RFA-HD-00-008: PATHOPHYSIOLOGY, EPIDEMIOLOGY AND TREATMENT OF VULVODYNIA

Department of Health
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PATHOPHYSIOLOGY, EPIDEMIOLOGY AND TREATMENT OF VULVODYNIA Release Date: February 7, 2000 RFA: HD-00-008 National Institute of Child Health and Human Development Office of Research on Women’s Health Letter of Intent Receipt Date: March 15, 2000 Application Receipt Date: May 5, 2000 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The Center for Population Research (CPR) of the National Institute of Child Health and Human Development (NICHD) and the NIH Office of Research on Women’s Health (ORWH) invite new and experienced basic scientists, epidemiologists, and clinical investigators to submit research grant applications to further our understanding of the etiology, prevalence, criteria for accurate diagnosis, underlying pathophysiology and pain mechanisms, and treatment strategies for vulvodynia. Research grant applications are encouraged that address preclinical or clinical, biomedical and/or behavioral research that concentrates on studies of relevance to vulvodynia. This solicitation is intended to stimulate and strengthen a multidisciplinary approach to this complex, underresearched area of women’s health and form a framework for assessing future research needs. The goal is to build a substantive scientific knowledge base related to this debilitating condition. This initiative continues and expands the scientific objectives represented in PA-98-112, Vulvodynia Systematic Epidemiologic, Etiologic or Therapeutic Studies, and is responsive to the FY 2000 House and Senate Appropriations Report Language directives recommending that NICHD expand and intensify vulvodynia research. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS- led national activity for setting priority areas. This Request for Applications (RFA), Pathophysiology, Epidemiology and Treatment of Vulvodynia, is related to one or more of the priority areas. Potential applicants may obtain "Healthy People 2010" at http://odphp.osophs.dhhs.gov/pubs/hp2000. 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, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This RFA is a one-time solicitation. 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 date is September 29, 2000. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm For this RFA, funds must be requested in $25,000 direct cost modules, up to a total direct cost of $200,000 per year. FUNDS AVAILABLE The NICHD and ORWH intend to commit approximately $1 million in total costs (direct plus Facilities and Administrative [F & A] costs) in FY 2000 to fund four to six new grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $200,000 per year, including F & A costs on consortium arrangements. 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 the NICHD and ORWH 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 Vulvodynia is one of the poorly understood complex focal pain syndromes, representing a complex, multifactorial clinical syndrome of unexplained vulvar pain, sexual dysfunction, and psychological disturbance. On April 2- 3, 1997, the NICHD, in collaboration with the Office of Research on Women’s Health, Office of Rare Diseases, and the National Institute of Arthritis, Musculoskeletal and Skin Diseases, convened the Vulvodynia Workshop: Current Knowledge and Future Directions to explore the state-of-the-science by reviewing current definitions, etiology, epidemiology, and treatment modalities. In response to recommendations made at the conclusion of this workshop, emphasis was placed on stimulating clinically relevant research on promising biomedical, clinical or behavioral studies that would expand our knowledge of vulvodynia. The Program Announcement (PA-98-112), Vulvodynia Systematic Epidemiologic, Etiologic or Therapeutic Studies, was published on September 29, 1998. It was anticipated that studies in this underresearched area would form a foundation for assessing future research needs and complement our overall commitment to support research important to women’s health. As a result of the workshop and subsequent PA, the research community was made aware of our interest in this area. Notwithstanding this programmatic emphasis, additional efforts are now needed to strengthen the science base. This RFA represents an expansion of ongoing research efforts to reduce the burden of this disease and ultimately improve the quality of life for women affected with this disorder. Moreover, this initiative reflects the NICHD and ORWH research agendas for identifying and characterizing the pathophysiologic factors, and potential avenues for treatment related to benign gynecologic disorders. Vulvodynia is a clinical condition with several different and poorly defined antecedents. There is a need to increase knowledge and understanding about vulvodynia and the biological processes that lead to its development and long-term sequelae. The factors influencing a patient’s decision to seek care and the criteria by which the clinician selects therapy are not uniform. Patients frequently experience dyspareunia, persistent vulvar irritation, burning and pain. Symptoms also may be associated with the urinary and gastrointestinal tracts. In addition, diagnostic criteria that define the categories and subtypes of vulvodynia are neither well defined nor utilized consistently by many clinicians. While the true prevalence of vulvodynia remains unknown, there are several common diagnostic subtypes that are recognized, including (1) vulvar vestibulitis, (2) dysesthetic vulvodynia, and (3) vulvar dermatosis and dermatitis. Vulvar vestibulitis, thought to be the most common subtype, has been found in 15 percent of patients in a general clinical practice in some studies. While histologic studies suggest a chronic inflammatory reaction, the causes of the inflammation as well as its significance remain unclear. The role of pelvic floor dysfunction as a catalyst for the development of vulvar pain syndromes, particularly dysesthethic vulvodynia, has been proposed in several published studies, but its true impact is uncertain. Published studies also comment on the influence of neurophysiological parameters as a potential association that should be taken into account. Surgery has been reported to be a successful intervention for selected cases of vulvar vestibulitis, and is reserved for women with severe and long- standing symptoms. However, optimum surgical management is still undetermined and very few well-designed, long-term studies document the outcome of surgical procedures. In addition, pharmacological and behavioral therapies would benefit from treatment standardization and prospective clinical studies. Despite the use of surgery, pharmaceutical regimens, psychological support, physical therapy, and pain management techniques, such as biofeedback and behavior modification, there is no consensus on which procedure(s) offers the most improvement and patient satisfaction. A combination of therapies is frequently utilized and, while there are several options available for the treatment of vulvodynia, most of the literature supports the conclusion that cures for vulvodynia are uncommon and a specific inciting cause can be diagnosed in a relatively small percentage of patients. Consideration of these factors must be an integral part of the management of patients with vulvodynia and this underscores the need to examine this condition in a multidisciplinary context. This elusive pain syndrome has many unexplored questions. Therefore, an overall strategy of augmenting and strengthening a multidisciplinary approach to this distressing condition, leading to improved diagnosis and therapy, is warranted. Improvements in pain management, as well as approaches to the treatment and prevention of vulvodynia will require insight and increased knowledge of the underlying etiology and pathophysiological mechanisms. Research Scope Several research strategies are deemed important for the potential development of new leads or approaches. Examples of the scope of research areas considered responsive to this RFA include, but are not limited to, the following: o Elucidation of pathogenic antecedents involved in stimulating the biological processes that lead to the development and long-term sequelae of vulvodynia. Evaluation of the role of pathologic vaginal microbial and viral agents or altered vagina flora in this process. o Development of novel experimental preclinical or clinical studies in animal models and/or humans to evaluate normal and dysfunctional neurophysiological parameters and mechanisms. Determination of the role of neurogenic irritability and/or regional autonomic dysfunction and its influence on symptoms, muscle instability, tissue injury, and repair in vulvodynia. o Documentation of the use and evaluation of the effects of adjunctive therapy in clinical trials, including behavioral, surgical, and medical treatment, in women with vulvodynia. Investigation and translation of promising, innovative, preclinical findings into clinical research applications, including designing small clinical trials of novel therapeutic interventions. o Assessment of the natural history of vulvodynia. Creation and validation of small population-based epidemiological studies that assist in defining the prevalence and resolution of vulvodynia and its subtypes. Feasibility and effectiveness of risk factor modification for prevention of vulvodynia. o Assessment of normal tissue structure, muscle integrity, cellular mechanisms, structural defects, and the factors involved in the transition between latent injury, symptoms, and tissue rehabilitation in vulvodynia. Detection of the role of nerve damage, muscular damage, and/or direct tissue disruption. o Determination of the influence of risk factors such as race, ethnicity, and co-morbid medical conditions or previous surgery associated with the occurrence of vulvodynia, treatment outcomes, and complications. Prospective applicants are encouraged to consider relevant topics other than those listed here and to discuss their ideas with the program staff listed under INQUIRIES. 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 subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided 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 research involving human subjects should read the NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research, published in the Federal Register of March 28, 1994 (FR 59 14508- 14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994, and available at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. 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 subject 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, published in the NIH Guide for Grants and Contracts, March 6, 1998, and available at: 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. 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 this RFA. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NICHD staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Estella Parrott, by March 15, 2000, at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research, on the Internet at http://grants.nih.gov/grants/funding/phs398/phs398.html, and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892- 7910, telephone 301-710-0267, E-mail: Grantsinfo@nih.gov. Application Instructions 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 Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Modular Grant applications in response to this RFA will request direct costs in $25,000 modules, up to a total direct cost request of $200,000 per year. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $200,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD: Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT: Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION: Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form Page. Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH: The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years, - List selected peer-reviewed publications, with full citations. o CHECKLIST: This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Submission Instructions The RFA label available in the PHS 398 (rev. 4/98) application form must be stapled to the bottom of the face page of the application and must display the RFA number HD-00-008. A sample RFA label is available at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is in the pdf format. 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. Submit a signed, typewritten original of the application, including the Checklist, and three 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) At the time of submission, two additional copies of the application should be sent to: Director Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03, MSC 7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) Applications must be received by May 5, 2000. 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 Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness to the RFA by NICHD and ORWH. 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 NICHD in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second level review by the National Advisory Child Health and Human Development 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? In addition to the above criteria, in accordance with NIH policy, all applications also will 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 also will be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed 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. SCHEDULE Letter of Intent Receipt Date: March 15, 2000 Application Receipt Date: May 5, 2000 Peer Review Date: June 2000 Council Review: September 2000 Earliest Anticipated Start Date: September 29, 2000 AWARD CRITERIA 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 questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Estella Parrott, M.D., M.P.H. Center for Population Research National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8B01, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-6515 FAX: (301) 496-0962 E-mail: ep61h@nih.gov Direct inquiries regarding fiscal matters to: Michael J. Loewe Lead Grants Management Specialist National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17J, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-7008 FAX: (301) 402-0915 E-mail: ml70m@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.864. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) 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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