Systematic Review of the Effectiveness and Cost-Effectiveness of Healozone® for the Treatment of Occlusal Pit/Fissure Caries and Root Caries

Home , Ozone therapy

2006; 16 10: No. Vol. ® HTA Health Technology Assessment Assessment Technology Health Health Technology Assessment Health Technology Programme NHS R&D HTA Systematic review of the effectiveness review of the Systematic of HealOzone and cost-effectiveness pit/ﬁssure of occlusal for the treatment caries and root caries S Fielding, C Fraser, M Brazzelli, L McKenzie, and N Waugh J Clarkson, M Kilonzo May 2006

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The website also provides information about the HTA Programme and lists the membership of the various committees. Systematic review of the effectiveness and cost-effectiveness of HealOzone® for the treatment of occlusal pit/fissure caries and root caries

M Brazzelli,1* L McKenzie,2 S Fielding,3 C Fraser,1 J Clarkson,4 M Kilonzo2 and N Waugh3

1 Health Services Research Unit, Institute of Applied Health Sciences, University of Aberdeen, UK 2 Health Economics Research Unit, Institute of Applied Health Sciences, University of Aberdeen, UK 3 Department of Public Health, Institute of Applied Health Sciences, University of Aberdeen, UK 4 Dental Health Services Research Unit, MacKenzie Building, Dundee, UK

* Corresponding author. Current affiliation: Department of Clinical Neurosciences, University of Edinburgh, Western General Hospital, UK

Declared competing interests of authors: none

Published May 2006

This report should be referenced as follows:

Brazzelli M, McKenzie L, Fielding S, Fraser C, Clarkson J, Kilonzo M, et al. Systematic review of the effectiveness and cost-effectiveness of HealOzone® for the treatment of occlusal pit/fissure caries and root caries. Health Technol Assess 2006;10(16).

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ISSN 1366-5278 © Queen’s Printer and Controller of HMSO 2006 This monograph may be freely reproduced for the purposes of private research and study and may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to NCCHTA, Mailpoint 728, Boldrewood, University of Southampton, Southampton, SO16 7PX, UK. Published by Gray Publishing, Tunbridge Wells, Kent, on behalf of NCCHTA. Printed on acid-free paper in the UK by St Edmundsbury Press Ltd, Bury St Edmunds, Suffolk. T Health Technology Assessment 2006; Vol. 10: No. 16

Abstract

Systematic review of the effectiveness and cost-effectiveness of HealOzone® for the treatment of occlusal pit/fissure caries and root caries M Brazzelli,1* L McKenzie,2 S Fielding,3 C Fraser,1 J Clarkson,4 M Kilonzo2 and N Waugh3

Objectives: To assess the effectiveness and cost- caries and one the effects of HealOzone for the effectiveness of HealOzone® (CurOzone USA Inc., management of root caries. Overall, the quality of the Ontario, Canada) for the management of pit and fissure studies was modest, with many important caries, and root caries. The complete HealOzone methodological aspects not reported (e.g. concealment procedure involves the direct application of ozone gas of allocation, blinding procedures, compliance of to the caries lesion on the tooth surface, the use of a patients with home treatment). In particular, there remineralising solution immediately after application of were some concerns about the choice of statistical ozone and the supply of a ‘patient kit’, which consists analyses. In most of the full-text studies analyses were of toothpaste, oral rinse and oral spray all containing undertaken at lesion level, ignoring the clustering of fluoride. lesions within patients. The nature of the Data sources: Electronic databases up to May 2004 methodological concerns was sufficient to raise doubts (except Conference Papers Index, which were about the validity of the included studies’ findings. searched up to May 2002). A quantitative synthesis of results was deemed Review methods: A systematic review of the inappropriate. On the whole, there is not enough effectiveness of HealOzone for the management of evidence from published RCTs on which to judge the tooth decay was carried out. A systematic review of effectiveness of ozone for the management of both existing economic evaluations of ozone for dental caries occlusal and root caries. The perspective adopted for was also planned but no suitable studies were the study was that of the NHS and Personal Social identified. The economic evaluation included in the Services. The analysis, carried out over a 5-year industry submission was critically appraised and period, indicated that treatment using current summarised. A Markov model was constructed to management plus HealOzone cost more than current explore possible cost-effectiveness aspects of management alone for non-cavitated pit and fissure HealOzone in addition to current management of caries (£40.49 versus £24.78), but cost less for non- dental caries. cavitated root caries (£14.63 versus £21.45). Given Results: Five full-text reports and five studies the limitations of the calculations these figures should published as abstracts met the inclusion criteria. The be regarded as illustrative, not definitive. It was not five full-text reports consisted of two randomised possible to measure health benefits in terms of controlled trials (RCTs) assessing the use of HealOzone quality-adjusted life-years, due to uncertainties around for the management of primary root caries and two the evidence of clinical effectiveness, and to the fact doctoral theses of three unpublished randomised trials that the adverse events avoided are transient (e.g. pain assessing the use of HealOzone for the management of from injection of local anaesthetic, fear of the drill). occlusal caries. Of the abstracts, four assessed the One-way sensitivity analysis was applied to the model. effects of HealOzone for the management of occlusal However, owing to the limitations of the economic iii

analysis, this should be regarded as merely speculative. present value of current management remained lower For non-cavitated pit and fissure caries, the HealOzone than that of the HealOzone comparator (£22.65 option was always more expensive than current versus £33.39). management when the probability of cure using the Conclusions: Any treatment that preserves teeth and HealOzone option was 70% or lower. For non- avoids fillings is welcome. However, the current cavitated root caries the costs of the HealOzone evidence base for HealOzone is insufficient to conclude comparator were lower than those of current that it is a cost-effective addition to the management management only when cure rates from HealOzone and treatment of occlusal and root caries. To make a were at least 80%. The costs of current management decision on whether HealOzone is a cost-effective were higher than those of the HealOzone option alternative to current preventive methods for the when the cure rate for current management was 40% management of dental caries, further research into its or lower. One-way sensitivity analysis was also clinical effectiveness is required. Independent RCTs of performed using similar NHS Statement of Dental the effectiveness and cost-effectiveness of HealOzone Remuneration codes to those that are used in the for the management of occlusal caries and root caries industry submission. This did not alter the results for need to be properly conducted with adequate design, non-cavitated pit fissure caries as the discounted net outcome measures and methods for statistical analyses.

iv Health Technology Assessment 2006; Vol. 10: No. 16

Contents

List of abbreviations ...... vii Budget implications to the NHS ...... 37

Executive summary ...... ix 7 Discussion ...... 41 Main results ...... 41 1 Aim of the review ...... 1 Need for further research ...... 41

2 Background ...... 3 8 Conclusion ...... 43 Dental caries ...... 3 Current service provision ...... 7 Acknowledgements ...... 45 Description of new intervention ...... 11 Key questions ...... 12 References ...... 47

3 Effectiveness ...... 13 Appendix 1 Literature search Methods for reviewing effectiveness ...... 13 strategies ...... 51 Results ...... 14 Discussion of results and conclusions on Appendix 2 Data extraction form ...... 55 the evidence for and against the intervention ...... 21 Appendix 3 Checklist for the quality assessment of randomised controlled 4 Systematic review of economic trials ...... 59 evaluations ...... 23 Methods ...... 23 Appendix 4 Characteristics of included Results ...... 23 studies: full-text reports ...... 61 Review of industry submission ...... 24 Appendix 5 Characteristics of included 5 Economic analysis ...... 29 studies: abstracts ...... 71 Methods for economic analysis ...... 29 Results ...... 33 Appendix 6 Structure of the economic Discussion ...... 36 model ...... 75

6 Implications for the NHS ...... 37 Health Technology Assessment reports National Service Framework ...... 37 published to date ...... 81 Health targets ...... 37 Fair access ...... 37 Health Technology Assessment Equity issues ...... 37 Programme ...... 93

Health Technology Assessment 2006; Vol. 10: No. 16

List of abbreviations

ANOVA analysis of variance NICE National Institute for Health and Clinical Excellence CDC Centers for Disease Control and Prevention NPV net present value

CI confidence interval ns not significant

DFS decayed and filled surfaces NS not stated

DMFS decayed, missing and filled ORCA European Organisation for surfaces Caries Research

DMFT decayed, missing and filled PRCL primary root carious lesion teeth QALY quality-adjusted life-years ECM electrical conductance measurement QLF quantitative light-induced fluorescence FDA Food and Drug Administration QOTI/FOTI quantitative fibre-optic GDS General Dental Services transillumination

IADR International Association for RCT randomised controlled trial Dental Research SD standard deviation ITT intention-to-treat SDR NHS Statement of Dental NCHS National Centre for Health Remuneration Statistics TACT tuned aperture computed NHANES III USA National Health and tomography Nutrition Examination Survey UCD ultrasound caries detector NHS EED NHS Economic Evaluation Database USPHS US Public Health Service criteria

All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices in which case the abbreviation is defined in the figure legend or at the end of the table.

vii

Health Technology Assessment 2006; Vol. 10: No. 16

Executive summary

Background Methods

Dental caries is a chronic disease caused by the Electronic searches were conducted to identify localised and progressive demineralisation of the published and unpublished studies. The following hard tissues of the coronal and root surfaces of the databases were searched: MEDLINE (1966 to teeth. Caries location, development and May 2004), EMBASE (1980 to May 2004), progression depend on a range of environmental, MEDLINE Extra (17 May 2004), Science Citation social and genetic factors, and vary greatly among Index (1981 to May 2004), BIOSIS (1985 to individuals. May 2004), AMED (1985 to May 2004), Cochrane Library (Issue 2, 2004) National Research Register Despite the decline in the prevalence of dental (Issue 2, 2004), Current Controlled Trials (18 May caries observed in the high-income countries 2004), Clinical Trials (18 May 2004), SCI during the past few decades as a consequence of Proceedings (1991 to May 2004), Conference the increased availability of fluoride products and Papers Index (1982 to May 2002), ZETOC improved oral hygiene, dental caries is still a conferences (1993 to May 2004) and IADR common disease experienced by almost 80% of meeting abstracts (2002 to 2004). Two reviewers children by the age of 18 years and by almost 90% independently assessed the methodological quality of adults. of included studies and extracted data. Criteria for assessment of study quality included method and The current management of early non-cavitated unit of randomisation, concealment of allocation, occlusal and root caries, and cavitated root caries, comparability of groups at baseline, blinding which are still accessible to cleaning, is based on procedures, number of withdrawals/dropouts and non-operative preventive strategies that include completeness of assessment at follow-up. information on oral hygiene, dietary advice, use of topically applied fluorides and application of A systematic review of the effectiveness of sealants. For cavitated occlusal caries and cavitated HealOzone for the management of tooth decay root caries that are not easily accessible to was carried out. A systematic review of existing cleaning, restorative interventions are adopted economic evaluations of ozone for dental caries (drilling and filling). was also planned but no suitable studies were identified. The economic evaluation included in HealOzone® (CurOzone USA Inc., Ontario, the industry submission was critically appraised Canada) has recently been proposed as a novel and summarised. method for the treatment of dental caries. It is suggested that HealOzone may reverse, arrest or A Markov model was constructed to explore slow the progression of dental caries. The possible cost-effectiveness aspects of HealOzone in complete HealOzone procedure involves the direct addition to current management of dental caries. application of ozone gas to the caries lesion on the tooth surface, the use of a remineralising solution immediately after application of ozone and the Results supply of a ‘patient kit’, which consists of toothpaste, oral rinse and oral spray all containing Number and quality of studies, and fluoride. direction of evidence Five full-text reports and five studies published as abstracts met the inclusion criteria. Of these, only Objective one was published in a refereed journal, but it lacked some study details. The remaining studies The review aims to assess the effectiveness and cost- were PhD theses, unpublished reports or effectiveness of HealOzone for the management of conference proceedings. The five full-text reports pit and fissure caries, and root caries. consisted of two randomised controlled trials ix

(RCTs) assessing the use of HealOzone for the reported very high success rates (from 86.6% to management of primary root caries and two PhD 99% of reversal of caries). theses of three unpublished randomised trials assessing the use of HealOzone for the Adding ozone to a fissure sealant did not seem to management of occlusal caries. Of the five studies produce better sealant retention in occlusal lesions published as abstracts, four assessed the effects of extending 2–4 mm into dentine. HealOzone for the management of occlusal caries and one the effects of HealOzone for the Data on the use of HealOzone for the treatment of management of root caries. occlusal lesion in the deciduous dentition were available from only one unpublished study. An Overall, the quality of the studies was modest, with overall reduction in clinical severity scores was many important methodological aspects not reported for non-cavitated occlusal lesions in reported (e.g. concealment of allocation, blinding primary molars treated with ozone. procedures, compliance of patients with home treatment). In particular, there were some On the whole, there is not enough evidence from concerns about the choice of statistical analyses. In published RCTs on which to judge the most of the full-text studies analyses were effectiveness of ozone for the management of both undertaken at lesion level, ignoring the clustering occlusal and root caries. of lesions within patients. The nature of the methodological concerns was sufficient to raise Costs doubts about the validity of the included studies’ The perspective adopted for the study was that of findings. A quantitative synthesis of results was the NHS and Personal Social Services. The deemed inappropriate. analysis, carried out over a 5-year period, indicated that treatment using current management plus Summary of benefits HealOzone cost more than current management Root caries alone for non-cavitated pit and fissure caries Two studies (one published and one unpublished) (£40.49 versus £24.78), but cost less for non- assessing the use of HealOzone for the cavitated root caries (£14.63 versus £21.45). Given management of primary non-cavitated root caries the limitations of the calculations these figures reported high success rates for ozone-treated should be regarded as illustrative, not definitive. lesions and no significant changes in the control lesions, despite application of topical fluoride. Cost per quality-adjusted life-year This is puzzling, since topical fluoride is known to It was not possible to measure health benefits in be effective. Results of cavitated root lesions were terms of quality-adjusted life-years. This was poorly defined and reported in one of these two mainly due to uncertainties around the evidence studies. Cavitated lesions did not seem to benefit of clinical effectiveness, and to the fact that the from ozone application. adverse events avoided are transient (e.g. pain from injection of local anaesthetic, fear the drill). One unpublished study showed that fissure sealants preceded by the application of ozone for Sensitivity analyses the preventive treatment of non-cavitated root One-way sensitivity analysis was applied to the lesions were more likely to remain intact (61% model. However, owing to the limitations of the versus 42%, p < 0.05). economic analysis, this should be regarded as merely speculative. For non-cavitated pit and Pit and fissure caries fissure caries, the HealOzone option was always One unpublished study did not show any more expensive than current management when significant benefits of HealOzone for the the probability of cure using the HealOzone option management of non-cavitated pit and fissure was 70% or lower. For non-cavitated root caries the lesions in the permanent dentition. Similarly, a costs of the HealOzone comparator were lower small unpublished pilot study did not show any than those of current management only when cure significant differences between cavitated occlusal rates from HealOzone were at least 80%. The costs lesions treated with or without ozone, apart from of current management were higher than those of an improvement in the hardness and visual clinical the HealOzone option when the cure rate for indices. In contrast, findings from conference current management was 40% or lower. proceedings (which provide little detail for the assessment of their methodological quality and One-way sensitivity analysis was also performed x therefore are of little use in systematic reviews) using similar NHS Statement of Dental Health Technology Assessment 2006; Vol. 10: No. 16

Remuneration codes to those that are used in the inappropriate. It was done merely to illustrate the industry submission. This did not alter the results key factors involved in economic modelling. The for non-cavitated pit fissure caries as the long-term effects of HealOzone are unknown and discounted net present value of current the assumption that reversed caries remains management remained lower than that of the inactive may not be reliable. HealOzone comparator (£22.65 versus £33.39). Recommendations for research Conclusions To make a decision on whether HealOzone is a Any treatment that preserves teeth and avoids cost-effective alternative to current preventive fillings is welcome. However, the current evidence methods for the management of dental caries, base for HealOzone is insufficient to conclude that further research into its clinical effectiveness is it is a cost-effective addition to the management required. Independent RCTs of the effectiveness and treatment of occlusal and root caries. and cost-effectiveness of HealOzone for the management of occlusal caries and root caries Limitations of the calculations need to be properly conducted with adequate The economic analysis was severely constrained by design, outcome measures and methods for the uncertainty over clinical effectiveness, and it statistical analyses. could be argued that such analysis was

Health Technology Assessment 2006; Vol. 10: No. 16

Chapter 1 Aim of the review

he review aims to assess the effectiveness and USA Inc., Ontario, Canada) for the management Tcost-effectiveness of HealOzone® (CurOzone of both pit and fissure caries, and root caries.

Health Technology Assessment 2006; Vol. 10: No. 16

Chapter 2 Background

Dental caries or inactive/arrested. A lesion that is considered to be progressive is described as active, whereas a Aetiology, pathology and prognosis lesion that has stopped further progression is Dental caries (tooth decay) is a chronic disease described as arrested. This distinction is clinically caused by the localised and progressive important as arrested lesions do not require any demineralisation of the hard tissues of the coronal further preventive interventions. and root surfaces of the teeth. The demineralisation is caused by the interaction of The occlusal surfaces (pits and fissures) of teeth acid-producing oral microorganisms (in particular are particularly susceptible to dental caries owing Streptococcus mutans, Lactobacillus and Actinomyces to their morphological structure (minute species) with dietary carbohydrates (sugar). dimensions of pits and fissures) and because microbial plaque is more likely to grow in these Caries occurs when the natural dynamic balance areas (plaque stagnation). The teeth are more between mineralisation and demineralisation of prone to plaque stagnation during eruption. dental tissues is disrupted. The process begins on Occlusal caries is seen more often in molar teeth the surface of the enamel (outer surface of the than in premolar or anterior teeth. tooth; see Figure 1). In enamel caries, the lesion may reverse or arrest by remineralisation. If The incidence of root caries begins at about remineralisation does not occur, the lesion may 30–40 years of age and tends to increase penetrate the enamel and consequently result in thereafter. Root caries is most prevalent in the the formation of a cavity, which may progress elderly because when people get older and retain through the dentine and the pulp of the tooth. In their natural teeth, their gums tend to recede and the absence of treatment, dental caries may expose the root surfaces. According to the ultimately destroy the tooth. Caries location, published NHS Plan for Modernising NHS development and progression are influenced by a range of environmental, social and genetic factors, and vary greatly among individuals. In most individuals dental caries tend to progress slowly Enamel over time, with lesions often taking more than 2 years to cavitate, although in some it can take a shorter time. Conversely, some lesions never Dentine cavitate. Pulp containing Crown blood vessels According to the anatomical location of carious and nerves lesions, it is possible to differentiate between Gum (gingiva) coronal lesions, which may affect the pits and Neck fissures or the smooth surfaces of a tooth, and root Bone lesions, which affect the exposed root cementum and dentine. Root caries occurs in the same Periodontal membrane manner as coronal caries, but demineralisation begins at a higher pH and it is more common in Root Cementum older people. The term primary caries is used to indicate lesions on the unrestored surfaces of Root canal teeth, while caries that develops adjacent to a Opening at tip filling is referred to as recurrent or secondary of root caries. Hidden caries is a term used to identify carious lesions in the dentine that are not detected by visual examination but are large enough to be FIGURE 1 Structure of a sound tooth. Reproduced with identified radiographically. According to their permission from www.mydr.com.au. Copyright CMPMedica activity, carious lesions may be classified as active Australia 2005. 3

Dentistry, “nearly 90% of people aged over counselling; and increased access to dental care. 65 years show some signs of gum disease Nevertheless, dental caries is still a common compared with 14% of 16–24 year olds”.1 disease, experienced by almost 80% of children by the age of 18 and by almost 90% of adults.2 Significance in terms of ill-health Impact on patient’s quality of life Prevalence in children Dental caries may have a significant impact on an Since the significant decline in the 1970s and individual’s life. The most common consequences 1980s, it seems that over the past 20 years caries of untreated lesions are discomfort and pain. prevalence rates have become relatively stable.2 Restorative dental treatments can now be provided The 2003 Children’s Dental Health Survey pain free, apart from the pain of the local commissioned by the UK Health Departments anaesthetic injection. However, for some people provides the most recent estimate of the restorative treatments are associated with fear and prevalence of dentine decay in children in anxiety, which, may become barriers to dental England and Wales.3 The 2003 survey is the fourth attendance. Treatment avoidance can subsequently in a series of dental health surveys carried out lead to further progression of caries which, in every 10 years since 1973. The criteria used in the turn, may cause more distress and long-term survey to assess dental caries were the following: complications. Gross decay may lead to disturbances in eating and sleeping patterns filled decay, otherwise sound: teeth with because of pain. Psychological distress can arise amalgam, or other fillings that had no cavitated from the embarrassment and self-consciousness of dentine caries present having missing or decayed teeth, especially in the obvious decay experience: all teeth with anterior dentition. Communication problems may cavitated dentine caries, restorations with ultimately occur as a possible result of tooth loss. cavitated dentine caries, teeth with filled decay (otherwise sound) and teeth extracted due to In addition to human cost, dental caries can be caries. The term relates to the DMFT (decayed, costly for the patients receiving treatment. For missing, and filled teeth) dental decay index. many patients NHS charges can be expensive, especially for those who earn just enough to The preliminary findings of this survey indicate disqualify them from exemption or remission of that: charges. Moreover, where provision of NHS dentistry is patchy, patients may have to depend there has not been a substantial change in the on private dental care. proportion of 5- and 8-year-olds who presented with obvious decay in the primary (milk) teeth Impact on the NHS between the 1993 and 2003 dental survey Treatments for dental care carry considerable costs (Table 1) for both the NHS and society. NHS General the proportion of filled primary teeth as well as Dental Services (GDS) data reveal that the total the proportion of the total obvious decay number of claims in England and Wales for dental experience represented by filled primary teeth interventions in the financial year 2002/03 was 34 in 5- and 8-year-olds has declined since 1983, million. Almost half (48%) of claims were for indicating a decline in restorative interventions treatments requiring no dental intervention (i.e. (Table 1) examination, simple scaling, X-ray, fissure sealant, the mean number of primary teeth with obvious topical fluoride). The total number of teeth filled decay has decreased since 1983 in 5- and was about 19 million, while the number of teeth 8-year-olds (Table 2), but the mean number of with roots filled was just over one million. Overall, primary teeth with obvious decay among the total gross fees authorised was £1634 million. children with decay has not changed The care and treatment for children accounted for considerably since 1993, apart from the decline 27% (£461 million) of all gross fees authorised. in the number of filled teeth in the 8-year-olds (Table 3) Epidemiology the proportion of 8-, 12- and 15-year-olds with There has been a significant reduction in dental obvious tooth decay and cavities into dentine in caries since the 1970s in industrialised countries, permanent teeth has decreased considerably due to environmental and educational factors such since 1983 (Figures 2 and 3) as the increased use of fluoride in public water the proportion of filled permanent teeth has supplies, dentifrices and dental products; declined considerably since 1983 in 12- and 4 improved oral hygiene and prophylaxis; dietary 15-year-olds, but not in 8-year-olds (Figure 4) Health Technology Assessment 2006; Vol. 10: No. 16

TABLE 1 Percentage of children with obvious tooth decay in TABLE 3 Mean number of primary teeth with obvious tooth primary teeth by age (Children’s Dental Health in the United decay in children with obvious decay experience by age Kingdom, 2003)3 (Children’s Dental Health in the United Kingdom, 2003)3

Year Year

Tooth condition 1983 1993 2003 Tooth condition 1993 2003

Percentage of children: Mean number of teeth Obvious decay experience Teeth with cavities into dentine 5-year-olds 50 45 43 5-year-olds 3.1 3.2 8-year-olds 70 61 57 8-year-olds 2.1 2.3 Teeth with cavities into dentine Filled decay (otherwise sound) 5-year-olds 41 40 40 5-year-olds 0.6 0.6 8-year-olds 49 50 50 8-year-olds 1.1 0.9 Filled decay (otherwise sound) Obvious decay experience 5-year-olds 23 15 12 5-year-olds 3.7 3.8 8-year-olds 47 33 26 8-year-olds 3.2 3.2 Filled teeth as a proportion of total obvious decay experience 5-year-olds 28 17 15 TABLE 4 Proportion of children with obvious tooth decay in 8-year-olds 50 35 28 permanent teeth by age (Children’s Dental Health in the United Kingdom, 2003)3

TABLE 2 Mean number of primary teeth with obvious tooth Year decay by age (Children’s Dental Health in the United Kingdom, Tooth condition 1983 1993 2003 2003)3 Percentage of children: Year Filled teeth as a proportion of total obvious decay experience Tooth condition 1983 1993 2003 8-year-olds 58 37 52 12-year-olds 70 58 70 Mean number of teeth 15-year-olds 74 68 77 Teeth with cavities into dentine 5-year-olds 1.3 1.4 1.4 8-year-olds 1.2 1.3 1.3 Filled decay (otherwise sound) 5-year-olds 0.5 0.3 0.2 presented with tooth decay in permanent or 8-year-olds 1.2 0.7 0.5 primary teeth. The proportion of children with untreated caries in permanent or primary teeth Obvious decay experience 5-year-olds 1.8 1.7 1.6 was 29% for the 6–8-year-olds and 20% for the 8-year-olds 2.3 2.0 1.8 15-year-olds (Figure 5).

Dental caries is not evenly distributed across the child population, with about 26% of children (worst cases) presenting with 75% of all carious lesions.6 the proportion of the total obvious decay This can be interpreted in the light of the fact that experience represented by the number of filled dental caries is a disease of lifestyle with strong permanent teeth in 8-, 12- and 15-year-olds has socio-economic and geographical differences. The increased since 1993, indicating an increase in use of deprivation categories in the assessment of restorative interventions (Table 4). Scottish schoolchildren aged 5 years is a good example of how measures of socio-economic status These findings are consistent with those found by may correlate with dental caries experience the USA Third National Health and Nutrition (Figure 6).5 The link between social status and Examination Survey (NHANES III), Centers for prevalence of caries is also supported by the data Disease Control and Prevention (CDC), National from the National Children’s Dental Health Survey Centre for Health Statistics (NCHS)4 and the carried out in the UK in 1993 (Figure 7).7 National Survey of Dental Caries in US School Children 1986–1987, where 52% of children aged Prevalence in adults 6–8 years and 61% of children aged 15 years Fewer prevalence data are available for adults. 5

100 90 80 70 60 1983 % 50 1993 40 2003 30 20 10 0 81215 Age (years)

FIGURE 2 Proportion of children with obvious decay experience in permanent teeth by age (Children’s Dental Health in the United Kingdom, 2003)3

45 40 35 30 % 25 1983 20 1993 15 2003 10 5 0 81215 Age (years)

FIGURE 3 Proportion of children with cavities into dentine in permanent teeth by age (Children’s Dental Health in the United Kingdom, 2003)3

90 80 70 60 50 1983 % 40 1993 30 2003 20 10 0 81215 Age (years)

6 FIGURE 4 Proportion of children with filled permanent teeth by age (Children’s Dental Health in the United Kingdom, 2003)3 Health Technology Assessment 2006; Vol. 10: No. 16

70 Tooth decay 60 Untreated caries 50 40 % 30 20 10 0 6–815 Age (years)

FIGURE 5 Proportion of children with tooth decay and untreated caries by age (NHANES III)4

5.0 4.5 4.0 3.5 3.0 2.5 2.0

Number of DMFT 1.5 1.0 0.5 0 1234567 Deprivation categories

FIGURE 6 Caries distribution by socio-economic ‘deprivation categories’ (DEPCAT) in Scottish schoolchildren aged 5 years.5 DEPCAT 1 = most affluent postcode sections. DECAT 7 = most deprived postcode sectors.

According to the UK 1998 Adult Dental Health surface fillings were found in 43% of people aged Survey,8 adults had an average of 1.5 decayed or 65 and older. unsound teeth (teeth with visual or cavitated caries or those with an unsound restoration) and 55% Similarly, in the USA, NHANES III – Phase 1 had at least one decayed or unsound tooth. The found evidence of coronal carious lesions in 94% numbers of adults with decayed or unsound teeth of the studied population. The mean score for varied according to the regions surveyed. The decayed and filled surfaces (DFS) on permanent proportion of dentate adults with tooth decay in teeth in adults was 22.2. Carious lesions were England, Wales, Scotland and Northern Ireland is found in 23% of all dentate adults and in 47% of shown in Figure 8. people aged 65 years and over (NHANES III 1998–1991).4 The mean proportion of filled permanent teeth ranged from 9% for people aged 16–24 years to 39% for people aged 45–54 years (Figure 9). Current service provision

Overall, 66% of the adult population showed at Current management of dental caries least one tooth with a root surface that was Increasing emphasis has been recently dedicated exposed, worn, decayed or filled. Overall, root to the provision of caries prevention and 7

3.5 3.0 2.5 2.0 I, II, III non-manual 1.5 III manual 1.0 IV, V

Number of DMFT 0.5 0 12 15 Age (years)

FIGURE 7 Average number of decayed, missing or filled teeth in adolescents in the UK by social class (National Children’s Dental Health Survey, 1993)7

% 30

0 England Wales Scotland Northern Ireland

FIGURE 8 Proportion of adults with decaying or unsound teeth by country (United Kingdom Adult Dental Health Survey, 1998)8

40 35 30 25 % 20 15 10 5 0 16–24 25–34 35–44 45–54 55–64 65 All

Age (years)

8 FIGURE 9 Mean proportion of filled teeth by age (United Kingdom Adult Dental Health Survey, 1998)8 Health Technology Assessment 2006; Vol. 10: No. 16

management strategies. In particular, attention to However, with the exception of digital radiology, risk assessment and to preventive non-operative these diagnostic procedures are not widely used in methods for assisting remineralisation of early dental practice. Some procedures need further caries has been advocated. Despite the investigation (e.g. QOTI/FOTI, QLF) or further acknowledged importance for the prevention of development (e.g. UCD) before their use could be caries, non-operative, preventive treatments are recommended in dental practice. Others are not fully funded by the NHS at present. Changes prone to false-positive measurements (e.g. small are likely to be introduced with the amount of plaque identified as a carious lesion by implementation of the new contract in 2006. DIAGNOdent) or unreliable findings (e.g. because of inadequate tooth isolation during ECM),10 Efficient management of dental caries depends on which require a careful interpretation and the knowledge of patients’ dental and medical sometimes correction by the dentist. In particular, history and risk assessment, correct identification to the authors’ knowledge the validity of of carious lesions and identification of the best DIAGNOdent as an instrument for detecting treatment options for dental caries. A thorough occlusal caries has yet to be demonstrated in in dental and medical history provides information vivo studies. about patients’ previous experience of dental caries, number of active lesions and factors that Treatment of early caries (non-cavitated pit and may affect caries activity (e.g. general oral fissure caries and root caries) hygiene, diet and sugar intake, exposure to Treatment options for early caries include the fluoride, salivary flow rate, certain medical following: conditions and medications). Caries risk assessment aims at identifying high-risk provision of information about oral hygiene individuals who may benefit more from preventive dietary assessment and advice treatments, and low-risk individuals for whom fluoride-delivery methods restorative treatments could be delayed. Carious application of chlorhexidine lesions are first identified on the basis of the pit and fissure sealants findings of the clinical examination (visual recall at regular intervals. criteria). For visual detection of occlusal caries and for predicting their activity and severity, the Oral hygiene ranked scoring system described by Ekstrand and Instructions on oral hygiene aim at improving colleagues9 is recognised as a valid and reliable personal removal of plaque by toothbrushing. tool, although mainly used in clinical research. For Regular toothbrushing in children may help to assessing the extent and severity of root caries the reduce the incidence of caries,11 and children tactile criteria of ‘soft, leathery and hard’ on whose level of oral hygiene is good experience less probing are commonly used in dental practice and decay.12 Despite the lack of evidence on the dental research. Radiographic investigations (X- effectiveness of oral hygiene instructions,13 rays) have been widely used for decades as an toothbrushing, together with the use of fluoride adjunct to clinical examination to estimate the toothpaste and the advice of reducing sugar intake, depth of occlusal lesions into dentine or to is usually recommended in the dental practice for identify lesions that are hidden from clinical maintaining a good level of oral hygiene. examination. More recently, other quantitative, more advanced methods have been proposed for Dietary assessment and advice the diagnosis of dental caries. These include Evidence from epidemiological and experimental methods based on: studies indicates that frequent consumption of fermentable carbohydrates is associated with digital radiology [e.g. digital image prevalence of dental caries. For some patients the enhancement, digital subtraction radiography, frequency of intake of a certain type of food may tuned aperture computed tomography (TACT)] primarily contribute to their caries risk and visible light [e.g. quantitative fibre-optic modification of this factor may be sufficient to transillumination (QOTI/FOTI), quantitative change their risk. The diet–caries association is, light-induced fluorescence (QLF)] however, complex and needs to be evaluated not laser fluorescence (e.g. DIAGNOdent) only on the basis of the quantity and type of electrical current [e.g. electrical conductance fermentable carbohydrates consumed, but also measurement (ECM)] considering several other background factors such ultrasound [e.g. ultrasound caries detector as age, total food intake, dietary habits, salivary (UCD)]. flow rate, use and type of medications, and use of 9

fluoride products. Dietary assessment is usually prevented fraction pooled estimate was 0.46 [95% recommended in patients with multiple active confidence interval (CI) 0.30 to 0.63, p < 0.0001], lesions. In contrast, no diet modifications are indicating a substantial benefit and demonstrating suggested for patients with inactive caries. The that fluoride varnish alone can result in reversal of dentist, however, may still provide information on early caries. Similarly, the meta-analysis of the how unhealthy dietary habits may become a three studies assessing the effect of fluoride problem, especially when associated with a poor varnish on deciduous teeth suggested a 0.33% level of oral hygiene.14 (95% CI 0.19% to 0.48%, p < 0.0001) reduction in DMFS. Another recent systematic review26 of Fluoride-delivery methods selected caries prevention methods reached Use of fluoride-delivery products and water similar conclusions, demonstrating that there is a fluoridation are among the factors that have fair body of evidence on the effectiveness of contributed to the observed progressive fluoride varnish to arrest or reverse non-cavitated improvement in oral health since the 1970s. carious lesions in permanent teeth. Other fluoride Evidence indicates that fluoridation of the water products such as fluoride supplements (e.g. supply is associated with an increased proportion fluoride tablets or drops) are regarded as less of children without caries and a reduction in the effective methods of delivering fluoride because number of teeth affected by caries.1,15,16 Topical they rely entirely upon patient compliance. Their fluoride-delivery methods in the form of use is usually limited to high-risk categories of toothpastes, mouth rinses, gels or varnishes are children, adults and, particularly, elderly people.27 effective measures to prevent dental caries. Their effectiveness has been established on evidence Application of chlorhexidine from randomised trials and more recently from a The effectiveness of chlorhexidine as an series of Cochrane systematic reviews of antimicrobial for preventing progression of non- randomised trials.17–22 Overall, fluoride toothpaste cavitated caries has yet to be established. Current is the cheapest and the most widespread method evidence is derived mainly from small studies to control dental caries.23–25 A recent randomised, evaluating the effects of different forms of double-blind, clinical trial examined the anticaries chlorhexidine (varnish, gel or rinse) in effectiveness of fluoride dentifrices containing combination with other concomitant preventive 1700, 2200 and 2800 ppm fluoride ion compared measures.26,28 with a 1100 ppm fluoride control toothpaste, in schoolchildren aged 6–15 years.24 The 1-year Pit and fissure sealants results demonstrated significant caries reductions Pits and fissures are sealed to prevent caries for higher fluoride dentifrices for all tooth development.28 Evidence indicates that caries does surfaces, but in particular for occlusal surfaces.24 not progress as long as the sealant remains in The use of fluoride mouth rinses and gels, as an place.29,30 Sealant applications may be suitable for adjunct to fluoride toothpaste, is usually advised both young children and older patients.31 for individuals at high risk of developing caries. Materials that are currently used to seal a lesion Fluoride varnish is used to provide fluoride include different types of composite resin and delivery to specific tooth sites and surfaces and is glass ionomer cement. The resin-based sealants usually applied at intervals of 3 or 6 months. A are divided into generations according to their recent systematic review by Marinho and mechanism for polymerisation and their content. colleagues17 looked at the effectiveness of fluoride The first generation sealants which were activated varnish in preventing dental caries in children and by ultraviolet light are no longer available and the adults and commented on the ability of fluoride most recently developed fourth generation varnish to promote remineralisation of early sealants contain fluoride. The effectiveness of caries. The included studies also considered “non- resin sealants for the prevention of caries in the cavitated incipient enamel lesions”, clinically permanent teeth of children and adolescents was visible as white spots or discoloured fissures, which demonstrated by Ahovuo-Saloranta and would be included among those lesions eligible for colleagues32 in a recent Cochrane systematic ozone application. The treatment effect was review. The review compared second, third and measured in terms of ‘prevented fraction’ (mean fourth generation resin-based sealants or glass increment in caries in controls minus mean ionomer sealants with a control (no sealant) and increment in fluoride group divided by the mean compared one type of fissure sealant with another increment in the controls). For the seven studies type. The focus of the review was on prevention, that contributed to the main meta-analysis, the and the children and adolescents included did not 10 decayed, missing and filled surfaces (DMFS) seem to present with obvious caries. The review Health Technology Assessment 2006; Vol. 10: No. 16

concluded that resin-based sealants are effective in subsequently manufactured under licence and preventing caries of the occlusal surfaces of distributed by KaVo-Dental GmbH & Co. permanent molars. Reduction of caries ranged (Germany) under the name ‘HealOzone’. Its use from 86% at 12 months to 57% at 48–54 months. has been pioneered by Professor Edward Lynch Resin sealant retention was good across studies and his team at Queen’s University in Belfast, and sealants were retained completely in 79% and Northern Ireland, and Barts and the London 92% of cases at 12 months. Sealant retention Queen Mary’s School of Medicine and Dentistry decreased with time and at 36 months ranged in London, UK. HealOzone is a certified from 61 to 80%. Evidence on the effects of glass Medical Device [Conformité Europèene (CE) ionomer-based sealants was less convincing. marked] for the management of occlusal pit and fissure caries, and root caries. According to the Treatment of cavitated pit and fissure caries and manufacturer, 294 HealOzone units (as at June root caries 2004) are currently in use in dental practices in For lesions that have progressed to the stage of the UK and more than one million people have cavity, restorative interventions are often used to already received HealOzone treatment. The remove the decayed tissue and fill the cavity to aid HealOzone technology has not yet received Food plaque control. However, cavitated root lesions and Drug Administration (FDA) approval in the that are still accessible to cleaning need not always USA. be filled because cleaning alone can arrest caries. A number of different materials can be used to The new version of HealOzone (Mark3) was restore a tooth. These include composite resin, launched in July 2004. According to the glass ionomer cement and amalgam. Amalgam is manufacturer previous models can be upgraded to still the material of choice for large restoration of the most recent technical functions. molar teeth. Root caries are usually restored with composite resin or glass ionomer cement. HealOzone procedure According to the NHS Dental Review The HealOzone procedure consists of a package, 2002–2003,33 in the quarter ending December which includes the application of ozone gas, the 2002 the number of teeth filled was 4,896,951 and use of remineralising agents, a patient kit and on average one tooth was filled for every two information on oral hygiene. The HealOzone claims (55%). Overall, restorations showed a device comprises an air filter, a vacuum pump, an median survival interval to next restorative ozone generator, a handpiece fitted with a sealing intervention of just over 8 years. The main factors silicone cup and a flexible hose. The silicone cups associated with different likelihoods of re- are available in a range of five sizes from 3 to intervention were the age of the patient at the 8 mm in diameter. The HealOzone unit requires date of restoration, the position of the tooth and high-voltage power to generate ozone from the air the type/material of restoration.33 and to convert ozone back to oxygen when the process is completed. The air is exposed to high- voltage current to generate ozone at a Description of new intervention concentration of 2100 ppm ± 10% and passes through the instrument hose and handpiece. The Rationale flow of air into the system, the delivery of ozone to The antimicrobial effects of ozone gas (O3) have the tooth and the removal of ozone from the been known for many years. Direct application of system after completion of treatment are achieved ozone gas to the coronal or root tooth surface is by a vacuum pump, which works at an adjustable claimed to have a sterilising effect. In particular, flow rate of 615 cm3 per minute to maintain the ozone is claimed to stop the action of the ozone concentration at 2100 ppm. acidogenic and aciduric micro-organisms responsible for the tooth decay. It is consequently The procedure usually takes between 20 and 120 alleged to be able to reverse, arrest or slow down seconds per tooth. Immediately after ozone the progression of dental caries. It is also application the tooth surface is treated with a maintained that ozone is useful for reducing the remineralising solution (reductant) containing microbial flora in cavitated lesions, before fillings fluoride, calcium, zinc, phosphate and xylitol are inserted. dispensed from a 2-ml ampoule. The reductant is supplied in packs of 100 ampoules. Patients are Development of HealOzone also supplied with a patient kit, which consists of The ozone unit for dental use was initially toothpaste, oral rinse and oral spray, all developed by CurOzone Inc. (Canada) and containing fluoride, calcium, zinc, phosphate and 11

xylitol, and aims to enhance the remineralisation advice, chlorhexidine/fluoride varnish and process. HealOzone application for the treatment fissure sealant? If so, is it a cost-effective of non-cavitated lesions is usually repeated at 3 alternative? and 6 months. There is no clear information on For the management of non-cavitated root how delivery of ozone at the correct concentration caries, is the HealOzone procedure more can be ensured by the device. clinically effective than the combination of oral hygiene, dietary advice and varnish? If so, is it cost-effective? Key questions For the management of cavitated caries, how often, if at all, is HealOzone procedure an This review aims to answer the following alternative to fillings? questions: For the management of cavitated caries, does the application of ozone gas and of a re- For the management of pit and fissure caries, is mineralising solution to the cavity before the HealOzone procedure more effective than restoration prolong the life of a filling? If so, is the combination of oral hygiene, dietary it cost-effective?

12 Health Technology Assessment 2006; Vol. 10: No. 16

Chapter 3 Effectiveness

Methods for reviewing DentalOzone; see Appendix 1 for full details), effectiveness were also identified. Reference lists of included studies were also checked for additional study Search strategy reports. Initial database searches were undertaken to identify relevant systematic reviews and other Inclusion and exclusion criteria evidence-based reports. Several websites were also All citations identified by the search strategy were consulted to obtain background information. Full assessed for relevance by two reviewers. Copies of details of the main sources consulted are listed in the full-text, published papers of those considered Appendix 1. to be relevant were then obtained. It was decided that studies reported in languages other than Electronic searches were conducted to identify English would be identified but not included in published and unpublished studies on the clinical the review. and cost-effectiveness of ozone therapy for dental caries. The electronic databases searched are For clinical effectiveness assessment, included detailed in Table 5. Full details of the search studies were randomised controlled trials (RCTs) strategies are documented in Appendix 1. It was of ozone treatment (HealOzone) versus at least anticipated that there was a small body of research one comparator (nil, placebo or active treatment). available, therefore a sensitive search strategy for Data from studies other than randomised trials clinical effectiveness studies was undertaken to were collected but not included in the review. The retrieve all useful information on ozone therapy outcome measures were required to be measures of for dental caries. Additional searches were carried clinical effectiveness (e.g. reversal/progression of out for economic data and these are detailed in caries). Only in vivo studies involving human Chapter 4. In addition, selected conferences subjects were deemed to be suitable for inclusion, proceedings that were not available electronically while studies reporting in vitro results were were handsearched. These were International excluded. Studies were also excluded if their Association for Dental Research (IADR) conference follow-up was less than 6 months or did not report proceedings for 1999–2001 and the annual clinically relevant outcome measures. European Organisation for Caries Research (ORCA) Congresses 2000–2003. Research abstracts, Data extraction strategy published on industry and users’ websites (KaVo A data abstraction form was designed (Appendix Dental, CurOzone USA, HealOzone and 2) to collect details from each individual study.

TABLE 5 Electronic databases searched

Database Coverage

MEDLINE/EMBASE/MEDLINE Extra multifile search MEDLINE: 1966 to May Week 1 2004 EMBASE: 1980 to Week 20 2004 MEDLINE: Extra: 17 May 2004 Science Citation Index (SCI) 1981 to 16 May 2004 BIOSIS 1985 to 12 May 2004 AMED 1985 to May 2004 Cochrane Controlled Trials Register (CCTR) Cochrane Library, Issue 2, 2004 National Research Register (NRR) Issue 2, 2004 Current Controlled Trials (CCT) 18 May 2004 Clinical Trials 18 May 2004 SCI Proceedings 1991 to 15 May 2004 Conference Papers Index 1982 to May 2002 ZETOC Conferences 1993 to May 2004 IADR Meetings Abstracts 2002 to 2004 13

TABLE 6 Number of screened and selected reports according to database searched

Database searched Number screened Number selected Included studies

MEDLINE/EMBASE/MEDLINE Extra 46 4 1 SCI 38 7 1 BIOSIS 38 1 0 CENTRAL 8 1 0 IADR abstracts 175 43 12 Handsearch 14 2 Websites 15 5 Other databases 26 0 0 Total 331 85 21

These included the type of study design, number 12 questions, which focus on the following of participants and their characteristics, methodological aspects: method of randomisation, intervention characteristics, caries information unit of randomisation, concealment of allocation, including location and severity of lesion, patient comparability of groups at baseline, blinding outcomes such as reversal/progression of caries, procedures, number of withdrawals/dropouts and and any reported adverse events. completeness of assessment at follow-up.

In particular, the outcomes sought for the For each question a ‘Yes’, ‘No’ or ‘Unclear’ answer included studies were as follows: was required. The quality assessment checklist is presented in Appendix 3. (a) Non-cavitated caries

reversal of caries Results progression of caries utilisation of dental services (e.g. visits to dental Quantity and quality of research care units; duration of dental treatment) available adverse events After removing duplicates a total of 331 reports patient-centred measures (e.g. patient was identified (Table 6): 78% (257) were abstracts satisfaction and preference, relief of and 22% (74) were full-text reports. Eighty-five pain/discomfort) reports (seven full-text papers and 78 abstracts) quality of life. were selected for full assessment, of which 21 (three full-text papers and 18 abstracts) met the (b) Cavitated caries predefined criteria for inclusion in the review. In addition, two reports, both PhD theses, were time to restorative interventions identified from reference lists. All 23 identified need for further restorative interventions and reports were written in English. length of time between restorations symptoms of pulpal pathology. Number of studies identified In total, five studies reported in five full-text Inclusion criteria were assessed independently by papers and 13 abstracts, and five studies reported two reviewers. Any disagreements were resolved by only as abstracts, met the inclusion criteria for consensus or referred to a third reviewer. studies of clinical effectiveness. In case of multiple Reviewers were not blinded to the names of study publications the report with the longest follow-up authors, institutions or publications. time and/or largest sample size was chosen as the main source of information. Quality assessment strategy Two reviewers assessed the methodological quality Number and type of studies excluded of all included studies and any disagreements were After identifying duplicates, several studies were resolved by discussion. The quality assessment of excluded as they did not meet the inclusion RCTs was formally assessed using a published criteria. The main reasons for exclusion, together checklist modified by the reviewers for the with the corresponding number of studies 14 purpose of this review.34 The checklist consisted of excluded are listed in Table 7. Health Technology Assessment 2006; Vol. 10: No. 16

TABLE 7 Number of studies and reasons for exclusion

Reason for exclusion Number of studies/abstracts

Follow-up less than 6 months 17 No HealOzone treatment; other experiments involving ozone 14 No measures of clinical effectiveness 6 HealOzone used on extracted teeth (in vitro studies) 4 Evaluation of diagnostic tests for detection of dental caries; no clinical effectiveness 5 measures Time studies, no clinical effectiveness measures 3 Discussion paper, no comparative information on clinical effectiveness 1 Costs, no clinical effectiveness measures 1 No random allocation 2 Patients’ attitudes, no effectiveness measures 7 Studies not involving ozone 4

Number and type of studies included The Abu-Naba’a main study37,45–50 had four The five full-text studies consisted of two RCTs treatment groups: ozone plus reductant versus air assessing the use of HealOzone for the treatment plus reductant, and ozone plus management of primary root caries – one reductant plus sealant versus reductant plus 35 published trial by Holmes and one unpublished sealant only. It involved 90 patients with 254 36 trial by Baysan and Lynch, and two PhD theses lesions. assessing the use of HealOzone for the management of pit and fissure caries, one by The Abu-Naba’a pilot study37,51,52 had two 37 Abu-Naba’a reporting two unpublished trials treatment groups: ozone plus reductant versus 38 and one by Abu-Salem reporting one reductant only. It involved eight patients with 34 unpublished trial. lesions.

Root caries studies The Abu-Salem study38 had two treatment groups: Holmes (2003): this published randomised HealOzone plus reductant versus reductant only. It trial35,39,40 of management of primary non- recruited 21 patients with 74 lesions, from Belfast cavitated root caries had two treatment groups: primary schools. ozone plus reductant plus patient care kit versus air treatment plus reductant plus patient care kit. Of the five studies published only as abstracts, This study was set in a general dental practice. four assessed the effects of HealOzone for the management of occlusal pit and fissure carious Baysan and Lynch (2004): this unpublished lesions,53–56 and one assessed the effects of randomised trial on cavitated and non-cavitated HealOzone on primary root carious lesions.57 root caries36,41–44 had four treatment groups: ozone plus reductant versus reductant only, and Tabulation of quality of studies, characteristics of ozone plus sealant versus sealant only. It recruited studies and evidence rating patients who attended the School of Dentistry in The characteristics of the five full-text studies Belfast. (type and number of participants and carious lesions, details of study design, inclusion criteria, Pit and fissure caries studies characteristics of intervention and main results) Abu-Naba’a PhD thesis37 included two randomised are shown in Appendix 4. studies: a main study (Abu-Naba’a, 2003) and a pilot study (Abu-Naba’a pilot study, 2003), which Method of randomisation was reported in three are considered separately as they do not include studies.35,37,38 Concealment of allocation was not the same patient population. The main study specified in any of the included studies. One study assessed exclusively non-cavitated occlusal lesions, was described as double blind35 and another study whereas the pilot study included cavitated occlusal stated that outcome assessment was undertaken by lesions. Patients were recruited from the School of a blinded examiner.38 In particular, the double- Dentistry in Belfast for both the main and pilot blind study by Holmes was reported to involve studies. three dentists: the first dentist performed the 15

initial assessment of primary root carious lesions; In the majority of the included studies, data the second randomised the lesions to treatment analysis was conducted at the level of the lesion. groups; the first then treated and assessed the Holmes used 2 statistics, but did not specify result without knowing which were given ozone whether they were for related samples (i.e. and which air, using a modified HealOzone McNemar 2 test). In the Baysan and Lynch machine; the third dentist independently assessed study no information was provided on the lesions in 15 patients. The practicality of the choice of statistical test used. In both Abu-Naba’a entire process is, however, doubtful. Holmes is the studies the unit of analysis was tooth-pair, but only author of the study and the other assessors it was unclear whether the occurrence of are neither listed as authors nor acknowledged in multiple pairs of lesions per mouth was taken the paper. into account. Abu-Salem used a mixed-effects analysis of variance (ANOVA) with random It was unclear whether blinding procedures were effects for patient and teeth within patient, secured in the remaining three included studies. and fixed effects for group and time of The total number of people in the studies was treatment. 287, with a total of 768 carious lesions. Across the studies, the ages of the participant groups ranged The characteristics of the five studies published as from 7 to 82 years. Only three studies provided abstracts are shown in Appendix 5. information on the gender of the participants.36–38 The length of follow-up ranged from 6 to Tabulation of results and assessment of 21 months. effectiveness The clinical effectiveness results are presented Each study involved either two or four according to type of carious lesions (root caries intervention groups. Ozone was always used in results are presented separately from occlusal combination with other active interventions (i.e. caries results). Within this categorisation studies ozone plus reductant, ozone plus reductant plus results are presented according to: patient care kit, ozone plus sealant, ozone plus reductant plus sealant) and compared to the same type of outcome measures intervention without ozone or to a sham type of publication (results of full-text studies procedure (air treatment). The dosage of ozone are presented separately from results of studies treatment varied between studies. In the Baysan published as conference proceedings) and Lynch study,36 the Abu-Salem study38 and the type of dentition (treatment results of primary Abu-Naba’a main study,37 ozone was administered teeth are presented separately from treatment for 10 seconds, whereas in the Holmes study35 and results of permanent teeth). the Abu-Naba’a pilot study37 ozone was administered for 40 seconds. In all studies ozone It was planned to undertake further statistical applications were repeated at some point before analyses of the data reported in the full-text the final follow-up. None of the included studies studies and when appropriate to combine them provided information on the model/version of the quantitatively. However, owing to the limited raw HealOzone device. data provided, this proved unfeasible. The p-values of statistical analyses in the results section The main outcome measure was reversal of are those originally quoted by the studies’ authors. caries. This included the proportion of carious However, as the data were not analysed as ‘paired lesions becoming hard and, for some of the data’ on a patient basis, their validity and included studies, the proportion of lesions reliability are open to question. reversing from ‘leathery’ to ‘leathery approaching hard texture’, but not necessarily hardening. The Primary root carious lesions proportion of lesions that deteriorated from Two full-text studies by Holmes35 and Baysan and leathery to soft was also recorded, although not Lynch36 and one abstract by Lynch and consistently. Where appropriate the proportion of colleagues57 assessed the use of ozone for the intact sealants was documented. Changes in the management of primary non-cavitated root ECM and DIAGNOdent readings were also carious lesions. The Baysan and Lynch study also reported in the identified studies, but not included the assessment of a non-specified considered in this review, owing to the number of cavitated root lesions. In the Holmes unreliability of their measurements (i.e. high-false studies the clinical criteria of ‘soft, leathery and positive rates) and poor correlation with clinical hard’ were adopted for the assessment of carious 16 outcomes.58 lesions, whereas in the Baysan and Lynch study Health Technology Assessment 2006; Vol. 10: No. 16

TABLE 8 Results of root carious lesions

Ozone final follow-up Control final follow-up No. (%) No. (%)

PRCLs becoming hard Baysan and Lynch, 200436 (12 months)a NR (47) NR (0) Holmes, 200335 (18 months)b 87/87 (100) 1/87 (1) PRCLs becoming less severe (from index 2 to 1) Baysan and Lynch, 200436 (12 months)a NR (52) NR (12) PRCLs becoming soft Holmes, 200335 (18 months)b 0/87 (0) 32/87 (37)

NR, not reported (the denominator was not clearly reported in the study, so the number of caries cannot be calculated, hence only percentages are given). a Baysan and Lynch: non-cavitated and cavitated primary root carious lesions. b Holmes: non-cavitated primary root carious lesions.

TABLE 9 Results of the Holmes study at each recall visit35

Ozone at follow-up Control at follow-up No. (%) No. (%)

PRCLs becoming hard 12 months 85/87 (98) 1/87 (1) 18 months 87/87 (100) 1/87 (1) 21 months 81/81 (100) 6/81 (8) PRCLs remaining leathery 12 months 2/87 (2) 65/87 (75) 18 months 0/87 (0) 54/87 (62) 21 months 0/81 (0) 65/81 (80) PRCLs becoming soft 12 months 0/87 (0) 21/87 (24) 18 months 0/87 (0) 32/87 (37) 21 months 0/81 (0) 10/81 (12)

lesions were classified according to a five-point between three degrees of ‘leathery’ seemed rather severity index as follows: artificial.

0 all ‘hard’ lesions Change in clinical severity Table 8 shows for each of 1 ‘leathery’ lesions considered to be small, easily the included studies the proportions of carious cleanable and approaching a ‘hard’ texture lesions that according to the studies’ authors 2 ‘leathery’ lesions judged to be shallow and reversed (became hard), improved (became less where the surface of the exposed sound dentine severe) or deteriorated in the ozone-treated group could be easily maintained plaque free and the control group. The Holmes study35 3 ‘leathery’ lesions judged to be in surfaces that reported that 100% of ozone-treated primary root were difficult to maintain plaque free, and large, carious lesions (PRCLs) had reversed by cavitated ‘leathery’ lesions where pulpal 18 months, while 37% of PRCLs in the control integrity was judged to be at risk group had worsened from leathery to soft and 1% 4 all ‘soft’ lesions. had reversed. However, comparisons of results at different follow-up points show some No information was provided on the validity and inconsistencies in the way data were reported reproducibility of the above severity index, or on (Table 9). In particular, the results at 21 months how lesions were clinically identified as ‘leathery’ (published as an abstract) showed an increase in ‘soft’ or ‘hard’. In particular, the distinction the number of control lesions that stabilised 17

(from 54/87 at 18 months to 65/81 at 21 months) improvement rates in the control groups are and a subsequent decrease in the number of therefore surprising. control lesions that had become soft (from 32/87 at 18 months to 10/81 at 21 months), indicating Summary: root carious lesions The two full-text an improvement over time in lesions receiving studies assessing the use of ozone for root carious treatment other than ozone. No comments on lesions both report very high success rates with these changes were provided by the authors. ozone and very low improvement rates in the controls. In the Baysan and Lynch study,36 47% of the ozone-treated lesions had arrested by 12 months, Fissure sealants after application of ozone for the whereas none had become hard in the control preventive treatment of non-cavitated root lesions group (p < 0.001), and 52% had reversed from are more likely to remain intact (61% versus 42%, index 2 (leathery) to index 1 (leathery p < 0.05). approaching hard texture) in the ozone group compared with 12% of lesions in the control group Pit and fissure carious lesions (p < 0.001). So, if one combines the ‘approaching The three remaining studies – the Abu-Naba’a hard’ (from index 2 to 1) and ‘hard’ lesions (from main study (2003),37 Abu-Naba’a pilot study index 2 to 0), 99% of lesions improved, as in the (2003)37 and Abu-Salem (2004) study38 – assessed Holmes study. This study included both cavitated the effects of ozone on pit and fissure carious and non-cavitated root lesions, but results were not lesions. Both Abu-Naba’a studies involved patients clearly presented according to the type of lesions aged over 12 years with primary lesions in the and it is unclear how many cavitated and non- permanent posterior teeth, while the Abu-Salem cavitated lesions were assessed in each study involved children 7–9 years old with carious intervention group. Only one figure in the paper lesions in the posterior primary teeth. The presented results for both types of lesions in the Abu-Naba’a main study and the Abu-Salem study ozone group: the percentage of cavitated lesions assessed non-cavitated lesions, while the that had reversed (become hard) decreased from Abu-Naba’a pilot study included lesions with 9.1% at 1 month to 1.4% at 9 months, indicating cavitation. an increase/progression in the severity of cavitated root lesions treated with ozone. No statistical Change in clinical severity: permanent dentition analysis was undertaken by the authors, no Results of full-text studies Tables 10 and 11 illustrate corresponding data were given for the control the results of the Abu-Naba’a main study.37 group, and no comments on reversal/progression Clinical severity of non-cavitated pit and fissure of cavitated lesions were provided in the text of lesions was assessed using the criteria described by the paper. Ekstrand and colleagues (0 = least severe, 1, 2, 3, 4 = most severe).9 The change in severity score is In addition, the abstract by Lynch and calculated as the score at follow-up minus the colleagues57 indicated that 80% (48/60) of non- score at baseline. Thus, a negative change cavitated PRCLs treated with ozone reversed from indicates an improvement, while a positive change severity index 4 to 3, whereas none of the soft implies a worsening of lesion severity. The mean lesions in the control group significantly changed, change from baseline in clinical severity score at and that 94% (189/200) of leathery lesions became 12 months was not significantly different hard and arrested in the ozone group, whereas (p = 0.112) between the two intervention groups: those in the control group did not significantly ozone (10 seconds) plus reductant group versus change. reductant only group (Table 10).

Marginal adaptation of the root sealant The Baysan It was also reported that a greater proportion of and Lynch study36 also assessed the effects of ozone-treated lesions improved or stabilised ozone with or without a fissure sealant using the compared with control lesions at all recalls modified US Public Health Service (USPHS) (Table 11). However, statistical analyses of these criteria. In the ozone plus sealant group 61% of data were not provided. The relationship between sealants were retained compared with 42% in the clinical severity score and the need for future sealant only group (p < 0.05) at 12 months. fillings was not explained.

It is worth noticing that both groups had the No significant difference in the clinical severity same other active interventions such as reductant, score was found between the ozone and control 18 patient care kits and sealants. The very low groups in the Abu-Naba’a main study. The Health Technology Assessment 2006; Vol. 10: No. 16

TABLE 10 Mean change in clinical severity score of pit/fissure lesions from baseline (Abu-Naba’a main study)37

Ozone group Control group p-Value Change in clinical severity score (n = 106) (n = 106)

Mean change from baseline 0.283 0.443 0.112 Standard deviation 0.64 0.74 Standard error 0.06 0.07

TABLE 11 Percentage of pit/fissure lesions that improved, remained stable, or increased in clinical severity at each recall visit (Abu- Naba’a main study)37

Month(s) of Treatment Decreased severity Stable Increased severity follow-up group (improvement) (worsening)

1 Ozone 11.4% 74.6% 14.0% Control 5.3% 81.6% 13.2% 3 Ozone 17.7% 63.9% 18.5% Control 8.4% 73.1% 17.6% 6 Ozone 10.8% 55.9% 33.3% Control 5.9% 59.8% 34.3% 9 Ozone 7.8% 57.8% 34.5% Control 6.9% 56.0% 37.1% 12 Ozone 7.4% 56.5% 36.1% Control 5.6% 48.6% 45.8%

reported proportions of lesions improved, This study was only a pilot study, which did not stabilised and deteriorated appeared similar add much to the results of the Abu-Naba’a main between groups, but no statistical analyses were study.37 undertaken and the clinical relevance of these findings was not explained in terms of fillings Results of abstracts The abstracts gave little detail of avoided. studies, their methodology could not be easily assessed and therefore their findings must be Abu-Naba’a pilot study In the Abu-Naba’a pilot interpreted with caution. They are included here study,37 17 lesions (with cavitation) were treated for completeness and as a guide to emerging with ozone plus reductant and 17 reserved as research. controls (reductant only) in eight patients. Outcomes were measured using Ekstrand and Three abstracts compared pit and fissure lesions colleagues’ clinical index9 as well as the following receiving ozone (at different concentrations) with clinical indices: hardness index (hard, leathery, pit and fissure lesions receiving no-ozone soft), visual index (sound, arrested, active), treatment.54–56 Their results are presented in cavitation score (1 = no cavitation, Table 13. The proportion of lesions reported as 2 = microcavitation, 3 = frank cavitation), colour clinically reversed, the extent of which was not index (normal, yellow, light brown, grey, dark specified, ranged from 86.6 to 99% in the ozone- brown, black), frosted enamel measure (mm), treated groups. All studies reported that no stained enamel measure (mm) and perceived significant clinical changes were observed in the treatment need index (e.g. requiring no control group, but no numerical information was intervention, requiring preventive resin given. restoration, requiring drilling and filling). Thirteen lesions in the treatment group and 12 Another abstract53 compared the use of ozone lesions in the control group were assessed at versus conventional treatment in 35 patients, each 6 months. Lesions treated with ozone showed a with two occlusal lesions extending significant reduction in the hardness and visual radiographically 2–4 mm into dentine. The indices (Table 12). No significant differences authors defined the occlusal lesions as non- between groups were found for any other indices cavitated, but lesions 2–4 mm into dentine on or for the Ekstrand clinical index (p > 0.05). radiographs are likely to have small cavities that 19

TABLE 12 Number of pit/fissure lesions showing a reduction in the clinical indices at 6 months (Abu-Naba’a pilot study)37

Colour index

Hardness indexa Visual indexb Cavitation scorec Darkerd Lightere Perceived treatment needf

Treatment 11/13 (84.6%) 8/13 (61.5%) 6/13 (46.2%) 3/13 (23.1%) 2/13 (15.4%) 12/13 (92%) Control 4/12 (33.3%) 1/12 (8.3%) 5/12 (41.7%) 2/12 (16.7%) 6/12 (50%) 9/12 (75%) p-Value <0.05 <0.05 ns 0.084 (ns) 0.16 (ns)

a The proportion of lesions becoming hard b The proportion of lesions with increasing score c The proportion of lesions with reduction in cavity score d The proportion of darker lesions e The proportion of lighter lesions f The proportion of lesions with a reduced treatment need

TABLE 13 Reversal of pit/fissure caries: findings from abstracts

Ozone at follow-up Control at follow-up No. (%) No. (%)

Holmes 200354 (12 months) 1918/1937 (99) 0/427 (0) Hamid, 200355 (6 months) 80/92 (86.9) 0/92 (0) Megighian and Bertolini, 200456 (6 months) p < 0.05 0/80 (0) (220 lesions treated)

trap plaque and are likely to progress unless only presented graphically. The graph showed a cleaned thoroughly. The ozone-treated lesions steady increase in the mean change from baseline received ozone for 40 seconds and application of a clinical severity scores for the control group, glass ionomer preventive sealing, which was compared with an initial slight decrease and a subsequently replaced with a posterior composite subsequent levelling in the ozone group at at 3 months. The control lesions received 12 months. The overall changes in the clinical conventional drilling and filling (posterior severity scores9 were analysed using a mixed- composite). All the ozone-treated lesions were effects ANOVA. This analysis assumed that reported to have reversed at 3 months. Six patients and teeth within patients had a random complaints (17.1%) of postoperative sensitivity were effect, while group and time of treatment had a reported after conventional drilling and filling at fixed effect. There was overall little reduction in 6 months compared with none after ozone clinical severity scores in the ozone-treated group, treatment (p < 0.05). Postoperative sensitivity is, while an overall increase was observed in the however, a measure commonly used to assess large control group. There was a statistically significant carious lesions and it is questionable whether it effect of treatment upon clinical severity scores should be used for early carious lesions. Moreover, with time (p < 0.01). complaints of postoperative sensitivity after occlusal restorations are rare. Sealant retention The Abu-Naba’a main study37 also assessed the use of ozone for 10 seconds with Clinical reversal of caries: primary dentition One and without a fissure sealant. No sealants were full-text study assessed the use of ozone for the reported to be lost in either the ozone plus sealant treatment of non-cavitated primary posterior teeth group or the sealant-only group. The percentage in children aged 7–9 years.38 Occlusal lesions were of partial loss in the ozone plus sealant group at assigned to receive ozone for 10 seconds followed 12 months was 32.7%, and in the sealant-only by a reductant or a reductant only. The proportion group was 29.8%, with no significant differences of lesions that improved, remained stable or between groups (this indicates similar rates of deteriorated in each intervention group was not reinterventions between groups for repairing 20 provided and the clinical severity findings were partial sealant loss). Health Technology Assessment 2006; Vol. 10: No. 16

Discussion of results and multilevel modelling procedures would need to conclusions on the evidence for be used. and against the intervention Baysan and Lynch36 stated that statistical tests were used, but they did not specify which Only a limited number of RCTs (five full-text 2 reports and five studies reported as abstracts) were particular tests. Holmes used tests, but did not specify whether they were McNemar 2 tests. available for assessing the effects of ozone for the 37 management of root carious lesions and pit and Abu-Naba’a (main and pilot studies) recognised fissure carious lesions. Of these only one was the fact that there were pairs of teeth. However, in published in a refereed journal, but lacked some some cases there were multiple pairs of teeth per person and it is not clear whether this was taken study details, while the remaining studies were 38 derived from PhD theses, unpublished reports or into account. Abu-Salem used analysis of conference proceedings. All full-text studies with variance for a mixed effects model. This type of the exception of the Holmes study were conducted analysis is hierarchical in nature, with one by the same research team that developed the component for the patients and one for the tooth procedure, led by Professor Lynch of Queen’s within the patient. However, as not enough University, but Holmes was at one time part of the information was provided by the author it was not same group, having done his PhD in Belfast. The possible to determine whether the statistical methodological quality varied across studies and analysis was conducted appropriately. information on method of randomisation, For primary non-cavitated root caries both the concealment of allocation, blinding procedures 35 36 and statistical methods was lacking in many of Holmes study and the Baysan and Lynch study them. Therefore, interpretation of studies results reported high success rates for ozone-treated was not straightforward. A quantitative synthesis of lesions compared with control lesions. However, results was not feasible owing to the differences the lack of reversal of caries among controls among studies regarding intervention, dosage of receiving conventional treatment (reductant) ozone and outcome measures. known to be efficacious is puzzling. Cavitated root lesions did not seem to benefit There were some concerns over the from ozone application, showing indeed a appropriateness of the methods of analysis negative effect over time, but no formal statistical adopted by study investigators. All studies in this analysis was presented. review were of a hierarchical structure, although not necessarily treated as such for analysis. Treatment results of pit and fissure caries of Specific types of analysis are required when data permanent teeth were not consistent across have a hierarchical structure. The hierarchy occurs studies. The Abu-Naba’a main study did not show as smaller units, such as lesions or teeth, are any significant differences between non-cavitated clustered together within a larger unit, the patient. lesions treated with or without ozone. Similarly, In most studies included in this review, the the Abu-Naba’a pilot study,37 which included statistical analysis was carried out at the lesion lesions with cavitation, did not demonstrate any level. However, two lesions within one patient are significant effect of ozone apart from an not strictly independent, so analysis at the lesion improvement in the hardness and visual clinical level is inappropriate. A more suitable statistical indices. In contrast, results from conference analysis takes into account the hierarchical 59 proceedings (methodologically less reliable) clustering of lesions within a subject. provided very high success rates (from 86.6% to 100% of reversal of caries). In the simple case of two lesions per person, one receiving control and one receiving the ozone Data on the use of ozone for the treatment treatment, paired data are produced. In this case, of primary teeth were available from only one the appropriate paired analysis would be a study, which suggested an overall reduction in McNemar 2 test for dichotomous data, clinical severity scores for non-cavitated occlusal a Wilcoxon signed rank test for ordinal data and lesions in primary molars treated with ozone a paired t-test for continuous data. The choice of (p < 0.01).38 statistical tests that ignore the pairing of the data is more conservative and may fail to detect The adjunct of ozone to a fissure sealant produced important differences found by paired analysis.59 a better sealant retention in root carious lesions In the case of more than two lesions per subject, (61% of sealant retention versus 42%, p < 0.05),36 21

but not in pit and fissure carious lesions (32.7% Important subgroup differences versus 29.8%).37 There are not enough data on which to assess the effects of ozone on cavitated caries in the On the whole, and despite the differences permanent dentition (both occlusal caries and root reported in some studies (e.g. Holmes), there are caries) or on non-cavitated occlusal caries in the as yet insufficient published full-text studies (only deciduous dentition (only one study involved one refereed journal article) to provide convincing children with primary teeth38). No data are evidence on the effectiveness of ozone for the available on cavitated occlusal caries in deciduous management of caries. teeth, secondary caries or high-risk patient categories. This review was done independently of the Cochrane systematic review on ozone therapy for Adverse effects of intervention the treatment of dental caries,60 which concluded None of the studies reported any adverse events in that at present there is no reliable evidence on the the intervention group. effectiveness of ozone applications to arrest or reverse the decay process. The present version of the Cochrane review does not include the Holmes (2003) and Abu-Salem (2004) studies.

22 Health Technology Assessment 2006; Vol. 10: No. 16

Chapter 4 Systematic review of economic evaluations

Methods results – summary of effectiveness and costs (point Search strategies estimate and, if reported, range or standard In addition to the electronic searches and deviation) handsearches detailed in Chapter 3, a search of – summary of cost-effectiveness/utility (point the NHS Economic Evaluation Database (NHS estimate and, if reported, range or standard EED) and the Health Management Information deviation) Consortium was undertaken for economic – sensitivity analysis evaluations of ozone for dental caries. Details of conclusions as reported by the authors of the the searches are provided in Appendix 1. study.

Studies that reported both costs and outcomes of Quality assessment HealOzone compared with any of the comparators A single economist assessed the quality of included were sought. The manufacturer’s submission to the studies using a published checklist.61 The National Institute for Health and Clinical questions were set out on a standard form Excellence (NICE) was also scanned for relevant generated before the review. economic evidence. Data synthesis Inclusion and exclusion criteria Data from included studies were assessed and To be included, studies needed to compare summarised by a single economist, and HealOzone with any of the existing comparators interpreted alongside the results of the systematic in terms of their costs and effectiveness. Studies review of effectiveness so that conclusions could be reported in languages other than English were drawn on the relative efficiency of HealOzone identified from the literature searches, but would compared with alternative treatments. not be included in the review unless a structured abstract was available from NHS EED. A single economist assessed all abstracts for relevance. Full- Results text papers were then obtained for all studies that appeared potentially relevant and were formally The search revealed no published economic assessed for relevance. evaluations of HealOzone. One published trial was found which discussed the costs and effectiveness Data abstraction of the management of primary root caries with The following data were extracted for each HealOzone.35 However, since the cost information included study: is limited to estimates of the total cost of dentistry, with no detail of costs and consequences of the study characteristics: alternatives, the study did not meet all of the – research question methodological criteria listed in Table 14 to be – study design classified as an economic evaluation and therefore – comparison was not further reviewed. Two abstracts – setting concerning studies on the costs and benefits of – basis of costing HealOzone for dental caries were found, but did characteristics of the study population or of the not provide sufficient details of study design or populations that formed the basis of data used data for the purpose of this review.62,63 However, in a modelling exercise: the industry submission from KaVo Dental (August – numbers receiving or randomised to each 2004) provided an economic evaluation. The intervention remainder of this section provides a summary and – dates to which data of effectiveness and costs critique of that submission. relate duration of follow-up for both effectiveness and The unpublished industry submission from KaVo costs Dental Ltd, UK (KaVo: Clinical and cost 23

TABLE 14 Quality assessment of the economic evaluation presented in the industry submission by KaVo

Quality component Assessment and comments

1. Was a well-defined question posed in an answerable form? Yes 2. Was a comprehensive description of the competing Yes: current treatments were defined as: alternatives given (i.e. can you tell who did what, to NC-PFC: sealants whom, where and how often)? C-PFC: glass ionomer, composite resin and amalgam restoration RC: glass ionomer and composite resin restoration 3. Was there evidence that the programme’s effectiveness Limited owing to short follow-up of included studies and had been established? inability to compare/combine results from more than one study owing to differences in study characteristics. None of the studies used specifically considered C-PFC, although the model does include such effectiveness data based on assumptions outlined in the following critique 4. Were all the important and relevant costs and Yes: the base-case analysis assumes that the capital consequences for each alternative identified? cost of HealOzone is borne by dental practices. This assumption is varied for sensitivity analysis 5. Were costs and consequences measured accurately in Yes appropriate physical units? 6. Were costs and consequences valued credibly? Not always: see critique of QALY estimation 7. Were costs and consequences adjusted for differential Yes: a discount rate of 3.5% was used timing? 8. Was an incremental analysis of costs and consequences Yes: see critique of alternatives performed? 9. Was allowance made for uncertainty in the estimates of Yes costs and consequences? 10. Did the presentation and discussion of study results Yes include all issues of concern to users?

C-PCF, cavitated pit and fissure caries; NC-PCF, non-cavitated pit and fissure caries; QALY, quality-adjusted life-year; RC, root caries.

effectiveness of HealOzone for the treatment and Summary of the industry submission management of dental caries, 2004) included an The submission by KaVo included a cost- economic model of HealOzone compared with effectiveness analysis over a 5-year time horizon of current treatment for non-cavitated pit and fissure HealOzone treatment versus current management caries, cavitated pit and fissure caries, and root for non-cavitated pit and fissure caries, cavitated caries. Both a base-case and a probabilistic analysis pit and fissure caries, and cavitated root caries. were included. The submission comprised both a The current management treatments were defined text document and supporting Excel spreadsheets. as follows:

Table 14 provides a summarised assessment of the non-cavitated pit and fissure caries: sealants KaVo industry submission based on the ten critical cavitated pit and fissure caries: glass ionomer, appraisal components.61 composite resin and amalgam fillings root caries glass ionomer and composite resin restorations. Review of industry submission These comparators were identified from the The first part of this section provides a summary expert opinion of four dentists. The submission of the methods and results from the economic does not consider preventive treatments such as evaluation of HealOzone reported in the industry oral hygiene or advice on diet along with surface submission. This is followed by a critical review of applications of fluoride and sealants as a 24 the evaluation. comparator. The intervention with HealOzone is Health Technology Assessment 2006; Vol. 10: No. 16

defined as an initial treatment with HealOzone for either non-cavitated pit and fissure caries, followed by 12 weeks of treatment with cavitated pit and fissure caries or root caries that mineralising toothpaste, oral rinse and spray, with would be suitable for treatment with HealOzone. the possible addition of restorative treatments. An This survey also asked dentists to estimate the opinion survey of 243 dentists practising proportion of HealOzone-treated teeth that would HealOzone treatment was used to estimate the require some restorative treatment either at the proportion of teeth that would require additional time of HealOzone treatment or sometime restorative treatment at the same time as the afterwards. These restorative treatments were HealOzone application or at any time defined similarly to current management subsequently, but only 48 provided usable treatments for each caries type. responses. The unit cost of HealOzone treatment was based Effectiveness data were obtained from a review of on the cost of patient consumables and dentists’ published evidence for HealOzone and the time (in practice, a dentist is remunerated by a fee current management of dental caries. Clinical per item of service as listed in the SDR and these outcomes included caries progression and reversal. fees are intended to reflect the costs incurred by dental practices). Using the results of a Costs included those of comparators plus costs of questionnaire survey of dentists who use rerestorations avoided. The costs of each current HealOzone in their own dental practice the treatment comparator were estimated from estimated unit cost for a course of HealOzone- published data for the treatments defined above. treatment was then adjusted to reflect the All cost data were estimated from the perspective estimated percentages of HealOzone-treated teeth of the NHS and were presented in UK pounds that would require additional restorative sterling (£) at 2003 prices. Their method was to treatment. On the basis of responses to this translate the treatments into relevant treatment questionnaire an additional cost of restoration codes listed in the Statement of Dental (using current management in addition to Remuneration (SDR codes)64 and then to use HealOzone) was applied to 44% of non-cavitated GDS65 data to identify the total annual numbers of pit and fissure caries, 84% of cavitated pit and such treatments. These data are presented fissure caries and 47% of root caries. separately for patients aged less than 18 years and those aged 18 years and over. The same source The cost to the NHS of HealOzone also took into (GDS) gives annual total treatment costs which, account the proportion of treatment fees paid by when combined with annual treatment numbers, the NHS rather than by patients as described gave a unit cost per treatment item. These figures above for current treatment costs. The unit cost were adjusted to take account of SDR codes for a course of HealOzone procedure was based on relating to more than one tooth and more than an assumption of more than one HealOzone one type of caries. The unit cost estimates do not application per course of treatment. The model appear to differentiate between primary used a mean of 2.5 HealOzone applications per restorations on virgin tooth surfaces and course of treatment (range 1–4). This was based secondary restorations, the latter being outside the on data from KaVo Dental. scope of the study since these would be unsuitable for treatment with HealOzone. Finally, these unit An additional cost was added to reflect the cost estimates were adjusted to reflect the fact that weighted average cost per tooth year of patients under 18 years receive free NHS dental rerestorations avoided. This was based on data care and those aged 18 years and over pay 80% of from a study that reported the average cost per their NHS dental fees, unless they are eligible for tooth year of restoration in teeth previously filled free treatment. It was assumed that the dental with amalgam or composite resin for each type of practice and not the NHS would fund the capital caries over 5 and 10 years. When calculating the cost and running cost of the actual HealOzone cost of rerestorations avoided the costs of the device. original restoration are removed to avoid double counting.66 Using these unit cost estimates the industry model assesses the annual cost to the NHS for each The model uses rates of caries progression and comparator. To estimate the annual cost to the regression taken from a variety of unpublished NHS of the HealOzone comparator the industry and published clinical studies. The mean values submission carried out a survey of dentists to for annual rates of caries progression for the estimate the proportion of teeth currently treated current treatments assumed in the industry 25

submission, along with the study reference from caries reversal per 100 cases treated with which these values were obtained, are: non- HealOzone were reported, with an estimated NHS cavitated pit and fissure caries 0%,67 cavitated pit cost case of per caries reversal of £7.38, again for and fissure caries 4.9%,68–70 and root caries all caries types. 3.9%.68,69 The estimated minimum utility gain (at 0.095) to The progression rates cited for HealOzone were achieve a cost per QALY of £30,000 was found to all 0%, taken from studies with follow-up of be for the use of HealOzone for root caries 3–21 months.35,40,42,44,53,71,72 treatment. This was estimated using alternative cost-effectiveness acceptability thresholds based on Caries reversal rates for non-HealOzone varying the length of time over which a utility gain treatments were assumed to be zero. The industry was accrued. submission does cite a 15% reversal rate found in a study reporting the use of varnish Sensitivity analysis indicated that the main drivers (chlorhexidine), but this value was excluded from of cost and cost-effectiveness were numbers of the industry submission on the grounds that such teeth treated per treatment session and the varnish is not cited in the SDR codes. Rates of numbers of treatments per course of therapy. caries reversal in teeth treated with HealOzone Multivariate analysis revealed that despite were derived from 11 studies with follow-up times uncertainty around the cost of HealOzone, ranging from 3 to 21 months. The annualised HealOzone would be likely to be cost-effective mean values used for base-case analysis were: non- over a 10-year follow-up period. cavitated pit and fissure caries 93.3%,53,55 cavitated pit and fissure caries 79.0%,72–77 and root caries The report also discusses the wider implications to 84.5%.35,40,42,44,57,71 the NHS, impact on patient health and equity issues. The results of the economic evaluation are Although no evidence was available to estimate used to estimate the budget impact to the NHS underlying QALY scores, the industry submission from the use of HealOzone technology for all model estimated alternative cost per QALY caries treatment of all eligible teeth. The figures thresholds of between £10,000 and £40,000 include both initial treatment costs and the assuming quality of life benefits from 1 day to estimated costs of rerestorations avoided. On this 1 month. The assumptions for QALY estimates basis, an annual net incremental cost of £48.1 were utility gains of 0.01, 0.02, 0.05 and 0.1 for million in year 1, reducing to £11.8 million by restorations avoided. year 5, was estimated for HealOzone. These results assume that the capital and running The model was run to provide results using base- costs of the HealOzone device are funded by case data. The deterministic base-case analysis dental practices, with no contribution from the used mean values from the minimum and NHS apart from the fee for service. If the maximum values inputted for each parameter. exchequer provided additional funds for the Both one-way analysis and multivariate sensitivity device this would cost the NHS an additional analysis were also conducted. Stochastic analysis £110.4 million, assuming one device per dental was conducted using Monte Carlo simulation over practice in England and Wales. Additional 10,000 cycles. Random numbers were used to annual servicing costs are estimated at £10.8 select data inputs from those provided. million.

Results Although the evaluation does not include patient The average baseline figure estimated in the health as an outcome in the model, the results industry model, across all caries types, for the include a brief description of possible effects on incremental cost to the NHS per tooth treated patient health, based on studies of patient with HealOzone was £6.24. Allowing for the cost attitudes to dental treatment. of rerestorations avoided (see earlier description), the net incremental cost per tooth treated with Equity issues are also briefly discussed in the HealOzone was ‘minus’ £9.70. The industry model results. The report cites evidence suggesting a link also resulted in an estimated NHS cost of £61 per between caries incidence and deprivation, and case of caries progression avoided (for all caries that deprived populations would be one group less types) using a 5-year model time horizon, and likely to benefit from HealOzone technology as assuming up to 35 cases per 1000 avoided per long as it is only available through private dental 26 year (152 over 5 years). An estimated 846 cases of treatment. Health Technology Assessment 2006; Vol. 10: No. 16

Critique of industry submission practices would be offset by lowering subsequent On the whole, the economic evaluation submitted fees paid to dentists for the associated therapy. by KaVo Ltd is based on reasonable economic evaluation methodology. Nevertheless, a number Estimates of caries progression and reversal rates of concerns can be raised relating to the choice of were extracted from a range of studies of varying comparators and the quality of data used to degrees of quality, including published and parameterise the economic model. unpublished RCTs, conference abstracts and PhD theses. Some of the limitations of these data The comparators used in the industry submission sources are discussed in Chapter 3. Caries for non-cavitated caries were based on restorative progression rates for current management were treatment of caries. The evaluation did not extracted from studies that did not include consider preventive measures for early caries. HealOzone as a comparator and the patient mix However, the management of non-cavitated caries may be different. Caries progression rates for rarely requires fillings, as it is now well established HealOzone were estimated from studies with that preventive treatments for early lesions can be follow-up periods from as little as 3 months, all of effective in reversing and arresting further which claimed a 0% caries progression rate. Other progression of caries. Furthermore, HealOzone studies show higher caries progression rates. has been cited as being “most effective in the role Selecting the most favourable studies biases the of prevention and early management of lesions”.78 results. It would therefore have been appropriate for the industry model to include conservative treatments Rates of caries reversal with current management aimed at ensuring reversal of early caries as were assumed to be zero despite a 15% reversal additional comparators for non-cavitated caries. rate being reported in one study. This rate was excluded from the analysis on the grounds that it The HealOzone comparator includes an was associated with the application of assumption about the proportions of teeth that chlorhexidine varnish and this was assumed by the would require additional treatment to HealOzone authors of the industry report not to be a standard treatment alone. These assumptions are taken NHS dental treatment. However, dentists from a survey of 243 dentists who currently use commonly rank application of varnish among HealOzone, of whom only 48 provided usable ‘treatments for sensitive cementum or dentine’ responses. Given the absence of robust, objective (code 3631 in the SDR). clinical data, options to obtain relevant model parameter values are limited. Nonetheless, such Source data for caries reversal associated with the data are potentially biased and unreliable and the use of HealOzone came from 14 studies, three of considerable uncertainty would be reduced if which had follow-up of less than 3 months. Only actual clinical evidence were to exist. This was a the latter were included in the sensitivity analysis. non-randomised survey of opinion and cannot The remaining 11 studies differed in design and therefore be interpreted as having a strong quality. For non-cavitated pit and fissure caries evidence source. It does not appear that any effectiveness data were extracted from studies with random selection process was used to recruit 3–6-month follow-up.53,55 For cavitated pit and dentists for the survey, and therefore it is unclear fissure caries, despite finding no available whether any attempt was made to obtain a evidence, data from five studies were used in the balanced opinion. model. The assumption used to justify this is the following: The industry evaluation of implications to the NHS includes an assumption about the numbers “None of the available studies specifically describes of teeth suitable for treatment with HealOzone. the treatment of cavitated pit and fissure caries. In the These figures were again estimated from absence of such detail, the studies presented in this information taken from a survey of dentists who section refer to carious lesions, which are deemed to require drilling and filling. While non-cavitated caries are users of HealOzone. may be treated in this way, drilling and filling is the conventional treatment for cavitated caries and it is The assumption concerning the funding of the therefore assumed that these studies included a capital cost of providing a HealOzone device in proportion of cavitated caries.” (KaVo Dental, 2004). dental surgeries was that this would not affect the fee for service. In reality, however, it would be A further concern is that, although the industry expected that any additional contribution by the submission report does acknowledge the limitation NHS towards capital costs incurred by dental of combining data from more than one study, 27

given the disparity in inclusion/exclusion criteria the figures used should be interpreted with care. and other study characteristics, the reversal rates Realistically, such data could only be obtained and progression rates used as the mean rates for from the outcomes of a long-term study of the base-case analysis were calculated using the results effectiveness of the relevant comparators. QALY from more than one study. estimates are included in the economic evaluation, but are not based on quality of life data. Instead, Estimates of the cost of rerestorations avoided assumptions concerning the amount of utility gain are based on a number of assumptions and the and duration of gain were used to derive QALY report does acknowledge the absence of thresholds. Given the short duration of any published data for rates of future rerestorations. potential intermittent change in quality of life, Instead, the model uses published data for the along with the high degree of uncertainty average cost per tooth year of rerestoration in surrounding any estimates of QALY scores, the teeth previously filled with amalgam or additional information value of such QALY composite resin over 5 and 10 years (KaVo thresholds is dubious. industry submission, 2004). It is unclear in the report exactly how estimates of the numbers of Although the economic evaluation in the industry future rerestorations would be avoided as a submission is well presented, the choice of result of HealOzone treatment, although the comparator is questionable and considerable report does provide estimates for the cost of such uncertainty surrounds many of the parameter rerestorations avoided. Given the considerable values used in the model. Therefore, their results uncertainty surrounding the rate of rerestorations, overestimate the benefits of HealOzone.

28 Health Technology Assessment 2006; Vol. 10: No. 16

Chapter 5 Economic analysis

iven the current state of the clinical management of dental caries. A Markov model is Geffectiveness evidence, with little published in composed of a set of defined health states among full in peer-reviewed journals, it could be argued which a patient can move over successive periods that economic analysis is premature. However, and is run using a hypothetical cohort of patients. NICE always requests some attempt at economic The model incorporates both the logical and appraisal, if only to clarify the data deficits. temporal sequences of treatment, including the Therefore, the following analysis has been events that follow from the initial treatment produced more as illustrative modelling than as procedure and the outcomes for the patient that hard evidence. are associated with each possible scenario or clinical pathway. Transition probabilities are used to allow patients to move within and between Methods for economic analysis these states of health. A patient can only be in one state of health at any time and can only make one The economic evaluation aimed to assess the cost- transition per cycle. A relevant period is chosen effectiveness of HealOzone relative to the for the length of a cycle and the cycles then link alternative interventions for the treatment of both together to form a Markov chain. The length of occlusal pit and fissure caries and root caries. As cycle used in this study was 1 year. When the identified in the previous section, economic model is run over the defined number of cycles, a evaluations of HealOzone versus conventional discounted net present value (NPV) for the cost of treatments of dental caries were virtually non- an intervention is calculated, determined by the existent at the time of this review. This section occurrence of different states and the length of provides an economic evaluation using cost- time in various states. effectiveness analysis and presents economic models of the treatment of non-cavitated pit and The models were designed to estimate a typical fissure caries, and root caries. They compare patient’s costs and outcomes for the alternative current management versus current management treatments over a 5-year period. A 5-year time plus HealOzone. The results over the extended horizon was chosen to facilitate comparison with period must be qualified by the fact that follow-up the results from the industry model. Figure 10 data on HealOzone are limited to 2 years. The summarises the basic structure of the model. results reported in this section should be Similar models were developed to carry out the interpreted on the understanding that they analysis for non-cavitated pit and fissure caries, entirely depend on the model parameters and and non-cavitated root caries assumptions made. The authors recommend that the model be rerun in the future if evidence on Non-cavitated pit and fissure caries clinical effectiveness is published. The model for non-cavitated pit and fissure caries compares current management strategies (i.e. Markov model framework watchful waiting, oral hygiene/removal of plaque, This section presents a description of the Markov fluoride applications and sealants) versus the same model developed for the assessment, and of the strategy plus HealOzone. parameters that were common across all models. Key parameters specific to each model and Non-cavitated root caries results are then presented separately for each The model for non-cavitated root caries compares comparator. The section concludes with a current management strategies (i.e. removal of summary of the results for all comparators and of plaque, topical fluorides, chlorhexidine and a the factors deemed to be most critical in affecting sealant) versus the same strategy plus HealOzone. the results. Model pathways Markov modelling techniques were used to assess The pathways for each model were developed in the cost-effectiveness of HealOzone plus current accordance with the protocol for the assessment management, relative to the standard current along with expert opinion from members of a 29

Early caries initial treatment

Current management (watchful Current management plus waiting, oral hygiene/plaque HealOzone removal, fluoride, sealants)

Reversal of caries Reversal of caries Progression of caries

Initial treatment Tooth filled repeated

Progression of caries Reversal of caries

Tooth filled

FIGURE 10 Model for primary non-cavitated pit and fissure caries

local dental school. All models have simplified 5-year timescale of the model, and that a typical clinical event pathways, but are designed to reflect filling would last longer than 5 years, no states those clinical events of importance to the beyond filling were included. It was assumed that evaluation (Figures 15–18 in Appendix 6). once a tooth was cured it remained in a cured state for the rest of the 5 years. TREEAGE DATA 4.0 Non-cavitated pit and fissure caries and root software (TREEAGE Software, 2001) was used to caries construct the model. Following initial treatment carious lesions may either reverse or not reverse. Lesions that do not Estimation of parameters show reversal of caries progression after the initial Probabilities intervention require additional treatment. This is a The time horizon considered in the Markov model further application of the initial preventive/non- was a maximum of 5 years. The outcome restorative treatment or a restorative treatment (i.e. considered in the economic evaluation was the drilling and filling). In those receiving further numbers of carious lesions cured. The main preventive/non-restorative treatments, caries can probabilities used in the model were the rates of again be reversed or treated with filling (Figure 10). reversal (cure) of caries. These rates were derived The event pathway is split into two mutually from the effectiveness study (Chapter 3) and exclusive events, the reversal (cure) of caries and consultation with dental practitioners. The no reversal of caries. The arrows between these probability of cure rates (Table 15) obtained from states represent the possible transitions between the effectiveness studies and used in the first run them. Movement between the different states is of the economic model were: HealOzone 0.074 governed by the transition probabilities, such as (7.4%) for the non-cavitated pit and fissure the chance of the caries reversing. The absorbing caries37 and 0.98 (98%)35 for the non-cavitated state in this model is a tooth with a filling. While root caries. The rates used for current 30 this is not an absorbing state in reality, given the management were 0.056 (5.6%)37 for non- Health Technology Assessment 2006; Vol. 10: No. 16

TABLE 15 Probabilities used in the economic model

Intervention Probability Source

HealOzone cure rate (non-cavitated pit fissures) 0.074 Table 11, Chapter 3 Current management cure rate (non-cavitated pit fissures) 0.056 Table 11, Chapter 3 HealOzone cure rate (non-cavitated root caries) 0.98 Table 9, Chapter 3 Current management cure rate (non-cavitated root caries) 0.01 Table 9, Chapter 3 Percentage being retreated with initial treatment 0.50 Discussions with expert Percentage being retreated with filling 0.50 Discussions with expert

TABLE 16 Unit cost per itema

Type Current treatment (SDR code) Cost (£)

Non-cavitated pit and fissure caries Hygiene/diet advice (0601) 7.70 Chlorhexidine gel/varnish or fluoride varnish (3631) 4.60 Fissure sealant (0701) 6.95 Total (sum of above) 19.25 Non-cavitated root caries Hygiene/diet advice (0601) 7.70 Chlorhexidine gel/varnish or fluoride varnish (3631) 4.60 Total (sum of above) 12.30 Cavitated pit and fissure caries Sealant only (1441) 6.95 Composite resin (1442) 9.80 Glass-ionomer (1443) 10.55 Amalgam (1401 or 1421) 7.15 (posterior) 14.15 (anterior) Total (average of above) 16.98 HealOzone (No SDR code) 20 (estimate)

a Costs are those that would be incurred by the NHS and exclude patient contributions to dental fees. Further details of cost calculations are presented in Appendix 6.

cavitated pit and fissure caries and 0.01(1%) for Costs non-cavitated root caries.35 These values, which The perspective adopted for the study is that of are highly favourable to HealOzone, were different the NHS and Personal Social Services. The unit to those used in the industry model, which costs of dental treatments were taken directly from aggregated data from a number of studies, some cost data published by the NHS.65 Table 16 of which did not meet the inclusion criteria provides details of the different treatments with specified in this review. In the absence of any corresponding codes from the NHS SDR for each alternative information, it was assumed for the treatment item. Unit costs are listed for each purposes of the model that, following initial treatment item and represent the fee paid by the treatment, there was a 0.50 (50%) chance of NHS to the dentist for each item of service. subsequent treatment being the same treatment as the initial one received or a filling. Resource-use data were identified from existing literature, reports from manufacturers and advice The root caries cure rates are taken from the from experts in this field. Based on existing Holmes study,54 the results of which seem evidence and clinical opinion, patients were puzzling; they reflect a best possible case for assumed to visit the dentist every 6 months. Cost HealOzone. data were measured in pounds sterling (£) for the 31

TABLE 17 Weighted average costs used in the modela

Cost (£)

Intervention Under 18 Over 18 Weighted

Current management Non-cavitated pit and fissure caries 19.25 7.70 9.02 Non-cavitated root caries 12.30 4.92 6.09

Current management plus HealOzone Non-cavitated pit and fissure caries 39.25 15.70 20.03 Non-cavitated root caries 32.30 12.92 17.10

Restorative interventions Filling 19.67 7.87 12.75

a Costs are those that would be incurred by the NHS excluding patient contributions to dental fees.

year 2004. As specified by the guidelines for In the absence of separate effectiveness data for conducting health technology assessment, cost- adults and children it was decided to combine all effectiveness results should reflect the present age groups for the base-case analysis. A two-stage value of the stream of costs and benefit accruing process was required to weight the unit costs to over the time horizon of the analysis.79 To make represent a mixed population of adults and the analysis consistent with the model used in the children. Further details of the stages involved in industry submission the analysis was carried out the cost calculations are reported in Appendix 6. over a period of 5 years. An annual discount rate Published statistics65 indicate that adults and of 3.5% was applied to both costs and benefits children do not receive similar proportions of each accrued, the rate currently specified in the HTA treatment item among the different treatment guidelines.79 items listed in Table 16. The first stage was therefore to calculate the percentage mix of The per-item fee for service paid by the NHS was children and adults for each identified SDR used as a proxy for costs to the NHS of current component of the treatment. These proportions management. Under the current NHS dental were then weighted by the amount that the NHS system patients pay 80% of the dentist’s fee, with contributed using the figures described earlier, at the remaining 20% being paid by the exchequer 100% of the amount of a claim per child and 40% (except that there is a maximum charge for a per adult. Following this two-stage weighting course of dental treatment of £366). Some process, the adjusted costs to the NHS used in the patients, including all those less than 18 years old, model were £9.02 for the non-cavitated pit and are entitled to free treatment and the exchequer fissure caries and £6.09 for non-cavitated root pays the full cost of treatment. Recent figures caries, and a filling was estimated at £12.75. report that 25% of all claims for patients aged 18 Details of the costs are included in Table 17. years and over were exempt from patient charges.65 The other 75% of claims for patients The costs of HealOzone were calculated using the aged 18 and over therefore include a patient existing NHS methods and information from the contribution at 80% of the amount of the claim manufacturer. Most of the studies indicated that and an NHS contribution of 20%. Taking these HealOzone treatment is given at the start, and data into account, the average net NHS repeated at 3 and 6 months. The cost of contribution equates to 40% [25% + (20% of HealOzone therefore took into account that 75%)] of any NHS dental claim for patients aged patients could receive between one and three 18 and over. As children (persons under 18 years applications. The cost of HealOzone treatment of age) are exempt from paying NHS dental also included that of current management as treatment fees, the full cost of all claims for those HealOzone was considered as an additional less than 18 years old was used as the cost to the treatment and not as a stand-alone treatment. The NHS. The data used in the industry model weighted average cost of ‘current management indicated that the NHS contribution to those aged plus HealOzone treatment’ used in the model was 32 18 and over was 52%. £20.03 for non-cavitated pit and fissure caries and Health Technology Assessment 2006; Vol. 10: No. 16

£17.10 for non-cavitated root caries. These values HealOzone and 0.01% were filled. The present were not similar to those used in the industry authors remain sceptical about these results. model as they focused on costs and benefits to the NHS in England and Wales as a whole, rather Sensitivity analysis than on costs and benefits faced by the average There was very little suitable evidence on the patient. effectiveness of the HealOzone comparator. One- way sensitivity analysis was applied to the model to Quality of life assess the robustness of the results to variations in It was not possible to measure health benefits in the underlying data. The probability of caries terms of QALYs. This was mainly because the being cured was varied for each comparator adverse events avoided are transient: a few separately, using the baseline cure rate for the seconds’ pain from injection of local anaesthetic; alternative comparator. These results indicated the anxiety/fear of having a drill and numbness that when higher probability cure rates were used until the local anaesthesia wears off. the proportion of teeth filled was lower at 12 months. These results were similar to those of Sensitivity analysis the Cochrane review by Ahovuo-Saloranta and As every economic analysis contains some degree colleagues.32 However, as the focus of the of uncertainty, imprecision or methodological Cochrane review was on the prevention of dental controversy, and this one more than most, a decay in the permanent teeth of children and sensitivity analysis was performed. Given the adolescents, the extrapolation of its results to an limited effectiveness data for estimating rates of adult population with dental caries might be caries reversal, the models were rerun using questionable. different probability values of reversal of caries. Assumptions were also made about what items to The results of the one-way sensitivity analyses are include in each of the interventions and sensitivity illustrated in Figures 11–14 and presented in analysis was performed using different codes to tabular form in Appendix 6 (Tables 29–32). determine the costs, namely the SDR codes used in the industry submission. In Figure 11 the costs refer to those of current management when the baseline cure rates of HealOzone are used (0.074). The discounted NPV Results for the cost of HealOzone was £40.49. The above results indicate that the discounted NPV of the The analysis, carried out over a 5-year period cost of the HealOzone comparator, using baseline using the data reported in the trials, indicated that parameter values for HealOzone, was higher than treatment using current management plus that of current management at any probability of HealOzone cost more than current management cure with current management. This is mainly alone for non-cavitated pit and fissure caries attributable to the fact that the baseline cure rate (£40.49 versus £24.78), but cost less for non- used in the model is less than 10%. The results cavitated root caries (£14.63 versus £21.45). For also indicate that as the probability of cure rate non-cavitated pit and fissure caries 91.8% of the increases, the cost reduces and the number of teeth treated using current management received teeth filled also reduces. a filling and 8.2% of teeth were cured. For teeth treated with current management plus In Figure 12 the costs refer to those of HealOzone HealOzone, 89.2% received fillings and 10.8% plus current management when the baseline were cured. This was different from the results of annual cure rate of current management is used the Cochrane review by Ahovuo-Saloranta and (0.056). The discounted NPV for the cost of colleagues,32 which reported that the reduction in current management was £24.78. Varying the caries ranged from 86% at 12 months to 57% at probability of the cure rates of HealOzone plus 48–54 months. This review focused, however, on current management, and using the baseline cure the prevention (and not the treatment) of tooth rate probability for current management, decay in children and adolescents who presented indicated that the HealOzone option was always with no obvious caries. Based on the Holmes more expensive than current management when study,54 1.5% of teeth were cured at 5 years in the the probability of cure using the HealOzone non-cavitated root caries group treated with option was 70% or lower. current management and 98.5% teeth were filled, while 99.9% of teeth were cured by the In Figure 13 the costs of HealOzone reflect the combination of current management and costs when the baseline probability of cure of 33

45.00

40.00

35.00 Current management 30.00 HealOzone 25.00

20.00 NPV (£) 15.00

10.00

5.00

0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability of current management cure rate

FIGURE 11 One-way sensitivity analysis for non-cavitated pit and fissure caries: discounted NPV of each comparator at alternative cure rates for current management, holding the baseline cure rate for HealOzone plus current management constant

45.00 Current management 40.00 HealOzone

35.00

30.00

25.00 NPV (£) 20.00

15.00

10.00

5.00

0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability of HealOzone cure rate

FIGURE 12 One-way sensitivity analysis for non-cavitated pit and fissure caries: discounted NPV of each comparator at alternative cure rates for HealOzone plus current management, holding the baseline cure rate for current management constant

current management (0.01) was used and the In Figure 14 the costs of current management reflect probability of cure of HealOzone management was the costs when the baseline probability of cure of varied accordingly. The one-way sensitivity analysis HealOzone (0.98) was used and the probability of results show that discounted NPVs for the costs of cure of current management was varied accordingly. current management plus HealOzone were lower The discounted NPVs for the costs of current than those of current management only when cure management were higher than those of current rates from current management plus HealOzone management plus HealOzone when the cure rate 34 were at least 80% and above. for current management was 40% or lower. Health Technology Assessment 2006; Vol. 10: No. 16

45.00 Current management 40.00 HealOzone 35.00

30.00

25.00

20.00 NPV (£) 15.00

10.00

5.00

0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability of HealOzone cure rate

FIGURE 13 One-way sensitivity analysis for non-cavitated root caries: discounted NPV of each comparator at alternative cure rates for HealOzone plus current management, holding the baseline cure rate for current management constant

25.00

Current management

20.00 HealOzone

15.00 NPV (£) 10.00

5.00

0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability of current management cure rate

FIGURE 14 One-way sensitivity analysis for non-cavitated root caries: discounted NPV of each comparator at alternative cure rates for current management, holding the baseline cure rate for HealOzone plus current management constant 35

TABLE 18 Industry submission model inputs for annual treatment items and cost for patients under 18 years of agea

Procedure SDR code Unit cost (£)

Non-cavitated pit and fissure caries Fissure sealant: sealant only 1441 6.50 Fissure sealant: composite resin 1442 9.15 Fissure sealant: composite resin and glass ionomer 1444 13.71 Root caries Composite/synthetic: one filling 1421 13.22 Composite/synthetic: two or more fillings 1421 10.32 Glass ionomer: one filling 1426 12.08 Glass ionomer: two or more fillings 1426 8.22

a The current costs of treatment were estimated using the GDS treatment items reported for the year ending March 2003 (KaVo Dental Ltd, industry submission, 2004, p. 62).

One-way sensitivity analysis was also carried out therefore, the results should be regarded mainly as using similar SDR codes to those used in the illustrations of the key variables and hence industry submission. Table 18 shows the SDR codes interpreted cautiously as they reflect the used by the industry for patients under 18 years of parameter values and assumptions used in the age. The figures for those over 18 years were model. A further constraint was the lack of long- similar. This did not alter the results for non- term data on the effectiveness of HealOzone (it is cavitated pit fissure caries as the discounted NPV not known whether caries that is reversed will of current management remained lower than that always stay in the inactive/arrested state or of the HealOzone comparator (£22.65 versus whether future treatments will be required). To £33.39). These results could be attributed to the attempt to model longer term effects the available fact that it was assumed that patients received the 12-month data were extrapolated to 5 years. It is same treatment as the initial one and the cost of not known at this stage whether this assumption is current management plus HealOzone is much valid. Another possible area of uncertainty was higher than that of current management alone, related to whether the response to HealOzone given that HealOzone is an additional treatment treatment would increase with increasing dose rather than an alternative treatment. Results using levels. the SDR codes used for non-cavitated root caries in the industry model gave similar results to those It was not possible to model the treatment of in the base-case analysis. HealOzone cost less than cavitated caries since no effectiveness data on current management (£17.66 versus £30.41). direct comparisons were available. The analysis was carried out on a hypothetical cohort of teeth with carious lesions and did into take into account Discussion the proportion of teeth that are unsuitable for HealOzone treatment. Further research is The economic analysis was greatly constrained by therefore necessary to support a complete the uncertainty over clinical effectiveness; economic evaluation.

36 Health Technology Assessment 2006; Vol. 10: No. 16

Chapter 6 Implications for the NHS

National Service Framework was estimated that there were 294 HealOzone units in the UK (at June 2004). Were ozone The majority of general dental practitioners in the therapy to be made available, provision of UK are contracted to the NHS through GDS, HealOzone units would have to be increased much although, as independent contractors, dentists beyond this to allow all suitable patients fair access who offer NHS treatment may also offer certain to the treatment. treatments on a private basis. Dentists receive fixed fees per item of treatment for adults, while for children they receive a combination of fixed Equity issues fees per item and capitation fees. Under this NHS system patients can pay up to 80% of the cost of The availability of HealOzone treatment is their treatment up to a maximum cost of around currently limited to those people who are able £366. Some patients are entitled to free NHS and willing to pay for the treatment privately. dental treatment, including children, young However, in the present state of knowledge, it people in full-time education, pregnant women cannot be said that people suffer by being unable and those with a child under 1 year old, and to afford it. people on low incomes. The costs of running a dental practice, including capital costs of equipment, are met by the dental practice rather Budget implications to the NHS than the NHS, and recovered from the fee for service charges paid by the patients and the NHS. At present, HealOzone is only available to patients In addition to dentists contracted to provide NHS through private dental care. The aim of this treatment, some of whom also offer private section is to estimate what the implications would treatment, there are many dentists in the UK who be to the NHS if HealOzone were made available only provide treatment on a private basis. as an NHS dental service. Currently, HealOzone treatment is only available as a private treatment from a limited number of The models used in the economic evaluation dentists. described in Chapter 5 considered the costs and effectiveness of current treatment with and without the addition of HealOzone for arresting the Health targets progression of dental caries (further details of these cost calculations are presented in Appendix There are no specific health targets, although in 6). The evaluation does not consider those teeth England the Department of Health set a target to with carious lesions, which would be unsuitable for reduce tooth decay in 5-year-olds to low levels by HealOzone therapy. These could be considered in 2003, while in Wales the official target was to the estimated implications to the NHS for the achieve no more than 48% of 5-year-olds having total population of teeth with carious lesions if tooth decay by 2002.80 estimated numbers of such teeth were available. To achieve this it is necessary to make assumptions The new Base Dental Contract (based on the about the proportion of teeth currently treated for personal dental services model) will be introduced caries that would be suitable for alternative for all practices in April 2006. The new contract HealOzone treatment. This proportion would be will be more likely to have a greater preventive used to calculate the total annual number of and capitation element.81 treated teeth.

Data from GDS provide statistics for the numbers Fair access of teeth treated by SDR code in a year for adults and children in England and Wales. At the time of At the time of writing HealOzone treatment was writing the latest available GDS data were those only available through private dental care and it pertaining to the year ending March 2003. 37

TABLE 19 NHS annual cost for treatment of non-cavitated pit and fissure caries

NPV of treatment cost over 5 years (£)

Current management 8,565,765 HealOzone plus current management 13,996,280 Net difference in cost 5,430,515 Net difference in cost per tooth treated initially 15.71

TABLE 20 NHS annual cost for treatment of non-cavitated root caries

NPV of treatment cost over 5 years (£)

Current management 7,371,882 HealOzone plus current management 5,876,885 Net difference in cost –1,494,997 Net difference in cost per tooth treated initially –4.35

The following results were calculated by difference in numbers of teeth filled at 5 years for combining the GDS data with assumptions about the HealOzone comparator and current the SDR codes relevant to each caries type to management (308,340–317,327). The incremental estimate annual numbers of teeth treated for non- cost per filling avoided, using these assumptions, cavitated pit and fissure caries and non-cavitated would be estimated at £604.23. root caries. Again, teeth with cavitated caries were not considered given the absence of evidence on The industry submission estimates for the the effectiveness of HealOzone as a comparator percentage of teeth currently treated that would treatment for cavitated caries. be suitable for HealOzone, obtained from the opinion of current users of HealOzone, were 92% Non-cavitated pit and fissure caries for non-cavitated pit and fissure caries, 76% for The discounted NPV for the cost over 5 years of cavitated pit and fissure caries, and 76% for root teeth treated initially with current management or caries. These figures were derived from Table 15 in HealOzone plus current management was the industry submission. reported in Chapter 5. These figures were combined with the numbers of teeth treated Non-cavitated root caries initially using annual GDS data for the SDR codes The total discounted NPV over 5 years for treating in the present treatment definitions. The results non-cavitated root caries, using the best case for should, however, be interpreted with extreme HealOzone again, would be estimated at caution given that they are based on the limited £7,371,882 for current management and effectiveness data available for the economic £5,876,885 for HealOzone therapy. The net analysis, as reported in Chapters 3 and 5 of this difference in these two costs shows that report. HealOzone therapy would save the NHS £4.35 per tooth treated initially with HealOzone in addition The total discounted NPV over 5 years for treating to current management for root caries, a total cost non-cavitated primary fissure caries was estimated saving over 5 years of £1,494,997 (Table 20). at £8,565,765 for current management and £13,996,280 for HealOzone therapy (Table 19). These figures are estimated using base-case values The base-case results showed that by 5 years for caries reversal rates. Limited suitable fillings were present in 91.8% of teeth treated with effectiveness data were available for reversal rates current management compared with 89.2% of of root caries, apart from a single study reporting teeth treated with HealOzone plus current reversal rates of 1% for current management and management. Using these figures the incremental 98% for HealOzone treatment. Given the extreme cost per tooth treated would be £15.71, at an values of reversal rates for the comparators, based initial total cost to the NHS of £5,430,515. The on the limited effectiveness data available at the incremental cost over 5 years for the HealOzone time of analysis, these results need to be comparator compared with current management interpreted with caution. It was only possible to 38 (£13,996,280–£8,565,765 ) was divided by the carry out limited one-way sensitivity analyses, Health Technology Assessment 2006; Vol. 10: No. 16

varying cure rates separately for the HealOzone on the tooth population. For example, it is and current management comparators (see unknown how long an arrested carious lesion Chapter 5). From the results of the sensitivity remains inactive. Any prospective trial should have analyses it can be seen that the net difference in sufficient follow-up to allow for this. cost per tooth treated initially was higher for current management unless the probability of cure Importantly, the above results are based on the for the HealOzone comparator was lower than authors’ assumptions for the management of the approximately 80%. different types of caries.

It is advisable that the reader interprets all such In addition, it is difficult to estimate the actual results merely as an illustration of possible cost of HealOzone to the NHS. Assuming that scenarios. In the light of limited evidence on patients who pay some of their dental treatment effectiveness, a more detailed analysis of budget fees are willing to pay no more than current implications was not considered likely to add any treatment for the same condition initially, what useful information to the evaluation. would the cost-effectiveness ratio be? Would patients opt for this treatment if it was more The cost implications over time are difficult to expensive? ascertain since there are many uncertain factors to take into account. Further research is required to Finally, would patients be given a choice for caries model the cost implications over time, taking into management or would dentists have to follow account the cost of rerestorations beyond the some guidelines about the best treatment? This lifetime of first fillings and their effects over time has implications on the numbers of teeth treated.

Health Technology Assessment 2006; Vol. 10: No. 16

Chapter 7 Discussion

Main results removal of plaque by a dentist or hygienist), which has been used effectively in the management of Clinical effectiveness dental caries in adults. A recent study assessing the The literature on ozone treatment is still at a outcomes of a 30-year preventive programme relatively early stage, in the sense that only one based on professional and self-performed plaque paper has been published in full in a refereed control has shown how high standards of oral journal. Most of the reports are available only in hygiene are associated with a very low incidence of abstract form, as conference proceedings, and dental caries and periodontal disease in adults.82 inevitably give few details. Many trials are still very short term and none of the studies has followed Cost-effectiveness up the patients after they have stopped ozone If HealOzone led to a reduction in future fillings, treatment for a reasonable length of time. It is also then the extra cost might be justified. The authors worthwhile remembering that caries is a dynamic do not believe that the evidence base yet supports process: a lesion can remineralise without the that. need for any intervention, and the rate of caries progression can be very slow. Need for further research HealOzone is supposed to kill the microorganisms (bacteria) responsible for dental plaque formation. Nearly all the research to date comes from the However, unless patients have improved their same group who developed and pioneered the plaque control and eliminated the causes of the procedure, and have the greatest experience in its increased numbers of microorganisms, the plaque use. There is a need for large, well-conducted will re-form and the lesion will progress again. RCTs to assess the effectiveness and cost- This raises the question of whether HealOzone is effectiveness of HealOzone for the management of a reasonable preventive technology. Furthermore, both occlusal and root caries. In particular, future treatments based on HealOzone would need to be trials: repeated for an indeterminate numbers of years to be beneficial, with obvious cost implications. should be conducted by independent research teams The available evidence is conflicting, with the root should be properly randomised so that an equal caries treatment showing much better results than number of lesions, or paired lesions, per mouth treatment for pit and fissure caries. However, the are allocated to intervention groups results are surprising, partly because the ozone should apply appropriate statistical methods for group did so well, with 99% cure or improvement, the analysis of paired-data on a patient basis; but mainly because the control group performed should use validated and reproducible criteria very badly, despite receiving the same care for the assessment of caries package (oral hygiene, topical fluoride, etc.) but should measure relevant outcomes such as without the application of ozone. Compliance of reduction in caries incidence over a reasonable patients with treatment, however, was not assessed period (at least 2 years, but realistically much in the included studies. longer) should mask participants and outcome assessors In particular, it proved difficult to identify the should provide both a statistical and a clinical additional role of ozone gas from the patient kit interpretation of their findings or the synergistic effect between ozone and the should conform to the CONSORT guidelines patient kit, which contained, among other for the reporting of RCTs.83 elements, fluoride and xyliton. It would have been useful, for example, to know the effects of ozone Owing to the natural history of the caries process, alone, namely ozone gas, together with the any future trial would need to include a very long patient’s normal brushing or how HealOzone follow-up, which would have a significant impact compares to professional plaque control (the on trial costs. 41

There also appears to be a need for evaluation of It should be based on data from properly the different methods of assessing caries severity. conducted RCTs of HealOzone versus The base case could be clinical examination, with appropriate comparators (e.g. no treatment or the marginal benefits and costs of more current management). sophisticated techniques assessed. Although the Follow-up of patients should be long enough to economic evaluation was not able to provide allow identification of both short-term and results that could be used by decision-makers, it long-term resource use and effectiveness. was a valuable exercise in highlighting the paucity Outcome data must include both short-term of good quality data on key parameters. In and long-term rates of caries reversal, caries particular, the paucity of suitable data from progression, retreatment and/or rerestoration. published clinical trials comparing the Separate consideration is needed for cavitated effectiveness of HealOzone with appropriate and non-cavitated caries. comparators restricted the scope of the economic Sufficient power is needed to allow for robust model. No comparable quality of life data were subgroup analyses for deciduous and available for the comparators, thus limiting the permanent teeth, and for variation in caries range of outcomes available for an evaluation. severity. These gaps in the data needed to undertake an An estimate of the unit cost of HealOzone to informative economic evaluation of HealOzone the NHS should be based on calculations can only be filled through further research in the similar to those underlying the SDR figures for form of prospective RCTs. current dental treatments provided by the NHS. Factors affecting patients’ quality of life should To provide adequate information to assess the be considered, both at the point of treatment cost-effectiveness of HealOzone, any future and during follow-up (e.g. the effect on quality economic evaluation of HealOzone should feature of life due to pain from toothache). the following characteristics:

42 Health Technology Assessment 2006; Vol. 10: No. 16

Chapter 8 Conclusion

ny treatment that preserves teeth and avoids conclude that it is a cost-effective addition to the A fillings is welcome. However, the current management and treatment of occlusal and root evidence base for HealOzone is insufficient to caries.

Health Technology Assessment 2006; Vol. 10: No. 16

Acknowledgements

rateful thanks to Heather Mackintosh for her joint venture between the Health Services Gsecretarial support. Research Unit at Aberdeen and the Medical Care Research Unit at Sheffield University forms the The views and opinions expressed are those of the Review Body for Interventional Procedures authors and do not necessarily reflect those of the (ReBIP) Programme within NICE. ReBIP funding bodies. undertakes systematic reviews and, where appropriate, establishes UK registries to collect Publication information and analyse data on the efficacy and safety of The Aberdeen Health Technology Assessment selected procedures. Group is part of the Institute of Applied Health Sciences (IAHS). The Institute of Applied Health Contribution of authors Sciences within the College of Medicine and Life Miriam Brazzelli (Research Fellow) and Shona Sciences of the University of Aberdeen is made up Fielding (Medical Statistician) completed the of discrete but methodologically related research review of effectiveness. Lynda McKenzie (Research groups. The HTA Group is drawn mainly from the Fellow) conducted the review of economic Health Services Research Unit, the Department of evaluations. Lynda McKenzie and Mary Kilonzo Public Health and the Health Economics (Research Fellow) conducted the economic Research Unit. evaluation. Cynthia Fraser (Information Scientist) developed and ran the search strategies. Norman The HTA Group carries out independent health Waugh (Professor of Public Health) provided technology assessment reports (TARs) for the UK oversight and contributed to drafting the review. HTA Programme, which commissions TARs for Jan Clarkson (Honary Consultant in Paediatric the National Institute for Health and Clinical Dentistry) provided clinical advice and Excellence (NICE) and other bodies, such as the commented on the draft review. National Screening Committee. In addition, a

Health Technology Assessment 2006; Vol. 10: No. 16

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23. Clarkson JE, Ellwood RP, Chandler RE. A URL: http://www.kavo.com/forum/upfiles/4/ comprehensive summary of fluoride dentifrice Db84539.pdf. Accessed April 2004. caries clinical trials. Am J Dent 1993;6 (Special No.): 37. Abu-Naba’a LA. Management of primary occlusal pit S59–106. and fissure caries using ozone [PhD thesis]. Queen’s 24. Biesbrock AR, Gerlach RW, Bollmer BW, Faller RV, University Belfast; 2003. Jacobs SA, Bartizek RD. Relative anti-caries efficacy 38. Abu-Salem O. Reversal of occlusal caries in primary of 1100, 1700, and 2800 ppm fluoride ion in a teeth [MPhil thesis]. Queen’s University Belfast; sodium fluoride dentifrice over 1 year. Community 2004. Dent Oral Epidemiol 2001;29:382–9. 39. Holmes J. Ozone treatment of root caries after 25. Ripa LW. A critique of topical fluoride methods 18-months. IADR/AADR/CADR 82nd Annual (dentifrices, mouthrinses, operator-applied, and Conference, Honolulu, Hawaii, March 2004 self-applied gels) in an era of decreased caries and [conference proceedings on the Internet]. increased fluorosis prevalence. J Public Health Dent URL: http://iadr.confex.com/iadr/2004Hawaii/ 1991;1:23–41. techprogram/abstract_47251.htm. 26. Bader JD, Shugars DA, Bonito AJ. A systematic 40. Holmes J. Ozone treatment of root caries after 21- review of selected caries prevention and months. BSDR Annual Scientific Meeting, management methods. Community Dent Oral Birmingham, UK, April 2004 [Conference Epidemiol 2001;29:399–411. proceedings on the Internet]. URL: 27. Ellwood R, Fejerskov O. Clinical use of fluoride. http://iadr.confex.com/iadr/bsdr04/techprogram/ In Fejerskov O, Kidd E, editors. Dental caries: the abstract_49444.htm. disease and its clinical management. Oxford: Blackwell 41. Baysan A, Lynch E. Clinical reversal of root caries Munksgaard; 2003. pp. 189–222. using ozone. IADR/AADR/CADR 80th Annual 28. Diagnosis and management of dental caries throughout Conference, San Diego, California, March 2002 life. NIH Consensus Statement 26–28 March [conference proceedings on the internet]. 2001;18(1):1–30. URL: http://iadr.confex.com/iadr/2002SanDiego/ techprogram/abstract_20439.htm. 29. Handelman SL. Effect of sealant placement on occlusal caries progression. Clinical Preventive 42. Baysan A. Management of primary root caries using Dentistry 1982;4(5):11–16. ozone therapies [PhD Thesis]. University of London; 2002. 30. Mertz-Fairhurst EJ, Curtis JW Jr, Ergle JW, Rueggeberg FA, Adair SM. Ultraconservative and 43. Baysan A, Lynch E. 12-month assessment of ozone cariostatic sealed restorations: results at year 10. on root caries. 81st Annual Conference of IADR, J Am Dent Assoc 1998;129:55–66. Goteborg, Sweden, June 2003 [conference proceedings on the Internet]. 31. Ripa LW. Sealants revisited: an update of the URL: http://iadr.confex.com/iadr/2003Goteborg/ effectiveness of pit-and-fissure sealants. Caries Res techprogram/abstract_36145.htm. 1993;27 Suppl 1:77–82. 44. Baysan A, Lynch E. Clinical assessment of ozone 32. Ahovuo-Saloranta A, Hiiri A, Nordblad A, on root caries. IADR/AADR/CADR 82nd Annual Worthington HV, Makela M. Pit and fissure sealants Conference, Honolulu, Hawaii, March 2004 for preventing dental decay in the permanent teeth [conference proceedings on the Internet]. of children and adolescents. Cochrane Database Syst URL: http://iadr.confex.com/iadr/2004Hawaii/ Rev 2004; Issue 3. Art. No. CD001830. DOI techprogram/abstract_47326.htm. 10.1002/14651858.CD001830.pub2. 45. Abu-Naba’a LA, Al Shorman HM, Stevenson M, 33. Dental Practice Board. Dental review of the general Lynch E. Ozone treatment of pit and fissure caries: and personal dental services of the NHS. 2002–2003 6-month results. 32nd Annual Meeting of AADR, [monograph on the Internet]. URL: San Antonio, Texas, March 2003 [conference http://www.dpb.nhs.uk/. Accessed July 2004. proceedings on the Internet]. 34. Verhagen AP. The Delphi list: a criteria list for URL: http://iadr.confex.com/iadr/2003SanAnton/ quality assessment of randomized clinical trials for techprogram/abstract_27269.htm. conducting systematic reviews developed by the 46. Abu-Naba’a LA, Al Shorman HM, Lynch E. Ozone Delphi consensus. J Clin Epidemiol 1998; treatment of primary occlusal pit and fissure caries: 51:1235–41. 12 month clinical severity changes. Caries Res 2003; 35. Holmes J. Clinical reversal of root caries using 37:272. ozone, double-blind, randomised, controlled 47. Abu-Naba’a LA, Al Shorman HM, Lynch E. Ozone 18-month trial. Gerodontology 2003;20:106–14. treatment of primary occlusal pit and fissure caries: 36. Baysan A, Lynch E. Management of root caries 12 month electrical impedance results and clinical 48 using ozone. KaVo Dental Ltd website. implications. Caries Res 2003;37:272. Health Technology Assessment 2006; Vol. 10: No. 16

48. Abu-Naba’a LA, Al Shorman HM. 6-months fissure DIAGNOdent measurements. J Oral Rehabil 2004; sealant retention over ozone-treated occlusal caries. 31:895–9. IADR/AADR/CADR 82nd Annual Conference, 59. Macfarlane TV, Worthington HV. Some aspects of Honolulu, Hawaii, March 2004 [conference data analysis in dentistry. Community Dent Health proceedings on the Internet]. 1999;16:216–19. URL: http://iadr.confex.com/iadr/2004Hawaii/ techprogram/abstract_45125.htm. 60. Rickard GD, Richardson R, Johnson T, McColl D, Ozone Hooper L. Ozone therapy for the treatment of 49. Abu-Naba’a LA, Al Shorman HM, Lynch E. Cochrane Database Syst Rev management of occlusal pit & fissure caries (PFC): 12 dental caries. 2004; Issue 3. Art. No. CD004153. DOI month review. DentalOzone website. London: Dental 10.1002/14651858.CD004153.pub2. Clinique. URL: http://www.dentalozone.co.uk/ research4.html. 61. Drummond M, O’Brien B, Stoddard G, Torrance G. Critical assessment of economic evaluation. Methods 50. Abu-Naba’a LA, Al Shorman HM, Lynch E. Ozone for the economic evaluation of health care programmes. efficacy in the treatment of pit and fissure caries. Oxford: Oxford University Press; 1997. J Dent Res 2003;82(Special Issue C):C-535. pp. 27–51. 51. Abu-Naba’a LA, Al Shorman HM, Lynch E. Clinical 62. Johnson N, Johnson J, Lynch E. Cost benefit indices changes in ozone treatment of pit and assessment of a novel ozone delivery system vs fissure caries. 32nd Annual Meeting of AADR, San conventional treatment. 32nd Annual Meeting of Antonio, Texas, March 2003 [conference AADR, San Antonio, Texas, March 2003 proceedings on the Internet]. [conference proceedings on the Internet]. URL: http://iadr.confex.com/iadr/2003SanAnton/ URL: http://iadr.confex.com/iadr/2003SanAnton/ techprogram/abstract_27273.htm. techprogram/abstract_27588.htm. 52. Abu-Naba’a LA, Al Shorman HM, Lynch E. 63. Domingo H, Holmes J, Abu-Naba’a LA, 6-month clinical indices changes after ozone Al Shorman HM, Baysan A, Freeman R. treatment of pit and fissure caries (PFC). 81st Economic savings treating root caries with ozone. Annual Conference of IADR, Goteberg, Sweden, DentalOzone website. URL: June 2003 [conference proceedings on the www.dentalozone.co.uk/research6.html. Accessed Internet]. URL: http://iadr.confex.com/iadr/ August 2004. 2003Goteborg/techprogram/abstract_35236.htm. 64. Amendment 92 to the Statement of Dental Remuneration 53. Holmes J, Lynch E. Reversal of occlusal caries using [document on the Internet]. UK Department of air abrasion, ozone and sealing. IADR/AADR/CADR Health. URL: http://www.dh.gov.uk/assetRoot/ 82nd Annual Conference, Honolulu, Hawaii, March 04/08/11/28/04081128.pdf. Accessed July 2004. 2004 [conference proceedings on the Internet]. URL: http://iadr.confex.com/iadr/2004Hawaii/ 65. General dental services statistics. Dental Practice techprogram/abstract_47218.htm. Board website. URL: http://www.dpb.nhs.uk/gds/ index.shtml. Assessed July 2004. 54. Holmes J. Clinical reversal of occlusal pit and fissure caries using ozone. 81st Annual Conference 66. NHS Centre for Reviews and Dissemination. Dental of the International Association for Dental restorations: what type of filling? Effective Health Research, Goteberg, Sweden, June 2003. Care 1999;5(2):1–12. 55. Hamid A. Clinical reversal of occlusal pit and 67. Florio FM, Pereira AC, Meneghim MC, Ramacciato fissure caries using ozone. IADR/AADR/CADR 82nd JC. Evaluation of non-invasive treatment applied to Annual Conference, Honolulu, Hawaii, March 2004 occlusal surfaces. Journal of Dentistry for Children [conference proceedings on the Internet]. URL: 2001;68:326–31. from: http://iadr.confex.com/iadr/2004Hawaii/ 68. Qvist V, Laurberg L, Poulsen A, Teglers PT. techprogram/abstract_47414.htm. Eight-year study on conventional glass ionomer and 56. Megighian GD, Bertolini L. In-vivo reversal of amalgam restorations in primary teeth. Acta Odontol occlusal caries with ozone after six months. Scand 2004;62:37–45. DentalOzone website. London: Dental Clinique. 69. Vilkinis V, Horsted-Bindslev P, Baelum V. Two-year URL: http://www.dentalozone.co.uk/research8.html. evaluation of class II resin-modified glass ionomer Accessed August 2004. cement/composite open sandwich and composite 57. Lynch E, Johnson J, Johnson J. Clinical reversal of restorations. Clinical Oral Investigation root caries using ozone. DentalOzone website. London: 2000;4:133–9. Dental Clinique. 70. Qvist V, Laurberg L, Poulsen A, Teglers PT. URL: http://www.dentalozone.co.uk/research7.html. Longevity and cariostatic effects of everyday Assessed August 2004. conventional glass-ionomer and amalgam 58. Kuhnisch J, Ziehe A, Brandstadt A, Heinrich- restorations in primary teeth: three-year results. Weltzien R. An in vitro study of the reliability of J Dent Res 1997;76:1387–96. 49

71. Baysan A, Lynch E. Effect of ozone on the oral 77. Megighian GD, Bertolini L, De Pieri A, Lynch E. microbiota and clinical severity of primary root In-vivo treatment of occlusal caries with ozone: caries. American Journal Dentistry 2004;17:56–60. one and two months effect with light induced fluorescence (QLF) as diagnostic methods. 81st 72. Morrison R, Lynch E. Remineralization of occlusal Annual Conference of the International Association pit and fissure caries after using ozone. 32nd for Dental Research, Goteberg, Sweden, June 2003 Annual Meeting of AADR, San Antonio, Texas, [conference proceedings on the Internet]. URL: March 2003 [conference proceedings on the http://iadr.confex.com/iadr/2003Goteborg/ Internet]. URL: from:http://iadr.confex.com/iadr/ techprogram/abstract_36918.htm. 2003SanAnton/techprogram/abstract_27482.htm. 73. Stinson P, Al Shorman HM, Abu-Naba’a LA. 78. Healozone Users Congresses. July 2003 [document Lynch E. Clinical reversal of occlusal pit and fissure on the Internet]. HealOzone website. caries after using ozone. 32nd Annual Meeting of URL: http://www.the-o-zone.cc/O3cong.doc. AADR, San Antonio, Texas, March 2003 Accessed April 2004. [conference proceedings on the Internet]. 79. National Institute for Clinical Excellence. Guide to URL: http://iadr.confex.com/iadr/2003SanAnton/ the methods of technology appraisal (reference N0515). techprogram/abstract_27499.htm. London: NICE, 2004. 74. Cronshaw MA. Treatment of primary occlusal pit and fissure caries with ozone: six-month results. 80. Primary dental care services in England & Wales 81st Annual Conference of the International [document on the Internet]. London: Audit Association for Dental Research, Goteberg, Sweden, Commission; 2002. URL: http://www.audit- June 2003 [conference proceedings on the commission.gov.uk/. Assessed August 2004. Internet]. URL: http://iadr.confex.com/iadr/ 81. NHS Dentistry: next steps in local commissioning 2003Goteborg/techprogram/abstract_34889.htm. [document on the Internet]. London: UK 75. Domingo H, Abu-Naba’a LA, Al Shorman HM, Department of Health; 2004. Holmes J, Marashdeh M, Abu-Salem O, et al. URL: http://www.dh.gov.uk/assetRoot/ Reducing barriers to care in patients managed with 04/08/68/59/04086859.pdf. Accessed ozone. 32nd Annual Meeting of AADR, San August 2004. Antonio, Texas, March 2003 [conference proceedings on the Internet]. 82. Axelsson P, Nystrom B, Lindhe J. The long-term URL: http://iadr.confex.com/iadr/2003SanAnton/ effect of a plaque control program on tooth techprogram/abstract_27392.htm. mortality, caries and periodontal disease in adults. Results after 30 years of maintenance. J Clin 76. Holmes J, Lynch E. Clinical reversal of occlusal Periodontol 2004;31:749–57. fissure caries using ozone. 81st Annual Conference of the International Association for Dental 83. Moher D, Schulz KF, Altman D, for the CONSORT Research, Goteberg, Sweden, June 2003 Group. The CONSORT statement: revised [conference proceedings on the Internet]. recommendations for improving the quality of URL: http://iadr.confex.com/iadr/2003Goteborg/ reports of parallel-group randomized trials. JAMA techprogram/abstract_36308.htm. 2001;285:1987–91.

50 Health Technology Assessment 2006; Vol. 10: No. 16

Appendix 1 Literature search strategies

Sources searched for systematic Search strategies used to identify reviews, other evidence-based reports assessing ozone therapy reports and background for dental caries information MEDLINE (1966 to week 1 2004), Databases EMBASE (1980 to week 20 2004), Cochrane Database of Systematic Reviews (CDSR). (MEDLINE Extra 17 May 2004) The Cochrane Library (Issue 2, 2004). Ovid Multifile Search. Database of Abstracts of Reviews of Effectiveness URL: http://gateway.ovid.com/athens (NHS Centre for Reviews and Dissemination), 1 (healozone or curazone).tw. April 2004. 2 ozone/ (14334) HTA Database (NHS Centre for Reviews and 3 (ozone or o3).tw. Dissemination), April 2004. 4 (oxidat$ or oxidis$).tw. Trip database. URL: http://www.tripdatabase.com/. 5 or/2-4 Accessed May 2004. 6 exp tooth demineralization/ use mesz 7 dental caries/ use emez Websites 8 demineralization/ use emez The Dental, Oral and Craniofacial Data Resource 9 Dental Caries Susceptibility/ use mesz Center (DRC). URL: http://drc.nidcr.nih.gov/ 10 Dental Enamel Solubility/ default.htm. Accessed July 2004. 11 (caries or carious).tw. National Center for Health Statistics. 12 ((tooth or teeth or dental or dentine or enamel URL: http://www.cdc.gov/nchs/nhanes.htm. or root? or occlusal) adj5 decay$).tw. Accessed July 2004. 13 ((tooth or teeth or dental or dentine or enamel British Association for the Study of Community or root? or occlusal) adj5 cavit$).tw. Dentistry. URL: http://www.bascd.org/ Accessed 14 ((tooth or teeth or dental or root? or dentine or July 2004. occlusal or enamel or cavitated) adj5 KaVo Dental Ltd. URL: http://www.kavo.com/En/ lesion?).tw. default.asp. Accessed April 2004. 15 ((tooth or teeth or dental or dentine or CurOzone USA Inc. enamel) adj5 (minerali$ or deminerali$ or URL: http://www.curozone.com/. Accessed April reminerali$)).tw. 2004. 16 or/6-15 DentalOzone. London: Dental Clinique. 17 1 or (5 and 16) URL: http://www.dentalozone.co.uk/. Accessed 18 human/ April 2004. 19 animal/ use mesz HealOzone. Dr Julian Holmes. URL: 20 nonhuman/ use emez http://www.the-o-zone.cc/. Accessed April 2004. 21 (19 or 20) not 18 NHS Dental Practice Board. 22 17 not 21 URL: http://www.dpb.nhs.uk/gds/index.shtml. 23 remove duplicates from 22 Accessed July 2004. Department of Health. URL: http://www.dh.gov.uk/Home/fs/en. Accessed April 2004.

Science Citation Index 1981 to 16 May AMED (1985 to May 2004) 2004) Ovid. URL: http://gateway.ovid.com/ Web of Science Proceedings 1990 to athens 15 May 2004) 1 (healozone or curazone).tw Web of Knowledge. 2 (ozone or o3).tw. URL: http://wok.mimas.ac.uk/ 3 (oxidat$ or oxidis$).tw. #1 TS= (Healozone or curazone) 4 or/2-3 #2 TS= (ozone or o3) 5 (caries or carious).tw #3 TS=(oxidat* or oxidis*) 6 ((tooth or teeth or dental or dentine or enamel #4 #2 or #3 or root? or occlusal) adj5 decay$).tw #5 TS=(caries or carious) 7 ((tooth or teeth or dental or dentine or enamel #6 TS=((tooth or teeth or dental or dentine or or root? or occlusal) adj5 cavit$).tw enamel or root* or occlusal) SAME decay*) 8 ((tooth or teeth or dental or root? or dentine or #7 TS=((tooth or teeth or dental or root* or occlusal or enamel or cavitated) adj5 lesion?).tw dentine or occlusal or enamel or cavitated) 9 ((tooth or teeth or dental or dentine or SAME lesion*) enamel) adj5 (minerali$ or deminerali$ or #8 TS=((tooth or teeth or dental or dentine or reminerali$)).tw enamel or root* or occlusal) SAME cavit*) 10 or/5-9 #9 TS=(( tooth or teeth or dental or dentine or 11 1 or (4 and 10) enamel) SAME (minerali* OR deminerali* 12 OR reminerali*)) #10 #5 OR #6 OR #7 OR #8 OR #9 Cochrane Library Issue 2, 2004 #11 #4 AND #10 URL: http://www.update-software.com/ #12 #1 OR #11 clibng/cliblogon.htm National Research Register BIOSIS (1985 to 12 May 2004) (Issue 2, 2004) Edina. URL: http://edina.ac.uk/biosis/ URL: http://www.update- (tn: (humans)) and (((al: (healozone)) or al: software.com/National/ (curazone)) or ((((al: (oxidat*)) or al: (oxidis*)) or #1. (healozone or curazone) ((al: (ozone)) or al: (o3))) and ((((((al: (caries)) or #2. OZONE single term (MeSH) al: (carious)) or ((((al: (root n5 decay*)) or al: #3. (ozone or o3) (roots n5 decay*)) or (((al: (dentine n5 decay*)) or #4. (oxidat* or oxidis*) al: (enamel n5 decay*)) or al: (occlusal n5 #5. (#2 or #3 or #4) decay*))) or (((al: (tooth n5 decay*)) or al: (teeth #6. TOOTH DEMINERALIZATION explode n5 decay*)) or al: (dental n5 decay*)))) or ((((al: tree 1 (MeSH) (root n5 cavit*)) or al: (roots n5 cavit*)) or (((al: #7. DENTAL CARIES SUSCEPTIBILITY single (dentine n5 cavit*)) or al: (occlusal n5 cavit*)) or term (MeSH) al: (enamel n5 cavit*))) or (((al: (tooth n5 cavi*)) #8. DENTAL ENAMEL SOLUBILITY single or al: (teeth n5 cavit*)) or al: (dental n5 cavit*)))) term (MeSH) or (((((al: (root n5 lesion*)) or al: (roots n5 #9. (caries or carious) lesion*)) or (((al: (dentine n5 lesion*)) or al: #10. ((tooth or teeth or dental or dentine or (enamel n5 lesion*)) or al: (occlusal n5 lesion*))) enamel or root* or occlusal) and decay*) or (((al: (tooth n5 lesion*)) or al: (teeth n5 #11. ((tooth or teeth or dental or dentine or lesion*)) or al: (dental n5 lesion*))) or (al: enamel or root* or occlusal) and cavit*) (cavitated n5 lesion*)))) or ((((((al: (tooth n5 #12. ((tooth or teeth or dental or dentine or minerali*)) or al: (tooth n5 reminerali*)) or al: enamel or root* or occlusal or cavitated) and (tooth n5 deminerali*)) or (((al: (teeth n5 lesion*) mineral*)) or al: (teeth n5 reminerali*)) or al: #13. ((tooth or teeth or dental or dentine or (teeth n5 deminerali*))) or (((al: (dent* n5 enamel) and (mineralis* or demineralis* or minerali*)) or al: (dent* n5 reminerali*)) or al: remineralis*)) (dent* n5 deminerali*))) or (((al: (enamel n5 #14. ((tooth or teeth or dental or dentine or minerali*)) or al: (enamel n5 reminerali*)) or al: enamel) and (mineraliz* or demineraliz* or (enamel n5 deminerali*)))))) remineraliz*)) #15. (#6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14) #16. (#5 and #15) 52 #17. (#1 or #16) Health Technology Assessment 2006; Vol. 10: No. 16

DARE, NHS Economic Evaluation IARD/AADR/CADR 82nd General Session, Database and HTA Databases Honolulu, March2004 (April 2004) AADR 32nd Annual Meeting and Exhibition, San NHS Centre for Reviews and Antonio, March 2003 Dissemination IADR 81st General Session, Goteberg 2003 URL: http://nhscrd.york.ac.uk/ IADR, Irish Division Annual Meeting, Belfast, welcome.htm 2004 Ozone or healozone or oxid* - all fields BSDR Ann Scientific Meeting, Birmingham, April Dental or caries or carious – all fields 2004

Clinical Trials (18 May 2004) ozone or healozone or oxid* URL: http://clinicaltrials.gov/ct/gui/c/r Current Controlled Trials (18 May Handsearching 2004) URL: http://www.controlled-trials.com/ Journal of Dental Research Ozone or healozone or oxid* – all fields Vol. 79 (Special Issue 2000): 78th General Session of IADR, Washington, USA, April 2000. Health Management Information Vol. 79(5) 2000: British Section: Annual Scientific Consortium (May 2004) Session, Lancaster, UK, April 2000; Irish Section: 1 (healozone or curazone).tw. Annual Scientific Meeting, Newcastle, Ireland, 2 dental caries/ January 1999. 3 (caries or carious).tw. Vol. 80 (Special Issue, AADR Abstracts, January 4 ((tooth or teeth or dental or dentine or enamel 2001): 30th Annual Meeting AADR/25th Annual or root? or occlusal) adj1 decay$).tw. Meeting CADR, Chicago, USA, March 2001. 5 ((tooth or teeth or dental or dentine or enamel Vol. 80(4) (April 2001): British Society for Dental or root? or occlusal) adj1 cavit$).tw. Research and Irish Division, Continental 6 ((tooth or teeth or dental or dentine or enamel European (1999 and 2000). or cavitated) adj1 lesion?).tw. 7 ((tooth or teeth or dental or dentine or Caries Research enamel) adj1 (minerali$ or deminerali$ or Vol. 37(4): 50th Annual ORCA Congress, Konstanz reminerali$)).tw. Germany, July 2003. 8 or/1-7 Vol. 36(3): 49th Annual ORCA Congress, Naantali 9 limit 8 to yr=1995 – 2004 Finland, July 2002. Vol. 35(4): 48th Annual ORCA Congress, Graz, Conference Papers Index (1982 to Austria, July 2001. May 2002) Vol 34(4): 47th Annual ORCA Congress, Alghero, Cambridge Scientific Abstracts Sardinia, July 2000. URL: http://www.csa1.co.uk/ KW=(healozone or curazone) or (KW=(ozone or oxidat* or oxidis*) and KW=(caries or carious or Websites dental)) or (KW=(ozone or oxidat* or oxidis*) and KW=(teeth or tooth or cavit*)) or KaVo Dental Ltd. URL: http://www.kavo.com/En/ (KW=(ozone or oxidat* or oxidis*) and default.asp. Accessed April 2004. KW=(occlusal or decay* or lesion*)) CurOzone USA Inc. URL: http://www.curozone.com/. Accessed April Zetoc Conference Search (1993 to 2004. May 2004) DentalOzone. London: Dental Clinique. MIMAS URL: http://zetoc.mimas.ac.uk/ URL: http://www.dentalozone.co.uk/. Accessed Ozone or healoaone or oxid* and (conference: April 2004. dental or dentist or caries) HealOzone. Dr Julian Holmes. URL: http://www.the-o-zone.cc. Accessed April IADR Meeting abstracts 2004. URL: http://www.iadr.com/Meetings/ index.html IARD/AADR/CADR 80th General Session, San Diego, March 2002 53

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Appendix 2 Data extraction form

‘HEALOZONE’ TECHNOLOGY ASSESSMENT REVIEW

DATA EXTRACTION FORM

Reviewer ID: Date information extracted:

Study Details

Study ID: ______

Study identifier: ______(Surname of first author + year of publication)

Study origin: ______

Language: ______

Published Unpublished

Full text Abstract only

Study Design

RCT Other ______

Quasi – RCT

Observational Study

For RCTs only: What is the unit of randomisation?

Patient

Tooth/lesion

Tooth/lesion pair

Participants

Number of eligible patients: Number of patients randomised:

Inclusion criteria: Exclusion criteria:

Interventions

Type of intervention Number of participants

Group 1:

Group 2:

Group 3:

Patient Characteristics

Intervention 1 Intervention 2 Intervention 3 Total Age (mean, range) Sex (M/F) Permanent/Deciduous teeth Primary or Secondary caries Comparability at baseline

Characteristics of the intervention

Location of trial centre(s):

Source of participants:

Method of recruitment: 56 Health Technology Assessment 2006; Vol. 10: No. 16

Method of randomisation:

Dosage of HealOzone application:

Repeated applications:

Was a reductant applied? If yes, what was its formulation?

Did patient receive the aftercare kit (e.g. toothpaste, mouth rinse and spray)?

Length of follow-up:

Compliance with the treatment:

Number lost to follow-up:

Caries Information

Method of caries examination:

Tooth location, lesion location, and type of lesion:

Severity of caries:

Outcomes

Intervention 1 Intervention 2 Intervention 3 Non-cavitated caries

Reversal of caries

Progression of caries

Utilisation of dental resources

Adverse reactions

Patient–centred measures (e.g. patient satisfaction and preference, relief of pain/discomfort)

Quality of life

Cavitated caries

Time to restorative interventions

Need for further restorative interventions

Symptoms of pulpal pathology

Other comments

58 Health Technology Assessment 2006; Vol. 10: No. 16

Appendix 3 Checklist for the quality assessment of randomised controlled trials

(adapted from Verhagen, 199834)

Criteria Yes No Unclear Comments

1. Was the assignment to the treatment groups really random? Adequate approaches to sequence generation computer-generated random tables random number tables Inadequate approaches to sequence generation use of alternation, case record numbers, birth dates or week days 2. Was the unit of randomisation clear? 3. Was the treatment allocation concealed? Adequate approaches to concealment of randomisation centralised or pharmacy-controlled randomisation serially-numbered identical containers on-site computer based system with a randomisation sequence that is not readable until allocation other approaches with robust methods to prevent foreknowledge of the allocation sequence to clinicians and patients Inadequate approaches to concealment of randomisation use of alternation, case record numbers, birth dates or week days open random numbers lists serially numbered envelopes (even sealed opaque envelopes can be subject to manipulation) 4. Were the groups similar at baseline in terms of prognostic factors? 5. Were the eligibility criteria specified? 6. Were the groups treated in the same way apart from the intervention received? 7. Was the outcome assessor blinded to the treatment allocation? 8. Was the care provider blinded? 9. Were the patients blinded? 10. Were the point estimates and measures of variability presented for the primary outcome measures? 11. Was the withdrawal/dropout rate likely to cause bias? 12. Did the analyses include an intention-to-treat analysis?

Health Technology Assessment 2006; Vol. 10: No. 16

Appendix 4 Characteristics of included studies: full-text reports

© Queen’s Printer and Controller of HMSO 2006. All rights reserved. Appendix 4 continued , but no ” presented with any “ form of discomfort were immediately treated with conventional drilling and filling procedures further information was provided Methods for statistical analyses not clearly reported. Unclear whether the results were adjusted for covariates/risk factors Emphasis on non-cavitated lesions The number of lesions in each intervention group was not clearly reported All subjects enrolled in the study received preventive advice, including oral hygiene and dietary advice, and were given a toothbrush and toothpaste (Natural White, Natural White Inc., USA, 1100 ppm F) Unclear whether cleaning of the root surface was performed before treatment in groups 2, 3 and 4 It was reported that subjects who < 0.001). 52% p < 0.001) p + sealant group compared < 0.001) < 0.001) 3 p p Reversal of caries, groups 1 and 2: Reversal at 12 months 47% of PRCLs reversed from severity index 1 to 0 (hard) in the ozone group, while none became hard in the control group ( of lesions reversed from 2 to 1 in the ozone group compared with 11.6% in the control group ( Cavitated lesions in the ozone group did not show the same trend of improvement non- of cavitated lesions. Percentage lesions that became hard decreased from 9.1 at 1 month to 1.4 at 9 months, suggesting worsening of cavitated carious lesions. Data for the control group were not given Marginal adaptation of the root sealant (modified USPHS criteria): 61% intact sealants in the O with 26.1% in the sealant-only group ( Significant differences in the changes in both the ECM readings and DIAGNOdent readings in the ozone and control groups ( Adverse events: none observed + sealant (Seal 3 + reductant 3 & Protect, Dentsply, & Protect, Germany) The procedure was repeated at 3 months. Sealants were reapplied only if a partial or complete loss of the sealant was suspected Group 4: sealant only (Seal Dentsply, & Protect, Germany) Sealants were reapplied after 1 and 3 months only if a partial or complete loss of the sealant was suspected formulation: Reductant Sodium fluoride (1100 ppm F), xylitol, sodium benzoate, among other active ingredients Ozone dosage: 10 seconds Group 1: cleaning of the tooth surface, application of O The procedure was repeated after 1 month without ozone and at 3 months with ozone Group 2: reductant only. The procedure was repeated after 1 month and at the 3-month follow-up Group 3: O Two or four Two primary non- cavitated and cavitated root carious lesions with severity index II (leathery lesions) Design: RCT (unpublished) Unit of randomisation: lesion Method of randomisation: NS Concealment of allocation: NS Blinding: unclear no ITT: Length of follow- up: 12 months Lost at follow-up: five subjects Comparability of groups at baseline: unclear Setting: general dental practices 72) years – =79 (220 primary Gender (M/F): 49/30 and lesion location: Tooth root surface lesions. Caries risk assessment: NS n cavitated and non- cavitated root carious lesions) Age, mean ± SD (range): 65 ± 14.76 (30 carious lesions of participants and criteria 44 Characteristics of full-text reports – 36,41 Author(s) No. and characteristics Design Inclusion Interventions Results Notes and caveats (Belfast, UK) Baysan and Lynch, 2004 Root caries: permanent dentition Root

62 21 TABLE Health Technology Assessment 2006; Vol. 10: No. 16 continued Caries assessment: ECM III The (Lode Diagnostics BV, Netherlands), DIAGNodent Germany) and (KaVo, clinical criteria. The severity of lesions was assessed on a scale (0 = hard four-point lesions; 4 = soft lesions). In addition, modified USPHS criteria were used for assessing groups 3 and 4 Assessors/operators: single operator (A. Baysan) Ozone device output: NS of participants and carious lesions criteria Characteristics of full-text reports (cont’d) Author(s) No. and characteristics Design Inclusion Interventions Results Notes and caveats

TABLE 21 TABLE 63

© Queen’s Printer and Controller of HMSO 2006. All rights reserved. Appendix 4 continued seem to 40 contradict those reported in the full text All subjects enrolled in the study received information on oral hygiene, brushing techniques and diet. In all subjects particular, received instructions on how to use the remineralising toothpaste the mineral twice a day, mouthwash twice a day and the remineralising spray four times a day All subjects were offered a pharmacological treatment, which they all accepted as an alternative to the traditional drilling and filling. No details of the pharmacological treatment were provided The two dentists who allocated subjects to intervention groups and assessed severity of lesions, and the third dentist who assessed reproducibility of data, were not acknowledged in the paper The 21-month findings published in abstract format (Holmes, 2004 . < 0.01) p 18 months follow-up of caries: 87/87 lesions in Reversal the ozone group reversed (became hard) compared with 1/87 in the control group ( Progression of caries: 32/87 Progression lesions in the control group worsened from leathery to soft and 54/87 did not change Adverse events: none observed 3 3 Group 1: application of O + reductant patient care kit Group 2: air treatment + reductant only + patient care kit applications of O Repeated + reductant at 3, 6, 12 and 18 months formulation: Reductant xylitol, fluoride, calcium, phosphate and zinc (no concentrations provided) Ozone dosage: 40 seconds Caries assessment: ECM The (Lode Diagnostics BV, Netherlands), DIAGNodent Germany) and (KaVo, visual/tactile examination method Assessors/operators: the ozone treatment was applied by a different operator to the one recording the severity of lesions. Unclear whether the operator who assessed outcomes was the same one who did allocated subjects to intervention groups. A sample of 15 subjects (30 lesions) was examined by a third dentist to test reproducibility of results Adults with two leathery non-cavitated PRCLs Design: RCT Unit of randomisation: lesion Method of randomisation: computer- generated random tables Concealment of allocation: NS Blinding: double blind ITT: no Length of follow- up: 3, 6, 12, 18 and 21 months Lost at follow-up: two at 18 months Comparability of groups at baseline: unclear Setting: general dental practice 82) – leathery roof = 89 (178 primary non- Tooth and lesion Tooth location: surface lesions (severity index II) Caries risk assessment: NS n cavitated root carious lesions, 89 lesions in each group) Age, mean ± SD (range): 70.8 ± 6 (60 carious lesions of participants and criteria 35,39,40 Characteristics of full-text reports (cont’d) Holmes, 2003 (Berkshire, UK) Author(s) No. and characteristics Design Inclusion Interventions Results Notes and caveats

64 21 TABLE Health Technology Assessment 2006; Vol. 10: No. 16 continued Ozone device output: it was reported that the HealOzone unit was fitted with a modified control integrated electronic chip. Unclear whether this modified chip could allow better calibration and monitoring of ozone doses carious lesions of participants and criteria Characteristics of full-text reports (cont’d) Author(s) No. and characteristics Design Inclusion Interventions Results Notes and caveats

TABLE 21 TABLE 65

© Queen’s Printer and Controller of HMSO 2006. All rights reserved. Appendix 4 continued application 3 attendance to ’ All subjects enrolled in the study received preventive advice and were given a toothbrush and toothpaste (Natural White; Natural White Inc., UK, 1100 ppm F) Sealant was reapplied if necessary and O follow-up visits varied. The number of subjects assessed by ECM differed from the number of subjects assessed by DIAGNOdent at follow- up visits repeated Subjects e > 0.05) at any follow- = 0.75) = 0.54 p p p = 0.112) p up visits Groups 3 and 4 Secondary caries: no significant differences between groups (two secondary caries in the ozone group and two secondary caries in the control group) Excluding teeth with baseline ECM score 0: Group 1 (77 lesions): 0.327 (1.32) Group 2 (69 lesions): 0.073 (1.37); DIAGNOdent values: no significant differences between groups ( change 0.020 (1.4) Group 2 (109 lesions): 0.073 (1.61) ( Groups 1 and 2 of caries: no significant Reversal differences between groups in the mean change from baseline: Group 1: 0.283 (0.64) Group 2: 0.443 (0.74); ( ECM values: no significant differences in the mean change from baseline values between groups: Group 1 (109 lesions): mean log 3 + reductant 3 In addition, modified 9 Before treatment all lesions were disclosed and cleaned system with an air-abrasive (PROPHYflex 2, KaVo, Germany) Group 1: application of O fissure sealant (Guardian, Kerr) Group 4: reductant + sealant formulation: Reductant Sodium fluoride (1100 ppm F), xylitol and zinc chloride among other active ingredients Ozone dosage: 10 seconds Caries assessment: ECM The (Lode Diagnostics BV, Netherlands), DIAGNodent Germany) and (KaVo, clinical severity (Ekstrand, 1998). + reductant Group 2: reductant only/control Group 3: O USPHS criteria + radiographic assessments were used for assessing groups 3 and 4 Males and females >12 years old with primary occlusal pit and fissure carious lesions in at least two teeth of the permanent posterior dentition, which were accessible for the diagnostic procedures = 0.055). p Design: RCT (unpublished) Unit of randomisation: lesion Method of randomisation: random sampling digit tables Concealment of allocation: NS Blinding: unclear no ITT: Length of follow- up: 1, 3, 6, 9 and 12 months Lost at follow-up: 32 subjects Comparability of groups at baseline: more severe lesions (index scores of 2 and 3) in the treatment group ( More molars in the treatment group than in the control group. Setting: general dental practice = 90 n (258 primary occlusal pit and fissure carious lesions) Age: 79 subjects between 12 and 31 years, 8 subjects between 32 and 41 years, and 3 subjects >41 years Gender (M/F): 35/55 and lesion location: Tooth all posterior teeth in the upper and lower jaws. Central grooves and pits were the most commonly observed lesions Caries risk assessment: NS of participants and criteria carious lesions 50 – a, 2003, 37,45 ’ Characteristics of full-text reports (cont’d) Author(s) No. and characteristics Design Inclusion Interventions Results Notes and caveats (Belfast, UK) Abu-Naba main study Pit and fissure caries: permanent dentition

66 21 TABLE Health Technology Assessment 2006; Vol. 10: No. 16 continued > 0.05) p + sealant group 3 Sealant retention: partial loss in the margins of sealants in 32.7% in the O compared with 29.8% in the sealant-only group ( No significant differences in terms of fissure sealant colour and radiographic depth of radiolucency between groups a) ’ Ozone device output: NS Assessors/operators: three operators were reported to assess radiographs. A single operator assessed the lesions and interpreted ECM and DIAGNOdent findings (L. Abu-Naba of participants and criteria carious lesions Characteristics of full-text reports (cont’d) Author(s) No. and characteristics Design Inclusion Interventions Results Notes and caveats

TABLE 21 TABLE 67

© Queen’s Printer and Controller of HMSO 2006. All rights reserved. Appendix 4 continued All subjects enrolled in the study received preventive advice and were given a toothbrush and toothpaste (1100 ppm F) < 0.05) > 0.05) p p > 0.05) < 0.05) p p > 0.05) > 0.05) > 0.05) p p p Clinical severity scores: not significant differences between groups at any follow-up visits ( ECM and DIAGNOdent readings: no significant differences between groups ( Clinical indices Hardness index score: 11 lesions in the ozone group became harder compared with four in the control group ( lesions in the control group Two became softer Change in the visual index score: eight teeth in the treatment group changed positively at the 6-month follow-up compared with one tooth in the control group ( Change in the cavitation score: six teeth had a decreased cavity score in the ozone group compared with five teeth in the control group. The difference between intervention groups was not significant ( Change in colour: no significant differences between groups ( Change in frosted enamel and undermined enamel: no significant differences between groups ( 3 a) ’ 9 3 Ozone device output: 33% of the outcome expected + reductant Group 2: reductant only At 3 months group 1 received another application of O formulation: Reductant sodium fluoride (1100 ppm F), xylitol and zinc chloride among other active ingredients Ozone dosage: 40 seconds Caries assessment: ECM The (Lode Diagnostics BV, Netherlands), DIAGNOdent Germany), and (KaVo, clinical criteria (Ekstrand, 1998) Assessors/operators: It would seem that Unclear. a single operator assessed the lesions and interpreted ECM and DIAGNOdent findings (L. Abu-Naba Before treatment all lesions were disclosed and cleaned system with an air-abrasive (PROPHYflex 2, KaVo, Germany) Group 1: application of O Males and females >12 years old with primary occlusal pit and fissure carious lesions in at least two teeth of the permanent posterior dentition, which were accessible for the diagnostic procedures Design: RCT (unpublished) Unit of randomisation: lesion Method of randomisation: random sampling digit tables Concealment of allocation: NS Blinding: unclear no ITT: Length of follow- up: 1, 3 and 6 months Lost at follow-up: unclear Comparability of groups at baseline: more severe lesions (index score of 3) in the control group Setting: general dental practice = 8 n (38 occlusal pit and fissure lesions, 19 in each group) of participants and criteria carious lesions a, 2003, 37,51,52 ’ Characteristics of full-text reports (cont’d) Author(s) No. and characteristics Design Inclusion Interventions Results Notes and caveats (Belfast, UK) Abu-Naba pilot study

68 21 TABLE Health Technology Assessment 2006; Vol. 10: No. 16 ECM e All subjects received preventive advice and were given a toothbrush (Brilliant, soft toothbrush; UK) Brilliant Products, and toothpaste (Natural White, Natural White Inc., UK 1100 ppm F) at each recall to be used throughout the study The mean log readings, mean DIAGNOdent readings, ECM scores, DIAGNOdent scores and clinical severity index were analysed (mixed using ANOVA effect model) reported in a Results format that did not allow any further analysis < 0.05) p ECM readings e < 0.001) and an overall < 0.001). There was < 0.001) and the mean < 0.01) p p p increase in the DIAGNOdent scores in the control group compared with the ozone group ( also an overall significant effect of time and treatment on ECM scores ( DIAGNOdent readings ( 12-month follow-up Clinical severity scores: overall there was a little reduction in clinical severity scores in the ozone group and an increase in scores the control group. There was a significant effect of treatment on clinical severity scores over time (mixed models ANOVA p Log ECM and DIAGNOdent readings: there was a significant effect of time and treatment on the mean log ( + reductant 3 9 Group 2: reductant only formulation: Reductant sodium benzoate (1100 ppm F), xylitol, zinc chloride and sodium citrate among other active ingredients Ozone dosage: 10 seconds Caries assessment: ECM The (Lode Diagnostics BV, Netherlands), DIAGNOdent Germany) and (KaVo, clinical criteria (Ekstrand, 1998) Before treatment, teeth were cleaned using the PROPHYflex-2 system for 5 seconds Group 1: O 9 years old – Children 7 with at least two carious lesions in the posterior primary teeth and absence of occlusal restoration, fissure sealants, hypoplastic pits and fractures extending into dentine or cavitations resulting from carious attack on the occlusal surface < 0.01). p Design: RCT (unpublished) Unit of randomisation: lesion Method of randomisation: computer-generated random tables Concealment of allocation: NS Blinding: examiner blinded to results of previous tests and outcomes of previous records no ITT: Length of follow-up: 3, 6, 9 and 12 months Lost at follow-up: four subjects (16 lesions) Comparability of groups at baseline: there was a significant difference in mean DIAGNOdent scores at baseline ( Lesions in ozone group appeared to be more severe than those in the control group. Setting: general dental practice , ozone gas. 3 9 years – = 21 n (74 non-cavitated occlusal carious lesions in primary molars) Age range: 7 (7 years 28%, 8 48%, 9 years 24%) Gender (M/F): 9/21 Caries risk assessment: NS of participants and carious lesions criteria 38 Characteristics of full-text reports (cont’d) Author(s) No. and characteristics Design Inclusion Interventions Results Notes and caveats (Belfast, UK) Abu-Salem, 2004 Pit and fissure caries: primary dentition NS, not stated; ITT, intention-to-treat, O NS, not stated; ITT,

TABLE 21 TABLE 69

Health Technology Assessment 2006; Vol. 10: No. 16

Appendix 5 Characteristics of included studies: abstracts

© Queen’s Printer and Controller of HMSO 2006. All rights reserved. Appendix 5 continued is a measure ’ Sensitivity used to assess large necrotic lesions and it is considered inappropriate for assessing early carious lesions Progression of caries in the Progression conventional treatment group not reported ‘ : 189/200 of : at 6 months, 48/60 of < 0.01) p < 0.01) p Reversal of caries: Reversal Soft lesions ozone-treated soft PRCLs had reversed (from index 4 to 3), no significant changes in control soft lesions ( Leathery lesions ozone-treated PRCLs had reversed from index 1 to 0 (hard to arrested), no significant changes for control lesions ( Adverse events: none observed No post-operative sensitivity was associated with ozone treatment, while 6/35 subjects in the conventional treatment group complained of some postoperative sensitivity of caries: at 3 months all Reversal ozone dentine caries was hard and required no additional removal Adverse events: none observed 3 (260 lesions) 3 Group 1: O Group 1: air abrasion + O Group 2: no treatment (260 lesions) Ozone dosage: NS Caries assessment: clinical assessment + mineral wash glass ionomer sealant. After 3 months the glass ionomer sealant was dissected and replaced with a posterior composite Group 2: conventional drilling and filling using posterior composite Ozone dosage: 40 seconds Caries assessment: radiographic and clinical assessment 4 mm into – Two primary Two root carious lesions non- Two cavitated early occlusal carious lesions with radiographic radiolucencies extending 2 dentine Design: RCT Unit of randomisation: lesion Concealment of allocation: NS Blinding: blinded outcome assessor no ITT: Length of follow-up: 6 months Lost at follow-up: NS Setting: NS Design: RCT Unit of randomisation: lesion Concealment of allocation: NS Blinding: NS no ITT: Length of follow-up: 6 months Lost at follow-up: three subjects Setting: general dental practice lesions) (no. and type of criteria 260 (two PRCLs: 60 subjects with two soft PRCLs and 200 with two leathery non- cavitated PRCLs, least severe category) 38 (76 non-cavitated occlusal caries lesions) Characteristics of abstracts (Belfast, (Belfast, et al., 57 53 Author(s) No. of participants Design Inclusion Interventions Results Notes UK) Holmes and Lynch, 2004 UK) Lynch Lynch 2004 Pit and fissure caries Root caries Root

72 22 TABLE Health Technology Assessment 2006; Vol. 10: No. 16 continued A total of 1937/2364 received ozone application. Unclear how many lesions were randomly allocated to each group (unbalanced randomisation?) < 0.01) p < 0.05) p Reversal of caries: 99% in the Reversal ozone group (1918 lesions); the control lesions did not change significantly The DIAGNOdent values correlated with the clinical findings ( Adverse events: none observed of caries: 86.6% in the Reversal ozone group; the control lesions did not change significantly ( The DIAGNOdent values correlated with the clinical findings Adverse events: none observed treatment treatment 3 3 Group 2: no treatment Ozone dosage: 10, 20, 30 or 40 seconds depending on the clinical severity. Applications were repeated every 3 months if reversal had not occurred Caries assessment: DIAGNOdent (KaVo, Germany) and clinical assessment (92 lesions) Group 2: no treatment (92 lesions) Ozone dosage: 40 seconds at baseline and 3 months Caries assessment: clinical assessment and DIAGNOdent (KaVo, Germany) Group 1: O Group 1: O Primary occlusal fissure lesions with caries judged to extend 2 mm into dentine (1170 teeth) early Primary occlusal pit/fissure lesions with caries extending up to 1 mm into dentine Design: RCT Unit of randomisation: lesion Concealment of allocation: NS Blinding: NS no ITT: Length of follow-up: 12 months Lost at follow-up: 61 Setting: general dental practice Design: RCT Unit of randomisation: patient Concealment of allocation: NS Blinding: NS unclear ITT: Length of follow-up: 6 months Lost at follow-up: unclear Setting: NS lesions) (no. and type of criteria 376 (2364 primary non- cavitated occlusal fissure lesions) 184 (184 non-cavitated pit and fissure carious lesions) 54 55 Characteristics of abstracts (cont’d) Author(s) No. of participants Design Inclusion Interventions Results Notes Hamid, 2003 (Berkshire, UK) (London, UK) Holmes, 2003

TABLE 22 TABLE 73

© Queen’s Printer and Controller of HMSO 2006. All rights reserved. Appendix 5 Unclear whether the proportion of lesions that clinically reversed or showed a reduction in DIAGNOdent readings were all ozone-treated lesions or included some control lesions < 0.05), while control lesions p Reversal of caries: ozone-treated Reversal lesions clinically reversed ( did not DIAGNOdent: significant overall reduction in readings for ozone- treated lesions, while control lesions showed an increase in DIAGNOdent readings 85% of teeth clinically reversed and showed a DIAGNOdent reduction (220 lesions) 3 Group 2: no treatment (80 lesions) Ozone dosage: 20, 30 or 40 seconds according to clinical severity Caries assessment: clinical assessment and DIAGNOdent (KaVo, Germany) Group 1: O Pit and fissure carious lesions Design: randomised clinical trial Unit of randomisation: lesion Concealment of allocation: NS Blinding: double blind no ITT: Length of follow-up: 6 months Lost at follow-up: NS Setting: private practice, Italy lesions) (no. and type of criteria 80 (300 pit and fissure carious lesions) 56 Characteristics of abstracts (cont’d) Author(s) No. of participants Design Inclusion Interventions Results Notes Megighian and Bertolini, 2004 Italy) (Verona,

74 22 TABLE Health Technology Assessment 2006; Vol. 10: No. 16

Appendix 6 Structure of the economic model

Decision models to assess costs consequences that occur over a series of years (in and benefits of HealOzone this study up to 5 years). At the beginning of the first year each patient receives current The four models depicted in Figures 15–18 have a management plus HealOzone and hence a similar structure; therefore, only current probability of 1 is attached. At the end of the first management plus HealOzone is described here. year there is a chance that the patients are cured Markov models can be used to estimate costs and (caries are reversed) or they have progressed. If

Cure Current management Cured post current management plus HealOzone probcurel plus HealOzone Retreatment 1 Retreatment Progress probretreat # New treatment Filled tooth # Cured post current management plus HealOzone Current management plus HealOzone 0 M Cured Cured post retreatment Retreatment probcure Progress 0 Filled tooth 1-probcurel Cured post retreatment 0 Filled tooth 0

FIGURE 15 Decision model to assess the cost and benefits of current management plus HealOzone of non-cavitated root caries (Markov model)

Cure Cured post current management probcure Current management Retreatment 1 Retreatment Progress probretreat # New treatment Filled tooth # Cured post current management

Current management 0 M Cured Cured post retreatment Retreatment probcure 0 Progress Filled tooth 1-probcure Cured post retreatment 0 Filled tooth 0

FIGURE 16 Decision model to assess the costs and benefits of current management of non-cavitated root caries 75

Cure Cured post current management probcure Current management Retreatment 1 Retreatment Progress probretreat # New treatment Filled tooth # Cured post current management

Current management 0 M Cured Cured post retreatment Retreatment probcure 0 Progress Filled tooth 1-probcure Cured post retreatment 0 Filled tooth 0

FIGURE 17 Decision model to assess the costs and benefits of current management of non-cavitated pit and fissure caries

Cure Current management Cured post current management plus HealOzone probcurel plus HealOzone Retreatment 1 Retreatment Progress probretreat # New treatment Filled tooth # Cured post current management plus HealOzone Current management plus HealOzone 0 M Cured Cured post retreatment Retreatment probcurel 0 Progress Filled tooth 1-probcurel Cured post retreatment 0 Filled tooth 0

FIGURE 18 Decision model to assess the costs and benefits of current management plus HealOzone of non-cavitated pit and fissure caries

they have progressed there is a chance that they of cure does not change in the third branch and receive the same treatment or a new treatment those who go into the third branch are either (filling). The chance of a patient being cured is cured or filled. The filled tooth state is a terminal ‘pbcure1’ and not being cured is ‘1-pbcure1’. The state and patients do not leave it. The model also chance that a patient will receive the same assumes that when a patient is cured they remain treatment is ‘probretreat’. In the model it is cured for as long as the model runs. assumed that the patient has a 50% chance of receiving the same treatment or having a filling. If Details of cost calculations are shown in the first treatment fails the patient moves to the Tables 23–30. 76 third branch or the fifth branch. The probability Health Technology Assessment 2006; Vol. 10: No. 16

TABLE 23 Annual treatment numbers for non-cavitated caries based on each relevant SDR code by age group for year ending March 200365

Treatment No. of Total teeth SDR code numbers caries types No. of teeth treated

Age <18 years Non-cavitated pit and fissure caries 601 3,930 2 1 1,965 3631 2,393 2 1 1,196.5 701 73 1 1 73 Total 3,234.5 Non-cavitated root caries 601 3,930 2 1 1,965 3631 2,393 2 1 1,196.5 Total 3,161.5

Age ≥18 years Non-cavitated pit and fissure caries 601 11,728 2 1 5,864 3631 669,304 2 1 334,652 701 1,922 1 1 1,922 Total 342,438 Non-cavitated root caries 601 11,728 2 1 5,864 3631 669,304 2 1 334,652 Total 340,516

Where one SDR code was relevant to more than one type of caries the published treatment numbers were divided by the number of relevant types of caries. Similar adjustments were provided for the numbers of teeth to which any one SDR code applied.

TABLE 24 Percentage teeth treated by age group of patient, based on numbers in Table 23

SDR code <18 years (%) ≥18 years (%)

Non-cavitated pit and fissure caries 601 25.1 74.9 3631 0.4 99.6 701 3.7 96.3 Non-cavitated root caries 601 25.1 74.9 3631 0.4 99.6

TABLE 25 Calculation for cost to NHS based on 100% treatment items paid for those <18 years and 40% all treatment items paid for those ≥ 18 years

NHS cost (£)

SDR code <18 years ≥18 years Unit cost <18 years ≥18 years Weighted (£) average NHS fee across all age (£)

Non-cavitated pit and 601 25.1% 74.9% 7.70 7.70 3.08 4.24 fissure caries 3631 0.4% 99.6% 4.60 4.60 1.84 1.85 701 3.7% 96.3% 6.95 6.95 2.78 2.93 Total 19.25 7.70 9.02 Non-cavitated root caries 601 25.1% 74.9% 7.70 7.70 3.08 4.24 3631 0.4% 99.6% 4.60 4.60 1.84 1.85 Total 12.30 4.92 6.09

TABLE 26 Cost calculations for treatment of cavitated caries

SDR code Total annual Annual No. of No. of Total teeth treatment treatment caries teeth treated numbers numbers types

Age <18 years Cavitated pit and fissure caries 1441 1,025,404 1 1 1442 201,308 1 1 201,308 1443 163,379 1 1 163,379 Anterior teeth 1401a 557,753 278,876.5 1 1 278,876.5 Posterior teeth 1421a 386,061 193,030.5 1 1 193,030.5 1421a 35,681 17,840.5 1 2 35,681 Age ≥18 years Cavitated pit and fissure caries 1441 147,980 1 1 147,980 1442 86,667 1 1 86,667 1443 68,353 1 1 68,353 1401a 1,671,224 835,612 1 1 835,612 1421a 4,141,954 2,070,977 1 1 2,070,977 1421a 346,816 173,408 1 2 346,816

Figures assume a treatment mix of SDR codes 1441, 1442 and 1443 plus either 1401 or 1421. All patients also receive SDR code 0101 (initial dental assessment). It is also assumed that 50% of treatments are for anterior and 50% for posterior teeth. a 50% mix assumed.

TABLE 27 Steps used to calculate the mean cost of a filling when different proportions of children and adults receive different treatment mixes by SDR code

% treatment for NHS cost (£) cavitated caries (fillings)

SDR <18 years 18 years Unit cost <18 years 18 years Weighted code (£) average NHS fee across all age (£)

1441 87.4 12.6 6.95 6.95 2.78 6.42 1442 69.9 30.1 9.80 9.80 3.92 8.03 1443 70.5 29.5 10.55 10.55 4.22 8.68 1401a 25.0 75.0 7.50 7.50 3.00 4.13 1421a 8.5 91.5 14.15 14.15 5.66 6.38 1421a 9.3 90.6 14.15 14.15 5.66 6.45 63.10 63.10 25.24 40.10 Overall % mix children/adults for fillings and mean cost per filling 45.1 54.9 12.62 12.62 5.05 8.02 Initial dental assessment 101 100 100 7.05 7.05 2.82 4.73 Total average cost per filling visit 19.67 7.87 12.75

a 50% mix assumed.

78 Health Technology Assessment 2006; Vol. 10: No. 16

TABLE 28 HealOzone cost calculations

% who have caries treatmenta Cost to NHS (£) 1st year initial treatment Unit cost <18 years 18 years <18 years 18 years Weighted option (£) average cost to NHS (£)

Non-cavitated pit and fissure caries Currentb 19.25 19.25 7.70 9.02 HealOzone 20.00 20.00 8.00 25.1 74.9 11.01 Current + HealOzone 39.25 15.70 20.03 Non-cavitated root caries Currentb 12.30 12.30 4.92 6.09 HealOzone 20.00 20.00 8.00 25.1 74.9 11.01 Current + HealOzone 32.30 12.92 17.10

a Non-cavitated pit and fissure caries treatment or non-cavitated root caries treatment (see Table 25). b See Tables 24 and 25.

Non-cavitated pit and fissure caries

The combined cost of HealOzone and current management is £40.49 and the cost of current management alone is £24.78.

TABLE 29 Results of one-way sensitivity analysis for non-cavitated pit fissure caries (current management versus current management and HealOzone) holding ‘current management plus HealOzone’ cost constant

Current Additional cost of Probability Proportion cured Proportion filled management HealOzone HealOzone

0 0 1 £26.06 £40.49 £14.43 0.1 0.015 0.985 £23.81 £40.49 £16.68 0.2 0.145 0.855 £21.67 £40.49 £18.82 0.3 0.28 0.72 £19.66 £40.49 £20.83 0.4 0.405 0.595 £17.77 £40.49 £22.72 0.5 0.52 0.48 £16.00 £40.49 £24.49 0.6 0.625 0.375 £14.36 £40.49 £26.13 0.7 0.72 0.28 £12.84 £40.49 £27.65 0.8 0.805 0.195 £11.44 £40.49 £29.05 0.9 0.88 0.12 £10.17 £40.49 £30.32 1 1 0 £9.02 £40.49 £31.47

TABLE 30 Results of one-way sensitivity analysis for non-cavitated pit fissure caries (current management versus current management and HealOzone) holding current management cost constant

Current Additional cost of Probability Proportion cured Proportion filled management HealOzone HealOzone

0 0 1 £24.78 £42.58 £17.80 0.1 0.015 0.985 £24.78 £39.77 £14.99 0.2 0.145 0.855 £24.78 £37.08 £12.30 0.3 0.28 0.72 £24.78 £34.52 £9.74 0.4 0.405 0.595 £24.78 £32.08 £7.30 0.5 0.52 0.48 £24.78 £29.76 £4.98 0.6 0.625 0.375 £24.78 £27.57 £2.79 0.7 0.72 0.28 £24.78 £25.50 £0.72 0.8 0.805 0.195 £24.78 £23.55 –£1.23 0.9 0.88 0.12 £24.78 £21.73 –£3.05 1 1 0 £24.78 £20.03 –£4.75 79

Non-cavitated root caries

The combined cost of HealOzone and current management is £14.63 and the cost of current management alone is £21.45 (Tables 31 and 32).

TABLE 31 Results of one-way sensitivity analysis for non-cavitated root caries (current management versus current management and HealOzone) holding current management cost constant

Current Additional cost of Probability Proportion cured Proportion filled management HealOzone HealOzone

0 0 1 £21.45 £38.18 £16.73 0.1 0.145 0.855 £21.45 £35.52 £14.07 0.2 0.28 0.72 £21.45 £32.98 £11.53 0.3 0.405 0.595 £21.45 £30.57 £9.12 0.4 0.52 0.48 £21.45 £28.27 £6.82 0.5 0.625 0.375 £21.45 £26.10 £4.65 0.6 0.72 0.28 £21.45 £24.06 £2.61 0.7 0.805 0.195 £21.45 £22.13 £0.68 0.8 0.88 0.12 £21.45 £20.33 –£1.12 0.9 0.945 0.055 £21.45 £18.65 –£2.80 1 1 0 £21.45 £17.10 –£4.35

TABLE 32 Results of one-way sensitivity analysis for non-cavitated root caries (current management versus current management and HealOzone) holding ‘current management plus HealOzone’ cost constant

Current Additional cost of Probability Proportion cured Proportion filled management HealOzone HealOzone

0 0 1 £21.67 £14.63 –£7.04 0.1 0.145 0.855 £19.56 £14.63 –£4.93 0.2 0.28 0.72 £17.57 £14.63 –£2.94 0.3 0.405 0.595 £15.70 £14.63 –£1.07 0.4 0.52 0.48 £13.96 £14.63 £0.67 0.5 0.625 0.375 £12.34 £14.63 £2.29 0.6 0.72 0.28 £10.84 £14.63 £3.79 0.7 0.805 0.195 £9.47 £14.63 £5.16 0.8 0.88 0.12 £8.22 £14.63 £6.41 0.9 0.945 0.055 £7.09 £14.63 £7.54 1 1 0 £6.09 £14.63 £8.54

80 Health Technology Assessment 2006; Vol. 10: No. 16

Health Technology Assessment Programme

Director, Deputy Director, Professor Tom Walley, Professor Jon Nicholl, Director, NHS HTA Programme, Director, Medical Care Research Department of Pharmacology & Unit, University of Sheffield, Therapeutics, School of Health and Related University of Liverpool Research

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Programme Director, Professor Ann Bowling, Professor Fiona J Gilbert, Dr Linda Patterson, Professor Tom Walley, Professor of Health Services Professor of Radiology, Consultant Physician, Director, NHS HTA Programme, Research, Primary Care and Department of Radiology, Department of Medicine, Department of Pharmacology & Population Studies, University of Aberdeen Burnley General Hospital Therapeutics, University College London University of Liverpool Professor Adrian Grant, Professor Ian Roberts, Professor Dr Andrew Briggs, Public Director, Health Services Chair, of Epidemiology & Public Health Career Scientist, Health Research Unit, University of Professor Jon Nicholl, Health, Intervention Research Economics Research Centre, Aberdeen Director, Medical Care Research Unit, London School of University of Oxford Unit, University of Sheffield, Hygiene and Tropical Medicine Professor F D Richard Hobbs, School of Health and Related Professor John Cairns, Professor Professor of Primary Care & Research Professor Mark Sculpher, of Health Economics, Public General Practice, Department of Professor of Health Economics, Deputy Chair, Health Policy, London School of Primary Care & General Centre for Health Economics, Professor Jenny Hewison, Hygiene and Tropical Medicine, Practice, University of Institute for Research in the Professor of Health Care London Birmingham Social Services, University of York Psychology, Academic Unit of Psychiatry and Behavioural Professor Nicky Cullum, Professor Peter Jones, Head of Dr Jonathan Shapiro, Senior Sciences, University of Leeds Director of Centre for Evidence Department, University Fellow, Health Services School of Medicine Based Nursing, Department of Department of Psychiatry, Management Centre, Health Sciences, University of University of Cambridge Birmingham York Dr Jeffrey Aronson Professor Sallie Lamb, Reader in Clinical Mr Jonathan Deeks, Professor of Rehabilitation, Ms Kate Thomas, Pharmacology, Department of Senior Medical Statistician, Centre for Primary Health Care, Deputy Director, Clinical Pharmacology, Centre for Statistics in University of Warwick Medical Care Research Unit, Radcliffe Infirmary, Oxford Medicine, University of Oxford University of Sheffield Professor Deborah Ashby, Professor Stuart Logan, Professor of Medical Statistics, Dr Andrew Farmer, Senior Director of Health & Social Ms Sue Ziebland, Department of Environmental Lecturer in General Practice, Care Research, The Research Director, DIPEx, and Preventative Medicine, Department of Primary Peninsula Medical School, Department of Primary Health Queen Mary University of Health Care, Universities of Exeter & Care, University of Oxford, London University of Oxford Plymouth Institute of Health Sciences 93 Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)

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94 Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk) Health Technology Assessment 2006; Vol. 10: No. 16

Therapeutic Procedures Panel Members Chair, Dr Carl E Counsell, Clinical Ms Maryann L Hardy, Professor James Neilson, Professor Bruce Campbell, Senior Lecturer in Neurology, Lecturer, Division of Professor of Obstetrics and Consultant Vascular and Department of Medicine and Radiography, University of Gynaecology, Department of General Surgeon, Department Therapeutics, University of Bradford Obstetrics and Gynaecology, of Surgery, Royal Devon & Aberdeen University of Liverpool Exeter Hospital Professor Alan Horwich, Ms Amelia Curwen, Executive Dr John C Pounsford, Director of Clinical R&D, Director of Policy, Services and Consultant Physician, Academic Department of Research, Asthma UK, London Directorate of Medical Services, Radiology, The Institute of North Bristol NHS Trust Professor Gene Feder, Professor Cancer Research, of Primary Care R&D, London Karen Roberts, Nurse Department of General Practice Consultant, Queen Elizabeth Hospital, Gateshead and Primary Care, Barts & the Dr Simon de Lusignan, London, Queen Mary’s School Senior Lecturer, Dr Vimal Sharma, Consultant Dr Aileen Clarke, of Medicine and Dentistry, Primary Care Informatics, Psychiatrist/Hon. Senior Lecturer, Reader in Health Services London Department of Community Mental Health Resource Centre, Research, Public Health & Health Sciences, Cheshire and Wirral Partnership Policy Research Unit, Barts & Professor Paul Gregg, St George’s Hospital Medical NHS Trust, Wallasey the London School of Medicine Professor of Orthopaedic School, London & Dentistry, London Surgical Science, Department of Dr L David Smith, Consultant General Practice and Primary Cardiologist, Royal Devon & Professor Neil McIntosh, Dr Matthew Cooke, Reader in Care, South Tees Hospital NHS Exeter Hospital A&E/Department of Health Trust, Middlesbrough Edward Clark Professor of Advisor in A&E, Warwick Child Life & Health, Professor Norman Waugh, Emergency Care and Ms Bec Hanley, Co-Director, Department of Child Life & Professor of Public Health, Rehabilitation, University of TwoCan Associates, Health, University of Department of Public Health, Warwick Hurstpierpoint Edinburgh University of Aberdeen

95 Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk) Health Technology Assessment Programme

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Professor Douglas Altman, Mr John Dunning, Dr Duncan Keeley, Professor Chris Price, Director of CSM & Cancer Consultant Cardiothoracic General Practitioner (Dr Burch Visiting Chair – Oxford, Clinical Research UK Med Stat Gp, Surgeon, Cardiothoracic & Ptnrs), The Health Centre, Research, Bayer Diagnostics Centre for Statistics in Surgical Unit, Papworth Thame Europe, Cirencester Medicine, University of Oxford, Hospital NHS Trust, Cambridge Institute of Health Sciences, Dr Donna Lamping, Professor Peter Sandercock, Headington, Oxford Mr Jonothan Earnshaw, Research Degrees Programme Professor of Medical Neurology, Consultant Vascular Surgeon, Director & Reader in Psychology, Department of Clinical Professor John Bond, Gloucestershire Royal Hospital, Health Services Research Unit, Neurosciences, University of Director, Centre for Health Gloucester London School of Hygiene and Edinburgh Services Research, University of Tropical Medicine, London Newcastle upon Tyne, School of Professor Martin Eccles, Dr Eamonn Sheridan, Population & Health Sciences, Professor of Clinical Mr George Levvy, Consultant in Clinical Genetics, Newcastle upon Tyne Effectiveness, Centre for Health Chief Executive, Motor Genetics Department, Services Research, University of Neurone Disease Association, St James’s University Hospital, Mr Shaun Brogan, Newcastle upon Tyne Northampton Leeds Chief Executive, Ridgeway Professor James Lindesay, Dr Ken Stein, Primary Care Group, Aylesbury Professor Pam Enderby, Professor of Community Professor of Psychiatry for the Senior Clinical Lecturer in Elderly, University of Leicester, Public Health, Director, Mrs Stella Burnside OBE, Rehabilitation, Institute of Leicester General Hospital Peninsula Technology Chief Executive, Office of the General Practice and Primary Assessment Group, Chief Executive. Trust Care, University of Sheffield Professor Julian Little, University of Exeter Headquarters, Altnagelvin Mr Leonard R Fenwick, Professor of Human Genome Hospitals Health & Social Epidemiology, Department of Professor Sarah Stewart-Brown, Services Trust, Altnagelvin Area Chief Executive, Newcastle upon Tyne Hospitals NHS Trust Epidemiology & Community Professor of Public Health, Hospital, Londonderry Medicine, University of Ottawa University of Warwick, Professor David Field, Division of Health in the Ms Tracy Bury, Professor of Neonatal Medicine, Professor Rajan Madhok, Community Warwick Medical Project Manager, World Child Health, The Leicester Medical Director & Director of School, LWMS, Coventry Confederation for Physical Royal Infirmary NHS Trust Public Health, Directorate of Therapy, London Clinical Strategy & Public Professor Ala Szczepura, Mrs Gillian Fletcher, Health, North & East Yorkshire Professor of Health Service Professor Iain T Cameron, Antenatal Teacher & Tutor and & Northern Lincolnshire Health Research, Centre for Health Professor of Obstetrics and President, National Childbirth Authority, York Services Studies, University of Gynaecology and Head of the Trust, Henfield Warwick School of Medicine, Professor David Mant, University of Southampton Professor Jayne Franklyn, Professor of General Practice, Dr Ross Taylor, Professor of Medicine, Department of Primary Care, Senior Lecturer, Department of Dr Christine Clark, Department of Medicine, University of Oxford General Practice and Primary Medical Writer & Consultant University of Birmingham, Care, University of Aberdeen Professor Alexander Markham, Pharmacist, Rossendale Queen Elizabeth Hospital, Director, Molecular Medicine Mrs Joan Webster, Edgbaston, Birmingham Professor Collette Clifford, Unit, St James’s University Consumer member, HTA – Professor of Nursing & Head of Ms Grace Gibbs, Hospital, Leeds Expert Advisory Network Research, School of Health Deputy Chief Executive, Dr Chris McCall, Sciences, University of Director for Nursing, Midwifery General Practitioner, The Birmingham, Edgbaston, & Clinical Support Services, Hadleigh Practice, Castle Mullen Birmingham West Middlesex University Hospital, Isleworth Professor Barry Cookson, Professor Alistair McGuire, Director, Laboratory of Professor of Health Economics, Dr Neville Goodman, London School of Economics Healthcare Associated Infection, Consultant Anaesthetist, Health Protection Agency, Southmead Hospital, Bristol Dr Peter Moore, London Freelance Science Writer, Ashtead Professor Alastair Gray, Professor Howard Cuckle, Professor of Health Economics, Dr Sue Moss, Associate Director, Professor of Reproductive Department of Public Health, Cancer Screening Evaluation Epidemiology, Department of University of Oxford Unit, Institute of Cancer Paediatrics, Obstetrics & Research, Sutton Gynaecology, University of Professor Robert E Hawkins, Leeds CRC Professor and Director of Mrs Julietta Patnick, Medical Oncology, Christie CRC Director, NHS Cancer Screening Dr Katherine Darton, Research Centre, Christie Programmes, Sheffield Information Unit, MIND – Hospital NHS Trust, Manchester The Mental Health Charity, Professor Tim Peters, London Professor Allen Hutchinson, Professor of Primary Care Director of Public Health & Health Services Research, Professor Carol Dezateux, Deputy Dean of ScHARR, Academic Unit of Primary Professor of Paediatric Department of Public Health, Health Care, University of Epidemiology, London University of Sheffield Bristol

96 Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk) HTA

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The website also provides information about the HTA Programme and lists the membership of the various committees. 2006; 16 10: No. Vol. ® HTA Health Technology Assessment Assessment Technology Health Health Technology Assessment Health Technology Programme NHS R&D HTA Systematic review of the effectiveness review of the Systematic of HealOzone and cost-effectiveness pit/ﬁssure of occlusal for the treatment caries and root caries S Fielding, C Fraser, M Brazzelli, L McKenzie, and N Waugh J Clarkson, M Kilonzo May 2006