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PROCEEDINGS |
1 Centre for Clinical Innovations and Dental Health Services Research Unit, University of Dundee, The Mackenzie Building, Kirsty Semple Way, Dundee DD2 4BF, Scotland, UK; n.b.pitts{at}dundee.ac.uk; and
2 School of Dentistry, #7450, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7450, USA; john_stamm{at}dentistry.unc.edu
KEY WORDS: caries clinical trials • caries diagnosis • consensus development
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MISSION |
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 TOP MISSION OVERVIEWOBJECTIVE 1: Critically Review...OBJECTIVE 2: Critically Review...OBJECTIVE 3: To Debate...OBJECTIVE 4: Critically Review...OBJECTIVE 5: To Ensure... |
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OVERVIEW |
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TOPMISSIONOVERVIEWOBJECTIVE 1: Critically Review...OBJECTIVE 2: Critically Review...OBJECTIVE 3: To Debate...OBJECTIVE 4: Critically Review...OBJECTIVE 5: To Ensure... |
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Twenty-five formal scientific papers were delivered at the ICW-CCT. Following the presentations relevant to each objective/theme, an extensive moderated discussion was held by the Workshop participants, and a record was made of the key points raised and agreed. At the end of each day, the presenters for each thematic session (matching objectives 1–4) were invited to gather in groups with session Chairs and any interested participants. This allowed for further reaction and discussion related to the daily record of key points, as well as the identification of areas of scientific consensus and any issues in need of further clarification or investigation.
To complete objective 5, the Workshop concluded with a half-day plenary session that evaluated all draft consensus statements with respect to their scientific content as well as their fit under one or the other of the themes/objectives of the Workshop. In the pages that follow, for each of the Workshop objectives, a brief summary of the context of the discussions is given. These are followed by the agreed consensus statements. In the aggregate, these sequential statements represent the consensus achieved by the Workshop participants. It is hoped that the ICW-CCT proceedings and consensus statements will provide increased understanding and guidance for the future conduct of caries clinical trials.
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OBJECTIVE 1: Critically Review Modern Caries Definitions and Measurement Concepts |
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TOPMISSIONOVERVIEWOBJECTIVE 1: Critically Review...OBJECTIVE 2: Critically Review...OBJECTIVE 3: To Debate...OBJECTIVE 4: Critically Review...OBJECTIVE 5: To Ensure... |
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Lesions at a wide range of progression states can be arrested by regular disturbance of the biofilm. Dentifrices with effective active agents will also halt lesion progression and promote remineralization, which can arrest or reverse a lesion prior to cavitation. Such a halt in lesion progression and, if possible, lesion repair through remineralization are very desirable outcomes of an anticaries intervention.
Consensus Statements
(1.1) The Caries Process occurs as an interaction between the biofilm and the tooth surface and subsurface. The Caries Lesion is the manifestation of the stage of the process at one point in time.
[Note for readers: For clinical and epidemiological purposes, it is useful to know at one point in time whether a lesion is active, but within the clinical trial context, consecutive measures of lesion behavior provide sufficient information to establish efficacy between products.]
(1.2) Caries progression occurs when the demineralization and remineralization equilibrium is out of balance, leading to net mineral loss.
(1.3) Remineralization can arrest or reverse progression of disease and can lead to changes in mineral quality.
(1.4) The understanding of the caries process has progressed far beyond the point of restricting the evidence for dental caries to the D2 (caries in enamel only) or D3 (caries in enamel and dentin) level of cavitation.
(1.5) One of the desired outcome measures in future caries clinical trials should be the arrestment or reversal of the progress of mineral loss.
(1.6) Caries in enamel, dentin, and on root surfaces are all variations on the same theme of bacterially induced demineralization, alternating with remineralization, over many cycles in a lifetime.
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OBJECTIVE 2: Critically Review the Evidence on Caries-diagnostic Methods |
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TOPMISSIONOVERVIEWOBJECTIVE 1: Critically Review...OBJECTIVE 2: Critically Review...OBJECTIVE 3: To Debate...OBJECTIVE 4: Critically Review...OBJECTIVE 5: To Ensure... |
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There have been attempts over many years to find improved methods of caries detection, and ordinally graded or continuous measures of mineral density have been developed or are under development for the measurement of net mineral loss in caries lesions over time. Proposed measures are based on disciplined standardized observations according to established techniques, technologically enhanced visual observations, new imaging technologies, and combinations of these.
There is some confusion with the terminology used in the literature around caries diagnosis (which should imply a human professional summation of all available data), lesion detection (which implies some objective method of determining whether or not disease is present), and lesion assessment (which aims to characterize or monitor a lesion, once it has been detected).
Consensus Statements
Existing methods of caries detection and assessment
(2.1) For future clinical trials, recording only cavitated lesions as an outcome measure is becoming outmoded.
(2.2) Visual inspection is the standard of caries diagnosis in Europe.
(2.3) The use of additional methods of caries lesion assessment to supplement visual techniques should be explored further.
(2.4) Bitewing radiography may add information about many of the clinical stages of the carious process at approximal surfaces and, in the case of more advanced stages, occlusal surfaces. Diagnostic yield with contemporary caries presentations must be evaluated, and, for use in caries clinical trials, the prospects of radiographic examinations adding to product discrimination should be assessed.
(2.5) Low-dose radiographic systems and/or subtraction radiography should be considered when radiography is used for caries trials.
(2.6) Fiber-Optic Transillumination (FOTI) has been used successfully for caries diagnosis in some countries. Its wider use in caries clinical trials should be considered.
Validation of methods of caries detection and assessment
(2.7) In vitro and/or in situ studies are still required, both to develop and to evaluate new diagnostic techniques.
(2.8) For extrapolation of the results of laboratory studies on caries diagnostic techniques to clinical use, the clinical environment—e.g., soft-tissue equivalents, moisture, etc.—should be simulated as closely as possible within the laboratory setting.
(2.9) There is concern about the so-called ‘gold standards’ currently used in caries diagnosis/detection research, particularly for assessing occlusal and approximal surfaces.
(2.10) Given the deficiency of current ‘gold standards’, and the challenges of achieving appropriate validation, new reference standards and validation protocols should be developed. When the accuracy and precision of new caries-diagnostic methods are determined, it is necessary that the distribution of caries lesions in the in vitro or in situ assessment include all disease stages in which the diagnostic method will be used in vivo.
(2.11) It should be appreciated that validation studies using immature teeth, or only premolars and third molars, may not be sufficiently representative to provide accurate and precise data for validation purposes.
Newer methods of caries detection and assessment
(2.12) The assessment of non-cavitated lesions is essential for future CCTs, and new caries assessment methods have the prospect of helping in this task.
(2.13) It would be desirable that the stage at which the carious process is measured with new diagnostic techniques will relate to the extent to which the particular technique has been validated at the corresponding level of sensitivity.
(2.14) New assessment techniques should, in the clinical context, be capable of measuring a wide range of lesion depths and changes in degree of mineralization, either directly or indirectly. Ideally, a continuous scale should be used.
(2.15) The inherent nature of some of the techniques restricts the surface types which can be assessed and the range of lesions which can be measured.
(2.16) Ideally, new caries assessment technologies should have the capacity to monitor changes on a highly targeted surface- and site-specific basis.
(2.17) New measurement methods should continue to be developed. Electro-physical phenomena may have the potential to detect lesions and quantify changes in the caries process. Current examples are in various stages of development and include Electronic Caries Monitors (e.g., ECM), DIAGNOdent, Quantitative Light Fluorescence (QLF), Digitized Fiber Optic Transillumination (DIFOTI), and Optical Coherence Tomography (OCT). Other techniques are under development.
(2.18) The new technologies should be further refined and adopted in modern Caries Clinical Trials if they demonstrate the ability to improve trial outcomes, reduce subject numbers, and/or reduce costs.
(2.19) Since some trials may in future be conducted in general-practice settings, and to optimize translation of research into practice while minimizing the risk of over-prescription, developers of new diagnostic techniques should specify their appropriate uses in Caries Clinical Trials and/or in dental practice.
(2.20) The importance and challenges of assessing newly erupted teeth with immature enamel should be recognized fully.
(2.21) All new methodologies should have an in vitro assessment on natural caries lesions as part of the validation process.
(2.22) Some new diagnostic techniques may exceed the accuracy, sensitivity, and resolution of existing validation reference standards.
(2.23) Further investigation into how new technologies assess root, recurrent/secondary, and residual caries is required.
(2.24) This field should be reviewed periodically to chart developments in technology and see whether the new methods can improve on current methodology in the Caries Clinical Trial context.
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OBJECTIVE 3: To Debate Potential Designs for Modern Caries Clinical Trials to Provide Pivotal Evidence of Anti-caries Efficacy |
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TOPMISSIONOVERVIEWOBJECTIVE 1: Critically Review...OBJECTIVE 2: Critically Review...OBJECTIVE 3: To Debate...OBJECTIVE 4: Critically Review...OBJECTIVE 5: To Ensure... |
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The choice of caries measure(s) should be appropriate to the subject population, distribution of disease, and mechanism of action of the therapies studied. Site-specific determinations of mineral content and quality are not surrogate measures, but rather are primary indicators of the cumulative destructive impact of the caries process. It is an ongoing necessity to validate such measures for their power to discriminate between therapies relative to currently accepted observational methods.
Clear and specific study aims are always essential to achieving a successful caries clinical trial. In addition, the use of ordinal or continuous measures of cumulative disease progression/regression, or rates of their occurrence, when these are adequately standardized and precise, coupled with improved subject retention, offer hope of increased efficiency in the conduct of clinical trials of anticaries therapies.
Consensus Statements
For confirmatory caries clinical trials, the statements below were the object of broad consensus by the assembled Workshop participants:
Study objectives and efficacy variables
(3.1) In conventional caries trials, the primary objective is to reduce DMFS increment, and the primary efficacy variable is, accordingly, reduction of DMFS increment (over a two- to three-year period).
(3.2) In new caries trials, the study objectives should be directed at measuring changes in the continuum of the caries process. The efficacy variables should be a measure of further demineralization and/or stimulation of remineralization in lesions (substantially beyond what would naturally occur).
(3.3) Measures of mineral density change are not surrogate outcomes but rather are primary indicators of the cumulative status of the dental caries lesion. Surrogate variables are unacceptable as primary endpoints in caries clinical trials.
Target/sample population
(3.4) As is the case in all disease-focused clinical trials, caries studies need to identify subjects at high caries risk for inclusion in the study. This may mean, for example, that there will be age restrictions in the study’s inclusion criteria.
(3.5) Within the context set by the above, caries studies should attempt to have broad representation with respect to gender, race, and socio-economic status. These inclusions are to promote generalizability to the target population.
Study designs
(3.6) The randomized maximally blinded parallel group design is the preferred study design for caries trials.
(3.7) As in other areas of health sciences, multi-center caries trials may be necessary to achieve sample size goals or may contribute certain other advantages in some circumstances.
(3.8) Factorial designs can permit the possibility of investigating multiple therapeutic objectives.
(3.9) All studies should be adequately sized and powered (conventionally, 0.05 level of significance and power at least equal to 0.80). This should be the case for superiority, non-inferiority, and equivalence trials.
(3.10) In non-inferiority trials, the demonstration of compliance and adherence to protocols, a definition of non-inferiority margin, and a rigorous attempt to demonstrate that the active control was effective are essential.
Randomization
(3.11) The randomization process should be clearly stated and documented. Blinding/masking should be maximal to the extent possible, considering the constraints inherent in trial design and the therapies to be used.
Trial monitoring
(3.12) The use of an Ethics Committee/Institutional Review Board (IRB) is essential. In addition, a Data Safety Monitoring Board (DSMB) may be required for monitoring safety and efficacy.
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OBJECTIVE 4: Critically Review the Statistical Approaches That Could be Used to Analyze Modern Caries Clinical Trial Data |
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TOPMISSIONOVERVIEWOBJECTIVE 1: Critically Review...OBJECTIVE 2: Critically Review...OBJECTIVE 3: To Debate...OBJECTIVE 4: Critically Review...OBJECTIVE 5: To Ensure... |
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The participants in caries trials generally are healthy volunteers rather than patients. The healthy volunteer has less at stake in the study intervention than has the ill patient, often creating higher participant attrition in caries trials. On the other hand, caries-preventive treatments are generally benign and almost universally well-accepted. Therefore, caries trial participants generally do not drop out due to effects linked to a poorly tolerated treatment regimen. Managing participant attrition as well as regimen compliance without incurring bias are important issues for the data analysis of caries trials.
Although caries trials have generally been analyzed by the treatment of caries increment as a continuous variable, validation studies of existing ordinally scaled clinical visual assessments should be conducted based on existing data from two- to three-year studies, comparing the results from ordinal scaling analyses with those from the traditional caries increment analyses.
Consensus Statements
Following the presentation of all statistical methods papers, and the resultant plenary discussions, the Workshop participants elaborated the following consensus statements relative to Objective 4.
(4.1) The statistical analysis of a caries trial should utilize the maximum information available for the scale of measurement and the properties of the response variable (ordinal, counts, or continuous).
(4.2) The statistical analysis should rely on robust techniques and be reported in a clinically interpretable manner.
(4.3) Numerous statistical methodologies are available for the analysis of data from ordinal or continuous measures of change in mineralization. From among these, statistical methods should be chosen that appropriately reflect the experimental designs and efficiently capture the information produced. These include scoring of ordinal data, ordinal categorical data models, general and generalized linear models, as well as survival analysis methodology.
(4.4) All methods should properly account for the possibility of intra-subject correlation.
(4.5) For caries clinical trials, dichotomization of outcomes is often inefficient and should be avoided unless specifically justified by the declared goals of the trial.
(4.6) The Intention-to-Treat (ITT) approach is problematic for extended caries trials, in view of the virtual unavoidability of extensive subject attrition, the typical loss of efficiency relative to analysis restricted to the subset of subjects who complete the full protocol (‘per protocol’ [PP] analysis), and the strong rationale and experiential basis for believing that dropouts occur randomly with respect to treatment. However, ITT analysis is generally recognized as the scientific standard for controlling bias and enhancing validity across the full range of medical clinical trials.
(4.7) Modern statistical imputation methods may be useful in reducing the loss of efficiency from ITT relative to PP analyses, and should be evaluated for their utility in caries trials.
(4.8) To ensure that pivotal trials are sized adequately, the acceptability of primary PP analysis should be confirmed with regulatory authorities prior to data collection.
(4.9) The appropriateness of a primary PP analysis should be explicitly justified in reports taking this approach, and a secondary ITT analysis should be provided.
(4.10) In long-term caries trials reporting a primary ITT analysis, a secondary PP analysis may yield further understanding of the data.
(4.11) It is essential that all the trial participants are accounted for as part of the reporting process, as recommended by the CONSORT guidelines.
(4.12) A considerable quantity of statistical literature exists on analytical methods when multiple outcomes are necessary to track a common underlying biological or target effect. Such methods include (a) the use of a multivariate test statistic accounting for outcome variable correlation, or (b) appropriately standardized linear or non-linear combinations of outcomes to generate a composite variable or scale for analysis utilizing a global test statistic.
(4.13) The magnitude of statistically significant treatment effects should be estimated and interpreted in clinical context. The interpretation of caries trials in terms of clinical significance requires further consideration.
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OBJECTIVE 5: To Ensure that, in Meeting Objectives 1–4, the Workshop Formulates Key Elements of Protocol(s) for Shorter and More Efficient Modern Caries Clinical Trials and a Framework for Validating Them Endorsed by the Group of Leading International Experts Present at the Meeting |
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TOPMISSIONOVERVIEWOBJECTIVE 1: Critically Review...OBJECTIVE 2: Critically Review...OBJECTIVE 3: To Debate...OBJECTIVE 4: Critically Review...OBJECTIVE 5: To Ensure... |
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Consensus Statements
Caries assessment methods
(5.1) In light of the evidence reviewed, both here and elsewhere, pertaining to modern caries definitions and measurement concepts, the participants supported a statement recommending that, in future CCT protocols, caries measurement methods are used which:
(5.2) If they are valid and contribute to the ability to improve trial efficiency, the new caries assessment technologies should be refined further and adopted in modern Caries Clinical Trials.
Validation of new assessment methods with clinical trials
(5.3) Methods capable of recording the continuum of the caries process (including non-cavitated lesions) should be evaluated and their results compared with those of the conventional caries assessment methods over a two- to three-year study.
(5.4) New caries assessment methods should have the ability to measure demineralization and also remineralization of non-cavitated lesions.
(5.5) While there are many other ways in which the design of CCTs might be improved further, through better diagnostic, design, and analytical techniques, it is paramount that the overriding principle behind CCT design validation must be that the results and conclusions from any new design are in line with those shown previously by ‘conventional’ CCTs.
(5.6) Any new design of Caries Clinical Trial must not compromise the standard of proof of either efficacy or safety.
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FOOTNOTES |
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This article has been cited by other articles:
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  J. Beauchamp, P. W. Caufield, J. J. Crall, K. Donly, R. Feigal, B. Gooch, A. Ismail, W. Kohn, M. Siegal, and R. Simonsen Evidence-Based Clinical Recommendations for the Use of Pit-and-Fissure Sealants: A Report of the American Dental Association Council on Scientific Affairs J Am Dent Assoc, March 1, 2008; 139(3): 257 - 268. [Abstract] [Full Text] [PDF]
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A. F. Zandona and D. T. Zero Diagnostic tools for early caries detection J Am Dent Assoc, December 1, 2006; 137(12): 1675 - 1684. [Abstract] [Full Text] [PDF]
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 M.L. Barnett and B.L. Pihlstrom Methods for Enhancing the Efficiency of Dental/Oral Health Clinical Trials: Current Status, Future Possibilities J. Dent. Res., October 1, 2004; 83(10): 744 - 750. [Abstract] [Full Text] [PDF]
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