Release Date:  December 13, 2001

RFA:  RFA-DC-02-002

National Institute on Deafness and Other Communication Disorders

Letter of Intent Receipt Dates:  February 18, 2002 and September 25, 2002
Application Receipt Dates:       March 18, 2002 and October 25, 2002



The purpose of this request for applications (RFA) is to support the 
development of alternative strategies and new approaches for the prevention 
and treatment of otitis media (OM). OM (middle ear infection) in children is a 
ubiquitous health problem in the United States that has been estimated to cost 
5 billion dollars per year. The hearing loss associated with OM can lead to 
developmental sequelae including delayed acquisition of speech and language 
skills. The widespread use of oral antibiotics to treat OM has resulted in an 
alarming increase in antibiotic-resistance of the bacterial strains that cause 
OM, as well as other potentially fatal diseases including pneumonia, 
meningitis and septicemia. State-of-the-art molecular, genetic, genomic and 
bioengineering-based technologies hold tremendous promise for the development 
of new strategies that could dramatically impact this major pediatric health 
problem. Therefore, the purpose of this RFA is to support the application of 
new technologies to the development of alternative strategies and new 
approaches for the analysis, prevention and treatment of otitis media.


The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of "Healthy People 2010," a PHS-led national 
activity for setting priority areas.  This Request for Applications (RFA), 
Otitis Media: New Approaches for Analysis, Treatment and Prevention, 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/.


Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, eligible 
agencies of the Federal government, and foreign institutions (specific 
guidelines for foreign applicants can be found in the PHS 398 instructions.) 
Racial/ethnic minority individuals, women, and persons with disabilities are 
encouraged to apply as Principal Investigators.


This RFA will use the National Institutes of Health (NIH) R21 
GRANT) award mechanisms. Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant. This 
RFA will have two submission dates: March 18, 2002 and October 25, 2002. 
Beyond those dates, future unsolicited competing continuation applications 
will compete with all investigator-initiated applications and be reviewed 
according to the customary peer review procedures. The anticipated award dates 
are December 1, 2002 and July 1 2003. Investigators may not submit more than 
one application for this RFA. However, applications submitted for the first 
submission date may be revised and resubmitted for the second submission date.

Use of the R21 or R01 mechanism

Generally, applicants proposing exploratory/feasibility studies with limited 
preliminary data should use the R21 mechanism, while applicants proposing more 
extensive projects based on significant published and preliminary results 
should use the R01 mechanism. In addition, applicants are strongly encouraged 
to contact the Program Officer listed below under INQUIRIES to discuss which 
mechanism (R21 or R01) would be most suitable for the proposed research 
project. Because of the exploratory nature of the R21, applicants submitting 
an R21 may only request a budget for direct costs of up to $125,000 per year 
for a maximum of three (3) years. R01 applicants may request a project period 
of up to five (5) years. Because the nature and scope of the research proposed 
are expected to vary for both R21s and R01s, it is anticipated that the size 
of each R21 and R01 award will vary. Additional specific application 
instructions, budget considerations and review criteria for the R21 and the 


The NIDCD intends to commit approximately $2,000,000 in FY 2003 to fund 5 to 7 
new R21 and 3 to 5 new R01 grants in response to this RFA. Although the 
financial plans of the NIDCD 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. 



Otitis media causes significant childhood morbidity and is increasingly 
impacting upon general public health.  OM is the primary reason for visits to 
the Emergency Room; the second ranking reason for visits to a physician's 
office; the number one reason for prescriptions for antibiotics in childhood 
(accounting for greater than 40% of all outpatient use of oral antibiotics); 
the primary reason for hearing loss in children; and the primary reason for 
the use of general anesthesia in the pediatric population (for the purpose of 
inserting tympanostomy tubes). The direct and indirect cost of medical and 
surgical management of OM is approximately 5 billion dollars in the United 
States alone. The alarming emergence of multiple antibiotic resistant bacteria 
in all three of the predominant bacterial Genera that cause OM (Streptococcus 
pneumoniae, non-typeable Haemophilus influenzae, and Moraxella catarrhalis) is 
due to overuse of broad-spectrum antibiotics for the treatment of middle ear 
infections. Importantly, this trend has begun to leave first and second line 
antibiotics ineffective against OM as well as other diseases including 
pneumonia and meningitis. Therefore, the development of novel approaches for 
the study, treatment and prevention of OM is urgently needed to: 1) reduce OM 
morbidity and the associated costs; and 2) preserve the efficacy of 
antibiotics used for the treatment of OM and other common serious diseases. 

This highly significant clinical problem has a complex etiology. The basic 
pathogenesis of OM often begins with viral infection of the upper respiratory 
tract. This viral infection elicits responses from the host that rapidly 
change the micro-environment of the upper respiratory tract, Eustachian tube 
and middle ear. These micro-environmental changes result in bacteria of the 
nasopharynx invading and actively multiplying in the middle ear. Importantly, 
the bacterial phenotype is significantly altered in response to the inherent 
differences between the nasopharynx and the middle ear space. The host 
responds to the presence of dividing bacteria by releasing numerous extra- and 
intra-cellular signaling molecules. Therefore, a complex series of molecular 
events and host/pathogen interactions drive the pathogenesis, sequelae and 
resolution of this multifactorial disease. 

Specific research areas and goals

Clearly, OM is a significant health problem with ramifications far beyond the 
disease itself. The multifactorial nature of OM etiology, and the complex 
host/pathogen interactions involved further exacerbate the difficulty in 
developing treatment alternatives. However, the multifactorial nature of the 
disease may also provide novel opportunities for treatment and prevention. 
State-of-the-art technologies in a number of disciplines including genomics, 
genetics, molecular biology and bioengineering must be creatively and 
aggressively applied to the development of new treatments for this ubiquitous 
disease. The following research areas are examples of promising novel 
approaches that have yet to be comprehensively applied to solving the problems 
associated with treating OM. However, this list is not exhaustive. Therefore, 
responsive research areas include but are not limited to the following:

o  Targets for Treatment and Prevention: OM pathogenesis is a continuum of  
"checkpoints" at which key molecules facilitate the process of bacterial 
colonization of the middle ear. Novel technologies including microarray 
analysis and other approaches may be used to profile host and pathogen gene 
expression throughout the entire disease process to identify genes and their 
products that appear to have a critical role in the initiation, continuation 
or resolution of OM. Such gene products (including those newly identified and 
those strongly implicated based on known etiology of OM), must be thoroughly 
studied and tested as potential new targets for therapeutic intervention.

o  OM Initiation by Viral Infection: Viral upper respiratory infection, very 
often the first "checkpoint" in OM pathogenesis, must be completely analyzed 
at the molecular, cellular and population levels. A primary aim must be the 
identification of target molecules essential for upper respiratory viral 
infection and the accompanying molecular changes that facilitate bacterial 
invasion. New tools, assays and other novel approaches must be developed to 
enable the comprehensive study of the viruses most commonly found in specific 
populations of children and those that most often predispose an individual to 
subsequent OM. 

o  Genetic Predisposition of the Host to OM: Several heritability studies 
suggest that individuals carry genetic loci that confer susceptibility or 
resistance to OM. The identification of these loci and the study of the 
specific genes involved offers the possibility for screening individuals to 
predict OM susceptibility. A complementary genetic approach involves the study 
of specific polymorphisms in genes such as cytokines and chemokines that have 
been shown to increase susceptibility to a number of infectious diseases. 
Whether these known polymorphisms correlate with increased susceptibility to 
OM is an important area that has yet to be explored. The study of such marker 
polymorphisms, combined with the identification of specific genes that confer 
susceptibility to OM, could result in DNA-based screening protocols that would 
assist physicians in determining which patients are at risk for recurrent OM 
and therefore, require aggressive treatment and increased surveillance. 

o  Diagnostic Development: An area that could have a significant impact on the 
use of antibiotics is the development of non-invasive diagnostics capable of 
identifying the specific pathogen(s) residing in the middle ear. Because each 
of the major pathogens has a unique antibiotic resistance profile, 
identification of the microbial species causing the infection would allow 
physicians to prescribe a pathogen-specific antibiotic regimen. State-of-the-
art strategies for detecting specific signatures of middle ear pathogens must 
be developed including those that utilize light spectra, release of volatile 
compounds (odors) or other emissions of middle ear fluids that would give a 
characteristic pattern that would identify each pathogen. Importantly, the 
critical technologies such as advanced sensing systems and artificial neural 
networks have already been developed and are in use in other settings 
including automated food inspection. The ultimate goal would be the 
development of an affordable device that could rapidly identify the pathogens 
present in the middle ear of OM patients in the pediatrician's office. Such 
non-invasive, "point-of-care" diagnostics would allow pathogen-specific 
treatments and reduce the overuse of broad-based, often ineffective 

o  Genomic Animal Models: Current animal models of OM are not amenable to 
genetic studies or manipulations, a powerful analytical approach facilitated 
by the sequencing of the genomes of a number of model organisms, particularly 
the mouse. Therefore, there is a need for the development of a variety of 
mouse models of OM, which could then be used to identify the effects of the 
introduction of transgenes and the mutation of specific genes on OM 
pathogenesis. Knockout mice lacking specific genes of interest could be 
crossed with a mouse model of OM to study the effects of the knockout on OM 
pathogenesis. Ethylnitrosourea (ENU) mutagenesis of mice, followed by a well-
designed strategy to screen mutants for susceptibility to middle ear infection 
by OM pathogens, is just one example of a range of methods that have been 
successful for developing other mouse models of disease.

o  Comprehensive Genomic Approaches to Vaccine Development: Genome-based 
technologies must be applied to the development of vaccines for OM to 
comprehensively examine and identify potential bacterial epitopes that would 
result in vaccines with widespread pathogen coverage. Such approaches include 
the examination of genomes from multiple clinical isolates of each bacterial 
pathogen in order to facilitate this type of multi-valent, broad coverage 
immunization strategy. In addition, a complex vaccine regimen for OM, 
consisting of multiple injections for multiple pathogens, might not be 
tolerated by parents or adopted by physicians. Therefore, a challenging but 
potentially important long-term goal would be the development of a single 
multi-epitope, multi-valent vaccine for the three major OM pathogens: 
Streptococcus pneumoniae, non-typeable Haemophilus influenzae, and Moraxella 


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 
a complete copy of the updated Guidelines are available at 
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 


It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by the 
NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for receipt 
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in 
Research Involving Human Subjects that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address:  https://grants.nih.gov/grants/guide/notice-files/not98-024.html.

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


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 found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website: 


All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites. Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.


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:

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.


Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, the identities of other key personnel 
and participating institutions, and the number and title of the RFA in 
response to which the application may be submitted.  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 NIDCD staff 
to estimate the potential review workload and plan the review.

The letter of intent is to be sent by February 18, 2002 for the March 18, 2002 
receipt date and September 25, 2002 for the October 25, 2002 receipt date to 
the NIDCD Program Officer listed below under INQUIRIES.


The PHS 398 research grant application instructions and forms (rev. 5/2001) at
https://grants.nih.gov/grants/funding/phs398/phs398.html must be used in 
applying for both the R21 and R01 grants. This version of the PHS 398 is 
available in an interactive, searchable format.  For further assistance 
contact GrantsInfo, Telephone 301/710-0267, Email:  GrantsInfo@nih.gov.


All application instructions in the PHS 398 research grant application 
instructions and forms (rev. 5/2001) apply to the R21 with the exception of 
the following modifications: 

1.	R21 applications may request up to five (5) $25,000 modules for a maximum 
direct cost of $125,000 per year for up to a maximum of three (3) years.
2.	The Research Plan for the R21 application may not exceed 10 pages. Tables 
and Figures (color and black and white) must be included within the 10-page 
limit. However, to aid reviewers, additional original color figures should 
be included in the appendices if the data cannot be adequately evaluated 
when copied in black and white (see APPLICATION SUBMISSION.)

PHS 398 instructions and forms (rev. 5/2001) are available at the following 
URL:  https://grants.nih.gov/grants/funding/phs398/phs398.html.

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only when 
there is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and NIH staff.  
The research grant application form PHS 398 (rev. 5/2001) at 
https://grants.nih.gov/grants/funding/phs398/phs398.html must be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.  

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: 

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed photocopies (minus appendices), in one package to:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

Send two additional copies of the application and five sets of appendices to: 

BETHESDA, MD  20892-7180 
ROCKVILLE, MD  20852 (for express/courier service) 

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 Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed. This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an Introduction addressing the previous critique. 


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDCD.  Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NIDCD in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will receive a written critique and 
undergo a process in which only those applications deemed to have the highest 
scientific merit, generally the top half of the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the NDCD National Advisory Council.
Review Criteria

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments reviewers will be asked to discuss the following aspects 
of the application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals.  Each of these 
criteria will be addressed and considered in assigning the overall score, 
weighting them as appropriate for each application.  Note that the application 
does not need to be strong in all categories to be judged likely to have major 
scientific impact and thus deserve a high priority score.  For example, an 
investigator may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward. 

(1) Significance:  Does this study address an important problem? If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that drive 
this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or 
methods? Are the aims original and innovative? Does the project challenge 
existing paradigms or develop new methodologies or technologies?

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

(5) Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success? Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements? Is there evidence of institutional support?


(6) Because Exploratory/Developmental studies may contain little preliminary 
data, is the rationale for the study well-developed and is the proposed 
research likely to generate data that will lead to an expanded research 

(7) Is there potential for ground-breaking, precedent-setting significance 
from the proposed research, with particular emphasis on novel and innovative 
approaches that clearly require additional preliminary data for their value to 
be established?

(8) Is there potential to stimulate new concepts or approaches regarding the 
problems discussed in the RFA, or provide a technique/system of wide 

(9) In the case of proposed research that is technology-driven or design-
driven, will the project generate a body of data, a technological advance or 
product that will be useful to address the goals of the RFA?

(10) How will the successful completion of the proposed studies impact the 
concepts, methods, or technologies that drive the field? 

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 

o The reasonableness of the proposed budget and duration in relation to the 
proposed research and the use of the appropriate mechanism (either R21 or R01) 
based on the scope and feasibility of the research. 

o The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.

Submission, Review and Award Schedule

Letter of Intent Receipt Date:    February 18, 2002   September 25 2002
Application Receipt Date:         March 18, 2002      October 25, 2002
Peer Review Date:                 June/July, 2002     Feb/March, 2003
Council Review:                   Sept/Oct, 2002      May/June, 2003
Earliest Anticipated Start Date:  December 1, 2002    July 1, 2003


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

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Thomas M. Johnson
Program Director
Scientific Programs Branch
National Institute on Deafness and Other Communication Disorders
Executive Plaza South-400C
6120 Executive Blvd.
Bethesda, MD  20892-7180
Telephone:  301-402-3461
Fax:  301-402-6251
Email:  tj65y@nih.gov

Direct inquiries regarding fiscal matters to:

Sara Stone 
Grants Management Office 
Division of Extramural Research 
National Institute on Deafness and Other Communication Disorders 
6120 Executive Boulevard, EPS Room 400B, MSC-7180 
Bethesda, MD  20892-7180 
Telephone:  (301) 402-0909 
Fax:  (301) 402-1758 
Email:  sara_stone@nih.gov


This program is described in the Catalog of Federal Domestic Assistance No. 
93.173. Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and administered 
under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 
74 and 92. This program is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and promote the non-use of all tobacco products. In addition, Public 
Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain 
facilities (or in some cases, any portion of a facility) in which regular or 
routine education, library, day care, health care, or early childhood 
development services are provided to children. This is consistent with the PHS 
mission to protect and advance the physical and mental health of the 
American people.

Return to Volume Index

Return to NIH Guide Main Index

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS)
  USA.gov - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.