RFA from NIH Guide l/ll/9l EVALUATION OF TREATMENTS FOR CLEFT LIP AND/OR PALATE National Institute of Dental Research Letter of Intent Receipt Date: November 1, 1991 Application Receipt Date: December 4, 1991 RFA: DE-91-04 P.T. 34; K.W. 0755015, 0715148, 0785210, 0795005 PURPOSE The National Institute of Dental Research (NIDR) seeks research grant applications from United States and foreign institutions to conduct prospective and/or retrospective clinical trials evaluating treatment procedures for nonsyndromic, unilateral cleft lip and palate. This Request for Applications (RFA) is for a single competition with a receipt date of December 4, 1991. The RFA may be reissued at a later date. BACKGROUND INFORMATION The incidence of cleft lip and palate in the United States is difficult to determine. According to the latest estimate, based on 1982-85 data, 5354 new cases occur each year, making it the most common craniofacial birth defect. There is a racial gradient in incidence; Orientals and American Indians have the highest incidence, blacks the lowest, and whites intermediate. More males than females are born with cleft lip or cleft lip and palate, more unilateral clefts occur on the left side, and the severity is greatest among males. Clefts are often associated with other congenital anomalies. The objective of treatment is to correct the facial disfigurement and improve oral function to allow normal speech, mastication, hearin,g and psychosocial interactions. Comprehensive treatment calls for a multidisciplinary team approach, often involving specialists in pediatrics, plastic and reconstructive surgery, oral surgery, orthodontics, pediatric dentistry, speech pathology, audiology, prosthodontics, otolaryngology, psychology, and genetics. The treatment sequence, timing, methods, and surgical techniques are all controversial. The long-term impact on maxillofacial growth and speech production are primary considerations but numerous other factors enter into treatment decisions. Lip repair is commonly performed at four to ten weeks of age but many surgical teams wait until later while others prefer the perinatal period. Either active or passive presurgical orthopedic procedures to improve the form of the maxillary arch are used in about 60 percent of centers. Alveolar bone grafting is utilized in many centers but the timing of grafting and the source of grafted bone differ. Repair of the soft and hard palate is commonly, though by no means always, performed synchronously between six and 18 months of age. Surgical closure of the hard palate is sometimes delayed until the preschool years or even the mid-teens. Secondary palatal surgery may be required to achieve velopharyngeal competence and lip and nose revision is often performed in late adolescence. Numerous orthopedic, orthodontic, and surgical treatment techniques have been advocated. There is suggestive evidence that the skill of the surgeon may be more important than the specific technique in determining outcomes. Minimal standards for reporting the results of surgery on patients with cleft lip and palate have been proposed to address the anatomic and functional integrity of the affected structures and facial aesthetics, over time. Assessments may involve visual examinations, still and video photography, instrumental assessments of airway patency and mode of breathing, cephalometric and panoramic radiography, impressions for dental casts, evaluation of feeding and speech including dynamic assessment of velopharyngeal function, auditory function, and psychosocial adjustment. Developments in methodology and instrumentation allow quantitation of some of these parameters and can permit reporting of the efficacy of certain procedures with reasonable confidence. Most evaluations of cleft treatments consist of anecdotal reports or case series. Numerous retrospective comparisons of two or more treatments have been conducted but observer bias and the equivalency of the pretreatment characteristics of the different treatment groups are major concerns. When detailed and durable records are available, retrospective matching might alleviate some of these concerns. Changes in surgical technique and personnel over time are additional causes for concern. Only rarely have prospectively controlled clinical trials been attempted to evaluate treatments for clefts. Long-term follow-up is needed for many types of studies, during which time treatment methods evolve and undergo modification. Assessment of treatment outcomes with respect to growth and several functions demands a well orchestrated team approach. Widely accepted assessment and analytical methods have not been available. There is great diversity in surgical methods and treatment management within and between centers. The small number of cases of any particular cleft sub-type treated at any one center generally precludes hypothesis testing, unless sound consortial arrangements can be made. Ethical concerns in randomized designs and the desirability of maintaining operator anonymity may be significant impediments to conducting trials. Nevertheless, it appears likely that several clinically significant aspects of cleft treatments could be evaluated prospectively. The existence of several extensive, cleft treatment data bases, in the U.S. and abroad, suggests that retrospective analyses also may prove fruitful. RESEARCH GOALS AND SCOPE The objective of this RFA is to solicit applications for support of clinical trials to evaluate procedures widely used in the treatment of nonsyndromic, unilateral cleft lip and/or palate. It is not intended to support studies on bilateral isolated clefts and syndromic clefts or other major congenital or acquired craniofacial defects. The following list provides examples of the types of issues that might be addressed. The list is not intended to be inclusive and applicants are free to propose clinical trials concerning other issues in cleft treatment. 1 The effect of various surgical techniques used for lip closure on the alignment of palatal segments. 2 The effect of neonatal treatment with passive and/or active orthopedic devices in correcting and maintaining acceptable maxillary arch morphology. 3 The effect of early alveolar bone grafting on the position and quality of the primary dentition. 4 Comparison of iliac crest, rib, mandible, and calvaria as sources for alveolar bone grafts. 5 The effect of timing of palatal repair on early speech and language development. 6 Comparison of the effects of different palatoplasty techniques on velopharyngeal function. 7 The efficacy of secondary palatal management procedures for velopharyngeal incompetence. 8 The effect of surgical repair of cleft palate on middle ear pathology. 9 Retrospective comparisons of surgical and related procedures for primary treatment of unilateral clefts. 10 Retrospective, multidisciplinary evaluations of long-term outcomes of cleft treatments. It is essential that the majority of the specific aims can be met during the initial period of support (3-5 years). It is likely that consortium arrangements will be required to assess sufficiently large numbers of patients or patient records. This also may reduce the effects of differences in patient management. Applications from U.S. and foreign investigators and those including collaborative arrangements between U.S. and foreign investigators are encouraged; studies involving non-U.S. populations may facilitate standardization of treatments and record keeping and provide large, homogeneous study populations. Experiences with responses to other RFAs for related clinical trials indicate the desirability of proposing very focused studies, often designed to answer a single or very few questions presented in the form of a hypothesis(es). Significant input from an experienced biostatistician during preparation of the application and the conduct of the trial is mandatory. Statistical power calculations, inclusion-exclusion criteria, recruitment procedures, attrition rate determinations, methods for randomization, treatment regimens, outcome measures, and data processing procedures must be clearly defined. The use of appropriate controls or normative data bases and ethical aspects of design of the trial must be addressed. Consortial arrangements designed to ensure successful conduct and completion of the trial must be documented. Consideration might be given to archiving raw data and the physical records from which they are derived and making them accessible to qualified investigators, while assuring the privacy of patients and clinicians. The development of such a shared data base could be an important outcome. SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Section 2, A-D of the Research Plan AND summarized in Section 2, E, Human Subjects. Applicants/offerors are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. MECHANISM OF SUPPORT Support for this program will be through research project grants (R01). It is anticipated that up to four awards will be made, if a sufficient number of high quality applications is received. Although funds have been allocated for this initiative in NIDR's plans for Fiscal Years 1992 through 1996, award of grants resulting from this RFA is contingent upon receipt of appropriated funds for this purpose. Applicants may request up to five years of support. Subsequent support will be contingent upon program needs and grantees' performance, as determined by peer review. Policies that govern research grant programs of the National Institutes of Health will prevail. Applicants are encouraged to seek support from other public sources as well as private sector sources, including foundations and industrial concerns, for studies that will complement and expand the research supported by the NIDR. A summary of the objectives and financial support for such studies must be included in the application. REVIEW PROCEDURES AND CRITERIA Applications in response to this RFA will be reviewed by a Special Review Committee convened by the NIDR's Scientific Review Branch. Secondary review will be by the National Advisory Dental Research Council in May 1992. Review criteria include the significance and originality of the research goals and approaches; feasibility of the research and the adequacy of the study design; availability and appropriateness of the study populations or clinical data, including efforts to include females and minorities in study populations; training, experience, and research competence of the investigator(s); adequacy of facilities; provisions for protection of human subjects; and the appropriateness of the requested budget for the work proposed. Funding decisions will be based on the initial review group's and the National Advisory Dental Research Council's recommendations concerning scientific merit, program relevance and balance, total cost to the NIDR, and the availability of appropriated funds. The earliest funding date is July 1, 1992. METHOD OF APPLYING It is recommended that prospective applicants contact program staff early in the planning phase of application preparation. Such contact may help ensure that applications are responsive to this RFA. It is suggested that prospective applicants submit a letter of intent as soon as possible, but no later than November 1, 1991, giving a descriptive title of the proposed research; the name, address, and telephone number of the Principal Investigator; and names of other key personnel and collaborating institutions. A letter of intent is not binding nor is it a prerequisite for acceptance of an application but it will assist staff in planning for timely review of applications. Applications must be submitted on form PHS-398 (Rev. 10/88), available in the business or grants office of most academic or research institutions or from the Division of Research Grants, National Institutes of Health. Applications received after December 4, 1991 and those that are deemed nonresponsive to the RFA will be assigned to a Division of Research Grants Study Section for initial review and will be considered with other nonsolicited grant applications. To identify the application as a response to this RFA, check "yes" on item 2 of page 1 of the application and enter "RFA: DE-91-04, EVALUATION OF TREATMENTS FOR CLEFT LIP AND/OR PALATE." The RFA label available in the 10/88 revision of Application Form 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of your application such that it may not reach the review committee in time for review. The original and four copies must be received by December 4, 1991, at: DIVISION OF RESEARCH GRANTS National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892-4500** At the time of submission two (2) additional copies of the application must be sent to: John D. Townsley, Ph.D. Extramural Program National Institute of Dental Research Westwood Building, Room 506 Bethesda, MD 20892-4500 Telephone: (301) 496-7807 Inquiries concerning this RFA and letters of intent may be addressed to Dr. Townsley. This program is described in the Catalog of Federal Domestic Assistance No. 93.122. Awards will be 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 PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review, April 6, 1988.