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An overview of the current status of national reporting systems for adverse reactions to dental materials
Journal of Dentistry (2004) 32, 351–358
www.intl.elsevierhealth.com/journals/jden
An overview of the current status of national reporting systems for adverse reactions to dental materials ¨rkmand, Richard van Noorta,*, Nils R. Gjerdetb, Andreas Schedlec, Lars Bjo e Anders Berglund a
Department of Adult Dental Care, School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, UK b Department of Odontology, University of Bergen, NO-5009 Bergen, Norway c University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria d Norwegian Adverse Reaction Unit, UNIFOB, NO-5009 Bergen, Norway e ˚ University, SE-901 85 Umea ˚, Sweden Department of Odontology, Umea Received 2 December 2003; accepted 3 February 2004
KEYWORDS Adverse; Reaction; Dental; Materials patient; Occupational; Monitoring
Summary Objectives. Since all dental materials pose a potential risk to patients and members of the dental team, the post-market monitoring of adverse reactions caused by dental materials should be considered essential. This article reviews the current status of post-market monitoring of adverse reactions to dental materials and highlights some of the issues that arise in trying to establish an evidence base on the characteristics of adverse reactions to dental materials. Methods. Norway, Sweden and more recently the UK have sought to monitor adverse reactions to dental materials systematically and proactively in an effort to add to the evidence base on the safety of dental materials. Their experiences in undertaking post-market surveillance have been combined in preparing this article. Results. To date the Norwegian, Swedish and the UK projects has received 1268 reports over 11 years, 848 reports over 5.5 years and 1117 reports over 3 years, respectively, relating to adverse reactions seen or experienced by dental personnel and patients. Presently, there are no harmonized criteria for what can be classified as an adverse reaction related to dental materials. Under reporting is a recognised problem and lack of awareness and lack of clarity as to what constitutes an adverse reaction may be contributory factors. A pro-active reporting system takes a considerable time to become established, but can generate a lot of potentially useful information. Conclusions. There is a need to raise the awareness among dental professionals of the potential for adverse reactions due to dental materials and to develop an internationally accepted system of data gathering that can produce the evidence that reflect the extent, severity and incidence of adverse reactions to dental materials. q 2004 Elsevier Ltd. All rights reserved.
*Corresponding author. Tel.: þ 44-114-271-7910/7911 (Office); fax: þ 44-114-266-5326. E-mail addresses: [email protected], gjerdet@ odont.uib.no, [email protected], lars.bjorkman@ odont.uib.no, [email protected]. 0300-5712/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jdent.2004.02.001
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Introduction Dental materials are among the most extensively employed materials for incorporation in the human body. Many dental treatments involve the use of a wide range of materials, which continue to grow in number and complexity. A primary concern with the use of dental materials is whether or not they are safe as these materials have the potential to cause a variety of adverse reactions such as local or general toxicity, hypersensitivity reactions or irritation.1 – 4 Both patients and the professionals are at risk. Added to this are the concerns expressed by certain sections of the population about mercury in dental amalgam. This is demonstrated by an Australian survey, where 37.5% expressed such concerns.5 When one examines the evidence for the extent to which dental materials may cause adverse reactions then figures vary wildly. The frequency of adverse biological reactions to dental materials in general practice has been reported to be anything from 1:700 to 1:2600.6,7 In specialist practices it has been observed that the frequency is higher.8,9 A regional investigation in Sweden during 1985 – 1988 revealed that between 0.5 and 1% of the population suspected that they had some type of reaction associated with dental materials. However, an objective connection could be established in only 0.02% of the population per year.10 In an investigation from Eastern Bavaria in Germany, it was indicated that about 0.01% of the population had suspected local adverse reactions to dental casting alloys.11 Thus literature data suggests that the risk of an adverse reaction to a dental material varies from 1:10 000 to 1:100. Without more authoritative evidence it has to be considered that a significant number of the population in developed countries will react in some way to the exposure to dental materials, given the number of people who undergo dental treatment. Where projects have been set up to encourage the reporting of adverse events suspected to be related to a dental material, irrespective of the severity of the incident, then the numbers of reports have increased substantially, such as in Norway, Sweden and the UK. Dental materials, being classified as medical devices in many countries, are subject to approval procedures which involve pre-marketing evaluation. However, it is generally accepted that premarket testing only can identify relatively common safety issues, but not rare incidents, or reactions where the underlying mechanisms are not known. The real issue is to know the extent to which
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a dental material may cause adverse reactions and whether or not the incidence rate is acceptable. In a recent guest editorial for the Journal of Dental Research,12 Werner Geurtsen said: “It is our responsibility, and duty, to investigate in vitro and in vivo whether current restorative materials do or do not have the potency to generate systemic diseases and/or chronic local adverse events over time. It is obvious that these important ‘evidencebased’ data are of great significance for the development of new biocompatible dental materials, and thus for the future of restorative dentistry.” Thus, post-marketing evaluation fits in with the growing recognition for the need to practice in an evidence-based environment. In the context of evidence-based medicine, safety is a primary consideration.13 The purpose of this article is to provide an overview of the current situation with regard to the monitoring of adverse reactions to dental materials and also use this opportunity to highlight some of the issues that arise in trying to establish an evidence base on the incidence and/or prevalence of adverse reactions to dental materials. Examples of the types of information that can be acquired are presented, but also the strengths and weaknesses of adverse reporting process are discussed.
Adverse reaction reporting systems Both in the EU and in USA there are reporting systems aimed at medical devices, but none are specifically designed for the purpose of recording adverse reactions seen with dental materials on a national or cross-national basis. The reporting procedures in USA are the responsibility of the US Food and Drug Administration (FDA) via the MedWatch program.14,15 In a review of dental device associated problems reported to the FDA during a 35-month period in 1996 – 1999 it was shown that 10.5% ðn ¼ 28 555Þ of all reports received involved dental devices. More than 90% of the reports were associated with endosseous implants.16 For most dental materials the reporting of incidents or malfunction is voluntary. The reports are entered into a database, called the Manufacturer and User Facility Device Experience Database (MAUDE).15 Unlike in the USA, EU member states are not required to provide procedures for voluntary reporting concerning medical devices. Potentially severe incidents should be reported to the national Competent Authority. The European Commission
An overview of the current status of national reporting systems for adverse reactions to dental materials has provided guidelines on a Medical Devices Vigilance reporting system, but these are not legally binding.17 Dental materials are defined as medical devices in this context, but it would be fair to say that very few reports are received by the Competent Authorities. There is no generally accessible database on the reports, as in USA. The Directive recommends that in order to enhance the efficacy of the Medical Device Vigilance system, Competent Authorities should encourage the reporting of adverse incidents.
Specific reporting systems Norway. In Norway a ‘Dental Biomaterials Adverse Reaction Unit’ (http://www.uib.no/ bivirkningsgruppen/ebivirk.htm) was initiated by the Norwegian Board of Health in 1992, partly as a response to the public concern about the safety of dental amalgam. The Unit began its activities in 1993, funded by the Royal Ministry of Welfare and Health. The main purpose of the project is to obtain experience in the field of adverse reaction reporting and care-taking of patients with adverse reactions associated with all types of dental biomaterials. The project included a reporting procedure aimed specifically at patient reactions.18 Sweden. A national reporting procedure, based on the Norwegian system, was implemented by the National Board of Health and Welfare in Sweden in 1996. It was run by the Faculty of Dentistry, Department of Dental Materials Science, University of Umea ˚, Sweden. The aim was to elucidate the nature and the occurrence of side-effects that could be connected with dental materials. Information arising out of the work was distributed by those responsible for the register to the health and medical services, including dental care services, and to other interested parties. In 2002 the specialized reporting procedure described above was replaced by the more general procedures based on the EU-procedures. The reporting is made mandatory in cases of (potentially) serious events. Reports are now handled by the Swedish Medical Products Agency. United Kingdom. The UK Adverse Reaction Reporting Project (ARRP) (http://www.shef.ac. uk/~arrp/) was set up in 1999 to develop the evidence base for adverse reactions to dental materials in the UK and was funded by the NHS National R&D Programme of Primary Dental Care. It regularly sends out a reporting form, known as the green form to differentiate it from the yellow form
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used for the reporting of drug adverse reactions to all general dental practices in the UK.
The reporting process The reporting process of the specific reporting procedures is based on spontaneous and voluntary reporting by reporting form designed specifically for that purpose. The forms are to be returned by a health professional (the responsible dentist/physician). Forms are available at Internet sites, provided through journals and magazines and sent directly to dental practices. For example, in Norway the form is published regularly in the Norwegian Dental Journal. The reporting form consists of a simple two-page sheet. The data requested are: Name and affiliation of the dentist or physician. General patient data (including known diseases, medication, etc.) The reaction(s) in question is to be classified as subjective or objective symptoms, findings and signs. The location of the reaction(s) is divided into local, oro-facial and/or general reactions. The relevant dental procedures as well as the materials involved should be stated by the doctor. The opinion about the association between the material and the reaction is requested, both the doctor’s opinion and the patient’s. Tick boxes are used whenever possible to facilitate the completion of the form. The design of the form used in the UK is based on examples from the Adverse Reaction Units in Bergen (Norway) and Umea ˚ (Sweden). The form is available via the website (http://www.sheffield. ac.uk/~arrp) as are some results of the survey. Dentists and physicians are prompted to report adverse reactions, independent of the patient being referred for clinical examination or not. That is, reactions handled by the patient’s primary doctor should also be reported. The terms ‘Adverse reaction’, ‘Adverse event’, ‘Side-effect’ and ‘Unwanted effect or event’ are used synonymously. Adverse reactions are described as unexpected or unusual events or reactions. At this stage, doctors are requested to report reactions even when there is doubt as to the association between the reaction and the material(s). Thus there are wide-ranging criteria for reporting. In principle each project wants to receive reports when there is suspicion that a material-related adverse reaction is present. The materials are classified based on an early draft proposal by the European Committee for Standardization.19
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Figure 1
Distribution of adverse reactions to dental materials reported to the ARRP in the UK ðn ¼ 1117Þ:
Results In the Norwegian study about 80% of the reports are submitted by dentists, the remainder from physicians. The number of women involved in adverse reactions are about twice that of men. The most common age-group is 40 – 49 years for both men and women. Fillings and associated procedures account for a majority treatments involved in the reported adverse biological reactions.18 In the UK a similar picture has developed with female patients experiencing more adverse reactions that male patients. However, this is not so for dental professionals who have experienced an adverse reaction, where the number of reports are more evenly spread between males and females (Fig. 1).20 The UK data for patient adverse reactions show that the presence of a metal restoration is the most commonly cited reason for an adverse reaction. As shown in Fig. 2, out of the 193 metal adverse reactions the most common metal was amalgam ðn ¼ 140Þ:
The UK programme has not been going long enough to consider trends, but the Norwegian study has shown that after a peak in 1994, the reports related to amalgam has levelled out at 60 – 70% of reports per year (Fig. 3). Generally speaking, reactions associated with dental amalgam are of a more subjective nature than are reactions to other dental biomaterials. Furthermore, the onset of amalgam-related reactions are usually seen after a long time (several months to years) following the insertion of amalgam.21 Intraoral reactions are noted in about onethird of the reports, where lichenoid reactions are the most common finding.18 This is less than that reported in the UK, where 86% of the reactions were suspected to be associated with oral lichenoid type lesions, although very few of these were confirmed. The subjective symptoms range from local pain and discomfort such as ‘Burning mouth symptoms’ to widespread and generalised symptoms including tiredness, exhaustion and muscle and joint pain.22 Generally, subjective symptoms are most often
Figure 2 Distribution of materials causing an adverse reaction in patients in the UK ðn ¼ 495Þ:
An overview of the current status of national reporting systems for adverse reactions to dental materials
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Figure 3 Data from the Norwegian registry from 1993 to 2002. Percent of reports per year. No. of reports is about 100 per year on average.
linked to the presence or earlier exposure to dental amalgam.21 In both the UK and Norwegian studies, for about 25% of the patients it was the dentist/physician was the one who first noticed the reaction, i.e. the patient was most likely unaware of the condition. The UK experience of occupational reactions in dental personnel show a high frequency of reactions to rubber products (Fig. 4). By far the largest proportion of adverse reactions are associated with the wearing of latex gloves, which accounted for 395 out of the 547 adverse reactions reported.20 In contrast, the Norwegian study has received only a few reports of this kind since the reporting was aimed at patients reaction from the outset. In Sweden, the materials reported to cause reactions among dental personnel were mainly composites and gloves, 52 and 25%, respectively. During the period from April 1996 to December 2001 a total of 848 reports were received, 665 on patients (78%) and 183 on dental personnel (22%).
Figure 4
As in the UK, in Sweden, a relatively high proportion of the reports concern dental personnel.23
Discussion There are no harmonized criteria for what can be classified as an adverse reaction related to dental materials. Most dental procedures involve a range of different materials which could elicit unexpected reactions. Moreover, there could be mechanical trauma, or mechanically derived reactions caused by, e.g. roughness or other surface defects. In the UK only 40% of cases reported, where referred for further diagnosis. Of the 1117 cases reported only 204 (18%) were reported as being severe. Even so a third of these were not referred for a more detailed diagnosis. Thus the process of referral was very patchy. In the case of glove adverse reactions by dental professionals it was found that 4% of cases were associated with a Type
Occupational adverse reactions to dental materials in the UK ðn ¼ 547Þ:
356 1 adverse reaction.20 It is not known to what extent this figure of 4% severe adverse reactions out of all reported adverse reactions could possibly be extrapolated to the patient experience. Thus it would appear that only a very small proportion of adverse reactions associated with dental materials develop into a life threatening situation.
Spontaneous reporting procedures It is recognised that voluntary and spontaneous drug reporting systems are cost-effective procedures of detecting rare side-effects that have not been detected in the clinical trials. It has a potential to supervise the whole population at all occasions, is relatively cheap and may lead to that materials are being withdrawn from the market.24,25 Spontaneous reporting systems have strengths and weaknesses.24 There is the potential to reach a large number of potential respondents, which could assist in identifying relatively rare events, particularly useful for materials used by general practitioners.26 Availability of reporting forms and knowledge about the reporting procedures among health professionals is essential, but takes a considerable length of time to develop. Motivation to report is crucial and in this regard it is important that the dental profession is kept informed of the outcomes of these studies, either through articles in national journals or the worlds wide web. On the other hand, it has to be recognized that voluntary reporting systems will suffer from a degree of underreporting.24
Frequency of reporting There appears to exist no information on largescale reporting systems concerning dental materials. Reporting of adverse effects seen with drugs are well established and practitioners’ attitudes towards such systems have been evaluated.27 Data from the British reporting system for drugs indicates that about 10% of the serious side-effects are being reported, while the corresponding number for the non-serious reactions are 2 – 4%.24 Furthermore, in a study on 8000 general practitioners and 44 000 patients in all regions of Britain examined the degree of under-reporting in a reporting system for drugs. The side-effects were monitored during a period of one year and it was found that about 2% of the side-effects were reported to the register.28 Why so few reports concerning dental materials are received by the Competent Authorities is not clear, but probably is partly due to a lack of awareness amongst general dental practitioners
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that there is an obligation to report adverse incidents associated with a medical device such as a dental material. Also there is a lack of clarity as to what constitutes an adverse incident that needs to be reported.
Criteria for reporting It may be difficult for practitioners to recognize side-effects as the diagnosis of side effects may be subjective and unreliable. Reactions which definitely should be reported are cases where there is an obvious time association between exposure and an objective reaction. Local reactions in the oral mucosa, topographically related to dental materials, are familiar to dentists. Therefore, it is likely that such reactions are reported. However, sometimes reactions occur remote from the dental materials. The reaction might be a skin problem in the oro-facial region or elsewhere on the body. The dentist or physician may not associate such reactions with dental materials until, for example, skin patch testing has been performed and the combined dermatological and dental expertise points to a connection.29 – 34 Reactions which definitely should be reported are cases where there is an obvious time association between exposure and an objective reaction.35,36 Subjective symptoms are not easily classified, and doctors are sometimes sceptical about their relevance. Moreover, there are few, if any, established diagnostic tools to indicate an association to dental materials. The ‘burning mouth syndrome’ is an example. Several mechanisms have been suggested, including hypersensitivity to components in dental materials.37 – 41 Some patients link subjective symptoms of a general nature, e.g. fatigue and muscle and joint pain, with exposure to dental amalgam. It appears that the profile of symptoms resemble those seen in the ‘multiple chemical sensitivity syndrome’.42 It remains controversial as to what is the cause and what is the effect. The benefit of post-market surveillance procedures is that it allow such reactions to be reported. Reports on occupational reaction in health professionals are relative common in the Swedish and the UK registry, but not in the Norwegian one. The reason is most likely that the Norwegian registry was specifically aimed at patient reactions. Occupational reactions should be reported to the Norwegian Work Safety authority. This difference demonstrates that the way a registry is introduced affects the outcome. It seems
An overview of the current status of national reporting systems for adverse reactions to dental materials appropriate to separate the reporting from patients and from dental personnel in the future.
Identification and classification of materials involved It is sometimes problematic to identify and classify the materials in question. The quality of the information is frequently insufficient and more information from the reporting doctor is often necessary. New materials are introduced with a complex and usually undisclosed composition. Material safety data sheets do not need to specify minor components which could be relevant in, e.g. allergic reactions. Moreover, datasheets have been known to be incorrect.43 Work is in progress concerning a global medical device nomenclature which could facilitate the harmonization of data concerning the products involved.44
Causality assessment and validation The classification of causality used for drugs may not be directly applicable to adverse reactions to dental materials due to the difference in mode of exposure.45 Moreover, dental restorations can consist of several components which are not easily distinguished when it comes to adverse reactions. Oral lichenoid reactions are commonly reported. The aetiology of such reactions is still debated.41, 46 – 48 The clinical activities of the Norwegian registry have indicated that the identification of intraoral reactions, which are quite common, should be subject to continuous validation.18
Multiregional harmonization Electronic communication technology open up new possibilities for pooling data on adverse reports from several regions and thereby increasing the reporting base.49 In Norway and Sweden the population is about 13.3 million altogether, with nearly 11 000 dentists (full-time equivalents).50 In the UK there are some 22 000 dentists, serving a population of 55 million. The Norwegian, Swedish and UK registers have initiated a close cooperation in the field of harmonizing classification of materials, symptoms, as well as evaluation of association between reactions and the materials involved. In order to begin to make this a possibility, recently a uniformly agreed format for the reporting form has been developed which is available in English, French, German and Spanish. This form can be found on the FDI website (http:// www.fdiworldental.org/adverse.htm).51
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Conclusion Dental materials are widespread and diverse and intended for short-term to permanent use. There is a lack of information and established procedures concerning adverse reactions to dental materials, in spite of their widespread use. A spontaneous reporting system aimed at practitioners could identify signals and could be used for generation of hypotheses. Thus, reports should be evaluated by specialty units. There is a potential for international cooperation in this field, e.g. by establishing a system to collect ‘core information’ that could be pooled to increase the power of the potential signals generated.
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www.intl.elsevierhealth.com/journals/jden
An overview of the current status of national reporting systems for adverse reactions to dental materials ¨rkmand, Richard van Noorta,*, Nils R. Gjerdetb, Andreas Schedlec, Lars Bjo e Anders Berglund a
Department of Adult Dental Care, School of Clinical Dentistry, University of Sheffield, Sheffield S10 2TA, UK b Department of Odontology, University of Bergen, NO-5009 Bergen, Norway c University Clinic of Dentistry, Medical University of Vienna, Vienna, Austria d Norwegian Adverse Reaction Unit, UNIFOB, NO-5009 Bergen, Norway e ˚ University, SE-901 85 Umea ˚, Sweden Department of Odontology, Umea Received 2 December 2003; accepted 3 February 2004
KEYWORDS Adverse; Reaction; Dental; Materials patient; Occupational; Monitoring
Summary Objectives. Since all dental materials pose a potential risk to patients and members of the dental team, the post-market monitoring of adverse reactions caused by dental materials should be considered essential. This article reviews the current status of post-market monitoring of adverse reactions to dental materials and highlights some of the issues that arise in trying to establish an evidence base on the characteristics of adverse reactions to dental materials. Methods. Norway, Sweden and more recently the UK have sought to monitor adverse reactions to dental materials systematically and proactively in an effort to add to the evidence base on the safety of dental materials. Their experiences in undertaking post-market surveillance have been combined in preparing this article. Results. To date the Norwegian, Swedish and the UK projects has received 1268 reports over 11 years, 848 reports over 5.5 years and 1117 reports over 3 years, respectively, relating to adverse reactions seen or experienced by dental personnel and patients. Presently, there are no harmonized criteria for what can be classified as an adverse reaction related to dental materials. Under reporting is a recognised problem and lack of awareness and lack of clarity as to what constitutes an adverse reaction may be contributory factors. A pro-active reporting system takes a considerable time to become established, but can generate a lot of potentially useful information. Conclusions. There is a need to raise the awareness among dental professionals of the potential for adverse reactions due to dental materials and to develop an internationally accepted system of data gathering that can produce the evidence that reflect the extent, severity and incidence of adverse reactions to dental materials. q 2004 Elsevier Ltd. All rights reserved.
*Corresponding author. Tel.: þ 44-114-271-7910/7911 (Office); fax: þ 44-114-266-5326. E-mail addresses: [email protected], gjerdet@ odont.uib.no, [email protected], lars.bjorkman@ odont.uib.no, [email protected]. 0300-5712/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jdent.2004.02.001
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Introduction Dental materials are among the most extensively employed materials for incorporation in the human body. Many dental treatments involve the use of a wide range of materials, which continue to grow in number and complexity. A primary concern with the use of dental materials is whether or not they are safe as these materials have the potential to cause a variety of adverse reactions such as local or general toxicity, hypersensitivity reactions or irritation.1 – 4 Both patients and the professionals are at risk. Added to this are the concerns expressed by certain sections of the population about mercury in dental amalgam. This is demonstrated by an Australian survey, where 37.5% expressed such concerns.5 When one examines the evidence for the extent to which dental materials may cause adverse reactions then figures vary wildly. The frequency of adverse biological reactions to dental materials in general practice has been reported to be anything from 1:700 to 1:2600.6,7 In specialist practices it has been observed that the frequency is higher.8,9 A regional investigation in Sweden during 1985 – 1988 revealed that between 0.5 and 1% of the population suspected that they had some type of reaction associated with dental materials. However, an objective connection could be established in only 0.02% of the population per year.10 In an investigation from Eastern Bavaria in Germany, it was indicated that about 0.01% of the population had suspected local adverse reactions to dental casting alloys.11 Thus literature data suggests that the risk of an adverse reaction to a dental material varies from 1:10 000 to 1:100. Without more authoritative evidence it has to be considered that a significant number of the population in developed countries will react in some way to the exposure to dental materials, given the number of people who undergo dental treatment. Where projects have been set up to encourage the reporting of adverse events suspected to be related to a dental material, irrespective of the severity of the incident, then the numbers of reports have increased substantially, such as in Norway, Sweden and the UK. Dental materials, being classified as medical devices in many countries, are subject to approval procedures which involve pre-marketing evaluation. However, it is generally accepted that premarket testing only can identify relatively common safety issues, but not rare incidents, or reactions where the underlying mechanisms are not known. The real issue is to know the extent to which
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a dental material may cause adverse reactions and whether or not the incidence rate is acceptable. In a recent guest editorial for the Journal of Dental Research,12 Werner Geurtsen said: “It is our responsibility, and duty, to investigate in vitro and in vivo whether current restorative materials do or do not have the potency to generate systemic diseases and/or chronic local adverse events over time. It is obvious that these important ‘evidencebased’ data are of great significance for the development of new biocompatible dental materials, and thus for the future of restorative dentistry.” Thus, post-marketing evaluation fits in with the growing recognition for the need to practice in an evidence-based environment. In the context of evidence-based medicine, safety is a primary consideration.13 The purpose of this article is to provide an overview of the current situation with regard to the monitoring of adverse reactions to dental materials and also use this opportunity to highlight some of the issues that arise in trying to establish an evidence base on the incidence and/or prevalence of adverse reactions to dental materials. Examples of the types of information that can be acquired are presented, but also the strengths and weaknesses of adverse reporting process are discussed.
Adverse reaction reporting systems Both in the EU and in USA there are reporting systems aimed at medical devices, but none are specifically designed for the purpose of recording adverse reactions seen with dental materials on a national or cross-national basis. The reporting procedures in USA are the responsibility of the US Food and Drug Administration (FDA) via the MedWatch program.14,15 In a review of dental device associated problems reported to the FDA during a 35-month period in 1996 – 1999 it was shown that 10.5% ðn ¼ 28 555Þ of all reports received involved dental devices. More than 90% of the reports were associated with endosseous implants.16 For most dental materials the reporting of incidents or malfunction is voluntary. The reports are entered into a database, called the Manufacturer and User Facility Device Experience Database (MAUDE).15 Unlike in the USA, EU member states are not required to provide procedures for voluntary reporting concerning medical devices. Potentially severe incidents should be reported to the national Competent Authority. The European Commission
An overview of the current status of national reporting systems for adverse reactions to dental materials has provided guidelines on a Medical Devices Vigilance reporting system, but these are not legally binding.17 Dental materials are defined as medical devices in this context, but it would be fair to say that very few reports are received by the Competent Authorities. There is no generally accessible database on the reports, as in USA. The Directive recommends that in order to enhance the efficacy of the Medical Device Vigilance system, Competent Authorities should encourage the reporting of adverse incidents.
Specific reporting systems Norway. In Norway a ‘Dental Biomaterials Adverse Reaction Unit’ (http://www.uib.no/ bivirkningsgruppen/ebivirk.htm) was initiated by the Norwegian Board of Health in 1992, partly as a response to the public concern about the safety of dental amalgam. The Unit began its activities in 1993, funded by the Royal Ministry of Welfare and Health. The main purpose of the project is to obtain experience in the field of adverse reaction reporting and care-taking of patients with adverse reactions associated with all types of dental biomaterials. The project included a reporting procedure aimed specifically at patient reactions.18 Sweden. A national reporting procedure, based on the Norwegian system, was implemented by the National Board of Health and Welfare in Sweden in 1996. It was run by the Faculty of Dentistry, Department of Dental Materials Science, University of Umea ˚, Sweden. The aim was to elucidate the nature and the occurrence of side-effects that could be connected with dental materials. Information arising out of the work was distributed by those responsible for the register to the health and medical services, including dental care services, and to other interested parties. In 2002 the specialized reporting procedure described above was replaced by the more general procedures based on the EU-procedures. The reporting is made mandatory in cases of (potentially) serious events. Reports are now handled by the Swedish Medical Products Agency. United Kingdom. The UK Adverse Reaction Reporting Project (ARRP) (http://www.shef.ac. uk/~arrp/) was set up in 1999 to develop the evidence base for adverse reactions to dental materials in the UK and was funded by the NHS National R&D Programme of Primary Dental Care. It regularly sends out a reporting form, known as the green form to differentiate it from the yellow form
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used for the reporting of drug adverse reactions to all general dental practices in the UK.
The reporting process The reporting process of the specific reporting procedures is based on spontaneous and voluntary reporting by reporting form designed specifically for that purpose. The forms are to be returned by a health professional (the responsible dentist/physician). Forms are available at Internet sites, provided through journals and magazines and sent directly to dental practices. For example, in Norway the form is published regularly in the Norwegian Dental Journal. The reporting form consists of a simple two-page sheet. The data requested are: Name and affiliation of the dentist or physician. General patient data (including known diseases, medication, etc.) The reaction(s) in question is to be classified as subjective or objective symptoms, findings and signs. The location of the reaction(s) is divided into local, oro-facial and/or general reactions. The relevant dental procedures as well as the materials involved should be stated by the doctor. The opinion about the association between the material and the reaction is requested, both the doctor’s opinion and the patient’s. Tick boxes are used whenever possible to facilitate the completion of the form. The design of the form used in the UK is based on examples from the Adverse Reaction Units in Bergen (Norway) and Umea ˚ (Sweden). The form is available via the website (http://www.sheffield. ac.uk/~arrp) as are some results of the survey. Dentists and physicians are prompted to report adverse reactions, independent of the patient being referred for clinical examination or not. That is, reactions handled by the patient’s primary doctor should also be reported. The terms ‘Adverse reaction’, ‘Adverse event’, ‘Side-effect’ and ‘Unwanted effect or event’ are used synonymously. Adverse reactions are described as unexpected or unusual events or reactions. At this stage, doctors are requested to report reactions even when there is doubt as to the association between the reaction and the material(s). Thus there are wide-ranging criteria for reporting. In principle each project wants to receive reports when there is suspicion that a material-related adverse reaction is present. The materials are classified based on an early draft proposal by the European Committee for Standardization.19
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Figure 1
Distribution of adverse reactions to dental materials reported to the ARRP in the UK ðn ¼ 1117Þ:
Results In the Norwegian study about 80% of the reports are submitted by dentists, the remainder from physicians. The number of women involved in adverse reactions are about twice that of men. The most common age-group is 40 – 49 years for both men and women. Fillings and associated procedures account for a majority treatments involved in the reported adverse biological reactions.18 In the UK a similar picture has developed with female patients experiencing more adverse reactions that male patients. However, this is not so for dental professionals who have experienced an adverse reaction, where the number of reports are more evenly spread between males and females (Fig. 1).20 The UK data for patient adverse reactions show that the presence of a metal restoration is the most commonly cited reason for an adverse reaction. As shown in Fig. 2, out of the 193 metal adverse reactions the most common metal was amalgam ðn ¼ 140Þ:
The UK programme has not been going long enough to consider trends, but the Norwegian study has shown that after a peak in 1994, the reports related to amalgam has levelled out at 60 – 70% of reports per year (Fig. 3). Generally speaking, reactions associated with dental amalgam are of a more subjective nature than are reactions to other dental biomaterials. Furthermore, the onset of amalgam-related reactions are usually seen after a long time (several months to years) following the insertion of amalgam.21 Intraoral reactions are noted in about onethird of the reports, where lichenoid reactions are the most common finding.18 This is less than that reported in the UK, where 86% of the reactions were suspected to be associated with oral lichenoid type lesions, although very few of these were confirmed. The subjective symptoms range from local pain and discomfort such as ‘Burning mouth symptoms’ to widespread and generalised symptoms including tiredness, exhaustion and muscle and joint pain.22 Generally, subjective symptoms are most often
Figure 2 Distribution of materials causing an adverse reaction in patients in the UK ðn ¼ 495Þ:
An overview of the current status of national reporting systems for adverse reactions to dental materials
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Figure 3 Data from the Norwegian registry from 1993 to 2002. Percent of reports per year. No. of reports is about 100 per year on average.
linked to the presence or earlier exposure to dental amalgam.21 In both the UK and Norwegian studies, for about 25% of the patients it was the dentist/physician was the one who first noticed the reaction, i.e. the patient was most likely unaware of the condition. The UK experience of occupational reactions in dental personnel show a high frequency of reactions to rubber products (Fig. 4). By far the largest proportion of adverse reactions are associated with the wearing of latex gloves, which accounted for 395 out of the 547 adverse reactions reported.20 In contrast, the Norwegian study has received only a few reports of this kind since the reporting was aimed at patients reaction from the outset. In Sweden, the materials reported to cause reactions among dental personnel were mainly composites and gloves, 52 and 25%, respectively. During the period from April 1996 to December 2001 a total of 848 reports were received, 665 on patients (78%) and 183 on dental personnel (22%).
Figure 4
As in the UK, in Sweden, a relatively high proportion of the reports concern dental personnel.23
Discussion There are no harmonized criteria for what can be classified as an adverse reaction related to dental materials. Most dental procedures involve a range of different materials which could elicit unexpected reactions. Moreover, there could be mechanical trauma, or mechanically derived reactions caused by, e.g. roughness or other surface defects. In the UK only 40% of cases reported, where referred for further diagnosis. Of the 1117 cases reported only 204 (18%) were reported as being severe. Even so a third of these were not referred for a more detailed diagnosis. Thus the process of referral was very patchy. In the case of glove adverse reactions by dental professionals it was found that 4% of cases were associated with a Type
Occupational adverse reactions to dental materials in the UK ðn ¼ 547Þ:
356 1 adverse reaction.20 It is not known to what extent this figure of 4% severe adverse reactions out of all reported adverse reactions could possibly be extrapolated to the patient experience. Thus it would appear that only a very small proportion of adverse reactions associated with dental materials develop into a life threatening situation.
Spontaneous reporting procedures It is recognised that voluntary and spontaneous drug reporting systems are cost-effective procedures of detecting rare side-effects that have not been detected in the clinical trials. It has a potential to supervise the whole population at all occasions, is relatively cheap and may lead to that materials are being withdrawn from the market.24,25 Spontaneous reporting systems have strengths and weaknesses.24 There is the potential to reach a large number of potential respondents, which could assist in identifying relatively rare events, particularly useful for materials used by general practitioners.26 Availability of reporting forms and knowledge about the reporting procedures among health professionals is essential, but takes a considerable length of time to develop. Motivation to report is crucial and in this regard it is important that the dental profession is kept informed of the outcomes of these studies, either through articles in national journals or the worlds wide web. On the other hand, it has to be recognized that voluntary reporting systems will suffer from a degree of underreporting.24
Frequency of reporting There appears to exist no information on largescale reporting systems concerning dental materials. Reporting of adverse effects seen with drugs are well established and practitioners’ attitudes towards such systems have been evaluated.27 Data from the British reporting system for drugs indicates that about 10% of the serious side-effects are being reported, while the corresponding number for the non-serious reactions are 2 – 4%.24 Furthermore, in a study on 8000 general practitioners and 44 000 patients in all regions of Britain examined the degree of under-reporting in a reporting system for drugs. The side-effects were monitored during a period of one year and it was found that about 2% of the side-effects were reported to the register.28 Why so few reports concerning dental materials are received by the Competent Authorities is not clear, but probably is partly due to a lack of awareness amongst general dental practitioners
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that there is an obligation to report adverse incidents associated with a medical device such as a dental material. Also there is a lack of clarity as to what constitutes an adverse incident that needs to be reported.
Criteria for reporting It may be difficult for practitioners to recognize side-effects as the diagnosis of side effects may be subjective and unreliable. Reactions which definitely should be reported are cases where there is an obvious time association between exposure and an objective reaction. Local reactions in the oral mucosa, topographically related to dental materials, are familiar to dentists. Therefore, it is likely that such reactions are reported. However, sometimes reactions occur remote from the dental materials. The reaction might be a skin problem in the oro-facial region or elsewhere on the body. The dentist or physician may not associate such reactions with dental materials until, for example, skin patch testing has been performed and the combined dermatological and dental expertise points to a connection.29 – 34 Reactions which definitely should be reported are cases where there is an obvious time association between exposure and an objective reaction.35,36 Subjective symptoms are not easily classified, and doctors are sometimes sceptical about their relevance. Moreover, there are few, if any, established diagnostic tools to indicate an association to dental materials. The ‘burning mouth syndrome’ is an example. Several mechanisms have been suggested, including hypersensitivity to components in dental materials.37 – 41 Some patients link subjective symptoms of a general nature, e.g. fatigue and muscle and joint pain, with exposure to dental amalgam. It appears that the profile of symptoms resemble those seen in the ‘multiple chemical sensitivity syndrome’.42 It remains controversial as to what is the cause and what is the effect. The benefit of post-market surveillance procedures is that it allow such reactions to be reported. Reports on occupational reaction in health professionals are relative common in the Swedish and the UK registry, but not in the Norwegian one. The reason is most likely that the Norwegian registry was specifically aimed at patient reactions. Occupational reactions should be reported to the Norwegian Work Safety authority. This difference demonstrates that the way a registry is introduced affects the outcome. It seems
An overview of the current status of national reporting systems for adverse reactions to dental materials appropriate to separate the reporting from patients and from dental personnel in the future.
Identification and classification of materials involved It is sometimes problematic to identify and classify the materials in question. The quality of the information is frequently insufficient and more information from the reporting doctor is often necessary. New materials are introduced with a complex and usually undisclosed composition. Material safety data sheets do not need to specify minor components which could be relevant in, e.g. allergic reactions. Moreover, datasheets have been known to be incorrect.43 Work is in progress concerning a global medical device nomenclature which could facilitate the harmonization of data concerning the products involved.44
Causality assessment and validation The classification of causality used for drugs may not be directly applicable to adverse reactions to dental materials due to the difference in mode of exposure.45 Moreover, dental restorations can consist of several components which are not easily distinguished when it comes to adverse reactions. Oral lichenoid reactions are commonly reported. The aetiology of such reactions is still debated.41, 46 – 48 The clinical activities of the Norwegian registry have indicated that the identification of intraoral reactions, which are quite common, should be subject to continuous validation.18
Multiregional harmonization Electronic communication technology open up new possibilities for pooling data on adverse reports from several regions and thereby increasing the reporting base.49 In Norway and Sweden the population is about 13.3 million altogether, with nearly 11 000 dentists (full-time equivalents).50 In the UK there are some 22 000 dentists, serving a population of 55 million. The Norwegian, Swedish and UK registers have initiated a close cooperation in the field of harmonizing classification of materials, symptoms, as well as evaluation of association between reactions and the materials involved. In order to begin to make this a possibility, recently a uniformly agreed format for the reporting form has been developed which is available in English, French, German and Spanish. This form can be found on the FDI website (http:// www.fdiworldental.org/adverse.htm).51
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Conclusion Dental materials are widespread and diverse and intended for short-term to permanent use. There is a lack of information and established procedures concerning adverse reactions to dental materials, in spite of their widespread use. A spontaneous reporting system aimed at practitioners could identify signals and could be used for generation of hypotheses. Thus, reports should be evaluated by specialty units. There is a potential for international cooperation in this field, e.g. by establishing a system to collect ‘core information’ that could be pooled to increase the power of the potential signals generated.
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