kristoff@GENBANK.BIO.NET (Dave Kristofferson) (08/23/90)
REQUEST FOR APPLICATIONS FOR COOPERATIVE AGREEMENT RFA: DC-90-02 National Institute on Deafness and Other Communication Disorders P.T. 34; K.W. 0715050, 0745070 RECOGNITION AND MANAGEMENT OF PERILYMPHATIC FISTULA Application Receipt Date: 11-16-90 Letter of Intent Receipt Date: 10-08-90 INTRODUCTION: The National Institute on Deafness and Other Communication Disorders (NIDCD) invites applications for assistance awards to support two-phase studies leading first to the development and validation of a marker to be used for the intraoperative diagnosis of perilymphatic fistula (PLF), and subsequently, to studies of the clinical diagnosis and treatment efficacy of PLF. These awards will be cooperative agreements in which substantial involvement with the funded investigators by NIDCD staff is anticipated during performance of the projects. Awards will be made for total project periods of five years. $7.5 million total (direct and indirect) costs is available for the entire project period of five years. Phase 1 costs may be significantly less than those for Phase 2. Budget increments after the first year will be limited to approved programmatic changes or to necessary cost-of-living increases but the specific amount and the number of awards will depend on the merit and scope of the applications received. The NIDCD anticipates making 3-5 awards. Although this project is provided for in the financial plans of the NIDCD, the award of cooperative agreements pursuant to the Request for Applications (RFA) is contingent on the availability of funds appropriated in fiscal year 1991. CONTENTS: A. Background information B. Research Goals and Scope C. Mechanism of Support - RFA D. Terms of Award: Cooperative Agreement E. Appeals F. Patent Coverage G. Eligibility Requirements H. Special Instructions I. Review Procedures and Criteria J. Applications K. Letter of Intent L. Inquiries A. BACKGROUND INFORMATION: Perilymphatic fistulae (PLFs) are abnormal communications between the fluid surrounding the membranous labyrinth of the inner ear and the normally air-filled middle ear space, causing sudden or progressive hearing loss, dizziness or vertigo, nausea, or a feeling of fullness in the ear. They may occur spontaneously, recurrently, or as a result of head trauma, ear surgery, barotrauma, physical exertion, or congenital temporal bone anomalies. When head trauma, barotrauma, or coincident physical exertion is associated with the onset of symptoms, the clinical diagnosis of perilymphatic fistula often can be established with reasonable confidence, and a patent fistula in the round and/or oval window covering may be readily apparent on middle ear exploration. Prompt surgical repair of the defect often produces permanent relief of the symptoms. In the absence of such history, the clinical and differential diagnosis of perilymphatic fistula in children and adults is more controversial. There is no generally accepted radiologic, laboratory, or electrophysiologic test that provides objective, unequivocal evidence of perilymphatic fistula. The diagnosis becomes even more difficult with very young children, who are unable to provide information concerning the onset or nature of their symptoms, which may vary widely, and who often cannot be tested with many of the usual clinical tests of auditory and vestibular function. At present, surgical exploration of the middle ear is the only means by which the presence of PLF can be confirmed. Contributing to the controversy is the subjectivity of the intraoperative diagnosis. There is no pathologic specimen that can be subjected to laboratory analysis, and photographic documentation has been inadequate, leaving confirmation of the clinical diagnosis solely to the perception of the surgeon and his/her criteria for identifying a fistula. Thus, a potentially serious anatomic defect lacks adequate diagnostic criteria as indications for exploratory surgery, and there is no objective means of documenting the lesion. As a result, estimates of the incidence and prevalence of perilymphatic fistula in children and adults vary widely throughout the United States, although it is possible that it is a significant and often unrecognized factor in the sudden onset of, or progression of, hearing loss and idiopathic, nonspecific dizziness. Three important issues related to the recognition and management of PLF, then, are: 1) The clinical and differential diagnosis of PLF and the development of data-based criteria for surgical intervention; 2) the intra-operative diagnosis of perilymph and/or cerebrospinal fluid in the middle ear and its differentiation from other adventitious fluids, such as plasma or local anesthetic agents; and 3) the relative efficacy of various surgical and non-surgical treatment options for the alleviation of the auditory and vestibular symptoms associated with PLF. Of these, the development of an objective means of identifying/verifying the presence of perilymph and/or cerebrospinal fluid in the middle ear can be viewed as pivotal. Once that goal is achieved, the sensitivity and specificity of diagnostic tests can be directly assessed; accurate figures as to incidence and prevalence of the defect can be generated; and the efficacy of treatment alternatives can be evaluated relative to the outcome of the intra-operative test. B. RESEARCH GOALS AND SCOPE: The goals of this RFA are threefold, encompassed within a two-phase program. Phase 1 is intended to assist groups of investigators in their attempts to develop and validate a marker substance or procedure to identify and differentiate perilymph in the middle ear. The goals for Phase 1 must be met before proceeding to Phase 2 studies, as described in Section D.1. Phase 2 has two goals: first, to conduct clinical studies on objective diagnostic tests for perilymphatic fistula, leading to the establishment of clinical criteria for middle ear exploration; and second, to evaluate the efficacy of surgical and non-surgical treatments in alleviating symptoms. All applicant groups are expected to participate fully in both phases of the project. Proposed diagnostic efficacy studies may determine the predictive efficiency of batteries of auditory, vestibular, psychological, and otologic tests for identifying PLF. Proposed treatment efficacy studies may involve comparing nonsurgical treatment options such as bedrest or vestibular exercises, with conventional methods of surgical intervention. Other questions that may be addressed by these studies include, but are not limited to: o Are there patterns of auditory, vestibular, psychological, and otologic tests that correlate with the presence of perilymph in the middle ear? o What are the mechanisms underlying spontaneous or recurrent PLF? o What persons are at risk of developing perilymphatic fistula? o What is the natural history of spontaneous and traumatic PLF? C. MECHANISM OF SUPPORT: Awards will be made as cooperative agreements. These awards reflect an assistance relationship in which substantial involvement with the funded investigators by NIDCD staff is anticipated during performance of the project. There is no intent, real or implied, for NIDCD staff to direct research activities or to limit the freedom of participating investigators. Cooperative agreements resulting from this RFA will be subject to the same administrative requirements pertaining to all assistance awards of the U.S. Public Health Service. Except as might be otherwise stated in the RFA, awards will be administered under PHS grants policy as stated in the Public Health Service Grants Policy Statement, DHHS Publication No. (OASH) 82-50,000, revised January 1987. This RFA is a one-time solicitation. Should the NIDCD determine that there is a sufficient continuing program need for the studies initiated under this RFA, with the same parameters as before, competing continuation applications will be invited from awardees through individual written communications. If, however, there are significant changes in award objectives, approaches or costs, or if the NIDCD seeks new awardees to add to or replace current ones, a new RFA will be issued and applications will be invited for cooperative agreement applications that will be reviewed according to the procedures described in Section I. NIDCD anticipates making 3-5 awards for project periods of up to five years. Up to $7.5 million total (direct and indirect) costs is available for the entire project period of five years. Funding in response to this RFA is dependent on the receipt of a sufficient number of applications of high scientific merit. The earliest feasible start date for the initial awards will be April 1991. D. TERMS OF AWARD: The Cooperative Agreement will require cooperation between an NIDCD representative and the principal investigators in order to assure smooth and productive interactions among the cooperating institutions. NIDCD will be represented by the Health Scientist Administrator responsible for hearing and auditory research in the NIDCD Division of Extramural Activities, hereinafter referred to as the "NIDCD representative". As described more fully in Section D.2, the designated representative will assist in coordinating the activities of the research groups and by facilitating exchange of information. 1. ORGANIZATION AND ROLE OF THE COORDINATING COMMITTEE The NIDCD and the participating research groups will be responsible for forming a Coordinating Committee as defined below. Operating policies governing the conduct and integration of the studies will be developed by the Coordinating Committee with the input of the NIDCD representative. NIDCD will review the operating policies for compatibility with and facilitation of progress toward the goals set forth in the RFA. Recommendations for modification of the operating policies will be discussed as necessary with the Coordinating Committee. The Coordinating Committee will consist of two members from each cooperating institution, one of whom is the principal investigator, and the NIDCD representative. The Coordinating Committee will be responsible for electing a chairperson (who shall not be the NIDCD representative). This can be a rotating position. The Chairperson of the Committee will be responsible for coordinating the Committee activities, preparing meeting agendas, and scheduling and chairing meetings. The NIDCD representative will attend and participate as a non-voting member in all meetings of the Coordinating Committee and should be informed of major inter-group interactions. The Committee will meet at least twice a year at the National Institutes of Health in Bethesda, Maryland. These meetings are aimed at coordinating the activities of the participating laboratories and clinical centers, establishing policies and priorities, reviewing progress, and monitoring the safety and efficacy of treatments and procedures conducted within the scope of the awards. The first Coordinating Committee meeting, to be held within six weeks of the Notification of Grant Award, will also require the presence and participation of a statistician or biometrist from each cooperating institution to assist in developing uniform statistical procedures and methods of data acquisition and analysis. Travel funds and per diem expenses for Coordinating Committee meetings are to be identified as a budget line item in each project budget. The Coordinating Committee will prepare an annual progress report which will include individual reports from each participating research group. Each group is responsible for the timely and complete preparation of its report. At the end of two years an ad hoc Advisory Committee appointed by NIDCD will review the progress made by the participating groups in achieving the goals of Phase 1, i.e. development and validation of a perilymph marker. After completing such review, the Advisory Committee may recommend to NIDCD that: 1) Phase 1 studies should be extended for a specified period of time; or 2) Phase 2 - diagnostic and treatment efficacy studies using as the "gold standard" the marker developed in Phase 1 - should proceed; or 3) the study should be terminated. Additional authorities and responsibilities of the Coordinating Committee are summarized as follows: o Review the operating procedures proposed by the individual research groups to ensure that they are compatible with the overall goals of the RFA; o Develop uniform procedures for perilymph sampling and testing; o Develop uniform methods of gathering patient historical information, diagnostic test results, and statistical analysis of data; o Establish publication guidelines. 2. ROLE OF NIDCD REPRESENTATIVE The NIDCD representative will assist in coordinating the programs supported by this cooperative agreement, will attend and participate in all meetings of the Coordinating Committee, and will provide liaison between the Coordinating Committee and participating research groups. The NIDCD representative will assist the Coordinating Committee in developing operating policies, quality control procedures, and consistent policies for dealing with recurring situations that require coordinated action. During performance of the award, the NIDCD representative may provide appropriate assistance, advice, and guidance by participating in the design of activities; advising in the availability of resources, staff, etc.; coordinating or participating in analysis of data; advising in management and technical performance; and participating in the preparation of manuscripts. In all cases, the role of NIDCD will be to assist and facilitate and not to direct activities. To assure consistency and quality, NIDCD must concur in operating policies and procedures prior to their implementation. The NIDCD representative will, in concert with the Coordinating Committee, review the operations of individual laboratories for compliance with the quality control standards and operating policies developed by the Coordinating Committee. The NIDCD representative may recommend to the NIDCD Director the withholding of support, suspension or termination of an award to any participating group for lack of progress or failure to adhere to policies established by the Coordinating Committee. 3. RESPONSIBILITIES OF AWARDEES The authorities and responsibilities of the Principal Investigators of each participating institution are summarized as follows: o Development of general concepts for potential studies; o Development of protocols for clinical studies; o Conduct of clinical and epidemiological studies; o Coordination of basic science and clinical aspects of the projects; o Monitoring of progress, safety, and efficacy of studies; o Development of data management and quality assurance systems; o Ensuring the timely publication of results; o Providing membership/leadership to the Coordinating Committee and fulfilling the duties and responsibilities described for members of that committee in Section D-1. Funded investigators will be expected to provide a focus and capability for development of uniform marker validation protocols by consensus among participating investigators and for conducting the specific validation trials, diagnostic studies, and treatment efficacy studies as appropriate. This will involve the estimation of sample size requirements, preparation of data questionnaires, development of quality assurance and patient protection programs, and development of data management and analysis systems. The Government, via the NIDCD representative, will have access to data generated under this Cooperative Agreement and may periodically review the data. However, the awardees will retain rights to the data, and timely publication of major findings by the participants is encouraged. Publication or oral presentation of work done under this agreement will require appropriate acknowledgement of NIDCD support. Inclusion of women and minorities on the research teams and as part of the study population is encouraged. If they are excluded, reasons for this exclusion must be included in the application. (See NIH Guide for Grants and Contracts, Vol. 18, No. 21, June 16, 1989 for further information.) Investigators applying for these awards should have demonstrated or available collaborative expertise in otologic clinical studies and in cochlear biochemistry and/or pharmacology, audiology, vestibular function assessment, clinical trials, and data management/biometry. Investigators should provide, at a minimum, general designs for marker development and validation procedures, clinical diagnostic activities, and plans for treatment efficacy studies. Active collaboration with other professionals who might be involved in the diagnosis or treatment of patients with PLF is expected and encouraged. Recruitment potential for proposed validation studies should be documented. Applicants should also document the interest, capabilities, and commitment of all potential participating clinics identified; letters from potential participating clinic investigators should be provided as part of this documentation. 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 other HHS, PHS, and NIH grant administration policies. E. APPEALS These "Terms of Award" require that the NIDCD representative approve the following: changes in the Principal Investigator or Program Leaders; major changes in protocols; and reports intended for inclusion in clinical brochures. Disagreements arising pursuant to these approvals will be arbitrated by a panel composed of one Coordinating Committee designee, one NIDCD designee, and a third designee with expertise in the relevant area chosen by the other two. These special arbitration procedures in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. F. PATENT COVERAGE Since one of the goals of this effort is the development and validation of marker materials or methods to identify perilymph, it is essential that consideration be given to plans to assure coverage of patents. Each funded investigator group, therefore, will be required to provide a detailed description of the approach to be used for obtaining patent coverage and for licensing, where appropriate, with particular attention to a situation in which the invention may involve investigators from more than one institution. A formal patent agreement signed and dated by the organizational official authorized to enter into patent arrangements for each group member and member institution must be on file at the Division of Extramural Activities, NIDCD, within 60 days following the award. In addition, evidence must be presented that procedures are in place for resolution of any legal problems that may arise. G. ELIGIBILITY REQUIREMENTS: Any of the following organizations are eligible to apply: non-profit institutions of higher education; other non-profit and for-profit organizations; state and local governments and their agencies; and authorized federal agencies. Holding a currently funded NIH research, training, or center grant does not impair an organization's eligibility. Additional eligibility requirements include those listed under "Responsibilities of Awardees" in Section D.3. H. SPECIAL INSTRUCTIONS FOR PREPARATION OF COOPERATIVE AGREEMENT APPLICATIONS: General instructions for the preparation of the Cooperative Agreement application parallel those relevant to regular research grant applications and are contained in the Grant Application Form PHS 398 (revised 10/88 or 9/89). Forms are available at most institutional business offices or offices of sponsored research. These forms may also be obtained from: Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892. To identify the application as a response to this RFA, check "Yes" on line 2 of the face page on Form PHS 398 and enter the following: "RFA DC-90-02, Recognition and Management of Perilymphatic Fistula." Use the conventional format for research project grant applications, but ensure that the issues identified in "Review Procedures and Criteria" (Sections I.1 and I.2), are addressed. As specified in Section D.1, travel and per diem funds for attending the required Coordinating Committee meetings should be identified in the budget. Routine patient care costs will not be supported by these awards. Because the Terms of Award in Section D above will be included in all awards issued as a result of the RFA, it is critical that each applicant include specific plans for responding to these terms. I. REVIEW PROCEDURES AND CRITERIA: 1. REVIEW PROCEDURES Upon receipt, applications will be reviewed by the Division of Research Grants for completeness. Incomplete applications will be returned to the applicant without further consideration. Evaluation for responsiveness to this RFA is an NIDCD program staff function. Applications will be judged to determine how well they meet the goals and objectives of the program as described in the RFA. Applications which are judged non-responsive will be administratively withdrawn, and the proposed Principal Investigator and institutional business official will be notified. Should an application be judged non-responsive to this RFA, any of its constituent projects may be submitted as an investigator-initiated regular research grant application (R01) at the next receipt date. The new application would not be considered an application for a cooperative agreement, nor would it be considered a response to an RFA. In cases where the number of applications is large compared to the number of awards to be made, the NIDCD may conduct a preliminary scientific peer review to eliminate those which are clearly not competitive for award. Those applications judged to be noncompetitive will be withdrawn from further competition, and the Principal Investigator and institutional business official will be notified accordingly. Applications judged to be complete, competitive, and responsive will be further evaluated according to the review criteria stated below for scientific and technical merit by an appropriate peer review group convened by the Division of Extramural Activities, NIDCD. The second level of review is conducted by the NIDCD Advisory Council. 2. REVIEW CRITERIA Factors considered to be important for review include demonstrated expertise in cochlear biochemistry and pharmacology, otolaryngology, and evaluation of auditory and vestibular disorders; availability of an appropriate patient population; good interaction among collaborating institutions, scientists, and clinicians; and adequate facilities and ancillary personnel. Reviewers will be asked to review the grant applications by considering the following criteria: 1) Appropriateness, originality, feasibility, and relevance of the proposed project to the overall goals and objectives of the RFA. 2) Qualifications, experience, and proposed responsibilities of the principal investigators and key support personnel. 3) Scientific merit and organizational plans for implementing the proposed program. 4) Demonstration of availability of patient populations having a variety of auditory and vestibular disorders, including perilymphatic fistula. 5) Proposed collaborations with surgeons, basic scientists, and other key personnel within the applicant and collaborating institutions; adequacy of documented interest, capabilities, and commitment of all potential participating clinics. 6) Facilities and resources, and their availability for this project. 7) Adequacy of proposed overall administrative procedures and collaborative arrangements. 8) Reasonableness of the proposed budget. 9) Plans to protect the rights and welfare of human and animal subjects. 10) Commitment to accept NIDCD assistance in accordance with the guidelines outlined under Section D, "TERMS OF AWARD." J. APPLICATION: Complete applications are due no later than November 16, 1990, and must address all requirements in the RFA. Applications received after this date will not be accepted. If the application submitted in response to this RFA is substantially similar to a research grant application already submitted to the NIH for review, but has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application cannot be submitted in response to this RFA that is essentially identical to one that has already been 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. The RFA label (found in the 10/88 revision of application form PHS 398) must be affixed to the bottom of the face page of the original copy of the application. Failure to use this label could result in delayed processing of your application such that it will not reach the review committee in time for review. Send the completed and signed original application and four signed, exact photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892-4500** The photocopies must be clear and single sided. Send an additional two (2) copies of the application under separate cover to: Dr. Marilyn Semmes, Review and Special Projects Officer, National Institute on Deafness and Other Communication Disorders, Federal Building, Room 9C-14A, 7550 Wisconsin Avenue, Bethesda, MD 20892. K. LETTER OF INTENT: Prospective applicants are asked to submit, by October 8, 1990, a letter of intent that includes a descriptive title of the proposed project, the name and address of the principal investigator, the names of other key personnel and collaborating institutions, and the number and title of the RFA in response to which the application is being submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the NIDCD would like to emphasize the benefits of a letter of intent, which allows NIDCD staff to estimate the potential review workload and to avoid possible conflict of interest in the review. L. INQUIRIES: Written or telephone inquiries concerning the objectives and scope of the RFA, or inquiries about whether or not specific proposed research would be responsive, are encouraged and should be directed to Dr. Maureen Hannley at the address shown below. The program administrator welcomes the opportunity to clarify any issues or questions from potential applicants. The letter of intent and inquiries should be addressed to: Maureen T. Hannley, Ph.D. Program Administrator, Hearing Division of Communication Sciences and Disorders National Institute on Deafness and Other Communication Disorders Room 1C-04, Federal Building 7550 Wisconsin Avenue Bethesda, Maryland 20892 Telephone: (301) 496-5061 Fax: (301) 402-0104 Awards will be made under the authority of the Public Health Service Act, Section 301 (42 USC241), and administered under PHS grant policies and Federal Regulation 42 CFR Part 52, and 45 CFR Part 74. This program is not subject to review by a Health Systems Agency or to the intergovernmental review requirements of Executive Order 12372.