November 14, 2002
Sponsored by:
The National Institute of Dental and Craniofacial Research
National Institutes of Health
I. Background:
The National Institute of Dental and Craniofacial Research (NIDCR) is the primary sponsor of biomedical and behavioral research and of research training in oral, dental and craniofacial disease in the United States. The mission of the Institute is to promote and improve health through research. It accomplishes this mission by supporting research and training programs in intramural laboratories and in an extended external community of investigators working in academic institutions and in other research organizations. Support of extramural researchers is provided through the programs and initiatives of the Divisions of Basic and Translational Sciences and of Population and Health Promotion Sciences. Major programs in the first of these Divisions include biotechnology and biomaterials, developmental biology and mammalian genetics, epithelial cell regulation and transformation, oral infectious diseases and immunology, AIDS and oral manifestations of immunosuppression, pain, and autoimmune disease. The Division of Population and Health Promotion Sciences supports programs in behavioral and social sciences research, population sciences, clinical trials and patient oriented research and health disparities. The Division of Intramural Research includes laboratories located on the NIH campus in Bethesda, MD. Intramural scientists perform research in craniofacial and skeletal diseases, craniofacial development, gene therapy, oral and pharyngeal cancer, oral infection and immunity and pain.
Recognizing the importance of long-term scientific planning to capitalize on the rapid and significant advances that are occurring in biomedical and behavioral research, NIDCR established an internal study group with representatives from all its Divisions to identify broad areas of importance for the Institute's long-range scientific agenda. This group identified three priority areas of emphasis:
- Genomics and Proteomics of Dental, Oral and Craniofacial Diseases
- Repair and Regeneration of Dental, Oral and Craniofacial Tissues
- Clinical Approaches to the Diagnosis, Treatment and Prevention of Dental, Oral and Craniofacial Disorders.
The study group recommended that panels of experts be convened to work with the Institute to identify and catalogue potential opportunities for significant scientific advances within these areas of emphasis. The first panel, (Genomics and Proteomics), was held on May 22, 2002, and the second, (Repair and Regeneration), on September 5, 2002. The final reports and recommendations from these panels are posted on the NIDCR web page. This web page includes the following reports: Panel I - Genomics and Proteomics of Oral, Dental and Craniofacial Diseases; Panel on Training; and Panel II on Repair and Regeneration of Dental, Oral and Craniofacial Tissues. What follows is a summary of the deliberations and recommendations of the third panel, (Clinical Research), held on November 14, 2002.
Background information, including a summary of the current clinical research portfolio and summaries of the previous discussions on this topic was provided to the panelists prior to the meeting. The panelists were asked to consider four major issues/questions:
- Which of the areas previously identified through internal discussion and through interaction with the National Advisory Council represent the best long-range science/research opportunities?
- In what research areas are the most promising opportunities?
- What type of resources will be required to successfully address these opportunities?
- What approaches/initiatives are likely to create incentives for this type of research?
II. GENERAL DISCUSSION
A. Background Information:
Dr. Martinez opened the meeting by welcoming the members of the panel and thanking them for participating in this important activity. He reviewed the genesis of the panel and the designation of clinical research as a primary area of interest for NIDCR. A number of discussions, including those with the National Advisory Council, constitute the background provided to the panelists. The Panel was asked to address long-term research opportunities that would lead to a broad framework NIDCR can use in planning its research initiatives. The recommendations of all expert panels will contribute to the development of the Institute's Strategic Plan and provide the basis for the development of annual research programs.
Dr. Dushanka Kleinman, Deputy Director of NIDCR, emphasized the importance of clinical and translational research to the agenda of the new NIH Director as well as to NIDCR. She summarized the background material provided to the panelists and the series of activities/actions that NIDCR has undertaken in the last 2-3 years to review and to enhance clinical research. Recently, new clinical trial concepts and guidelines for clinical trial grant applications and management have been developed and discussed with the Advisory Council. Also, NIDCR sponsored a meeting of dental school deans in 2001 where the Director, National Center for Research Resources, highlighted resources and programs available for clinical research, including General Clinical Research Center (GCRC) Awards and Centers of Biomedical Research Excellence (COBRE) Awards. Several dental schools are currently benefiting from these programs. In addition a NIDCR Request For Applications (RFA) was issued to improve the research capacity and infrastructure of dental schools and a program announcement has been issued to support research curriculum development in dental schools
Other recent activities relevant to clinical research, include the development of initiatives to support patient registries (such as for patients with TMJ disorders, TMJ implants and those with Sjögren's syndrome); the creation of a special emphasis panel for the review of applications for clinical trials; enhanced interaction with FDA; identification, with the help of the Advisory Council, of a full range of areas of scientific opportunity and of the criteria for selecting the areas of emphasis and establishing priorities among others. Also, the reorganization of the extramural programs serves to highlight clinical research and recent efforts have resulted in recruitment of outstanding experts in clinical research and clinical trial management.
Dr. Bruce Pihlstrom, Director of the Division of Population and Health Promotion Sciences reviewed the current portfolio in clinical research, describing the distribution of the grants in patient-oriented research, population based studies and clinical trials. About 30% of the supported clinical trials address periodontal disease and its relationship to systemic disease. In response to questions, Dr. Pihlstrom indicated that 20% of the funding for clinical trials goes to studies on the effects of dental amalgam and 2% to oral cancer.
The current emphasis is placed on phase III clinical trials, which are, in the NIH definition, randomized controlled trials designed to provide evidence leading to a scientific basis for consideration of a change in policy or the standard of care.
NIDCR has prepared new guidelines for the submission of applications dealing with clinical trials. The application procedure was outlined by Dr. Pihlstrom. Panel members provided a number of suggestions in relation to the duration, funding and sequencing of applications for clinical trials. These suggestions were considered for inclusion in the guidelines that are now posted on the NIDCR web site.
B. GENERAL DISCUSSION
The Panel discussed several issues that need to be addressed to ensure the success of a long-term clinical research program. These include:
1) The necessary infrastructure for conducting patient-oriented research and for meeting all the regulatory requirement needs to be developed and/or enhanced in dental research institutions.
2) The capacity of the oral health research community to conduct clinical research and to use the findings from research needs to be augmented through enhanced training and the creation of a critical mass of investigators who are familiar with and can manage clinical trials and community-based research methodologies. Training should include well-constructed programs leading to a Master's degree in Clinical Research as well as shorter certificate programs and "hands-on" training within experienced research groups.
3) The development and maintenance of clinical research partnerships with other components of the academic health centers, the community and other sites need to be stimulated through the use of comprehensive award "packages" that support multidisciplinary research teams. Partnerships can make use of the resources of the NIH intramural program and Clinical Center and of enhanced participation in on-going medical clinical trials.
4) The culture of dental institutions needs to be modified to increase interest in clinical research and to enhance the acceptance of collaborative, interdisciplinary research and of the sharing of resources.
III. SCIENCE AREAS
The Panel reaffirmed the areas of science opportunity previously identified by the National Advisory Dental and Craniofacial Research Council. These include:
a) Prevention and diagnosis (general focus), including vaccine development and testing; salivary diagnostics; diagnostics for periodontal diseases, caries, and bone disorders.
b) Oral and Craniofacial conditions (specific focus), including caries, periodontal diseases, orofacial pain, TMJ, mucosal infections, oral cancer, and infectious diseases with oral manifestations.
c) Intervention studies that explore the oral-systemic health connection, including the study of the oral manifestations and complications of genetic conditions and of chronic systemic diseases and disorders such as cardiovascular disease, pulmonary disease and diabetes, and the impact of oral disease on systemic health, such as the link between periodontal disease and low, preterm birth.
d) Research on genetic and environmental determinants that affect oral health.
e) Restoration of form and function in oral, dental and craniofacial tissues through tissue engineering and biomaterials research.
The Panel also made the following comments in discussing the range of opportunities
that exist in these areas:
- Studies aimed at development and refinement of diagnostic measures and diagnostic criteria for oral and craniofacial diseases and health status should be given priority.
For both community-based studies and clinical trials testing preventive or therapeutic interventions, diagnostic codes for oral and craniofacial conditions need to be developed and put into use to ensure comparability among investigators/clinicians participating in the trials. Also, the development of quantifiable outcomes are needed, such as quantifiable clinical and radiographic measures of patient function and disease progression. Studies on pharmacoecomics are needed to establish the link between the clinical changes and the economic impact.
- There should be continued emphasis on studies aimed at achieving a greater understanding of the relationship among oral and systemic conditions. One approach can include NIDCR's encouragement and support of participation in on-going trials and cohort studies that have potential impact on the oral cavity. Ideally this could be incorporated at the initiation of studies. Examples of study areas include osteoarthritis and autoimmune disorders, among others.
- Increased emphasis should be placed on investigations of oral functions and symptoms and their management. Conditions such as "dry mouth" can capture a broad range or oral and systemic issues for study.
- The importance of supporting continual interaction between translational research and clinical and community-based research was stressed. One suggested approach includes providing support for taking and storing tissue and other samples for mechanistic studies. In addition, assessing the translational research portfolio may generate opportunities for clinical research. Inclusion of translational research in clinical and community-based studies, where possible, is recommended.
In terms of the types of resources that are required, the Panel acknowledged that both human and fiscal resources, as well as institutional commitment, are needed to address the scientific opportunities. They placed a priority on encouraging the oral health research community to take maximum advantage of partnering and using existing resources, and not recreating them. Examples include the use of epidemiologists and biostatisticians who may be available at the academic health center or the dental school. Other comments included:
- Support was expressed for the Institute's dental school research infrastructure and curriculum development initiatives that are underway. (See Funding Announcements)
- There are insufficient numbers of researchers capable of conducting clinical and community-based research. In addition to training and experience in research methods, researchers are needed with specific expertise in areas such as prevention and health promotion, diagnostic technology and drug development and testing, and community-based interventions, as well as in translational research.
- Support was articulated for the proposed clinical research masters program, including suggestions for a "phased" program that could include both part-time and full-time faculty. They acknowledged the support provided via the K23 mechanism and also suggested that the full range of training should be considered, ranging from certificate to doctoral programs.
- Regarding human resources, the Panel members recommended that participation in the K30 programs by oral health investigators be enhanced and recommended highlighting the availability of the loan repayment program. The critical role of mentors was emphasized, and the need to develop/support mentors for this type of research was recommended.
In discussing the approaches/initiative that can create incentive for this type of research, the Panel concluded that these are needed for both the oral health research community as well as for other research groups within the academic community to work with oral health researchers. The Panel recognized that a strong rationale is needed to attract experienced partners from the medical and social science fields to study questions related to oral health. Similarly, dental health care practitioners need to be prepared to adopt emerging technologies and interventions.
- The value of community-based research was acknowledged; at the same time, its inherent challenges were recognized. Of particular note is the need to ensure that benefits derived from the research are transmitted back to the community. In addition, the Panel recognized the importance of establishing and maintaining partnerships between academic health researchers and community programs and communities to foster community-based research.
- Partnerships with industry should further support efforts in clinical and community-based research. Opportunities for these partnerships include mutual use of tissue and fluid specimens and support for institutional infrastructure for research.
- Supporting interactions among all categories of investigators and with the practicing community was recommended. For example, Panel members recommended that teaming basic scientists with clinical and community-based researchers could benefit from the work of both groups. Also, the development of practitioner networks was recommended to contribute to the expanded conduct of clinical studies and ultimately to enhance science transfer.
The Panel also discussed other issues relative to clinical research and the approach that NIDCR can use to promote the expansion of its research portfolio into the areas of opportunity identified above. The Panel proposed several frameworks for promoting this type of research. One is using a general approach that emphasizes diagnosis, risk assessment, prevention and treatment. A second approach involves the use of markers for specific diseases and their validation through population-based studies. A third approach is to emphasize oral functions and to evaluate them in terms of specific diseases and mechanisms of disease.
Proposals submitted within this matrix can be assessed by using the criteria previously identified by the National Advisory Dental and Cranifacial Research Council, which include:
a) uniqueness to the NIDCR mission
b) not being addressed by other funding agencies
c) capable of producing the most benefit to the public
d) capable of addressing the greatest public health need
e) that can be leveraged by other activities/funds
f) that can be improved by NIDCR participation
Additional elements of evaluation include whether the science base is ready, whether the research community is ready and whether the proper measurements are available. An alternative approach to stimulating clinical research is to obtain input from stakeholders (including practitioners and patients) and to identify broad areas of public interest.
As the areas of emphasis are developed, possible partnerships with industry need to be considered. Incentives can be used for getting them involved in translational research. These partnerships can involve products and their applications. Partnerships can also be developed in terms of genomic efforts. Pharmaceutical and genomic companies are desperate for serum, saliva or any other type of specimens for tissues/sample banks, and partnering with them is a way to build the institutional infrastructure.
The incredible complexity of doing clinical research and the regulatory burden and capacity to comply have to be kept in mind, especially in multicenter trials involving more than one IRB, academic units, General Clinical Research Centers (GCRCs), etc. with different reporting and regulatory requirements.