INTEGRATED PRECLINICAL/CLINICAL PROGRAM FOR TOPICAL MICROBICIDES

RELEASE DATE:  June 9, 2003 

PA NUMBER:  PAR-03-137 ( This PAR has been reissued as RFA-AI-07-001)
(see clarification NOT-AI-03-051)


LETTER OF INTENT DATE:  August 22, 2003, August 23, 2004, 2005
APPLICATION RECEIPT DATE: September 23, 2003, 2004, 2005

EXPIRATION DATE:  September 24, 2005, unless reissued.

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

CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS:
No. 93.855, Immunology, Allergy, and Transplantation Research
No. 93.856, Microbiology and Infectious Diseases Research
No. 93.865, Center for Research for Mothers and Children

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this PA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators (PIs)
o Special Requirements 
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS PA 

The National Institute of Allergy and Infectious Diseases (NIAID) and the 
National Institute of Child Health and Human Development (NICHD), National 
Institutes of Health (NIH) invite multi-project, multi-disciplinary 
applications whose goal is to advance safe, novel topical microbicides and 
microbicide combination strategies that prevent the sexual transmission of 
HIV, from preclinical to clinical studies. For the purposes of this Program 
Announcement (PA), topical microbicides are defined as vaginally or rectally 
applied biomedical products with or without contraceptive activity that 
safely inactivate HIV or prevent HIV infection or spread from initial target 
cells.  The Integrated Preclinical/Clinical Program for HIV Topical 
Microbicides (IPCP-HTM) described in this PA links research with product 
development and initial clinical evaluation by supporting diverse research 
activities from multidisciplinary groups spanning discovery and preclinical 
development through early clinical trials.  The previously released RFA 
entitled "Microbicide Preclinical Development Program" (HD-00-018) to 
advance the discovery and preclinical development of novel microbicides has 
been integrated into this PA and will not appear separately.  Applications 
that aim to further an innovative topical microbicide may propose to initiate 
research at one of the following points: (1) discovery and preclinical 
development of a lead microbicide candidate/combination, (2) preclinical 
development research that transitions to iterative clinical/laboratory 
research directed toward optimization of the microbicide 
candidate/combination during the award period, or (3) iterative 
clinical/laboratory research in which a pilot clinical trial will be 
implemented within the first year of award.  In combining these activities 
into a single PA, the IPCP-HTM provides a spectrum of research opportunities 
for collaborative groups pursuing any aspect of the discovery and development 
of new topical microbicides. Applications are required to include a 
component(s) (a research project and/or a core) headed by and derived from 
the private sector.  Responsive applications will advance microbicide 
development with innovative microbicide research.  Excluded from this PA is 
research on, or development of, marketed spermicidal products.  Also excluded 
from this PA is research on, or development of, sulfated/sulfonated polymers 
or surfactants when advanced as the sole active ingredient in a microbicide 
candidate.  Research on sulfated/sulfonated polymers or surfactants as 
components of combination microbicides will be considered responsive.

RESEARCH OBJECTIVES

Background

In the absence of a fully effective HIV vaccine, topical microbicides 
represent an important potential strategy for preventing the transmission of 
HIV through sexual intercourse, the predominant mode by which HIV is 
transmitted worldwide.  In particular, the number of women with HIV infection 
and AIDS has been increasing steadily worldwide and according to the World 
Health Organization (WHO), 19.2 million women are living with HIV/AIDS 
worldwide, accounting for almost 50 percent of the 42 million adults living 
with HIV/AIDS.  The vulnerability of women of all ages for acquiring HIV 
infection - including older, postmenopausal women as well as adolescents - 
demands the development of safe, effective and acceptable female-controlled 
chemical and physical barrier methods, including topical microbicides, to 
reduce HIV transmission.  In addition, recent statistics from several major 
cities in the U.S. show an increase in unsafe sexual practices as indicated 
by an increase in sexually transmitted diseases.  Yet no safe and effective 
anti-HIV topical microbicide is currently available.  Only products 
containing the surfactant, nonoxynol-9 (N-9), have advanced to efficacy 
trials. Results from these trials of vaginal N-9-containing products have 
indicated that N-9 does not provide protection against the sexual 
transmission of HIV.  The safety and effectiveness of 6 additional candidate 
microbicides will be evaluated in trials scheduled to start in 2003.  
However, 4 of these are representative of the same class of active agent and 
one is a surfactant.  Research is continuing into other diverse products; 
candidate microbicides currently under investigation include products that 
kill or inactivate HIV nonspecifically, those that inhibit HIV entry and cell 
fusion, and those that inhibit post-fusion events early in the viral 
replication cycle.  The nonspecific candidate products fall predominantly 
into the category of surfactants and detergents, whereas most products 
targeted against specific steps in the HIV life cycle have been developed 
exclusively as potential therapeutics.  In addition, no combination of 
microbicides has yet been evaluated in animal or human trials.  Specifically, 
research needs to be conducted on the use of combinations of microbicides to 
determine if protective efficacy of the products is increased when 
microbicides with two or more different mechanisms of action are used 
together.  Furthermore, topical strategies to safely enhance or stimulate 
naturally occurring healthy mucosal defense mechanisms have not been 
sufficiently exploited.  Thus, there is a critical need to promote the 
discovery and development of safe, novel microbicides and combinations and to 
provide support for translational studies to advance new candidates and 
combinations that have proven safe in preclinical studies into early clinical 
trials.  This PA will support multi-project, multi-disciplinary research 
groups, whose goal is to advance topical microbicides and microbicide 
combination strategies from discovery through preclinical development to 
clinical studies, to assemble the diverse scientific expertise and ancillary 
resources needed to translate basic discoveries to innovative applied 
entities. 

Scope

The purpose of the IPCP-HTM is: (1) to encourage discovery and preclinical 
development of lead topical microbicide candidates and combinations, and (2) 
to foster translation of safe, new microbicides/combinations from preclinical 
studies to pilot clinical studies.  The ultimate goal of this research is the 
development and exploratory clinical evaluation of new and potentially 
effective microbicides for the prevention of HIV sexual transmission.  Such 
research is expected to increase the array of approaches and availability of 
potential candidates and combinations suitable for evaluations of safety and 
effectiveness in human clinical studies.  In line with this objective, the PA 
will support diverse and creative microbicides/combinations with sound 
scientific rationale that are new and innovative or understudied.  The PA 
provides a continuous spectrum of research opportunities - from discovery and 
preclinical development to pilot clinical studies - for interdisciplinary 
research groups to conduct. 

Examples of microbicide candidates of interest to the IPCP-HTM include, but 
are not limited to:

o Development of combination microbicides containing a cocktail of active 
agents with diverse mechanisms of action, including those addressed below;

o Discovery of novel microbicides including but not limited to: small 
molecules, metal and chelating agents, proteins, glycans, natural products, 
agents controlling pH, and bacterial and live vectors that may target viral 
or host elements essential for (i) HIV entry, including attachment, receptor 
engagement or fusion; (ii) early post-entry events in the HIV life cycle 
prior to and including reverse transcription, such as uncoating or 
translocation of the pre-integration complex into the nucleus; and/or (iii) 
HIV capture by, and dissemination from, initial target cells;

o Development of microbicides that enhance or stimulate naturally occurring 
healthy mucosal defense mechanisms; and

o Development of innovative virucidal agents that inactivate infectious HIV-1 
particles or HIV-1-infected cells without causing host cell toxicity.

Preclinical Research

The preclinical component of the IPCP-HTM supports discovery and preclinical 
development of topical microbicides and combination microbicide approaches.  
A new microbicide or combination should have relevance and future application 
to clinical evaluation.  As part of an integrated approach to the critical 
path development of a specific candidate product and advancement into pilot 
clinical trials, applicants are encouraged to incorporate research in areas 
of microbicide development that are largely underexplored e.g., (1) 
formulation science, (2) development of new and/or improved ex vivo (e.g., 
tissue explants) and in vivo animal models for evaluating the safety and 
efficacy of new microbicides, including models for reproductive toxicity, and 
(3) design and evaluation of delivery systems.  To be considered responsive 
to this PA, IND-enabling safety and other preclinical studies must comply 
with Good Laboratory Practice (GLP) regulations, as well as production and 
manufacture of microbicide products according to Good Manufacturing Practice 
(GMP) regulations,.  A successful group proposing preclinical studies would 
move a candidate microbicide, or combination, from discovery through advanced 
preclinical development such that at completion of the 4-year award period it 
would be poised for clinical evaluation.

Applicants seeking to transition from preclinical to clinical research during 
the award period are required to detail the discrete goals and measurable 
milestones considered necessary to enter the clinical phase.  These goals and 
milestones should also include plans and a timetable for obtaining the 
required institutional and government approvals [Institutional Review Board 
(IRB), Office of Human Research Protection (OHRP), FDA].  The peer review 
group will review the appropriateness of the goals and milestones. Funding of 
the final 2 years of the grant will be contingent upon successful completion 
of negotiated milestones and the feasibility of clinical testing within the 
funding period as determined by a mid-point review of progress to date (see 
Special Requirements).  

Clinical Studies

The clinical portion of the IPCP-HTM should exploit interdependent, iterative 
clinical/laboratory research designed to evaluate and optimize a microbicide.  
Research in the areas of identification/evaluation of markers and/or 
methodologies to establish product use compliance and assessment of state-of-
the-art technologies to measure bio-adhesive and bio-dispersion 
characteristics may be included as part of an integrated approach to advance 
a specific microbicide candidate.  Examples of other scientific areas 
appropriate for pilot clinical studies include, but are not limited to, 
evaluation of pharmacokinetics and tissue distribution of the proposed 
microbicide candidate, evaluation of the safety and acceptability of a novel 
delivery system, and preliminary evaluation of potential activity on viral 
load (if relevant to the proposed mechanism of action) recovered in vaginal 
and rectal mucosal specimens.  Proposals with projects focusing on new 
strategies that exploit pre-existing non-detergent microbicides, especially 
as combination microbicides, would also be considered responsive.  A 
successful application proposing clinical studies would develop and optimize 
a microbicide candidate to the point of determining its merits for further 
clinical evaluation.

A clinical application must be based on a strategy in an advanced stage of 
preclinical development that is suitable for evaluation in a small number (6-
12) of subjects in a pilot clinical study.  [When merited by the study, a 
larger number of subjects may be considered; prior approval by the Program 
Officer (see INQUIRIES, below) is required.]  Conventional Phase I through 
Phase III clinical trials are not supported by this Program Announcement.  
The application should include (1) a detailed plan of the iterative clinical 
and laboratory research to be conducted to optimize the proposed strategy, 
(2) a timetable to be followed, (3) plans for clinical studies, including a 
clinical concept, outline of a clinical protocol, or the clinical protocol, 
and (4) institutional and government approvals (IRB, FDA, OHRP), where 
applicable. 

NIAID and NICHD intend to support the following research groups through this 
PA:  (1) groups focusing exclusively on advanced preclinical optimization and 
IND-directed development of new topical microbicides [i.e., appropriately 
synthesized and manufactured microbicide products that will undergo safety 
testing as per U.S. Food and Drug Administration (FDA) Investigational New 
Drug (IND) guidelines], and (2) groups positioned to implement a pilot 
clinical study during the award period.  Pilot clinical studies are defined 
as early Phase I studies with small numbers of participants, exclusive of 
formal Phase I through Phase III clinical trials.  U19 applications submitted 
in response to this PA may not request in excess of $750,000 first-year 
direct costs for research involving preclinical studies, or $1,300,000 first-
year direct costs, exclusive of Facilities & Administrative (F & A) costs for 
consortium arrangements for translational research involving clinical 
studies.  Budgets exceeding these levels must be strongly justified and pre-
approved for submission by the Program contact person listed under 
"INQUIRIES."  Applications with budgets exceeding these levels that are 
submitted without prior Program approval will be returned without review.  
Groups proposing to transition from preclinical to clinical studies during 
the award period should submit a budget for each phase that reflects the 
limits given above.  

MECHANISM OF SUPPORT

This PA will use the NIH Multi-project Cooperative Agreement (U19), an 
"assistance" mechanism, rather than an "acquisition" mechanism.  The NIH U19 
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."  

Essential elements of the multi-project cooperative agreement mechanism also 
include: (1) a minimum of three interrelated individual research projects 
organized around a central theme; (2) collaborative efforts and interaction 
among independent projects and their investigators to achieve a common goal; 
(3) a single PI who will be scientifically and administratively responsible 
for the group effort; (4) a single applicant institution that will be legally 
and financially responsible for the use and disposition of funds awarded; and 
(5) support provided, as necessary, for "Core" resources or facilities, each 
of which is expected to be utilized by at least two research projects in 
order to facilitate the research effort

The level of support for clinical research under this PA may be insufficient 
to provide all the funds necessary to conduct the proposed clinical study.  
Prospective groups are therefore encouraged to develop plans to use existing 
infrastructure and organizational support to complement the award [including 
NIH-sponsored General Clinical Research Centers (GCRC), Centers for AIDS 
Research (CFAR), the HIV Prevention Trials Network (HPTN), the Adolescent 
Medicine Trials Network (ATN), the Contraceptive Clinical Trials Network 
(CCTN) and the Comprehensive International Program for Research on AIDS 
(CIPRA)].  These plans should be included in the application.

The total project period for applications submitted in response to this PA 
may not exceed five years for applications proposing clinical research; for 
applications focusing solely on preclinical development, the total project 
period may not exceed 4 years.

Applicants for U19 grants must follow special application guidelines in the 
NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT 
AWARDS; this brochure is available via the WWW at: 
http://www.niaid.nih.gov/ncn/grants/multibron.htm.

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 
o Faith-based or community-based organizations  

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

Milestones

Through the Scientific Coordinator (as described in the Collaborative 
Responsibilities section below), NIAID/NICHD may revise the proposed and 
peer-reviewed milestones and negotiate acceptance of the revised milestones 
with the PI, as necessary, prior to award.  The finalized milestones will be 
included in the Terms of Award.  Progress will be based upon the timely 
completion of these milestones. Decisions regarding funding beyond 3 years 
for groups transitioning to clinical studies will be based on the completion 
of milestones in the first 2.5 years.

Milestones Review

At the mid-point of the grant (2.5 years), based on the preceding 2 annual 
reports and any additional information that the PI elects to submit at the 
2.5-year anniversary, Program will determine whether the milestones have been 
accomplished and whether the progress as reported will allow, with high 
probability, initiation of a clinical study within 5 total years.  The mid-
point grant review will be conducted via a phone conference call or a meeting 
with the PI and NIAID/NICHD staff and may include members of the Scientific 
Advisory Panel (SAP) (as described in the Collaborative Responsibilities 
Section of this PA).  If NIAID/NICHD determines high feasibility for the 
grant to culminate in a human clinical study, the grantee will be funded for 
years 4 and 5.  If NIAID/NICHD determines that progress does not demonstrate 
likelihood of a clinical study, the grant will be phased out by the end of 4 
years, or sooner, if appropriate/feasible.

Patent Coverage

Since an application may include several institutions, including the private 
sector, complex patent situations may arise.  To avoid delays related to 
intellectual property issues, each multi-project group is required to submit, 
as part of the application, a plan detailing (1) the approach agreed to by 
all parties for obtaining patent coverage and licensing, where appropriate, 
(2) a statement demonstrating acceptance of the approach signed by all 
parties, and (3) procedures to be followed for the resolution of legal 
problems that may potentially develop. 

Meetings and Travel

All awardees will be strongly encouraged to attend a scientific conference of 
NIAID/NICHD Topical Microbicide Program investigators, organized by NIH and 
held every 12-18 months in the Washington, D.C. area.  Applicants should 
include estimated travel expenses for one such meeting per year to the 
Washington, D.C. metropolitan area in the application budget.  Estimated 
expenses for travel of the SAP members and key staff [e.g., PI, all Project 
Leaders (PL) etc.] should be based on one group meeting per year and should 
also be included in the budget.  No additional travel funds will be provided 
to attend other domestic or foreign meetings.

COOPERATIVE AGREEMENT TERMS AND CONDITIONS OF AWARD

The following terms and conditions will be incorporated into the award 
statement and provided to the PI 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 multi-
project cooperative agreement (U19), "assistance", 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/NICHD 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 PA and for performing the scientific activity. Specifically, awardees 
have primary responsibility as described below.

All awardees are required to host for the Scientific Coordinator and other 
NIAID/NICHD Program staff, an annual site visit.  The PI, all co-PIs, PLs and 
Core Leaders and the SAP (described in the Collaborative Responsibilities 
section below) members shall attend this meeting.  An update and summary of 
results generated on each project shall be presented by the PI and other 
relevant members of the cooperative agreement.  These presentations shall 
include summaries of all goals or milestones (refer to Special Requirements) 
and a description of all problems encountered that will impact on the 
achievement of future goals and milestones. In addition to annual site 
visits, the PI will be afforded the opportunity to submit in writing a mid-
point progress report delineating progress on each of the stated milestones 
and a clear plan for the initiation of a clinical study. Any such 
supplemental information must be provided to the Scientific Coordinator no 
later than 1 month prior to the date of the 2.5-year anniversary of the grant 
award. 

3. NIAID/NICHD Staff Responsibilities

NIAID/NICHD staff assistance will be provided by a Program Officer who will 
serve as NIAID/NICHD's Scientific Coordinator. The NIAID/NICHD 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.

o  Interacting with the PI(s) on a regular basis to monitor program progress 
and clinical study progress, compliance, adherence to protocol, and quality 
assurance in order to ensure the production of high-quality, unbiased 
results. Monitoring may include: (a) regular communications with the PI and 
staff, (b) periodic site visits for discussions with awardee research teams, 
(c) observation of field data collection and management techniques, quality 
control, fiscal review, and other relevant matters, as well as (d) attendance 
at and participation in SAP meetings and/or annual site visit meetings. The 
NIAID/NICHD retains, as an option, periodic external review of progress.  
NIAID/NICHD reserves the right to independently monitor the trial to ensure 
adherence to regulatory requirements.  Such review and monitoring may be 
conducted by an organization contracted by and acting on behalf of 
NIAID/NICHD.

o  NIAID/NICHD Program staff or designee will have access to and may 
periodically review all study protocols and data.

o  Serving as a resource with respect to ongoing NIAID/NICHD activities that 
may be relevant to the research to facilitate expeditious accomplishment of 
program goals and compatibility, avoid unnecessary duplication, and potentially 
forging collaborations that may enhance the quality and breadth of the study.

o  Providing substantial assistance in the design and coordination of research 
activities for awardees including:
a. Advice on planning, management and technical performance of the 
investigations
b. Access to and use of, when appropriate, reagents and assays, and other 
resources available through NIAID/NICHD contractors and awardees
c. Technical advice and assistance with meeting FDA requirements for 
investigational agents
d. Coordination of activities among awardees [for multi-institutional 
protocols, through participation on the SAP and with the agreements of the 
PI(s)] by assisting in the design, development, and coordination of a common 
research or clinical protocol and statistical evaluations of data; in 
preparation of questionnaires and other data recording forms; and in the 
publication of results
e. Review and approval of protocols to insure adherence to the scope of the 
original proposal, peer review comments and suggestions, and for adequacy of 
safety, protection of human subjects, and representation of women and 
minorities as required by Federal regulations and NIH policies. The NIAID/NICHD 
Program Officer will monitor protocol progress, and may require that a protocol 
be closed to accrual for reasons including: (a) accrual rate insufficient to 
complete study in a timely fashion, (b) accrual goals met early, (c) poor 
protocol performance, (d) patient safety, human subjects, and women/minority 
recruitment concerns, (e) study results that are already conclusive, and (f) 
emergence of new information that diminishes the scientific importance of the 
study. The NIAID/NICHD will not permit further expenditure of NIAID/NICHD funds 
for a study after requiring closure (except for patients/subjects on-study and 
final data analysis and reporting)
f. Advice regarding the establishment of mechanisms for quality control and 
study monitoring

o  Making recommendations for continued funding based on: (a) overall study 
progress including study subject and/or data accrual, (b) cooperation in 
carrying out the research e.g., following SAP meeting guidance, implementation 
of group decisions, compliance with terms of award and reporting requirements), 
and/or (c) maintenance of a high quality of research that will allow pooling of 
data and comparisons across multiple cooperative agreement awards for common 
data elements.

4. Collaborative Responsibilities

IPCP-HTM Group Scientific Advisory Panel 

Each IPCP HTM group will establish a Scientific Advisory Panel (SAP) i.e., 
Steering Committee of 2-3 investigators not affiliated with any of the 
institutions comprising the awardee(s).  Membership will be determined in 
consultation with the Scientific Coordinator. Applicants must not name the 
prospective Advisory Panel members in their applications nor should 
prospective members be contacted by applicants prior to completion of peer 
review of applications. However, a proposal should include identification of 
the proposed expertise to be represented on the panel.  The Panel will attend 
one or more of the IPCP-HTM group meetings each year, review the group's 
activities, and evaluate progress, adherence to the original time frame of 
activities, and the continued relevance of each project to the group's 
overall goals.  The Panel will recommend new directions as appropriate and 
will provide the PI with a comprehensive written evaluation of the group's 
activities and recommendations after each meeting. For applications proposing 
a clinical component, the Panel may, at the discretion of NIAID or NICHD, 
also be called upon to evaluate the feasibility of initiating a clinical 
study per the final goals and milestones.  A copy of the Panel's report is to 
be sent to the NIAID or NICHD Coordinator, as appropriate, within 30 days of 
each meeting. 

5. Arbitration

Arbitration. Any disagreement that may arise on scientific or programmatic 
matters (within the scope of the award), between award recipients and the 
NIAID/NICHD may be brought to arbitration. An arbitration panel will be 
composed of three members - one selected by the Steering Committee (with the 
NIAID/NICHD representation not voting) or by the individual awardee in the 
event of an individual disagreement, a second member selected by NIAID/NICHD, 
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.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this PA 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 your questions about NIAID scientific/research issues to:

Dr. Roberta Black
Division of AIDS
National Institute of Allergy and Infectious Diseases
Room 4110, MSC-7628
6700-B Rockledge Drive
Bethesda, MD 20892-7628
Telephone: (301) 496-8199
FAX:       (301) 496-8530
E-Mail:     rb31i@nih.gov

o Direct your questions about NICHD scientific/research issues to:

Dr. Patricia Reichelderfer
Center for Population Research
National Institute of Child Health and Human Development
Room 8B13G, MSC 7510
6100 Executive Boulevard 
Bethesda, MD 20892-7510
Telephone: 301-496-1661
FAX:       301-480-1972
E-mail:    pr20f@nih.gov

o Direct questions about peer review issues; address the letter of intent; 
mail two copies of the application and all five sets of appendices to:

R. V. Srinivas, Ph.D.
Chief, AIDS & Related Research IRG
Center for Scientific Review, NIH 
Room 5222, MSC 7852
6701 Rockledge Dr
Bethesda, MD 20892
(Use 20817 for express mail
Telephone: (301) 435-1167
FAX:       (301) 435-1167
E-Mail:     srinivar@csr.nih.gov 

o Direct questions about financial or grants management matters to:

Jane Unsworth
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases  
Room 2128, MSC-7614
6700-B Rockledge Drive  
Bethesda, MD  20892-7614 
Telephone: (301) 402-6824 
FAX:       (301) 480-3780 
Email:      ju3a@nih.gov

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 IC 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:

Dr. Roberta Black
Division of AIDS
National Institute of Allergy and Infectious Diseases
Room 4110, MSC-7628
6700-B Rockledge Drive
Bethesda, MD 20892-7628
Telephone: (301) 496-8199
FAX:       (301) 496-8530
E-Mail:     rb31i@nih.gov

SUBMITTING AN APPLICATION

Applicants for U19 Cooperative Agreements must follow special application 
guidelines in the NIAID brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR 
MULTI-PROJECT AWARDS; this brochure is available via the WWW at: 
http://www.niaid.nih.gov/ncn/grants/multibron.htm

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). The PHS 398 is available at 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted June 27, 2003, 2004, 2005.

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and five 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)

Applications that are not received as a single package on the receipt date or 
that do not conform to the instructions contained in PHS 398 (rev. 5/01) 
Application Kit (as modified in, and superseded by, the NIAID BROCHURE 
ENTITLED "INSTRUCTIONS FOR APPLICATIONS FOR MULTI-PROJECT AWARDS"), will be 
judged non-responsive and will be returned to the applicant. 

Investigators wishing to participate in a multi-project grant must be aware 
of this policy before making a commitment to the PI and awarding institution.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications requesting $500,000 or more in direct costs for any year must 
include a letter of intent identifying the NIAID/NICHD staff member who has 
agreed to accept assignment of the application. 

Applicants requesting more than $500,000 must carry out the following steps:

1) Contact the NIAID/NICHD program staff person listed in this PA at least 6 
weeks before submitting the application, i.e., as applicant is developing 
plans for the study

2) Obtain agreement from the NIAID/NICHD staff that the NIAID/NICHD will 
accept the application for review and potential consideration for award; and

3) Identify in the letter of intent, the NIAID/NICHD staff member you 
contacted, a proposed first year budget with the number of Projects, PIs and 
Institution for each project, specific aims for each project, and a projected 
budget for the proposed funding period. 

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html.

SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS PA:

Applicants for U19 Cooperative Agreements must follow special application 
guidelines in the NIAID Brochure entitled INSTRUCTIONS FOR APPLICATIONS FOR 
MULTI-PROJECT AWARDS; this brochure is available from NIAID listed under 
INQUIRIES via the WWW at: http://www.niaid.nih.gov/ncn/grants/multibron.htm.

This brochure presents specific instructions for sections of the PHS 398 
(rev. 5/01) application form that should be completed differently than usual. 
For all other items in the application, follow the usual instructions in the 
PHS 398.

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

The CSR will not accept any application in response to this PA 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 a substantial revision of an application 
already reviewed, but such application must include an Introduction 
addressing the previous critique.

Concurrent submission of an R01 and a Component Project of a Multi-project 
Application: Current 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 is an NIH policy 
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 PI and 
awarding institution.

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

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines. An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit. 

U19 applications that are complete and responsive to this PA will be 
evaluated for scientific and technical merit by an appropriate peer review 
group convened by the Center for Scientific Review.

As part of the initial merit review, all applications will:

o Receive a written critique
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 second level review by an appropriate national advisory council 
or board.

REVIEW CRITERIA

The general review criteria for U19 multi-project cooperative agreement 
applications are presented in the NIAID brochure entitled "INSTRUCTIONS FOR 
APPLICATIONS FOR MULTI-PROJECT AWARDS" at 
http://www.niaid.nih.gov/ncn/grants/multibron.htm

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

o  The potential biomedical significance and novelty of the project. 

o  The likelihood that the research will open new directions in the 
prevention of HIV sexual transmission, demonstrate a capacity to be 
translated to clinical practice, and merit evaluation in IND-directed 
clinical trials for safety and proof-of-concept. 

o  Appropriateness of the experimental approach, development plan, and 
methodology proposed, including laboratory capabilities of the investigators 
(preclinical and/or clinical).

o  The PI's and PLs' commitment to devote substantial time and effort to the 
program.  [Due to the complexity and time required to maintain a well 
coordinated and productive research effort, a minimum 20% (time) commitment 
by the PI and PLs is strongly suggested.]

o  The suitability of the proposed private sector component to the overall 
scientific objectives of the applicant; the scientific capability and 
commitment of the private sector component to the group's objectives and to 
the development of the proposed microbicide candidate; adequacy of the 
development plan to achieve the scientific goals of the proposed research and 
to move the proposed microbicide toward clinical application and toward 
approval of the proposed microbicide for clinical use.

Each of these review criteria will be addressed and considered by the 
reviewers 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 a 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. 

In addition to (not in lieu of) the review criteria detailed in the 
instruction brochure (see above), review criteria specific to this PA include 
an evaluation of the following:

For groups focusing on preclinical research:

o  Choice of the microbicide target or strategy, its contribution to the 
diversity of potential microbicides, and the likelihood that the microbicide 
candidate can be developed (e.g., following a prescribed preclinical 
development plan; selecting a clinical candidate) during the award period

o  Likelihood that work will progress through preclinical development during 
the award period, after which the microbicide candidate will be poised for 
clinical evaluation

For groups proposing clinical research:

o Adequacy and validity of the proposed discrete goals and measurable 
milestones for determining the readiness of the group to transition to 
clinical research; iterative research plan to develop and optimize the 
proposed microbicide candidate; general protocol design; short and long term 
development plans; contingency plans addressing the specific objectives; 
plans to guard the safety of subjects; plans to evaluate outcome even if 
unanticipated; and provisions to obtain the required institutional and 
regulatory approvals (IRB, FDA, OHRP) to conduct the clinical study
o Experience of the PI and PLs in filing INDs and in the planning, design, 
and conduct of small pilot clinical studies in healthy individuals and/or in 
the conduct of topical microbicide clinical trials; availability of a GCRC, 
CFAR, CIPRA, HPTN clinical site, ATN site, CCTN site or other additional 
source of institutional support and/or statistical support; the 
infrastructure required for the conduct of safe and efficient clinical 
research; and short and long range plans that will result in the successful 
implementation of clinical studies during the award period

In addition to evaluating the scientific merit of the application, all multi-
project applications are assessed for the soundness of the administrative and 
organizational structure that facilitates attainment of the objective(s) of 
the program.

Thus, the Administrative Core should detail short and long term management 
components of the Program, such as: communication, group meetings, sharing 
and transmission of information and reagents, awareness of development of 
other projects within the program, progress, problems and how will they be 
addressed, engagement of the SAP and NIAID and NICHD, as appropriate, in the 
group's research activities/meetings, consideration and integration of 
scientific input/recommendation from the SAP and NIAID and NICHD, as 
appropriate, into scientific direction and decision-making, timely reporting 
as required in the Terms of Award (provided at the time of award), and other 
aspects relevant to the cohesiveness and interactive nature of group 
activities.

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 will be assessed. 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 CONSIDERATIONS

DATA SHARING: The adequacy of the proposed plan to share data.
 
BUDGET: The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.

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

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.

MONITORING PLAN AND DATA AND SAFETY MONITORING BOARD: Research components 
involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures. In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (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). 

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. 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 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.

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 PA 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). Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003 (with the 
exception of small health plans which have an extra year to comply).  

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 PA 
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, No. 93.856, Microbiology and 
Infectious Diseases Research, and No. 93.865, Center for Research for Mothers 
and Children. 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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