1043
Foreword Peter Robinson
This conference had several purposes. First, it was designed to provide the essential information a clinical investigator needs to appropriately prepare a clinical trial to evaluate products designed to detect or treat Periodontitis. Secondly, this conference should also provide valuable information to the ADA Council on Dental Therapeutics relative to its development of guidelines for evaluation of therapeutics products which claim to be beneficial in the prevention or treatment of Periodontitis. Additionally, the product of this conference, this issue of the Journal of Periodontology, hopefully can serve as a design manual for clinical investigators in periodontics. A quarter of a century ago a conference, "Clinical Methods in Periodontal Diseases," with similar goals was held in Philadelphia.1 Some remarkable observations and contributions were made from that conference. In 1967 it was the battle of the gingival and periodontal indices; today it seems to be more the battle of the microbe and attachment level detection systems and facing the enigma of measuring risk factors. The common thread, however, for both of these conferences is an emphasis on the critical importance of the experimental design phase of a clinical trial. In the overview on clinical trial design presented by Jeffcoat, it is emphatically pointed out that a common major design pitfall is failure to clearly define the aims of a study resulting in an inability to properly focus on efficient, efficacious parameters. Jeffcoat provides a clear explanation of the problems associated with the Hawthorne effect and the importance (whenever possible) of incorporating a double-blind approach to a clinical trial. She discusses how surrogate variables (such as bleeding upon probing or smoking) may help provide better balance between test and control groups with respect to disease activity. The element of whether or not to include microbial parameters in the design of clinical trials is discussed by Jeffcoat, Ranney, and Goodson. Jeffcoat suggests that assessment for the presence of putative periodontopathic bacteria may aid in providing balance to the test and control groups with respect to disease activity. However, Ranney cautions that bacteriological definitions of subjects should not be used unless the objective is to study effects on those specific bacteria. Goodson provides an interesting point relative to the inclusion of microbiological response criterion in a study design by stating: "One should be aware, however, that specific definition of inclusion criterion will limit therapeutic claims to the subject population so defined." Ranney addresses the important design consideration of whether different forms of Periodontitis can be included within single population samples in studies of Periodontitis, and whether or to what extent results from studies of one
'Department Chicago, IL.
of
Stomatology, Northwestern University
Dental
School,
form of Periodontitis can be taken as applicable to other forms (there are 3 major categories of Periodontitis with some 6 or so subcategories). He concludes that for effective design, the study population should be categorized as to disease-type in such trials. This concept underscores the importance of carefully defining the study population to avoid mixing results with samples from a different disease than the one under study. The problem of not defining the study population by specific disease-types as is frequently found in the periodontal literature is compounded by the frequent improper choice of the overall experimental design. For example, the cross-over design has been used extensively in evaluating the effects of various treatments on gingivitis. Split-mouth designs have been a common approach in comparing various clinical modalities in the treatment of Periodontitis. Jeffcoat and Imrey and Chilton, however, examine the problems and limitation of these designs in evaluating treatment directed towards Periodontitis. Additionally, these authors guide the reader through such design factors to consider as a pre-treatment period, randomization, and blinding. Two options to the standard single institution random clinical trial are presented: multicenter trials and field testing. Multicenter trials, as presented by Goodson, overcome the difficulty of finding periodontal research centers that can enroll sufficient numbers of subjects within a 3- to 6month period to test agents for the treatment of Periodontitis. On the other hand, Kornman questions whether or not current clinical trial needs are being met by the randomized controlled trial in either a single center or multicenter settings. Kornman proposes the field trial as an alternative method for evaluating periodontal therapy as it is conducted in a private general practice or periodontal office. The field setting for studies provides an opportunity to focus on the application of new agents or devices into practical use. Kornman argues that institutional settings are best used to prove the principle; ie, the agent works better than the placebo at least in some patients. It is contended by Kornman that field trials have the potential to overcome the external biases often generated by random controlled institutional trials, allowing one to determine whether the effective therapy is actually of value as applied in routine practice. Both field testing and multicenter trials by their very nature present some major obstacles in attempting to assure the reliability of the methods applied. These approaches require much more stringent uniformity and control because of the obvious complicating factor of multiple examiners at separate sites. Common problems such as protocol violations and unauthorized adjunctive therapy and how to avoid them are well described by Goodson. Dramatic improvements have been made in the last decade in ways to measure changes in attachment levels, periodontal pathogens, and products of the host response.
J Periodontol 1044
FOREWORD
Pihlstrom describes advances that have been made in clinical instruments to measure attachment level, from the first through the third generation of instruments. It is pointed out that second generation controlled-force probes have greatly increased inter-examiner reliability. As the advantage and disadvantage of each probing system are reviewed, Pihlstrom reminds us that the details of selecting the appropriate instrument are dependent on its specific application in a clinical trial. Sometimes the advantage of improved reliability offered by sophisticated controlled-force probe systems can be overshadowed by economics in large group evaluations. Also, the improved resolution provided by the third generation probes does not always translate into improved measurement reliability. In contrast, Pihlstrom describes how simple averaging of repeated probing measurements improves the sensitivity and specificity of the test. Measuring the effectiveness of regenerative procedures presents special problems which are described by Lynch. Though it is ideal to use histological measurements following regenerative procedures, it is rarely practical to do so. Whether a re-entry surgery is indicated or whether clinical measurements of the soft tissue are adequate depends on whether the trial is aimed towards measuring regeneration or measuring new attachment. When periodontal regeneration is being evaluated and surgical re-entry is impractical, radiography is a reasonable alternative. Lynch points out radiography is the only non-invasive method for evaluating changes in the hard tissues around the teeth. Reddy observes that radiographs are unique in that they not only allow linear measurements of bone gain or loss, but also may provide area and volume measurements of the osseous topography associated with the periodontal defect. The advent of digital subtraction imaging and tomography have allowed for the first quantitative assessments of attachment loss in 3 dimensions. Reddy cautions that this new technology is not without cost compared to conventional radiography. Precision approaches such as subtraction imaging are exacting and labor-intensive and any increase in precision should be weighed against the manpower costs involved in the use of these approaches in clinical trials. Microbial identification methods are an important parameter for many clinical trials since work has indicated that a finite number of bacterial species are associated with Periodontitis. Therefore, many therapeutic approaches are directed toward the reduction of specific periodontal pathogens. There is, however, a wide variety of microbial identification methods available. The indications for and merits of these approaches (fluorescence immunoassay, DNA probles, and enzyme analysis) are described in some detail by Loesche and Wolff. Loesche explores the advantages and disadvantages of tests that identify specific bacteria (e.g., DNA probes) versus a group of anaerobic bacteria (e.g., ). Loesche
December 1992
(Supplement)
contends, ". .if an organism is only periodontopathic when .
it is in combination with other organisms, then tests to detect only 1 species will probably yield inaccurate results relative to clinical disease. ." The problems of accuracy in using the bacterial gold standard, culture methods, are discussed at length by Wolff and Loesche. DNA and immunological reagents are seen as more reliable primary reference standards than are traditional cultural methods. An evolution in microbial identification has occurred moving away from arduous, techniquesensitive approaches to highly sensitive, user-friendly .
techniques. Paralleling the
remarkable progress that has occurred in refinement of microbial identification are the advances in measurement of host response factors. Lamster outlines a very compelling argument for incorporating the biochemical evaluation of the host response as part of periodontal clinical trials including: 1) aids in balancing study groups; 2) provides another measure of how the patient is responding to particular therapy; and 3) is specifically recommended in evaluation of therapy directed towards modulation of the host response. Those biochemical factors in the gingival crevicular fluid that are discussed by Lamster as potential indicators of host response to periodontics include beta-glucuronidase, Prostaglandin E2, aspartate aminotransferase, elastase, and antibodies. The work of Ebersole and colleagues with antibody measurements reflects the state of the science and art in measuring host response in Periodontitis. Increasing evidence has supported the concept that active, specific antibody responses to selected members of the subgingival microbiota are noted in Periodontitis patients. On the other hand, changes in antibody with time or in relationship to disease resistance remains to be determined. Yet, despite these unknowns, evaluation of the level and specificity of serum antibodies can be a beneficial adjunct in designing and implementing clinical studies in Periodontitis. This issue of the Journal of Periodontology has been well-served by the many contributors who have provided a comprehensive guide to clinical trials for evaluating periodontal therapy. It is difficult to project which specific modes of patient measurement will endure over the next quarter century. Still, the center-piece of an effective clinical trial will continue to be the experimental design.
Acknowledgments
The design and organization of this conference was the result of the splendid and thoughtful efforts of the program committee, comprised of Kenneth Burrell, Neal Chilton, Marjorie Jeffcoat, Ray Williams, and Joseph Zambón.
REFERENCES 1. Cohen DW, Ship I. I.: Clinical methods in Periodontol 1967; 38:576-795.
periodontal
diseases. /
Foreword Peter Robinson
This conference had several purposes. First, it was designed to provide the essential information a clinical investigator needs to appropriately prepare a clinical trial to evaluate products designed to detect or treat Periodontitis. Secondly, this conference should also provide valuable information to the ADA Council on Dental Therapeutics relative to its development of guidelines for evaluation of therapeutics products which claim to be beneficial in the prevention or treatment of Periodontitis. Additionally, the product of this conference, this issue of the Journal of Periodontology, hopefully can serve as a design manual for clinical investigators in periodontics. A quarter of a century ago a conference, "Clinical Methods in Periodontal Diseases," with similar goals was held in Philadelphia.1 Some remarkable observations and contributions were made from that conference. In 1967 it was the battle of the gingival and periodontal indices; today it seems to be more the battle of the microbe and attachment level detection systems and facing the enigma of measuring risk factors. The common thread, however, for both of these conferences is an emphasis on the critical importance of the experimental design phase of a clinical trial. In the overview on clinical trial design presented by Jeffcoat, it is emphatically pointed out that a common major design pitfall is failure to clearly define the aims of a study resulting in an inability to properly focus on efficient, efficacious parameters. Jeffcoat provides a clear explanation of the problems associated with the Hawthorne effect and the importance (whenever possible) of incorporating a double-blind approach to a clinical trial. She discusses how surrogate variables (such as bleeding upon probing or smoking) may help provide better balance between test and control groups with respect to disease activity. The element of whether or not to include microbial parameters in the design of clinical trials is discussed by Jeffcoat, Ranney, and Goodson. Jeffcoat suggests that assessment for the presence of putative periodontopathic bacteria may aid in providing balance to the test and control groups with respect to disease activity. However, Ranney cautions that bacteriological definitions of subjects should not be used unless the objective is to study effects on those specific bacteria. Goodson provides an interesting point relative to the inclusion of microbiological response criterion in a study design by stating: "One should be aware, however, that specific definition of inclusion criterion will limit therapeutic claims to the subject population so defined." Ranney addresses the important design consideration of whether different forms of Periodontitis can be included within single population samples in studies of Periodontitis, and whether or to what extent results from studies of one
'Department Chicago, IL.
of
Stomatology, Northwestern University
Dental
School,
form of Periodontitis can be taken as applicable to other forms (there are 3 major categories of Periodontitis with some 6 or so subcategories). He concludes that for effective design, the study population should be categorized as to disease-type in such trials. This concept underscores the importance of carefully defining the study population to avoid mixing results with samples from a different disease than the one under study. The problem of not defining the study population by specific disease-types as is frequently found in the periodontal literature is compounded by the frequent improper choice of the overall experimental design. For example, the cross-over design has been used extensively in evaluating the effects of various treatments on gingivitis. Split-mouth designs have been a common approach in comparing various clinical modalities in the treatment of Periodontitis. Jeffcoat and Imrey and Chilton, however, examine the problems and limitation of these designs in evaluating treatment directed towards Periodontitis. Additionally, these authors guide the reader through such design factors to consider as a pre-treatment period, randomization, and blinding. Two options to the standard single institution random clinical trial are presented: multicenter trials and field testing. Multicenter trials, as presented by Goodson, overcome the difficulty of finding periodontal research centers that can enroll sufficient numbers of subjects within a 3- to 6month period to test agents for the treatment of Periodontitis. On the other hand, Kornman questions whether or not current clinical trial needs are being met by the randomized controlled trial in either a single center or multicenter settings. Kornman proposes the field trial as an alternative method for evaluating periodontal therapy as it is conducted in a private general practice or periodontal office. The field setting for studies provides an opportunity to focus on the application of new agents or devices into practical use. Kornman argues that institutional settings are best used to prove the principle; ie, the agent works better than the placebo at least in some patients. It is contended by Kornman that field trials have the potential to overcome the external biases often generated by random controlled institutional trials, allowing one to determine whether the effective therapy is actually of value as applied in routine practice. Both field testing and multicenter trials by their very nature present some major obstacles in attempting to assure the reliability of the methods applied. These approaches require much more stringent uniformity and control because of the obvious complicating factor of multiple examiners at separate sites. Common problems such as protocol violations and unauthorized adjunctive therapy and how to avoid them are well described by Goodson. Dramatic improvements have been made in the last decade in ways to measure changes in attachment levels, periodontal pathogens, and products of the host response.
J Periodontol 1044
FOREWORD
Pihlstrom describes advances that have been made in clinical instruments to measure attachment level, from the first through the third generation of instruments. It is pointed out that second generation controlled-force probes have greatly increased inter-examiner reliability. As the advantage and disadvantage of each probing system are reviewed, Pihlstrom reminds us that the details of selecting the appropriate instrument are dependent on its specific application in a clinical trial. Sometimes the advantage of improved reliability offered by sophisticated controlled-force probe systems can be overshadowed by economics in large group evaluations. Also, the improved resolution provided by the third generation probes does not always translate into improved measurement reliability. In contrast, Pihlstrom describes how simple averaging of repeated probing measurements improves the sensitivity and specificity of the test. Measuring the effectiveness of regenerative procedures presents special problems which are described by Lynch. Though it is ideal to use histological measurements following regenerative procedures, it is rarely practical to do so. Whether a re-entry surgery is indicated or whether clinical measurements of the soft tissue are adequate depends on whether the trial is aimed towards measuring regeneration or measuring new attachment. When periodontal regeneration is being evaluated and surgical re-entry is impractical, radiography is a reasonable alternative. Lynch points out radiography is the only non-invasive method for evaluating changes in the hard tissues around the teeth. Reddy observes that radiographs are unique in that they not only allow linear measurements of bone gain or loss, but also may provide area and volume measurements of the osseous topography associated with the periodontal defect. The advent of digital subtraction imaging and tomography have allowed for the first quantitative assessments of attachment loss in 3 dimensions. Reddy cautions that this new technology is not without cost compared to conventional radiography. Precision approaches such as subtraction imaging are exacting and labor-intensive and any increase in precision should be weighed against the manpower costs involved in the use of these approaches in clinical trials. Microbial identification methods are an important parameter for many clinical trials since work has indicated that a finite number of bacterial species are associated with Periodontitis. Therefore, many therapeutic approaches are directed toward the reduction of specific periodontal pathogens. There is, however, a wide variety of microbial identification methods available. The indications for and merits of these approaches (fluorescence immunoassay, DNA probles, and enzyme analysis) are described in some detail by Loesche and Wolff. Loesche explores the advantages and disadvantages of tests that identify specific bacteria (e.g., DNA probes) versus a group of anaerobic bacteria (e.g., ). Loesche
December 1992
(Supplement)
contends, ". .if an organism is only periodontopathic when .
it is in combination with other organisms, then tests to detect only 1 species will probably yield inaccurate results relative to clinical disease. ." The problems of accuracy in using the bacterial gold standard, culture methods, are discussed at length by Wolff and Loesche. DNA and immunological reagents are seen as more reliable primary reference standards than are traditional cultural methods. An evolution in microbial identification has occurred moving away from arduous, techniquesensitive approaches to highly sensitive, user-friendly .
techniques. Paralleling the
remarkable progress that has occurred in refinement of microbial identification are the advances in measurement of host response factors. Lamster outlines a very compelling argument for incorporating the biochemical evaluation of the host response as part of periodontal clinical trials including: 1) aids in balancing study groups; 2) provides another measure of how the patient is responding to particular therapy; and 3) is specifically recommended in evaluation of therapy directed towards modulation of the host response. Those biochemical factors in the gingival crevicular fluid that are discussed by Lamster as potential indicators of host response to periodontics include beta-glucuronidase, Prostaglandin E2, aspartate aminotransferase, elastase, and antibodies. The work of Ebersole and colleagues with antibody measurements reflects the state of the science and art in measuring host response in Periodontitis. Increasing evidence has supported the concept that active, specific antibody responses to selected members of the subgingival microbiota are noted in Periodontitis patients. On the other hand, changes in antibody with time or in relationship to disease resistance remains to be determined. Yet, despite these unknowns, evaluation of the level and specificity of serum antibodies can be a beneficial adjunct in designing and implementing clinical studies in Periodontitis. This issue of the Journal of Periodontology has been well-served by the many contributors who have provided a comprehensive guide to clinical trials for evaluating periodontal therapy. It is difficult to project which specific modes of patient measurement will endure over the next quarter century. Still, the center-piece of an effective clinical trial will continue to be the experimental design.
Acknowledgments
The design and organization of this conference was the result of the splendid and thoughtful efforts of the program committee, comprised of Kenneth Burrell, Neal Chilton, Marjorie Jeffcoat, Ray Williams, and Joseph Zambón.
REFERENCES 1. Cohen DW, Ship I. I.: Clinical methods in Periodontol 1967; 38:576-795.
periodontal
diseases. /
