in the process may not 
be successful and may need to be modified or reworked, NIAID staff, through 
the cooperative agreement grant mechanism, will be actively involved in 
evaluating the milestones of awardees and determining whether additional 
investment in the development is warranted.

RESEARCH OBJECTIVES

Background for Partnerships

In late 2000, the NIAID convened a panel of experts to discuss the role and 
nature of NIAID/industry collaborations in antimicrobial drug development for 
public health needs and to learn how NIAID could better facilitate and engage 
industry and academia in these endeavors ("Summit on Drug Development for 
Infectious Diseases.").  One of the recommendations from this meeting was a 
continued pursuit of innovative opportunities to form partnerships with the 
private sector for the control of a number of infectious diseases with public 
health importance.  A report of this meeting is available at 
http://www.niaid.nih.gov/dmid/drug/.  Since 2002, NIAID has identified a 
diverse set of priority areas for partnership solicitations that have 
included Partnerships for Novel Therapeutic, Diagnostic and Vector Control 
Strategies in Infectious Diseases (PAR-02-026, 
http://grants.nih.gov/grants/guide/pa-files/PAR-02-026.html), Partnerships 
for Hepatitis B and Vector Borne Diseases Control (RFA-AI-03-003, 
http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-03-003.html) and 
Partnerships for Vaccine and Diagnostic Development (RFA-AI-03-028), 
http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-03-028.html).  NIAID is 
also using this mechanism to solicit applications related to biodefense.  The 
importance of supporting the research specified by the current RFA has been 
emphasized by the need to address the increasing global problem of STIs and 
HIV transmission and infection. Development of safe, efficacious and 
acceptable topical microbicides for STIs and/or HIV, as a complement to 
vaccine development efforts, will provide an additional component to existing 
control and prevention strategies.

Investment by industry in the commercialization of products for the control 
of a number of infectious diseases of public health importance remains 
limited.  This initiative is designed to stimulate industry participation in 
transitioning potential compounds identified by basic research programs into 
available products.  

Background for Topical Microbicides

STIs are critical global and national health priorities because of the 
devastating impact on women and infants, and the inter-relationships with 
HIV/AIDS. Each year an estimated 15 million Americans suffer the 
effects of STIs at a cost exceeding $16 billion. STIs and HIV are linked both 
by biological interactions and by infections occurring in the same 
populations. Certain STIs can increase the risk of HIV acquisition and 
transmission, as well as alter the course of disease progression.  Recent 
studies indicate that the more prevalent STIs (Chlamydia trachomatis, 
Neisseria gonorrhoeae, Trichomonas vaginalis, and organisms 
associated with bacterial vaginosis) that cause non-ulcerative diseases, as 
well as the STIs that cause ulcerative diseases (herpes simplex virus type 2, 
Treponema pallidum and Haemophilus ducreyi) increase the risk of HIV 
transmission by at least two-to five-fold. While all sexually active persons 
are susceptible, women and their children bear a disproportionate burden of 
the harm caused by STIs.

Biologically, STIs are more easily passed from men to women than from women 
to men. Because some STIs can ascend to the upper female genital tract, the 
long-term consequences of infection are also more severe for women and may 
result in infertility, ectopic pregnancy or premature birth. In addition, 
many infections are often asymptomatic in women, resulting in a delay or lack 
of treatment. A lack of female controlled protective strategies may make it 
more difficult for women to avoid exposure to STIs and HIV.

STIs are an area of significant health disparity. African Americans are 
hardest hit with rates more than thirty times greater than white Americans 
for some STIs. Poverty, inadequate health care and partner mixing patterns 
contribute to the excess disease observed in this and other affected 
communities. In addition, STIs contribute to the spread of HIV, which is also 
increasingly concentrated among women and minorities in the United States.

Internationally, current estimates indicate that 35 to 45 million people are 
infected with HIV and that the majority of these infections were acquired 
through sexual intercourse. Therefore, there is an intensified need for the 
development of prevention strategies for controlling this global threat.

One approach to prevention in women is the development of topical 
microbicides, products a woman can use intravaginally to protect herself 
against infection. Results from Phase III efficacy trials of vaginal products 
containing the spermicidal detergent, nonoxynol-9 (N-9), have indicated that 
N-9 does not provide protections against the sexual transmission of HIV and 
when used frequently may increase the risk of HIV transmission. Until 
recently, no other microbicide candidates have advanced sufficiently to be 
considered for Phase III testing. Those candidates now poised for efficacy 
trials are predominantly representatives of a class of compounds that block 
HIV attachment with the exception of a direct virucidal agent that acts via 
acidification of the mucosal environment and a surfactant-based agent that 
preferentially attacks several STIs, including HIV. Candidates with other 
modes of action, or candidates that target multiple organisms, have been 
slower to progress in the product development pipeline. The goal of this RFA 
is to support the development of products that target multiple organisms.

Research Goals and Objectives

The proposed research should focus on development of a topical microbicide 
for the prevention of the vaginal transmission of STIs, targeting more than 
one of the following infections: gonorrhea, chlamydial infection, syphilis, 
chancroid, genital herpes, human papillomavirus, and HIV. Research targeting 
solely HIV, or any one organism, will not be supported under this RFA; 
however, research targeting HIV and another STI is responsive. The applicant 
should provide a rationale for the choice of multiple targets, e.g., a 
mechanism that would target both herpes simplex virus and HIV or a mechanism 
that would target both gonorrhea and chlamydial infection.

While the development of contraceptive products is not within the scope of 
this RFA, products in the development pipeline for contraception that also 
can target STIs and HIV are responsive. Whether or not a contraceptive 
indication will be sought for the product, the level of contraceptive 
activity must be defined for all microbicides. In addition, while the 
intended use of these products is for the intravaginal prevention of STIs and 
HIV, safety evaluations must encompass all potential routes of 
administration.

The research supported through this RFA is not required to result in a final 
marketable product, but must advance an identified candidate product through 
a preclinical development plan to obtain an initial product that may be 
suitable for clinical evaluation. In developing the proposed preclinical 
evaluation plan, applicants may want to refer to the International Working 
Group on Topical Microbicides Nonclinical Guidelines, JAIDS 2004, 36:541-552. 
It is anticipated that the clinical evaluation of the products developed 
through this Partnership Program will subsequently be supported through other 
mechanisms. 

A major objective of this RFA is to stimulate scientifically sound, original, 
and innovative research requiring a comprehensive, multidisciplinary team   
effort that is likely to advance promising candidate products through the 
product development pathway.  All applications should define the proposed 
project goal(s), interim objectives (development milestones), a general 
description of the potential ultimate product (a specific product profile 
that is defined by licensing indication is not requested), and provide a 
schedule or timeline for milestone and goal attainment.  When appropriate, 
research plans should include an awareness of and incorporate measures that 
address the guidelines that govern GLP (as defined by 21 CFR(58)) and GMP (as 
defined by 21 CFR(211). Manufacturing and/or IND enabling studies carried out 
under this award should be performed to provide evidence applicable to 
eventual product licensure in the U.S.
 
MECHANISM OF SUPPORT

This RFA will use the NIH cooperative agreement (U01). The applicant will be 
solely responsible for planning, directing, and executing the proposed 
project. This RFA is a one-time solicitation. Future unsolicited, competing-
continuation applications based on this project will compete with all 
investigator-initiated applications and will be reviewed according to the 
customary peer review procedures. The anticipated award date is August, 2005. 
Applications that are not funded in the competition described in this RFA may 
be resubmitted as NEW investigator-initiated applications using the standard 
receipt dates for NEW applications described in the instructions to the PHS 
398 application. 

The NIH U01 is a cooperative agreement award mechanism in which the Principal 
Investigator retains the primary responsibility and dominant role for 
planning, directing, and executing the proposed project, with NIH staff being 
substantially involved as a partner with the Principal Investigator, as 
described under the section "Cooperative Agreement Terms and Conditions of 
Award. 

The total project period for applications submitted in response to this RFA 
may not exceed five years. At this time, the NIAID has not determined whether 
and how this solicitation will be continued beyond the present RFA.

This RFA uses just-in-time concepts. It also uses the modular budgeting as 
well as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if 
the investigator is 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. This program 
does not require cost sharing as defined in the current NIH Grants Policy 
Statement at 
http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm. 

FUNDS AVAILABLE 

The NIAID intends to commit approximately $2.3 million in FY 2005 to fund 
approximately two to four new grants in response to this RFA. An applicant 
may request a project period of up to 5 years and a budget of not more than 
$750,000 in total costs per year. Applications requesting greater than 
$750,000 in total costs per year will be returned to the applicant without 
review.  Because the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and duration of 
each award will also vary. Although the financial plans of the 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. At this time, it is not known if this RFA will be reissued.

ELIGIBLE INSTITUTIONS

The applicant may submit (an) application(s) if the institution has any of 
the following characteristics: 

o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign institutions/organizations.  

FOREIGN ORGANIZATIONS

Several special provisions apply to applications submitted by foreign 
organizations. 
o  Funds for alterations or renovations cannot be requested.
o  Charge back of customs and import fees is not allowed.
o  Format: every effort should be made to comply with the format 
specifications, which are based 
upon a standard US paper size of 8.5" x 11."
o  Funds for up to 8% administrative costs can now be requested, 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-01-028.html)
o  Organizations must comply with federal/NIH policies on human subjects, 
animals, and biohazards.  
o  Organizations must comply with federal/NIH biosafety and biosecurity 
regulations
o  Proposed research should provide a unique research opportunity, not 
available in the U.S.

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 NIH programs. 

SPECIAL REQUIREMENTS

All applications must propose a research and development plan whose ultimate 
goal is to develop a topical microbicide targeted to the designated STIs, 
either alone or in combination with an HIV indication.  The application must 
document substantive involvement by the industry partner.  

In addition, all applications should include the following:

1.  Preliminary Data and Target Organisms

o  Preliminary data to support the development of the particular compound as 
a topical microbicide, including but not limited to, in vitro and in vivo 
toxicity/safety and activity/efficacy profiles.

o  A description of the proposed target organisms and the rationale for the 
proposed use, such as supporting in vitro activity against the organism or a 
discussion of the rationale for a non-specific mechanism.

o  Preliminary data for more advanced concepts or development plans should 
include assessment against a range of clinical isolates for the target 
organisms, if clinically significant;

2.  Product Development Plan

o  A description of the proposed development plan for the eventual product, 
including product manufacturing, formulation optimization, and GLP and GMP 
mandated product characterization and identification, such as stability 
testing, etc. 

o  A discussion of the strategies and approaches that will be used to provide 
appropriate placebos for animal testing and the role of the placebo in the 
development plan.

3.  Preclinical Testing

o  A description of the preclinical evaluation plan, including a discussion 
of the currently utilized animal models and any proposed comparison with 
other frequently used animal models. 

o  The preclinical development plan should describe and provide milestones 
for mandated preclinical pharmacology and toxicology assessments and should 
include plans for specifically assessing reproductive tract safety.

4.  Use in Resource Constrained Settings

A discussion of the applicability of the proposed product for use in 
developing or resource constrained settings.

5.  Milestones and Goals

Applications must propose clear project goal(s), including a description of 
the final product that will be proposed for subsequent clinical evaluation.  
The applicant must clearly state the interim objectives (developmental 
milestones) to be achieved during the project, identify impediments or 
critical decision points that could require a revision in the work plan or 
milestones, and provide a detailed schedule or timeline for the attainment of 
each milestone and/or goal.  For each critical decision point, the applicant 
must define criteria that clearly describe how decisions will be made to 
advance a product through the proposed development pathway. In other words, 
provide criteria by which go/no go decisions will be made for each milestone. 

Intellectual Property:  

The successful development of high priority products for STI and HIV 
prevention will require substantial involvement and support of private sector 
industries and may also involve collaborations with multiple organizations, 
including academic and/or non-profit research institutions.  It is the intent 
of this initiative to support the formation of the appropriate public-private 
partnerships that are essential to meet these urgent public health needs.  
NIAID recognizes that intellectual property rights are likely to play an 
important role in achieving the goals of this program.  To this end, the 
NIAID requires that at the time of application, all applicants provide a 
letter ("Proprietary Rights Assurance Letter") containing the following 
assurances, which is signed by a representative who is duly authorized to 
provide such assurances on behalf of the applicant organization:

o Applicant is solely responsible for the timely acquisition of all 
proprietary rights, including intellectual property rights, and all materials 
needed for applicant to perform the project;
o Applicant acknowledges that prior to, during, and subsequent to the award, 
the U.S. Government is not required to obtain for applicant any proprietary 
rights, including intellectual property rights, or any materials needed by 
applicant to perform the project;
o Applicant acknowledges the requirement to report to the U.S. Government all 
inventions made in the performance of the project, as specified at 35 U.S.C. 
Sect. 202 (Bayh-Dole Act).

Apart from the Proprietary Rights Assurance Letter, applicants are encouraged 
to reach early consensus with their proposed partners regarding intellectual 
property and other legal matters that may arise during the project.  In 
addition, applicants are expected to exercise their Bayh-Dole rights in a 
manner that does not conflict with the goals of this award or the intent of 
the Bayh-Dole Act to promote the utilization, commercialization and 
availability of U.S. Government-funded inventions for public benefit. 
Finally, applicants are expected to make new information and materials known 
to the research community in a timely manner through publications, web 
announcements, and reports to the NIAID or other mechanisms.

Mandatory Meetings

The Principal Investigators, one or two key personnel designated by the 
Principal Investigators, and NIAID program staff will meet once a year to 
review progress and aid program development, and to foster collaborations 
among the awardees. This meeting will be held at the NIH in Bethesda, MD and 
budget requests should include travel funds for these annual meetings.

COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the award 
statement and provided to the Principal Investigator as well as the 
institutional official at the time of award.

These special Terms of Award are in addition to, and not in lieu of, 
otherwise applicable OMB administrative guidelines, HHS Grant Administration 
Regulations at 45 CFR part 74 and 92, and other HHS, PHS, and NIH Grant 
Administration policy statements.

The administrative and funding instrument used for this program is the 
cooperative agreement (U01), an "assistance" mechanism (rather than an 
"acquisition" mechanism), in which substantial NIH scientific and/or 
programmatic involvement with the awardee is anticipated during the 
performance of the activity.  Under the cooperative agreement, the NIH 
purpose is to support and/or stimulate the recipient's activity by 
involvement in and otherwise working jointly with the award recipient in a 
partner role, but it is not to assume direction, prime responsibility, or a 
dominant role in the activity.  Consistent with this concept, the dominant 
role and prime responsibility for the activity resides with the awardees for 
the project as a whole, although specific tasks and activities in carrying 
out the research will be shared among the awardees and the NIAID Scientific 
Coordinator.  

1.  Monitoring Clinical Studies

When clinical studies or trials are a component of the research proposed, 
NIAID policy requires that studies be monitored commensurate with the degree 
of potential risk to study subjects and the complexity of the study. AN 
UPDATED NIAID policy was published in the NIH Guide on July 8, 2002 and is 
available at: http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html.
The full policy, including terms and conditions of award, is 
available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf.

2.  Awardee Rights and Responsibilities

Awardees will have primary responsibility for defining the research 
objectives, approaches and details of the projects within the guidelines of 
the RFA and for performing the scientific activity. Specifically, awardees 
have primary responsibility as described below.

Awardees will attend annual meetings at the NIH in Bethesda, to be 
coordinated by NIAID program staff.

The Principal Investigator retains primary responsibility for the performance 
of the scientific activity, and agrees to accept close assistance in 
coordination, cooperation and participation of NIAID staff in scientific and 
technical management of the project in accordance with the terms formally and 
mutually agreed upon prior to the award.  The responsibility for the 
planning, direction, and execution of the proposed project will be solely 
that of the Principal Investigator.

o  Publications: The Principal Investigator will be responsible for the 
timely submission of all abstracts, manuscripts, and reviews (co)authored by 
members of the grant and supported in part or in total under this Agreement.  
The Principal Investigator and Project Leaders are requested to submit 
manuscripts to NIAID program staff within 2 weeks of acceptance for 
publication so that an up-to-date summary of program accomplishments can be 
maintained and joint press conferences prepared.  Publications or oral 
presentation of work done under this Agreement is the responsibility of the 
Principal Investigator and appropriate Project Leaders and will require 
appropriate acknowledgement of NIAID support.  

Timely publication of major findings is encouraged.

o  Data: While the NIAID Scientific Coordinator and program staff have a 
right of access to the data (see NIAID staff responsibilities below,) the 
applicant will retain custody of and right to the data.  The awardee must 
have an approved data-sharing plan in place (see 
http://grants.nih.gov/grants/policy/data_sharing/index.htm).

3. NIAID Staff Responsibilities

NIAID staff assistance will be provided by the NIAID's Scientific 
Coordinator. The NIAID Scientific Coordinator will have substantial 
scientific/programmatic involvement during the conduct of this activity 
through technical assistance, advice and coordination above and beyond normal 
program stewardship for grants, as described below.  The Scientific 
Coordinator will coordinate other appropriate NIAID program staff assistance. 

During performance of the award, the NIAID Scientific Coordinator may provide 
appropriate assistance, advice, and guidance by: participating in the design 
of the activities; advising in the selection of sources or resources (e.g., 
determining where a particular organism can be found); coordinating or 
participating in the collection and/or analysis of data; advising in 
management and technical performance; or participating in the preparation of 
publications. The Scientific Coordinator will serve as a liaison/facilitator 
between the awardee, pharmaceutical and biotech industries, and other 
government agencies (e.g., FDA, USDA, CDC), and will serve as a resource of 
scientific and policy information related to the goals of the awardee's 
research. However, the role of NIAID will be to facilitate and not entirely 
to direct the activities.  It is anticipated that decisions in all activities 
will be reached by consensus and the NIAID program staff will be given the 
opportunity to offer input into this process. The manner of reaching this 
consensus and the final decision-making authority will rest with the 
Principal Investigator.

An NIAID Program Official will be responsible for the normal program 
stewardship of this award.  For clinical studies, a mandatory milestone is 
the approval of the final clinical protocol by NIAID. The Program Official 
may also serve as the Scientific Coordinator.

4.  Collaborative Responsibilities

The specific timelines, interim objectives and funding levels agreed to by 
the Principal Investigator and the NIAID shall be included in the terms and 
conditions of award.  Given the nature of product development, it is 
recognized that timelines and interim objectives may require revision and 
renegotiation during the course of the project period.  The Principal 
Investigator and NIAID must agree to all such revisions. Release of each 
funding increment by NIAID will be based on a NIAID review of progress 
towards achieving the previously agreed upon interim objective.   Where 
scientifically appropriate NIAID may ask recipients to collaborate or 
cooperate with other NIAID funded projects and/or US government agencies, for 
example CDC, FDA and USDA.

5. Arbitration

Any disagreement that may arise on scientific/programmatic matters (within 
the scope of the award), between award recipients and the NIAID may be 
brought to arbitration. An arbitration panel will be composed of three 
members - one selected by the Steering Committee (with the NIAID 
representation not voting) or by the individual awardee in the event of an 
individual disagreement, a second member selected by NIAID, and the third 
member selected by the two prior selected members. This special arbitration 
procedure in no way affects the awardee's right to appeal an adverse action 
that is otherwise appealable in accordance with the PHS regulations at 42 CFR 
Part 50, Subpart D and HHS regulation at 45 CFR Part 16.

These special Terms of Award are in addition to and not in lieu of otherwise 
applicable OMB administrative guidelines, HHS Grant Administration 
Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant 
Administration policy statements. 

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants. Inquiries may fall into three 
areas: scientific/research, peer review, and financial or grants management 
issues:

o Direct questions about scientific/research issues to:

Carolyn D. Deal, Ph.D.
Division of Microbiology & Infectious Diseases
National Institute of Allergy and Infectious Diseases
Room 5039, MSC-6604  
6610 Rockledge Drive
Bethesda, MD 20892-6604  
Telephone: (301)402-0443 
FAX: (301) 480-3617   
Email: [email protected]

o Direct questions about peer review issues to:

Hagit David
Division of Extramural Activities 
National Institute of Allergy and Infectious Diseases
Room 3137, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: (301) 402-4596
FAX: (301) 402-2638
Email:  [email protected]

o Direct questions about financial or grants management matters to:

Lesia Norwood
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2117, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614 
Telephone: (301) 402-7146 
FAX: (301) 480-3780
Email: [email protected]

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o 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 NIAID staff to estimate the potential review workload and 
plan the review.

The letter of intent is to be sent by the date listed at the beginning of 
this document. The letter of intent should be sent to:

Hagit David
Division of Extramural Activities 
National Institute of Allergy and Infectious Diseases
Room 3137, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: (301) 402-4596
FAX: (301) 402-2638
Email:  [email protected]

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a DUN and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The D&B number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/. The D&B number 
should be entered on line 11 of the face page of the PHS 398 form.  The PHS 
398 document is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
Email: [email protected].

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application. Type the RFA number on the label. 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. The RFA label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package by commercial carrier 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 exact copies of the grant 
application and all five sets of any appendix material must be sent to:

Hagit David
Division of Extramural Activities 
National Institute of Allergy and Infectious Diseases
Room 3137, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
BETHESDA, MD 20817 (for express mail or courier service)

APPLICATION PROCESSING: Applications must be received by the application 
receipt date listed in the heading of this RFA.  If an application is 
received after that date, it will be returned to the applicant without 
review.

The NIH 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. However, when a previously 
unfunded application, originally submitted as an investigator-initiated 
application, is to be submitted in response to an RFA, it is to be prepared 
as a NEW application. That is the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text must 
not be marked to indicate the changes. While the investigator may still 
benefit from the previous review, the RFA application is not to state 
explicitly how.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIAID.

Incomplete and/or non-responsive applications will be returned to the 
applicant without further consideration or review.  Applications submitted by 
an academic institution alone without an industrial partner will be 
considered non-responsive and will be returned without review.

Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by one or more appropriate peer review 
groups convened by the NIAID in accordance with the review criteria stated 
below. As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the National Advisory Allergy and 
Infectious Diseases 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 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:

o Significance
o Approach
o Innovation
o Principal Investigator and Other Staff
o Environment

The scientific review group will address and consider each of these 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.

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?

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? Are the interim objectives (developmental milestones) 
appropriate and feasible? Are the criteria for go/no go decision making 
clearly defined and reasonable?

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?

PRINCIPAL INVESTIGATOR AND OTHER STAFF: 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)? Are the other scientific and technical staff 
appropriate and qualified? Are the project management and administrative 
staff appropriate and qualified?

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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below)

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research. Plans for the recruitment and retention of subjects will also be 
evaluated. (See Inclusion Criteria in the sections on Federal Citations, 
below).

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 (rev. 5/2001) will be assessed. 

ADDITIONAL REVIEW CONSIDERATIONS

SHARING RESEARCH DATA:  Applicants requesting $500,000 or more in direct 
costs in any year of the proposed research are expected to include a data 
sharing plan in their application. The reasonableness of the data sharing 
plan or the rationale for not sharing research data will be assessed by the 
reviewers. However, reviewers will not factor the proposed data-sharing plan 
into the determination of scientific merit or priority score. (See 
instructions and URL to policy in the Federal Citations, below.)

BUDGET: The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:      November 19, 2004
Application Receipt Date:           December 20, 2004
Peer Review Date:                   April, 2005
Council Review:                     June, 2005
Earliest Anticipated Start Date:    August, 2005

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit of the proposed project as determined by peer review
o Availability of funds
o Programmatic priorities.

REQUIRED FEDERAL CITATIONS

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities 
involving live, vertebrate animals must comply with PHS Policy on Humane Care 
and Use of Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as 
mandated by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA 
Animal Welfare Regulations 
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained. 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II), efficacy, 
effectiveness and comparative trials (phase III). The establishment of data 
and safety monitoring boards (DSMBs) is required for multi-site clinical 
trials involving interventions that entail potential risk to the 
participants. (NIH Policy for Data Safety and Monitoring, NIH Guide for 
Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

SHARING RESEARCH DATA: Investigators submitting an NIH application seeking 
$500,000 or more in direct costs in any single year are expected to include a 
plan for data sharing or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing Investigators should seek 
guidance from their institutions, on issues related to institutional 
policies, local IRB rules, as well as local, state and Federal laws and 
regulations, including the Privacy Rule. Reviewers will consider the data 
sharing plan but will not factor the plan into the determination of the 
scientific merit or the priority score.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  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 clinical research projects unless a 
clear and compelling justification is 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 clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.

The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community. The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy 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. 

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 that is available at 
http://grants.nih.gov/grants/funding/children/children.htm.

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects. This policy announcement is in the NIH Guide for Grants and 
Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at http://stemcells.nih.gov/index.asp and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). 
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s) for the hESC line(s) to be used in the proposed research. 
Applications that do not provide this information will be returned without 
review. 

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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The 
Department of Health and Human Services (DHHS) issued final modification to 
the  Standards for Privacy of Individually Identifiable Health Information , 
the  Privacy Rule,  on August 14, 2002. The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR). 

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on  Am I a covered 
entity?  Information on the impact of the HIPAA Privacy Rule on NIH processes 
involving the review, funding, and progress monitoring of grants, cooperative 
agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.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. Furthermore, we 
caution reviewers that their anonymity may be compromised when they directly 
access an Internet site.

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 one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS

This program is described in the Catalogue of Federal Domestic Assistance at 
http://www.cfda.gov/ in the following citations: No. 93.855, Immunology, 
Allergy, and Transplantation Research and No. 93.856, Microbiology and 
Infectious Diseases 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 NIH Grants Policy Statement is available at 
http://grants.nih.gov/grants/policy/policy.htm. This document includes 
general information about the grant application and review process; 
information on the terms and conditions that apply to NIH Grants and 
cooperative agreements; and a listing of pertinent offices and officials at 
the NIH.  All awards are subject to the terms and conditions, cost 
principles, and other considerations described in the NIH Grants Policy 
Statement. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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