and Human Services (HHS)
EXPIRED
OTITIS MEDIA: NEW APPROACHES FOR ANALYSIS, TREATMENT AND PREVENTION Release Date: December 13, 2001 RFA: RFA-DC-02-002 National Institute on Deafness and Other Communication Disorders (http://www.nidcd.nih.gov/) Letter of Intent Receipt Dates: February 18, 2002 and September 25, 2002 Application Receipt Dates: March 18, 2002 and October 25, 2002 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN $250,000 PER YEAR IN ALL YEARS (R01 and R21). MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE 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. 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 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/. ELIGIBILITY REQUIREMENTS 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. MECHANISMS OF SUPPORT This RFA will use the National Institutes of Health (NIH) R21 (EXPLORATORY/DEVELOPMENTAL GRANT) and R01 (INVESTIGATOR INITIATED RESEARCH 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 R01 can be found below under APPLICATION PROCEDURES and REVIEW CONSIDERATIONS. FUNDS AVAILABLE 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. RESEARCH OBJECTIVES Background 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 antibiotics. 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 catarrhalis. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported 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 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: http://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. 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 found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, 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. R21 AND R01 APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://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. ADDITIONAL R21 APPLICATION PROCEDURES 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: http://grants.nih.gov/grants/funding/phs398/phs398.html. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 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 http://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: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies (minus appendices), 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) Send two additional copies of the application and five sets of appendices to: CHIEF, SCIENTIFIC REVIEW BRANCH DIVISION OF EXTRAMURAL RESEARCH NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS 6120 EXECUTIVE BOULEVARD, ROOM 400-C, MSC 7180 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. REVIEW CONSIDERATIONS FOR R21 AND R01 APPLICATIONS 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? ADDITIONAL CRITERIA FOR THE REVIEW OF R21 EXPLORATORY/DEVELOPMENTAL GRANT APPLICATIONS (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 project/program? (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 applicability? (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 evaluated. 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 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 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 AUTHORITY AND REGULATIONS 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.
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