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PROCEEDINGS |
The introduction and application of the randomized clinical trial to evaluate interventions for the prevention and/or treatment of dental caries have undergone enormous development during the past 50 years. Between 1968 and 1983, three formal initiatives occurred to take stock and report systematically on the then-state-of-the-art caries clinical trials field (American Dental Association, 1972a,b; Fédération Dentaire Internationale, 1982; Chilton and Schrotenboer, 1984). During the past nearly 20 years, further enormous changes have taken place with regard to dental caries epidemiology and disease severity, dental caries detection and measurement, and both the design and statistical analysis of randomized clinical trials. During the same interval, the ethical, economic, and regulatory environments for caries clinical trials have also undergone significant changes that have potential implications for the conduct of such studies. The recent NIH Consensus Development Conference, "Diagnosis and Management of Dental Caries Throughout Life", concluded that "The science of clinical research design has advanced rapidly in the past several decades. However, the panel deemed that the design and execution of caries trials and epidemiological studies have not kept pace with the current standard" (NIH Consensus Statement, 2001).
The incidence, prevalence, distribution, and severity of dental caries have changed in several ways that significantly affect caries clinical trials (Whelton, 2004). In many parts of the world, the incidence and prevalence of permanent tooth caries has declined, though evidence for such trends is only beginning to appear with respect to the primary tooth dentition. The distribution of caries across tooth surfaces within the mouth reveals the increasing relative susceptibility of occlusal and pit-and-fissure-containing surfaces to dentinal caries. With greater retention of the natural dentition into older age, root-surface caries becomes relatively more prominent. Within the population, especially among school-aged children, higher caries experience in permanent teeth is increasingly concentrated in the most caries-susceptible 20% of the population, primarily people in the lower socio-economic groups. (Epidemiological trends with regard to deciduous tooth caries in young children are less clear-cut.) Finally, the greater use of fluoridated water and fluoridated dentifrices, and possibly better oral hygiene, appears to restrain the severity of the caries attack, delaying progression and resulting in relatively fewer caries lesions cavitated into the dentin at a given age. This latter phenomenon has called into question the sensitivity, and hence the continuing appropriateness, of the classic, visual-tactile, cavitation-based caries diagnosis system, as well as the construction of caries indices based on classic visual-tactile diagnostic standards (Ismail, 2004). Two further and predictable consequences have been that caries trials were designed to run for three rather than two years, and such trials have required ever-larger sample sizes to maintain Type II errors at the 0.20 level. The latter two actions, among others, have greatly increased the cost of caries clinical trials (Stamm, 2004). It is plausible that the demonstrably higher cost of trials may be inhibiting sponsors’ ability to evaluate new caries prevention innovations, thus depriving the most caries-susceptible populations of urgently needed preventive benefits.
During the past 20 years, understanding of the biopathology of dental caries has undergone major refinement (Kidd and Fejerskov, 2004). Most significantly, it has been appreciated that dental caries is a phenomenon directly linked to continually present, highly complex molecular processes active at the interface of susceptible tooth surface areas and the microbial biofilms that cover them. In the multiple sites of teeth where such micro-ecosystems exist at various stages, a key feature is the constant oscillation between hard-tissue demineralization and remineralization. Such a perspective suggests that the term "caries-free" may be technically ambiguous, and its use should now be avoided. This highly dynamic model of caries etiology has implications for disease diagnosis and for preventive strategies, both agent- and host-related, as well as for further caries research.
A critical feature of the early stages of the caries disease process is the loss of mineral in a predictable pattern involving the surface and sub-surfaces of the tooth (Featherstone, 2004). When carefully calibrated visual techniques are applied, the methodical evaluation of early demineralization in the susceptible areas of the tooth surface provides the potential for reliable identification of a caries lesion at an appreciably earlier stage than is possible with the classic visual-tactile, cavity-based paradigm (Ekstrand, 2004; Ismail, 2004). Moreover, multi-category visual caries diagnostic methods have been demonstrated to be effective and efficient in the conduct of caries clinical trials (Biesbrock et al., 2004). The time may be ripe to combine the assessment of cavitated and non-cavitated caries lesions into a valid, accurate, practical, and widely agreed upon caries diagnostic system.
In recent years, considerable energies have been directed at the adaptation of a variety of micro-electronic-based technologies, many involving enhanced imaging methods, to the task of measuring sub-clinical variations in mineral density within caries-susceptible areas of the tooth (Pitts, 2004). A non-exhaustive list of such methods includes radiology, digital radiology and digital subtraction radiology (Wenzel, 2004), fiber optic transillumination (FOTI) and digital imaging fiber optic transillumination (DIFOTI), electrical conductivity measurement (ECM) (Longbottom and Huysmans, 2004), alternating current impedance spectroscopy (ACIST), and optical coherence tomography (OCT) (Hall and Girkin, 2004). As the above methods for measuring mineral have been improved, their sequential application for measuring net mineral loss within shorter time frames has become increasingly practical. Combined with other optical technologies, including laser-induced fluorescence measurement (DIAGNOdent) (Lussi et al., 2004) and quantitative light fluorescence (QLF) (Stookey, 2004), the direct technologies for measuring mineral loss over time have begun to demonstrate considerable promise for application in the caries clinical trial setting (Biesbrock et al., 2004).
The past two decades have also witnessed an explosion of statistical methods that potentially bring more efficiency to the analysis of caries clinical trial data (Imrey and Kingman, 2004). Moreover, the newer methods have implications for the types of designs, the sizes of samples, the approaches to measurement, the amount of information to be derived, and the length of caries trials, all of which will strongly shape the conduct of future caries clinical trials (D’Agostino and Massaro, 2004). One example of progress in methodology is the emergence of the "non-inferiority" and clinical equivalence trials (Blackwelder, 2004).
Caries clinical trials will increasingly be conducted in more heterogeneous settings. By this is meant that caries trials will be carried out in a larger variety of countries, and may also be conducted in coordinated multiple dental practice settings. Such developments would parallel recent trends in medical clinical trials, would be extremely positive with respect to increasing study generalizability, and would simultaneously encourage greater access to more caries-susceptible study participants. The Council for International Organizations of Medical Sciences, in conjunction with the World Health Organization, has developed internationally accepted ethical standards for research involving human participants (CIOMS/WHO, 1993). Continuous review is desirable to keep such guidelines appropriate and up-to-date for evolving ethical standards related to research involving human subjects.
Greater heterogeneity in clinical trial settings also heightens the need to ensure key study comparability in core methodological parameters and to adopt quality standards for the reporting of research involving human subjects. Good international guidance on the methodology and reporting of clinical trials is provided, respectively, by the International Conference on Harmonization (ICH) (www.ifpma.org/ich1/html) and the Consolidated Standards of Reporting Trials (CONSORT) (Begg et al., 1996). Routine compliance with CONSORT guidelines would be facilitated if investigators adopted recommendations for data exchange, and if journal editors could modify page restriction policies to allow full reporting for clinical trials.
The Mission of the International Collaborative Workshop on Caries Clinical Trials is to reach consensus about the design of protocols for caries clinical trials that are scientifically acceptable as pivotal evidence of the anti-caries efficacy of oral care products. A recurring theme of the ICW CCT was the desirability of identifying and evaluating methods that would lead to valid and reliable, yet shorter and more efficient, caries clinical trials. For the accomplishment of the ICW CCT mission, the five following objectives were set out for the Workshop participants:
Twenty-five formal presentations were developed and presented to the ICW CCT. These papers, and the resultant consensus statement, form the body of this Special Issue of the Journal of Dental Research. It is hoped that the ICW CCT proceedings and consensus statement will provide increased understanding and guidance for the future conduct of caries clinical trials.
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REFERENCES |
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American Dental Association (1972b). Principles for the Clinical Testing of Cariostatic Agents, 1968. Chicago: American Dental Association.
Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. (1996). Improving the quality of reporting of randomized controlled trials. The CONSORT statement. J Am Med Assoc 276:637–639.[ISI][Medline]
Biesbrock AR, Chesters RK, Elwood RP, Smith SR (2004). The challenges of validating diagnostic methods relative to a conventional two-year caries clinical trial. J Dent Res 83(Spec Iss C):C53–C55.
Blackwelder WC (2004). Current issues in clinical equivalence trials. J Dent Res 83(Spec Iss C):C113–C115.
Chilton N, Schrotenboer G (editors) (1984). Clinical caries trials. Proceedings of a Conference at the American Dental Association. J Dent Res 63(Spec Iss):693–828.
CIOMS/WHO (1993). International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS. (See also www.cioms.ch/draftguidelines_may_2001.htm.)
D’Agostino RB Sr, Massaro JM (2004). New developments in medical clinical trials. J Dent Res 83(Spec Iss C):C18–C24.
Ekstrand K (2004). Improving clinical visual caries detection—potential for caries clinical trials. J Dent Res 83(Spec Iss C):C67–C71.
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Hall AF, Girkin J (2004). A review of potential new diagnostic modalities for caries lesions. J Dent Res 83(Spec Iss C):C89–C94.
Imrey P, Kingman A (2004). Analysis of clinical trials involving non-cavitated caries lesions. J Dent Res 83(Spec Iss C):C103–C108.
International Conference on Harmonization (2002). www.ifpma.org/ich1/html.
Ismail AI (2004). Visual and visuo-tactile detection of dental caries. J Dent Res 83(Spec Iss C):C56–C66.
Kidd EA, Fejerskov O (2004). What constitutes dental caries? Histopathology of carious enamel and dentin related to the action of cariogenic biofilms. J Dent Res 83(Spec Iss C):C35–C38.
Longbottom C, Huysmans MC (2004). Electrical methods for use in caries clinical trials. J Dent Res 83(Spec Iss C):C76–C79.
Lussi A, Hibst R, Paulus R (2004). DIAGNOdent: an optical method for caries detection. J Dent Res 83(Spec Iss C):C80–C83.
NIH Consensus Statement (2001). Diagnosis and management of dental caries. AHRQ Evidence Reports. Report #36 (www.ahrq.gov/clinic/epcindex.htm#oral).
Pitts NB (2004). Modern concepts of caries measurement. J Dent Res 83(Spec Iss C):C43–C47.
Stamm J (2004). The classic caries clinical trial: constraints and opportunities. J Dent Res 83(Spec Iss C):C6–C14.
Stookey GK (2004). Optical methods (2)—quantitative light fluorescence. J Dent Res 83(Spec Iss C):C84–C88.
Wenzel A (2004). Bitewing and digital bitewing radiography for detection of caries lesions. J Dent Res 83(Spec Iss C):C72–C75.
Whelton H (2004). Overview of the impact of changing global patterns of dental caries experience on caries clinical trials. J Dent Res 83(Spec Iss C):C29–C34.
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