ALTERNATIVE TEST MODELS FOR ASSESSING GENITAL IRRITATION OF 
MICROBICIDAL/SPERMICIDAL PRODUCTS

RELEASE DATE:  March 19, 2003

PA NUMBER:  PAS-03-081

March 2, 2006 (NOT-OD-06-046)   Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. This announcement will stay active for 
only the May 1, 2006 AIDS and AIDS-related application submission date for these 
mechanisms. The non-AIDS portion of this funding opportunity for these mechanisms 
expires on the date indicated below. Other mechanisms relating to this announcement 
will continue to be accepted using paper PHS 398 applications until the stated 
expiration date below, or transition to electronic application submission. Parent 
R03 (PA-06-180) and R21 (PA-06-181) funding opportunity announcements have been 
issued for the submission date of June 1, 2006 and submission dates for AIDS and 
non-AIDS applications thereafter. Applications relating to R33 and R34 activities 
must be in response to NIH Institute/Center (IC)-specific announcements.

EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006
EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 
EXPIRATION DATE for All R01 Applications: April 1, 2006, unless reissued.

National Institute of Child Health and Human Development (NICHD)
 (http://www.nichd.nih.gov)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S):  93.854

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanisms of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
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 PAS  

This Program Announcement with Set-aside funds (PAS) encourages the 
development, standardization, and validation of new and innovative assays that 
determine and predict clinical vaginal and/or penile irritation.  Results from 
agents that have been evaluated in both animals and humans can be utilized 
retrospectively to validate the utility, sensitivity, and reproducibility of 
the assay. 

The Contraception and Reproductive Health Branch (CRHB), Center for Population 
Research (CPR) of the National Institute of Child Health and Human Development 
(NICHD invites applications for research projects leading to the discovery or 
validation of new test models for vaginal or penile irritation that will more 
accurately and readily predict results in humans. 

RESEARCH OBJECTIVES

Background

Recent advances in biology, molecular biology, and combinatorial chemistry 
provide unprecedented opportunities for discovery of new 
microbicides/spermicides.  However, in order to take advantage of these 
opportunities, we need to develop new screening technologies.  Drug discovery 
can now be focused on specific molecular or regulatory sites within the cell.  
It is expected that research focused on discovery and validation of new 
endpoints and screening design efforts to identify agents that affect these 
endpoints will result in a multitude of new chemical and biological agents 
with potential for clinical benefit.  However, before such agents can be 
tested in human trials, safety and acceptable irritation levels must be 
demonstrated.  Current practices and procedures for safety evaluations are 
costly and time consuming, utilizing large amounts of compounds and animals.   

Irritation of the epithelial surfaces of the vaginal tissue has been a source 
of concern in the product development process.  The current preclinical model 
for assessment of irritation is the rabbit vaginal irritation (RVI) model.  
Alternate models are needed that are cost effective, less time consuming, and 
more predictive of human experience.  Recent studies of vaginal and penile ex 
vivo cultures and research using cell lines suggest that they have the 
potential to be replacements for the RVI model for product screening.

New technology in chemistry that allows facile synthesis of millions of new 
chemicals and high-resolution structures of important target proteins are 
becoming available.  These advances, taken together and coupled with high 
throughput screening, allow identification of hundreds and maybe thousands of 
agents that could be seriously considered for clinical evaluation.  
Translation of these new technological discoveries may have clinical benefit 
for the prevention of HIV infection and for family planning through these 
newly discovered agents; however, the later stages in this drug development 
process are lengthy and costly.  New procedures are needed to decide which of 
the multitude of new agents should be tested in humans.  

Investigations focusing on the toxicity (including irritation) of potential 
microbicides and/or contraceptives to healthy tissues in intact experimental 
animals are the final steps in the preclinical stages of new drug development. 
Data generated from these studies on each new drug are evaluated in light of 
potential human toxicity and form a major portion of the information required 
by the Food and Drug Administration (FDA) for an Investigational New Drug 
(IND) exemption.  Because animal studies are very expensive and time- 
consuming, it is generally impractical to evaluate numerous analogs of a class 
of compounds prior to selection of the best developmental candidate for 
extensive preclinical evaluation.  Another concern is the lack of information 
gained from these irritational studies with regard to molecular mechanisms for 
observed toxicities.  It cannot be determined if toxicities of new agents 
designed to attack a key molecular target are related to actions of inhibition 
of that target or to other unknown aspects of the drug's action in various 
genital organs. 

New technologies to evaluate potential irritation and define toxicity at the 
molecular level are emerging, but as yet none have been validated and accepted 
for common use.  For example, bacterial strains and transgenic mice have been 
engineered to detect mutational activities of agents.  "Toxicogenomics," i.e., 
analysis of the gene transcription profile in a cell or organ following toxic 
agent administration, is under development using a variety of approaches, 
including DNA arrays.  Data analysis software programs are being written to 
predict toxicological endpoints.  Individually, these activities may not be 
sufficient, but they may be highly valuable when combined with other 
approaches to develop a total irritation profile of specific genital organ 
irritation and molecular mechanisms responsible for this toxicity.

Objectives and Scope

The goal of this PAS is the discovery, development, and validation of new 
assays and procedures to determine irritation profiles of potential 
microbicides and/or contraceptives.  It is expected that a molecular 
definition of irritation in the genital organ, tissue or cell could be a 
component of the procedure.  Approaches for new toxicology assays in response 
to this initiative are broad and are determined by the creativity of the 
applicant investigator.  Genetically modified animals or cell lines, various 
non-mammalian organisms, in vitro assays utilizing primary mammalian cells, 
tissue slices, isolated organs, sub-cellular fractions or purified enzymes 
could be utilized for the model.  Computer modeling utilizing existing 
biological and toxicological databases would be appropriate.  Genomic and 
proteomic technology could be exploited to profile total gene activity or 
protein expression and thereby establish molecular correlations with specific 
irritation.  Molecular endpoints to evaluate toxicity and high throughput 
toxicity screening could be used to help decide which agent of a chemical 
series should be pursued, to allow exploration of toxicity at an earlier stage 
in drug development, or to define the toxicity profile of agents selected for 
clinical trial.  

Examples of the assays that could be used to develop this model include, but 
are not limited to:

o  cytotoxicity assays (including multilayered co-culture models), 

o  assays for measuring changes in epithelial function (e.g., the fluorescein 
leakage test), and

o  organotypic tests.

MECHANISM OF SUPPORT

This PAS will use the NIH Research Project Grant (R01) and the 
Exploratory/Developmental Grant (R21) award mechanisms.  As an applicant, you 
will be solely responsible for planning, directing, and executing the proposed 
project.  

Applicants without extensive preliminary data or those who wish to explore the 
utility of new alternative test models are urged to submit applications for 
this PAS using the Exploratory/Developmental Grant (R21) mechanism.  The R21 
grants are non-renewable and investigators are encouraged to seek continued 
support after completing an exploratory/developmental grant project through a 
research project grant (R01).  

This PAS uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular 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_2001/part_i_1.htm.

FUNDS AVAILABLE

The total project period for an application submitted in response to this PAS 
may not exceed five years for an R01 application and two years for an R21 
application.  For R21 submissions, you may request up to $100,000 direct costs 
(four budget modules) per year unless your application includes consortium 
costs, in which case the limit is $125,000 direct costs (five budget modules) 
per year.  Because the nature and scope of the research proposed may vary, it 
is anticipated that the size of awards also will vary.  Although the financial 
plans of NICHD provide support for this program, awards pursuant to this PAS 
are contingent upon the availability of funds for this purpose and the receipt 
of a sufficient number of meritorious applications.

ELIGIBLE INSTITUTIONS 

You may submit an application if your 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.   

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PAS and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

June Lee, M.D., Ph.D.
Contraception and Reproductive Health Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B-13, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 435-6987
FAX:  (301) 480-1972
Email:  [email protected]

o Direct your questions about financial or grants management matters to:

Ms. Kathy Hancock
Grants Management Branch
National Institute of Child Health and Human Development
6001 Executive Boulevard, Room 8A17M, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5482
FAX:  (301) 402-0915
Email:  [email protected]

SUBMITTING AN APPLICATION

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:  [email protected].

APPLICATION RECEIPT DATES:  Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which are 
available at http://grants.nih.gov/grants/dates.htm.  Application deadlines 
are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications requesting 
up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at 
http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

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 cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

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

1) Contact the IC program staff at least six weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your application 
for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff member and 
IC who agreed to accept assignment of the application.  

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.

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)

APPLICATION PROCESSING:  Applications must be received by or mailed on or 
before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will not 
accept any application in response to this PAS 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.

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

PEER REVIEW PROCESS

Applications submitted for this PAS 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.  

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 the appropriate national advisory council 
or board.

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
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?

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?

INVESTIGATOR:  Is the investigator appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to the experience level 
of the principal investigator and other researchers (if any)?

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 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

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program 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.

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 "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 is 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.  You will find this policy announcement 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://grants.nih.gov/grants/stem_cells.htm 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 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 PAS 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.

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 PAS 
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 Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)  
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm.

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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