Metal-on-metal hip implants The performance of the medical device quality assurance chain needs to be improved Utrecht, May 2013
Metal-on-metal hip implants May 2013 Contents Summary 5 1 Introduction 7 1.1 Background and importance 7 1.2 Characteristics of metal-on-metal hip implants 7 1.3 Regulation framework for supervision 8 1.4 Aim of the investigation and questions addressed 10 1.5 Study method 10 1.5.1 Information procurement 10 1.5.2 Incident analysis 11 1.5.3 Assessment of technical files and post market surveillance 12 1.5.4 The patients' perspective 14 2 Conclusions and recommendations 15 2.1 The problem with metal-on-metal hip implants 15 2.2 Manufacturers' responsibilities 15 2.2.1 Market introduction: do products undergo sufficient clinical evaluation? 15 2.2.2 Product introduction: assuring training and expertise 16 2.2.3 Vigilance: risk management has to be improved 16 2.2.4 Post market surveillance: improve the quality 17 2.3 Responsibilities of the medical profession and hospitals 18 2.4 The responsibility of notified bodies 19 2.5 Product traceability implant register desirable 20 2.6 Recommendations and enforcement measures 20 3 Results 23 3.1 The problem with metal-on-metal hip implants 23 3.2 Analysis of incidents 24 3.3 Quality of technical files and post market surveillance 27 3.4 Comments from notified bodies 29 3.5 Observations from the patient's viewpoint 29 References 33 Annex 1 Research report by the National Institute for Public Health and the Environment (RIVM) 35 Page 3 of 35
Metal-on-metal hip implants May 2013 Summary In 2011, the Dutch Health Care Inspectorate (the Inspectorate) started an investigation prompted by growing signs of clinical problems with metal-on-metal hip implants. The aim of the investigation was to gain more insight into the quality assurance chain for medical devices, in this case metal-on-metal hip implants. Within this chain, manufacturers, medical doctors, 'notified bodies' and others each have a distinct role and responsibility in relation to assuring the safety and responsible use of medical devices. Medical devices are subject to European regulation. The regulatory system provides a framework for market entry, market introduction, incident response and the monitoring of a product's use following its market introduction. The Inspectorate wished to establish how well that system was working and how it might be improved. The investigation involved collecting and studying information about problems involving metal-on-metal hip implants, analysing incident reports received by the Inspectorate and an assessment of the product files requested from the manufacturers of such implants. Where metal-on-metal hip implants are concerned, the European quality assurance system for medical devices appears to be inadequate in various respects. Once the product has been introduced to the market, manufacturers operate only a limited quality cycle of active product evaluation and follow-up action where necessary. There is also scope for improvement in terms of the clinical evaluation prior to market introduction, assurance of users expertise during product introduction and active response to incident reporting. The Inspectorate believes that the role of notified bodies is unduly restricted to the assessment of product file conformity during market admission. Very little active monitoring of medical devices takes place in the post market phase. The Dutch Orthopaedic Association (NOV) has advised that, until more is known about the long-term effects, metal-on-metal hip implants should no longer be used in regular patient care, but used only in the context of clinical studies. The Inspectorate endorses that advice. The Inspectorate has observed that information from the orthopaedic surgeons' own quality monitoring activities is not being exchanged with other parties in the system. The investigation confirms the need for an implant registry in the Netherlands. Patients need to be more carefully informed about the possible risks associated with certain types of implants. Furthermore, the follow-up of patients experiencing problems with metal-on-metal implants should be carried out with more uniformity and more care by orthopaedic surgeons. The Inspectorate recommends tightening up the European system in various ways. The European legislation is currently being reviewed at EU level, offering the Netherlands an opportunity to actively propose appropriate amendments. Page 5 of 35
Metal-on-metal hip implants May 2013 1 Introduction 1.1 Background and importance Increasing indications of problems Since the middle of 2010, the Dutch Health Care Inspectorate has observed increasing indications of clinical problems with orthopaedic metal-on-metal hip implants. The indications in question were: Incident reports from manufacturers, relating to cases in the Netherlands where metal-on-metal hip implants required replacement (revision surgery) Withdrawal from the market of one particular brand and model of metal-onmetal hip implant in August 2010 A warning from a manufacturer regarding the importance of using appropriate implantation techniques and considering carefully which type of implant is indicated A report from the UK's competent authority regarding clinical problems affecting some patients with metal-on-metal hip implants The cautious stance adopted by and warnings from the Dutch Orthopaedic Association (NOV) with regard to the use of metal-on-metal hip implants Widespread problem Initially, it appeared that the problems related only to a particular metal-on-metal hip implant that was withdrawn from the market in 2010. However, it subsequently became clear that other metal-on-metal hip implants were associated with similar problems. The Inspectorate accordingly decided to initiate an investigation in 2011. 1.2 Characteristics of metal-on-metal hip implants Types and groups of hip implant A hip implant or hip prosthesis is an artificial hip joint, which is used to replace the natural joint. There are various types of hip implants, which differ from one another in various ways, including their mechanical design and the materials from which the stem, the head and the cup are fabricated. For a long time, ceramic and synthetics were the materials predominantly used for the head and cup. In metal-on-metal hip implants, however, the head and cup are made from an alloy of cobalt and chromium. Hip implants may be divided broadly into two groups (see figure 1). 1 The 'total hip prosthesis' consists of an artificial head, which completely replaces the ball of the natural hip joint; a cup, which is inserted into the pelvis (acetabulum) and a stem, which is inserted into the thigh bone (femur). The associated procedure is generally referred to as 'total hip replacement'. 2 The 'resurfacing prosthesis' is a prosthetic cap that is placed over the ball of the natural hip joint, which is largely retained. This type of implant has no stem. The associated procedure is generally referred to as 'hip resurfacing'. Page 7 of 35
Health Care Inspectorate Figure 1. A 'total hip prosthesis' (left) and a 'resurfacing prosthesis' (right) (Source: DePuy/Johnson & Johnson) Considerable increase in use Metal-on-metal implants were developed more than thirty years ago. However, their refinement and use has increased considerably in the last ten years, driven partly by the availability of improved manufacturing techniques and partly by the anticipated durability of such implants. Greater durability should make implants of this type more suitable for younger patients and those with active lifestyles. Hip implantation brings general and specific risks All hip implant procedures involve certain general risks, such as surgical infections, haemorrhaging and adverse responses to surgical anaesthesia. Various specific post-surgical risks also exist, including the fracture, displacement, detachment and dislocation of (parts of) the prosthesis. Metal-on-metal implants appear to be associated with an additional risk. When the prosthesis is implanted, the surgeon seeks to position the head and cup in such a way as to minimise the potential for friction between them. Nevertheless, it is impossible to totally prevent friction between the head and the cup resulting in the creation of metal debris. Ions from the debris enter the surrounding tissue or the blood and appear to adversely affect the health of some patients. The need for a revision surgery can be the final outcome. One brand and model withdrawn from the market In August 2010, it became apparent that one particular brand and model of metalon-metal hip implant frequently required replacement. Data from Australia and the UK indicated that 12 to 13 per cent of the relevant implants had to be replaced. The manufacturer accordingly implemented a recall procedure [1] to withdraw the product from the market. 1.3 Regulation framework for supervision Product legislation on medical devices The admission of medical devices to the European market is governed by harmonised European product legislation, in the form of Directive 93/42/EEC, [2] which is implemented in Dutch law by the Medical Devices Act. The principle underpinning of the legislation is that a manufacturer is responsible for the safety and quality of the medical devices it places on the market. Each product must therefore carry a CE mark (CE stands for Conformité Européenne), indicating that it conforms to a number of legal requirements. One of those requirements is that the product has undergone clinical evaluation on the basis of data from clinical studies or from published scientific literature. The risks associated with the product must also have been assessed and evidence must be available demonstrating that the Page 8 of 34
Metal-on-metal hip implants May 2013 medical device in question is capable of performing its intended purpose. In the context of the legislation, medical devices are categorized in risk classes. Hip implants are in the highest risk class, meaning that their conformity has to be assessed by a 'notified body'. The competent authority in each member state (which in the Netherlands is the Inspectorate) supervises the activities of the notified bodies in that country. A CE-marked product is admitted to the entire European market. Vigilance: compulsory incident reporting Once a product has been admitted to the market, the manufacturer has the legal obligation of vigilance. That implies that the manufacturer must report known incidents involving the medical device to the competent authority in the country where the incident occurred. When reporting an incident, the manufacturer must provide data regarding, amongst other things, the product, the patient, the health care institution and the nature of the incident. The data must be submitted in a standardised form, according to a European model. The manufacturer must also analyse the incident and, on the basis of the findings, indicate what follow-up action (if any) is required. Post market surveillance: compulsory product monitoring Manufacturers also have a post market surveillance obligation. That implies that they must monitor their medical devices throughout their life cycle. The obligation has been created with a view to ensuring that unforeseen problems associated with clinical use or with large patient groups can be identified. If such problems are detected, the manufacturer must take appropriate action, such as modifying the product, revising the instructions for use, warning users or, in the most extreme cases, recalling the product. The competent authorities in the various European member states collectively monitor compliance with the requirements. Revision of the European Directive The European Medical Device Directive is currently undergoing review. Following discussions with the competent authorities in the various member states, the European Commission has recently put forward proposals regarding the Directive's revision. Many of the proposed revisions involve tightening aspects of the rules, making the system less noncommittal, and closer cooperation between member states. The proposals will be considered and decided upon at the European level in the period ahead. In that context, the Netherlands will have the opportunity to influence the outcome of the review. a In response to the recent problems with PIP breast implants b, the European Commissioner for Health and Consumer Policy has proposed a joint action plan in 2012. Those arrangements included various amendments tightening the present European Directive. Regulation and supervision of the use of medical devices The Inspectorate is responsible for supervising the use of medical devices, in accordance with the national Health Institutions Quality Act and the Individual Medical Professions Act. The Inspectorate is also guided by standards and guidelines of the health care professions themselves. a b Both the Inspectorate and the Ministry of Health, Welfare and Sport are represented on various European committees that will review the legislation. Breast implants manufactured by the French company Poly Implant Prostheses. Page 9 of 35
Health Care Inspectorate 1.4 Aim of the investigation and questions addressed Qualitative investigation for the purpose of acquiring insight and formulating views The Inspectorate's largely qualitative investigation was intended to yield insight into the quality of the chain via which medical devices are introduced and used, and to provide a basis for the formulation of associated views. The chain for the life cycle of a medical device is illustrated in figure 2. In particular, the intention was to assess the following: How well the European system of market entrance, market introduction, vigilance and post market surveillance is working, where metal-on-metal hip implants are concerned The extent to which manufacturers, notified bodies and health care professionals in the quality chain are discharging their responsibilities Figure 2. Quality chain for the medical device life cycle Questions addressed by the investigation What clinical problems are associated with metal-on-metal hip implants and how can they be characterised within the Dutch health care system? To what extent does the European system of market entrance, market introduction, vigilance and post market surveillance provide adequate assurance that the clinical use of metal-on-metal hip implants is adequate in qualitative terms? Which improvements could be made within the existing regulatory framework? How do the manufacturers of metal-on-metal hip implants carry out post market surveillance? In the context of its supervision activities, what aspects should the Inspectorate focus on in order to improve the safe and appropriate use of medical devices? Relationship to Inspectorate policy The investigation is in line with the Inspectorate's existing policy. Monitoring of the post market surveillance undertaken by the manufacturers of medical devices in the higher risk classes is one of the Inspectorate's strategic focuses. 1.5 Study method 1.5.1 Information procurement Information sources In order to obtain insight into the clinical problems associated with metal-on-metal hip implants, the Inspectorate studied relevant information from 2011. The Page 10 of 34
Metal-on-metal hip implants May 2013 information was obtained from national and international scientific publications, research studies, news and media reports and information from medical professionals, counterpart authorities elsewhere, manufacturers and patients. Scope of the metal-on-metal issue in the Netherlands In order to gain insight into the extent of the problems associated with metal-onmetal hip implants in the Netherlands, the Inspectorate started by approaching the Dutch Orthopaedic Association (NOV). A National Orthopaedic Implant Registry (LROI) has been in operation under the auspices of the NOV since 2007. Orthopaedic surgeons in the Netherlands are encouraged to record all prosthetic implantation and revision procedures in the register. The register has been created from the perspective of medical science and is intended to provide information regarding the clinical effectiveness of implants (in terms of durability, complications and revision rates). The Inspectorate does not have access to the register and in 2011 therefore asked the NOV whether it was possible to provide the Inspectorate with data regarding the number and types of metal-on-metal hip prostheses implanted in the Netherlands. The Inspectorate additionally asked the manufacturers for information about the number of metal-on-metal hip implants sold in the Netherlands. International coordination Since March 2012, the Inspectorate has participated in an international conference forum concerned with metal-on-metal hip implants. The forum brings together the competent authorities of the various European member states, with the aim of exchanging information and coordinating policy. The forum initiated a request to the European Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) c, asking this body to consider the safety and the risk-benefit profile of metal-on-metal hip implants [3], in light of the uncertainty regarding the long-term health effects of such implants. SCENIHR is expected to report on the matter in the middle of 2013. Role and views of the medical profession Since late 2010, the Inspectorate has maintained contact with the NOV, with a view to learning more about the insights and views of the medical profession, so that they may be taken into account in the Inspectorate's policy on the problems associated with metal-on-metal hip implants. 1.5.2 Incident analysis Contact with manufacturer following recall Following the withdrawal of a particular model of metal-on-metal hip implant from the market in 2010, the Inspectorate has periodically made enquiries to the manufacturer regarding the situation in the Netherlands. In particular, the Inspectorate asked for the number of implants requiring revision, the follow-up of patients and the exchange of the information with orthopaedic surgeons. Analysis of incidents individually and collectively In the context of its regular supervisory activities, the Inspectorate analyses all reported incidents individually. Since 2011, the Inspectorate has additionally been analysing all manufacturers' incident reports in connection with each other. To that end, manufacturer-specific information regarding the implant, the revision surgery, the health care institution and the date of implantation and revision has been compiled and recorded. Where necessary, the Inspectorate has asked manufacturers c SCENIHR is an independent scientific advisory body at the disposal of the European Commission. Page 11 of 35
Health Care Inspectorate to provide additional information. In some cases, the Inspectorate was referred by a manufacturer to the company's own documentation, such as the instruction for use, an internal study report, a patient leaflet or surgical guidelines. In such cases, the relevant documentation was obtained and studied. The cumulative total number of incident reports and the cumulative number of reports per manufacturer/product have been recorded. The content of the manufacturers' vigilance reports has been analysed by the Inspectorate in order to ascertain how the manufacturers discharge their vigilance obligations. Contact with hospitals Various hospitals have informed the Inspectorate, either in the context of their regular annual discussions with the Inspectorate or by incident reports, that a substantial number of metal-on-metal hip implant revisions had to be performed. The Inspectorate asked the hospitals in question to provide information about matters such as the numbers of hip implant revisions, the provision of information to patients and the provision of information to manufacturers to facilitate incident analysis by the manufacturers. 1.5.3 Assessment of technical files and post market surveillance Selection of manufacturers In order to build up a picture of the manufacturers' post market surveillance activities, the Inspectorate requested them for the technical product files on their metal-on-metal hip implants. The manufacturers were selected on the basis of an inventory of all metal-on-metal hip implants used in the Netherlands. That inventory was compiled using information provided by the NOV and by analysing the manufacturers' product ranges. The resulting market overview is summarised in table 1. Table 1 Market overview of metal-on-metal hip implants used in the Netherlands Manufacturer DePuy/Johnson & Johnson DePuy/Johnson & Johnson Biomet Zimmer Smith&Nephew Wright Medical Technology Finsbury Orthopaedics/DePuy* 1 Stryker Corin Implantcast Orthodynamics/Eska* 2 Product name ASR Pinnacle M2a, Recap Durom Birmingham Conserve+ Adept Mitch Cormet Accis Bionik (* 1 : Finsbury was acquired by DePuy in 2009; * 2 : Eska was acquired by Orthodynamics in 2010.) Procurement of information on post market surveillance On 31 August 2011, the Inspectorate wrote to the Dutch representatives of the various manufacturers, indicating that the Inspectorate wished to study manufacturers' fulfilment of their post market surveillance obligations. They were asked to provide the Inspectorate with the following no later than 1 October 2011: Page 12 of 34
Metal-on-metal hip implants May 2013 A overview of the metal-on-metal hip implants supplied in the Netherlands (product name, type and numbers of products sold). The name of a contact person within the organisation representing the manufacturer in the Netherlands. A set of documentation from the product's technical file. Details of the specific documentation required and the form in which it was to be provided were given in an appendix to the letter to the manufacturers. The Inspectorate asked the manufacturers to describe their post market surveillance procedures and the follow-up activities undertaken specifically in the Netherlands. The list of technical file items requested was based on that required for the market admission of a CE-marked product and consisted of the following: 1 A description of the medical device 2 A reference to similar devices or previous generations of the device 3 The instructions for use 4 The risk analysis 5 The biocompatibility data 6 The clinical evaluation 7 The post market surveillance-procedure(s) 8 The summary and analysis of the post market surveillance data 9 The vigilance procedure(s) 10 Information regarding the training and instruction of medical professionals Assessment by the RIVM The Inspectorate asked the National Institute for Public Health and the Environment (RIVM) to assess the files provided by the manufacturers. In consultation with the RIVM, a scoring method was defined, on the basis of which each documentation item was assessed. Each file item was divided into a number of components, which were assessed individually. The scores were weighted, with the greatest weight attached to those components that the Inspectorate regarded as critical. A score for each file item was then calculated by aggregating the component scores. On the basis of its aggregate score, each item was graded 'good', 'moderate' or 'insufficient'. If any critical component was missing, the file item in question was graded 'insufficient'. The RIVM's report, describing and explaining the file assessment in detail, forms Annex 1 to this report. Second request for information In October 2011, the RIVM assessed the completeness of the files submitted to the Inspectorate. On the basis of the conclusions, the Inspectorate wrote to three manufacturers informing them that certain file items were missing or incomplete, and giving them the opportunity to provide the missing information. In December 2011, two of them provided the missing information as requested. Incomplete files were not excluded from assessment, but the missing items were scored accordingly. RIVM's final report The Inspectorate received the RIVM's final report in October 2012. The report was then sent to two notified bodies in the United Kingdom for comment, since the bodies in question had between them performed conformity assessments on eight of the eleven metal-on-metal hip implants under consideration. The two notified bodies were asked d to indicate: Their response to the results of the file assessments d The notified bodies in question are under the supervision of the Inspectorate's counterpart in the United Kingdom: the Medicines and Healthcare products Regulatory Agency (MHRA). The request was therefore made via the MHRA. Page 13 of 35
Health Care Inspectorate How they assessed the manufacturers' post market surveillance activities To what extent they had received vigilance reports from the manufacturers with regard to incidents involving metal-on-metal hip implants, and what they had done in response to any such reports How they assessed the manufacturers' clinical evaluation activities 1.5.4 The patients' perspective Relevant information obtained via a lawyer s office In the Netherlands, there is a specialist lawyer s office giving legal aid to several hundreds of patients who have experienced problems with metal-on-metal hip implants. The implants in question were made by various manufacturers. In December 2012, the law firm informed the Inspectorate in writing that it had relevant information in the form of patients' statements regarding the seriousness of the health problems associated with the implants and regarding the activities of manufacturers, doctors and hospitals. The Inspectorate itself had received little information from patients directly. For that reason, the Inspectorate asked the law firm to facilitate the investigation by providing a written specification and categorisation of the statements contained in its client files. Page 14 of 34
Metal-on-metal hip implants May 2013 2 Conclusions and recommendations 2.1 The problem with metal-on-metal hip implants Metal ions from wear debris can cause clinical problems In a patient with a metal-on-metal hip implant, metal ions from the implant can cause clinical problems in the surrounding tissue. The problem is complex. The mechanism by which the problems arise is not yet fully scientifically understood. Although the conditions can necessitate revision of the implant, the percentage of hip implants requiring revision differs according to manufacturer, product and implant type. It is therefore not possible to make an absolute and generally valid statement regarding the quality of metal-on-metal hip implants as a product group. Nevertheless, literature studies and incident registries support the conclusion that the reported clinical problems constitute a critical side-effect of this type of implant. NOV recommendation: use only in the context of clinical trials If a medical device such as a hip implant does not deliver the expected outcome in some patients, that is a serious matter. The Inspectorate therefore endorses the NOV recommendation that, until more information is available regarding the longterm effects, metal-on-metal hip implants should no longer be used in regular patient care in the Netherlands, but should be reserved for use only in clinical trials. The Inspectorate regards the NOV's recommendation as a field standard for orthopaedic professionals. Is there sufficient assurance of qualitatively appropriate patient care? Under the European system for regulating the market entrance of medical devices, the possibility of a product having unexpected clinical effects cannot be excluded. The Inspectorate recognises that fact. It is therefore pertinent to consider whether the system provides sufficient assurance of qualitatively appropriate patient care. The existence of such assurance depends upon all parties in the chain being sufficiently involved in the product evaluation, adverse effects being identified in good time and appropriate action being taken in response. Final conclusion of the investigation: the performance of the medical device quality assurance chain needs to be improved The existing European regulations are intended to ensure the integrated quality assurance of medical devices. In practice, however, the quality assurance of metalon-metal hip implants appears to be inadequate in various respects. There is scope for improvement in terms of the timely identification of adverse effects and the implementation of appropriate response measures. 2.2 Manufacturers' responsibilities An effective quality cycle for product evaluation is missing None of the investigated manufacturers of metal-on-metal hip implants were found to have a quality cycle for product evaluation that was effective in practice as a means of systematically monitoring product safety and performance. The Inspectorate's conclusions and recommendations regarding the various elements of such a cycle are set out below. 2.2.1 Market introduction: do products undergo sufficient clinical evaluation? The Inspectorate was not able to establish from the information provided that the metal-on-metal hip implants underwent sufficient clinical evaluation prior to market Page 15 of 35
Health Care Inspectorate introduction to allow proper assessment of the intended health benefits and the possible risks. The quality, quantity and type of the clinical data used varied. Furthermore, the Inspectorate found no evidence that the manufacturers used predefined, measurable criteria to assess the acceptability of their products' performance. The Inspectorate noted that, in the clinical evaluation of the implants, the principle of relative equivalence to competing metal-on-metal hip implants was widely used. e The existing European legislation allows this approach in fulfilling the clinical evaluation. Legal requirements require tightening The Inspectorate believes that the requirements made in the European product legislation regarding supervision of the clinical evaluation of high-risk medical devices, such as implants, need to be tightened. That need is already addressed by the European Commission's current proposals regarding the revision of the European legislation. For example, the proposals would, if implemented, considerably limit the scope for applying the equivalence principle to products such as implants. The Netherlands intends to support the proposed revisions. 2.2.2 Product introduction: assuring training and expertise No evidence was found in the files to indicate that, at the time of product introduction, the manufacturers had actively and systematically trained orthopaedic surgeons in the relevant implantation skills. Some manufacturers indicated that using the correct implantation method can influence the performance of the implant. The Inspectorate would therefore like to see manufacturers pay appropriate attention to ensuring that users have the requisite expertise. Need to assure training and expertise previously highlighted In this context, the Inspectorate would draw attention to her earlier annual report: The State of the Health Care 2008 ('Risks associated with medical technology underestimated') [4]. That report already drew attention to the importance of expertise and skill in the use of medical technology. The point was subsequently emphasised by the report 'Medical technology at risk?' [5], produced by a medical technology expert group in 2011. Furthermore, the procedures necessary for assurance of the competencies and skills required to utilise medical technology were defined in the national Covenant on the Safe Use of Medical Technology in Hospitals [6], produced by the united Dutch hospitals in 2011. 2.2.3 Vigilance: risk management has to be improved Manufacturers generally comply with their legal obligation to report any incidents that they are aware of. Nevertheless, active incident-based risk management linked to corrective actions where appropriate could be improved. The incident analyses undertaken are too product-focused. The Inspectorate believes that it is particularly important where implants are concerned that more attention is given to the relationship between the product and its clinical application. Clear acceptance criteria and intervention thresholds are lacking Moreover, in the context of incident follow-up, no clear criteria exist for determining whether a given incident percentage is acceptable or not. The European product legislation requires that, prior to market entrance, a risk analysis and assessment must be made. Nevertheless, manufacturers rarely define quantitative criteria, on the basis of which they themselves, patients, health care professionals or authorities e Application of the relative equivalence principle involves the use, for the purpose of clinical evaluation, of available clinical data regarding another similar product already been admitted to the market, if it can be demonstrated that sufficient equivalence exists between that product and the product under evaluation. Page 16 of 34
Metal-on-metal hip implants May 2013 may determine whether in practice a product brings greater risk than foreseen at the time of market introduction. As a result, it is unclear whether corrective action is required. In its incident monitoring activities, the Inspectorate will check whether manufacturers are in compliance with the legislation and will require them to take adequate corrective action. Limitations of the system The effectiveness of the incident vigilance arrangements for medical devices is further limited by a factor that stems from European medical device legislation being a product legislation. As such, the legislation is concerned primarily with manufacturers. Under the legislation, manufacturers are obliged to report incidents to the competent authorities. In order to do so, the manufacturers are dependent on information given to them by health care professionals and health care institutions. However, those groups have no legal obligation to report incidents to the relevant manufacturers. The Inspectorate has observed that, where metal-on-metal hip implants are concerned, the absence of any requirement to report incidents to manufacturers has been a significant impediment to obtaining a proper overview of the problem. The Inspectorate observes that manufacturers and health care providers have different interests and that the exchange of information is consequently not as transparent or as obvious as European medical device legislation envisaged. 2.2.4 Post market surveillance: improve the quality The Inspectorate believes that the post market surveillance activities of the investigated manufacturers are qualitatively lacking. There is no assured quality cycle for active product evaluation and associated intervention. Furthermore, risks and benefits are not in most cases evaluated to the initial risk analysis and riskbenefit assessment. There is consequently no basis on which to determine the need for preventive or corrective action. Nor is it apparent when manufacturers are to initiate appropriate action in response to post market surveillance findings. Systems are too limited, passive and noncommittal The systems for post market surveillance are too limited, too passive and too noncommittal to serve the function envisaged by the European medical device legislation. That legislation creates a mechanism with two primary elements: a relatively low-threshold system for market entrance on the basis of conformity, and a system under which manufacturers have a responsibility to monitor the entire life cycle of their products following market entrance. The latter responsibility is vital for assuring the safety and quality of medical device use in health care. Manufacturers' obligations need to be more strictly defined The Inspectorate advocates the stricter definition of manufacturers' post market surveillance obligations. The European legislation currently allows manufacturers too much freedom in their interpretation of what constitutes effective post market surveillance. In particular, the frequency of and criteria for intervention need to be defined in more concrete terms. In the context of the ongoing revision of the European medical device legislation, the Netherlands intends to make proposals regarding post market surveillance. The Inspectorate will require manufacturers to meet their obligations The Inspectorate intends to require manufacturers to meet their post market surveillance obligations adequately. However, the Inspectorate's ability to enforce compliance may be compromised by the fact that many manufacturers are based outside the Netherlands and by the lack of international harmonisation of enforcement activities. Page 17 of 35
Health Care Inspectorate 2.3 Responsibilities of the medical profession and hospitals The NOV actively advises members; adherence to guidelines requires attention In the Netherlands, the NOV actively informs and advises its members about problems with metal-on-metal hip implants. The Association highlighted the risks associated with such implants in various advisory publications for orthopaedic surgeons. Finally, the NOV advised that, in the context of the Dutch health care system, the implants should no longer be used in regular patient care, but reserved for use in clinical trials. The NOV also issued professional guidelines on periodically contacting and checking all patients with metal-on-metal hip implants. The Inspectorate considers that the profession needs to review the arrangements for ensuring that NOV guidelines are diligently followed by its members. Specialists are not sufficiently conscious of the importance of incident reporting It is desirable that orthopaedic surgeons report all revisions of hip implants as incidents to the relevant manufacturers. The manufacturers will then have the data they need to fulfil their vigilance obligations, and the removed prostheses. However, incident analysis and feedback from hospitals indicate that orthopaedic surgeons do not automatically report revisions. They are either unaware or do not fully recognise that incident reporting is essential in the context of assuring the safety of medical devices and thus the quality of care. Orthopaedic surgeons need to be encouraged to recognise that their experience with a medical device constitutes a vital link in the quality assurance chain. Clinical experiences are currently recorded only in the profession's own quality register. Incident reporting should be compulsory The Inspectorate accordingly believes that health care professionals should be obliged to report incidents involving high-risk medical devices to the relevant manufacturers. This recommendation is consistent with the action plan of the European Commissioner for Health and Consumer Policy, which calls for more to be done to involve health care professionals in highlighting undesirable incidents involving medical devices. Patients should be better informed prior to implantation The Inspectorate calls for attention to be given to improving the information given to patients prior to prosthesis implantation, with a view to ensuring that they have a clear understanding of the potential advantages and disadvantages. When the implantation of an innovative medical device whose long-term effects have not yet been properly determined is suggested to a patient, he or she must be told about alternative devices in established use and must be given objective support to help the patient arrive at a well considered personal decision. Moreover, patients must be more clearly informed about the brand and type of implant that they are ultimately given. Dissemination of information and problem monitoring appear variable The NOV recommends that patients with metal-on-metal hip implants should periodically be contacted and checked. However, that advice does not always appear to be proactively followed at the local level. Some hospitals have of their own volition organised special patient information evenings, at which patients are told about the reported problems and given the opportunity to ask questions. At the individual patient level, health issues are sometimes not detected (in time) and decision-making as to whether a hip implant revision is indicated appears to be inconsistent. Furthermore, patients apparently receive little feedback regarding the Page 18 of 34
Metal-on-metal hip implants May 2013 outcome of any examination of an explanted metal-on-metal hip implant. Indeed, such implants often do not undergo examination, but are simply disposed of or lost. The Inspectorate believes that the medical profession should seek to ensure that its members act more consistently and (in some cases) more diligently in the interests of the patient. Patients receive inadequate support in relation to their right to compensation The health impairment and material consequential damages suffered by some patients are considerable. However, neither manufacturers nor hospitals appear to accept any liability towards such patients. Furthermore, the pursuit of compensation from a manufacturer through the courts is a complex undertaking, because of the context. Hospitals and medical doctors appear to give patients inadequate support in relation to such matters or act in a way that is not in the patient's direct (legal) interest. Although issues of liability and compensation are not within the Inspectorate's supervisory jurisdiction, the Inspectorate considers it appropriate to record its observations. 2.4 The responsibility of notified bodies Response from notified body The Inspectorate approached two notified bodies, one of which responded. On the basis of that response, the Inspectorate makes the following observations. The notified body's response to the technical file examination was primarily procedural. Asked to comment on the observed shortcomings in manufacturers' activities, the notified body responded by describing the procedure followed. The notified body had checked whether the product files contained the relevant items and satisfied the requirements of the Directive in force at the time, on the basis of the risk classification criteria applicable at the time. The activities referred to by the notified body in its response consisted mainly of the assessment of file documents in connection with the issue of the CE declaration. So, for example, in the context of the post market surveillance, the notified body verified that the file included a plan demonstrating that the manufacturer was to gather clinical data in the future. The notified body also considered it sufficient to verify that the risk analysis and the user manual made reference to the risks specific to metal-on-metal hip implants. However, the Inspectorate found no evidence that the notified body systematically sought to verify that, following the market entrance of their products, manufacturers actually did as they said they would in their initial files. The notified body's activities in connection with incoming vigilance reports and file document revisions are regarded as passive by the Inspectorate. The notified body reported taking receipt of information from manufacturers and assessing it. The Inspectorate saw no evidence that the notified body had been proactive in its dealings with the manufacturers or the competent authorities. The notified body confirmed that the equivalence principle was applied in support of the clinical evaluation (as the Inspectorate also had observed during its examination of the product file). The role of notified bodies is too narrowly defined In relation to high-risk products, the role of the notified bodies is restricted to initial conformity assessment on the basis of product files. Rather little is currently done to actively monitor medical devices following their market entrance. The Netherlands supports proposed changes to European legislation Under the proposed changes to the European legislation, notified bodies' duties and the quality requirements that apply to them will be defined far more strictly. Page 19 of 35
Health Care Inspectorate Supervision of the notified bodies by the member states' competent authorities will also be tightened. The Netherlands supports the proposed changes. The Netherlands proposes joint inspections In a response to the interim action plan of the European Commissioner for Health and Consumer Policy, the Netherlands has proposed that the member states undertake joint inspections of the notified bodies. Hence, the periodic inspection of a notified body would be undertaken by a number of authorities working in tandem, and the inspection report would be available to all competent authorities. At present, supervision of each notified body is undertaken by the competent authority in that body's own country. 2.5 Product traceability implant register desirable Existing implant traceability arrangements inadequate The arrangements for ensuring traceability of orthopaedic implants in the Netherlands are inadequate at national level. If problems with an orthopaedic implant product arise, it is not possible to quickly, clearly and fully trace the patients who have received the relevant implant in the Netherlands. Similarly, in the event of a recall or the need to check the condition of patients who have received a particular device, it is not possible to identify the individual patients concerned. Central, independent implant register is desirable The Inspectorate accordingly considers a central, independent implant register to be necessary. In order to achieve the desired degree of traceability, the register should include at least the product details of each implant and the details of the patient concerned. Such a register could be used to record details not only of orthopaedic prostheses, but also of other types of implant, such as those used in cardiology and cosmetic surgery. The health care professionals that implant the products will in future be required to record the relevant data. Ministry has prepared a proposal This Inspectorate's recommendation that an implant register should be established has since been taken up by a steering committee set up by the Ministry of Health, Welfare and Sport (VWS). On 20 November 2012, the Minister of VWS submitted a proposal to Parliament [7] regarding the establishment and organisation of a national implant register for the Netherlands. Under the proposal, manufacturers and care providers will have a statutory obligation to provide the necessary data. Where possible, existing systems should be used to channel data to the implant register. The intention is also that patients should be able to consult the register in order to verify that the details of their implant are correctly recorded and to look up details of the implant they have received. Proposal in line with European plans The policy proposal outlined above is consistent with the interim action plan of the European Commissioner for Health and Consumer Policy, as referred to earlier in this report. The Commissioner's plan calls for steps to be taken to improve the traceability of medical devices. The Minister of VWS has previously expressed support for the action plan [8]. The proposal is also in line with the proposed revision to the European legislation, which make provision for the registration of medical devices. 2.6 Recommendations and enforcement measures On the basis of this investigation, the Inspectorate has formulated the following recommendations and enforcement measures: Page 20 of 34
Metal-on-metal hip implants May 2013 Recommendation: tighten European legislation The Inspectorate believes that the following aspects of the European Medical Device Directive should be more strictly defined: The requirements regarding the clinical evaluation of high-risk products, such as implants, prior to market introduction The requirements regarding the prior definition of measurable criteria to determine the acceptability of implant performance The requirements regarding post market surveillance by medical device manufacturers The duties of and quality requirements applicable to notified bodies. In the context of the European legislation review process, the Netherlands will make proposals to the relevant effect or lend its support to proposals already submitted. In anticipation of revision of the legislation, the interim action plan of the European Commissioner makes already provision for some of the changes outlined above. Recommendation: make reporting by health care professionals obligatory The Ministry of VWS is advised to require health care providers to report incidents involving high-risk medical devices to the relevant manufacturer. Recommendation: establish a register of 'side-effects' of medical devices The Ministry of VWS is advised to establish, in parallel to the implant register required for reasons of traceability, a system for the reporting and analysis of the 'side-effects' of medical devices, starting with implants. Measure: supervision of manufacturers The Inspectorate intends to assess whether manufacturers' vigilance reports demonstrate that the manufacturers are fulfilling their obligations adequately and will require them to take adequate corrective measures and to undertake active post market surveillance. Measure: supervision of compliance with the NOV's field standard The Inspectorate regards the NOV's recommendations that metal-on-metal hip implants should not be used any longer in regular Dutch patient care, that patients with metal-on-metal implants should be monitored and periodically checked and the way in which patients who experience problems with metal-on-metal implants should be followed up, as important field standards. The Inspectorate will accordingly ensure that these standards are adhered to, in accordance with the national Health Institutions Quality Act. Measure: consultation with orthopaedic surgeons The Inspectorate will engage in discussions with the national professional body representing orthopaedic surgeons regarding the importance of ensuring that patients are better informed about the implants they are to receive, the potential risks associated with those implants and (where relevant) the alternatives. The Inspectorate will also raise the subject of differences between orthopaedic surgeons and shortcomings in the follow-up of patients who experience problems with metal-on-metal implants. Measure: supervision of implant registration The Minister of VWS wishes to establish a national implant register in the Netherlands and to require health care providers to register relevant data. Following the establishment of such a register, the Inspectorate will supervise the registration of implants and will utilise the registered data in the context of its implant supervision activities. Page 21 of 35
Health Care Inspectorate Measure: intensified supervision of implants and their use The Inspectorate will intensify its supervision of implants and will develop risk identification tools to ensure problems with implants are highlighted more promptly. The intensification will be implemented on the basis of the provisions of the European Commissioner's interim action plan and by utilising data from the implant register. The Inspectorate considers it important that the supervision of implants and their use is considered in the context of the chain as a whole. Such an approach can be facilitated by, for example, a formal structure for consultation with the medical professions regarding the developments in the field of implants. Measure: supervision of notified bodies and of manufacturers' fulfilment of post market surveillance obligations Acting in conjunction with European member states, the Inspectorate will inspect the notified bodies active in this field. In connection with its supervision of manufacturers, the Inspectorate will insofar as it is able and has the legal authority to do so require the notified bodies in question to properly verify that manufacturers fulfil their post market surveillance responsibilities. Measure: consult patients' organisations with a view to encouraging reporting The Inspectorate will enter into discussions with the patients' organisations regarding initiatives to encourage patients to report incidents and complaints to their health care provider and/or to the relevant health care institution; where no satisfactory response is received, the matters should be reported to the Inspectorate. Page 22 of 34
Metal-on-metal hip implants May 2013 3 Results 3.1 The problem with metal-on-metal hip implants Alternative to conventional implants Metal-on-metal hip implants were developed as an alternative to conventional headcup combinations. Conventional implants were made with materials such as ceramic and synthetics. By using an alloy of cobalt and chromium, manufacturers sought to achieve greater implant durability and mobility, mainly for the benefit of younger, active patients. Clinical effects in patients Once the new implants had been in widespread use for a number of years, it emerged that some patients were reacting to varying degrees and with varying levels of seriousness to metal ions from wear debris created by friction between the bearing surfaces of the implant. In the affected patients, a hypersensitive response results in damage to the surrounding tissue. In the medical literature, the phenomenon is referred to as 'adverse local tissue reaction' (ALRT), 'adverse reactions to metal debris' (ARMD), 'aseptic lymphocytic vasculitis associated lesions' (ALVAL) or 'metallosis'. In some cases elevated levels of cobalt and chromium have been found in the blood. Affected patients experience discomfort or pain around the implanted joint, and the prosthesis may become detached. It is not always possible to establish a clear causal relationship between the patient's symptoms and the metal-on-metal hip implant. Medical science has yet to adequately define the mechanism by which clinical injury occurs; studies are ongoing. It has not yet been demonstrated that the released metal ions can be carcinogenic [9,10]. The patient's symptoms sometimes necessitate revision of the hip implant. In such cases, the metal-on-metal prosthesis is explanted and an alternative, conventional prosthesis is implanted. Widespread problem Initially, it appeared that the problems related only to a particular metal-on-metal hip implant that was withdrawn from the market in 2010. However, it subsequently became clear from studies [11,12] and incident reports that other metal-on-metal hip implants were associated with similar problems. The failure rates are found to vary from one product to another and from one manufacturer to another. It is not therefore possible to make a generally valid statement regarding the quality and performance of metal-on-metal hip implants as a product group. Each product requires individual investigation and analysis. Scope of the problem in the Netherlands The Inspectorate was unable to obtain data on the number and types of metal-onmetal prosthetic hips implanted in the Netherlands from the National Orthopaedic Implant Register of the orthopaedic society. According to the Dutch Orthopaedic Association (NOV), the recorded data were not yet sufficiently complete, not sufficiently corrected for mortality and not sufficiently validated. The Inspectorate therefore approached the Dutch representatives of the various manufacturers for data on the numbers of metal-on-metal hip implants sold in the Netherlands. An analysis of those data (which generally relate to the separate joint components: head, cup and stem) revealed that in the Netherlands more than 10,000 metal-on-metal hip implants have been sold, including approximately 1,000 of the particular implant that was withdrawn from the market. The larger Page 23 of 35
Health Care Inspectorate manufacturers have each sold several thousand implants, while the smaller manufacturers have sold several hundred to merely a few dozen. It should be stressed that the figures cited above are sales data; the number of prostheses actually implanted in patients will be smaller. On the other hand, some Dutch patients receive hip surgery in neighbouring countries, so their implants will not be included in the Dutch sales figures. Moreover, some patients undergo bilateral hip replacements, while others have only one hip replaced. Therefore the number of people in the Netherlands who have metal-on-metal hip implants does not directly correspond to the number sold. A survey of Dutch hospitals carried out by the Dutch medical journal Medisch Contact in 2012 [13] indicated that a total of approximately 8,400 patients have received metal-on-metal hip implants in Dutch health care. The NOV estimates that the total annual number of hip surgeries performed in the Netherlands including both metal-on-metal hip prostheses and conservative prosthetic hips is approximately 20,000. Role and views of the medical profession In August 2010, the NOV started providing Dutch orthopaedic surgeons with information about the problems associated with metal-on-metal hip implants. Ultimately, in January 2012, the NOV recommended that, until more is known about the long-term effects of such implants, they should no longer be used in regular patient care, but reserved for clinical trials only that satisfy the applicable criteria [14]. The NOV's advice related both to total metal-on-metal hip prostheses (with a head measuring more than 36 mm) as well as to the resurfacing prostheses. Furthermore, in January 2012, the NOV issued guidance [15], stating that all patients with metal-on-metal prosthetic hips should be contacted and periodically checked, and describing the diagnostic methods to be used. In its advisory report of 3 June 2012 [16], the NOV set out the considerations relevant to appraisal of the need to replace a hip implant and advised orthopaedic surgeons not to send explanted metal-on-metal prosthetic hips to the manufacturers for investigation, but to 'an independent retrieval laboratory'. 3.2 Analysis of incidents Numbers of incident reports received Between 2006 and 15 November 2012, the Inspectorate received a total of 271 vigilance reports from manufacturers regarding incidents involving metal-on-metal hip implants. By the latter date, five hospitals had also informed the Inspectorate of the need to replace hip implants. The Inspectorate additionally received two reports from patients. A full overview of the reports received by the Inspectorate, including the number per year, is presented in table 2. Table 3 shows the number of reports per manufacturer. Page 24 of 34
Metal-on-metal hip implants May 2013 Table 2 Overview of the number of incident reports regarding metal-on-metal hip implants received by the Inspectorate (as of 15 November 2012) Source Year Annual number Total number Manufacturers 2006 1 2007 1 2008 3 2009 10 2010 19 2011 111 2012 126 271 Hospitals 2011 3 2012 2 5 Patients 2010 1 2011 1 2 Table 3 Overview of the number of vigilance reports submitted by various manufacturers (as of 15 November 2012) Source Number DePuy 118 Zimmer 56 Biomet 44 Smith&Nephew 32 Wright Medical Technology 16 Stryker 2 Corin 2 Finsbury 1 Total 271 Page 25 of 35
Health Care Inspectorate Substantial increase in 2011 and 2012 In 2011 and 2012, the number of reports submitted by manufacturers increased considerably. The rise was probably linked to the recall of one particular metal-onmetal hip implant in 2010 and to the attention subsequently given to such implants by orthopaedic surgeons and by the media. Those events raised awareness of the metal-on-metal implant problem amongst doctors and patients. Analysis of the contents of the vigilance reports Analysis of the contents of the vigilance reports leads to the following observations: The manufacturer and product data submitted were generally complete. Additional information about revision (health care institution, patient details and incident definition and analysis) varied considerably and was often limited. Some reports consisted of product data only. In many cases, the incidents in question were not reported to the manufacturers by health care institutions or orthopaedic surgeons involved, but by lawyers acting for patients or insurers. In most cases, explanted metal-on-metal hip implants returned to the manufacturers by health care institutions were thoroughly examined in a laboratory. The Inspectorate received detailed reports on those examinations, indicating whether specific or excessive wear was discernible on the bearing surfaces. In most cases, the manufacturers reported that no such wear was apparent. Many of the reports referred to ALVAL or similar conditions or symptoms: pain, detachment of the prosthesis, pseudo tumours, cyst formation or elevated concentrations of cobalt and chromium in the blood. In many cases, reference was made to the instructions for use, in particular brief, general statements regarding possible allergies to cobalt or chromium. None of the manufacturers dealt in any detail with the effects of elevated concentrations of cobalt and chromium in the blood. However, in some cases, very high concentrations were reported, which in the literature [17] have been linked to systemic (non-local) physical effects. Some manufacturers reported suboptimal positioning of the prosthesis, resulting in undue friction, but did not draw any clear conclusions from that observation. Many reports were phenomenological, and apparently the manufacturer concluded not ultimately to be able to determine the cause. Such incident reports could not therefore be classified by cause. This could have led to manufacturers reporting relatively low failure percentages. The final conclusion of the manufacturers was usually that the metal-on-metal hip implant still conformed to their specifications. One manufacturer linked all incidents to the manner of implantation. The manufacturer in question accordingly clarified its surgical manual in 2009 and contacted all orthopaedic surgeons to warn them about the importance of correct implantation (by a Field Safety Notice). The orthopaedic surgeons were sent a training DVD, which they were required to watch and confirm (by registration) that they had watched. One manufacturer revised the indications and contraindications listed in the instructions for use and identified ALVAL as a possible risk. Lack of clinical information The incident reports and analyses received from manufacturers often lacked clinical information regarding the patient s context. In such cases, nothing is therefore known about, for example, the implantation and explantation dates, the patient's age and sex, the surgical procedure details, the radiological diagnostic images and the blood values. The absence of such information precludes analysis of the incident in its clinical context. The manufacturers repeatedly indicated that the health care institution or health care professional involved had not provided the information, or Page 26 of 34
Metal-on-metal hip implants May 2013 had provided incomplete information or was uncooperative. Furthermore, often the explanted prosthesis was not made available for examination or there were no product data. In cases where the manufacturer had not received the relevant information from a hospital despite repeated requests, the Inspectorate made contact with the hospital and explained the manufacturer's vigilance obligations and the need for information to be made available from the hospital. Underreporting to the Inspectorate Many metal-on-metal hip implant revisions performed in the Netherlands are not reported to the Inspectorate by manufacturers, because the manufacturers are themselves not informed about them by the health care institutions or health care professionals involved. The incident reports received involve only a proportion of all the Dutch hospitals at which metal-on-metal hip implant procedures have been performed [13]. No private orthopaedic clinics are amongst the institutions mentioned in the reports. Furthermore, it was apparent from contacts with hospitals that manufacturers did not know (exactly) how many implant revisions had been performed. Extrapolation to the Dutch situation of revision percentages reported in studies [11,12] also suggested that the number of revisions performed was likely to be considerably higher than the numbers reported to the Inspectorate. Causes of underreporting to manufacturers The failure of health care institutions and health care professionals to inform the manufacturers of some or all of the hip implant revision procedures they perform has a number of causes. Health care institutions and health care professionals have no legal obligation to report incidents involving medical devices to the relevant manufacturers. Orthopaedic surgeons and hospital administrators are apparently sometimes unaware of the manufacturers' statutory obligation to report incidents to the Inspectorate. They do not appreciate that the Inspectorate uses the incident reports to monitor the safety of medical devices and therefore the quality of health care. Some orthopaedic surgeons are reluctant to inform manufacturers and to involve them in the analysis of incidents, because manufacturers are perceived to have a subjective outlook that is inconsistent with the interests of orthopaedic surgeons. There is also some mistrust of the system for the market entrance of medical devices; orthopaedic surgeons often prefer to rely on their own quality register (the National Orthopaedic Implant Register). In that context, it is relevant that, on 3 June 2012 [16], the NOV recommended that explanted prostheses should not be returned to the manufacturers, but sent to an 'independent retrieval laboratory'. It additionally appears there are often legal obstacles. A number of hospitals are currently in discussions with manufacturers about legal liability. Where such discussions are not progressing easily, explanted prostheses and the clinical data acquire legal significance. Such circumstances are not conducive to the transparent exchange of information between hospital and manufacturer. 3.3 Quality of technical files and post market surveillance Assessments in relation to safety and performance The RIVM's assessment of the files requested from the manufacturers is contained in the report 'Metal-on-metal hip implants A critical review of the manufacturer s technical documentation items with a specific focus on post-market surveillance activities' (see Annex 1). The report covers all the file items previously listed. The tables show whether the various components were present and the accompanying Page 27 of 35
Health Care Inspectorate text provides a more qualitative assessment of the information in the files. The assessments are related to the safety and performance of the devices and the intentions of the legislation. The main results are summarised below. General On the basis of the devised scoring system 71 per cent of all assessed file items were graded 'insufficient', 14 per cent 'moderate' and 6 per cent 'good'; 8 per cent could not be assessed. None of the file items that are crucial for the control of risks potentially associated with the medical device the instructions for use, the risk analysis, the clinical evaluation and the post market surveillance plan were graded 'good'; some were graded 'moderate', but most (46 to 91 per cent) were 'insufficient'. Risk management Many of the risk analyses did not or not adequately address the specific risks associated with the release of metal ions, or stated that the risks were unknown. No evidence was found of active risk mitigation based on the feedback of analysis findings into a quality control cycle. The instructions for use usually contained incomplete definitions of the risks, which were not deemed sufficient to enable orthopaedic surgeons to make proper risk-benefit assessments in individual cases. Biocompatibility With regard to biocompatibility data, the file generally referred to nonharmonised, non-european standards. None of the cited data covered dynamic use of the relevant metals in circumstances such as those to which prosthetic hips are exposed (including the creation of wear debris due to friction between bearing surfaces). Clinical evaluation No initial clinical evaluations, as performed for the initial CE marking exercise, were provided. Subsequent evaluations were often based on a combination of clinical data regarding the product in question and regarding rival products. The quantity and quality of the data varied considerably. None of the manufacturers applied clear, predefined acceptance criteria to the durability of their products and relied instead merely on failure rate data concerning rival products. Post market surveillance The files rarely contained criteria for determining whether and on what time scale appropriate action should be taken in response to post market surveillance findings. Decision-making as to whether the manufacturer should undertake action was either somewhat inconsistent or based on the performance of rival products. Only a small number of the specified sources of post market surveillance data were actually included in the analysis. The information submitted to the Inspectorate did not clearly state how often post market surveillance data were analysed. Vigilance Most of the files included vigilance procedures, but the procedures were concerned mainly with the reporting of incidents to the competent authorities. Many did not address corrective action or active risk management. Page 28 of 34
Metal-on-metal hip implants May 2013 Training and instruction All the files included surgical manuals. However, neither the extent to which the manufacturers systematically introduced their products to orthopaedic surgeons nor the extent to which they sought to transfer specific clinical implantation skills by means of training courses or 'skill labs' was apparent. 3.4 Comments from notified bodies The Inspectorate asked two notified bodies to comment on its findings. Only one responded within the requested period of one month. The notified body in question was responsible for the conformity assessment of five of the eleven metal-on-metal hip implants involved. The notified body's comments are summarised below. All the items of information specified in the European Directive were present in the assessed files and met the applicable requirements. The specific risks associated with metal-on-metal hip implants are identified in the instructions for use. The conformity assessment included verification that the file contained a post market surveillance plan. The presence of both proactive elements (post market clinical follow-up studies f or ongoing clinical studies) and reactive elements (literature assessment, vigilance and complaints procedure) was also verified. The manufacturer's ability to demonstrate that they would collect clinical data throughout the anticipated life cycle of the product was considered as well. Under the terms of the contract, the manufacturer was obliged to submit incident reports to the notified body. The manufacturers had sent the notified body various revised file documents (instructions for use, surgical manual, PMCF plan and surgical training plan), which were assessed the notified body. The manufacturers had kept the relevant authority informed of those developments. Documents regarding the clinical evaluation were present in the files and were assessed by the notified body against version M4 g of European Directive 93/42/EEC, which was in force at the time. The safety and the performance of the products were considered to be satisfactory, on the basis of what was known at the time. Clinical data relating to products that were considered to be equivalent were used, and the rationale for equivalency was considered acceptable. The notified body pointed out that, at the time of the conformity assessment, the hip implants were in a lower risk class than is currently the case (IIb instead of III). 3.5 Observations from the patient's viewpoint The Inspectorate received information from a law firm, which was based on the files of people whom the firm was representing. Some information was also reported directly to the Inspectorate by patients. On this basis the following observations may be made. Seriousness of the health impairment The health impairment suffered by patients can be very significant, involving considerable pain and immobility and sometimes persisting for a long period before a decision is made to replace the hip implant. Many patients additionally suffer secondary material consequential damages. Such damages can be sizeable, as in cases of prolonged occupational disability. Patients are often unable to continue working or caring for their families and sometimes need to have modifications made to their homes. f A post market clinical follow-up (PMCF) study involves the collection of clinical data by means of clinical studies performed after the product has been placed on the market, to supplement the clinical trials carried out prior to market introduction. g A previous (2003) version of the current Direction 93/42/EEC (2007). Page 29 of 35
Health Care Inspectorate The health impairment generally consists of tissue damage and degradation of the bone in the immediate vicinity of the implant. Cardiovascular conditions, vision impairments and skin conditions have also been reported. Such problems may be symptomatic of systemic effects associated with the strongly elevated chromium and cobalt concentrations in the blood. In some cases, recovery does not proceed smoothly after revision of the implant, or the patient never fully recovers. Such problems are usually attributable to complications during or immediately following the revision surgery, or to the seriousness of the harm caused by the metal-on-metal hip implant. Many metal-on-metal hip implants have been given to relatively young patients. Such patients will frequently have sufficient life ahead of them to require a second implant revision later in life. Undergoing further surgical procedures increases the risk of complications. Provision of information to the patient Many patients were not or not properly informed about the risks associated with metal-on-metal hip implants. Patients frequently report having been told that they would be able to participate in sporting activities without inhibition and that the implant would last longer than a conventional prosthesis. Patients are often not fully aware of the brand and type of metal-on-metal hip implant they have received. Diagnosis and medical treatment of the problem Many patients who developed health problems associated with metal-on-metal implants were not taken seriously by their medical doctor or hospital, or were only taken seriously after a long time or after obtaining a second opinion. Reluctance to take patients seriously was often due partly to the absence of any evidence of a clinical problem on X rays. Only since the recall in 2010 and publication of the NOV guidance in 2011 have patients with metal-on-metal hip implants been given blood tests and, where appropriate, a specific MRI scan (which do usually show up the cause of the conditions). Some doctors/hospitals are much more inclined to replace metal-on-metal hip implants than others. Some doctors immediately advise replacement of the implant when it is ascertained that the patient has very high chromium and cobalt concentrations in the blood, even if the patient is not experiencing symptoms. Other doctors postpone revision as long as possible. The latter approach may be inconsistent with the NOV advice regarding the clinical implications of high cobalt levels in the blood. It is unclear how skilled orthopaedic surgeons are in recognising conditions potentially indicative of the systemic effects of metal poisoning and in responding appropriately, possibly in consultation with medical specialists in other fields outside orthopaedics. In at least two cases, it proved that the brand or type of metal-on-metal prosthesis received by the patient was not that which was discussed with the patient before the procedure. In a number of cases, metal-on-metal hip implants were lost or disposed of in the hospital following explantation. Hospitals rarely inform patients about the findings of the examination of explanted implants. The NOV has recommended that explants should not be returned to the manufacturers for examination, but sent to independent laboratories. It is not clear whether surgeons often follow that advice, what such examinations have revealed or what is done with the findings. The NOV's advice is not always proactively followed. In 2011 and early 2012, metal-on-metal-implant procedures were still being performed, despite the Page 30 of 34
Metal-on-metal hip implants May 2013 NOV's very cautious advice of June 2011. The continued use of the implants was highlighted by an investigation by the Dutch television programme KRO Reporter in conjunction with the Dutch medical journal Medisch Contact in May 2012. It was established that at least four hospitals did not stop using metal-onmetal hip implants until 2012. Furthermore, contrary to NOV advice, a number of patients were not contacted to arrange for them to be checked by an orthopaedic surgeon, or were contacted only after a long delay. The Inspectorate is aware of one case in which the patient only learnt the result of the examination (serious tissue damage) after calling the hospital to ask for it. Legal aspects - To date, no manufacturer or hospital in the Netherlands has admitted any liability to a patient for problems associated with metal-on-metal implants. In a few cases, a manufacturer offered patients amicable settlements before their implant revision procedures. This proposed settlements involved no admission of liability and the payment of modest sums in full and final settlement of the patients' claims. Two hospitals are known to have paid small sums in compensation, without accepting liability. The compensation was paid without prejudice to the rights of the patients, who therefore retain the ability to pursue claims for further damages. - In its dealings with patients, one of the manufacturers uses the services of a specialist claims handling firm. The firm in question seeks to conclude settlement agreements with the patients, under which the patients largely waive the right to pursue further claims. Hospitals and insurers appear to actively and explicitly refer patients to such complaints handling arrangements. - A number of hospitals have explicitly asked patients to sign documents authorising the hospital to claim the costs incurred directly from the manufacturer. Patients may sign these authorisations without being aware of the legal implications, which may include the provision of medical information to the manufacturer and possibly third parties. - Pursuing a product liability claim against a manufacturer is a complex undertaking, partly because of the international context and the applicable limitations and liability expiry provisions of European product legislation. A patient's entitlement to compensation can be further compromised by delays in medical diagnosis and by failure of the medical doctor or hospital to actively and properly inform the patient about matters such as the brand and type of implant concerned. Page 31 of 35
Metal-on-metal hip implants May 2013 References 1 DePuy International Ltd, Field Safety Corrective Action ASR-product, Leeds 24 August 2010 2 Directive 93/42/EEC of the Council concerning medical devices, 14 June 1993, last revised on 11 Nov 2007, http://eurlex.europa.eu/lexuriserv/lexuriserv.do?uri=consleg:1993l0042:20071011: EN:PDF 3 European Commission, Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) - requests http://ec.europa.eu/health/scientific_committees/emerging/requests/index_en. htm 4 Staat van de Gezondheidszorg 2008 ('Risico's van medische technologie onderschat') (The State of Health Care 2008 ('Risks associated with medical technology underestimated')), Dutch Health Care Inspectorate, The Hague 2008 (www.igz.nl) 5 Medische technologie at risk (Medical technology at risk), Expert Group on Medical Technology, Ministry of Health, Welfare and Sport (VWS), April 2011 6 Convenant Veilige toepassing van medische technologie in het ziekenhuis (Covenant on the Safe Use of Medical Technology in Hospitals), Dutch Hospitals Association / Dutch Federation of University Medical Centres / Netherlands Association for Medical Rehabilitation, Utrecht 2011 7 Parliamentary letter of 20 November 2012 regarding the proposal for an implant register, http://www.rijksoverheid.nl/documenten-enpublicaties/kamerstukken/2012/11/20/kamerbrief-over-het-voorstel-voor-eenregister-van-implanten.html 8 Parliamentary letter of 5 April 2012 regarding the response to EU Commissioner Dalli regarding the safety of medical implants, http://www.rijksoverheid.nl/documenten-enpublicaties/brieven/2012/04/06/afschrift-brief-aan-european-commission.html 9 Smith AJ, Dieppe P, Porter M, Blom AW. Risk of cancer in first seven years after metal-on-metal hip replacement compared with other bearings and general population: linkage study between the National Joint Registry of England and Wales and hospital episode statistics. BMJ 2012;344:e2383 10 Rosengren BE. Metal-on-metal hip implants and the risk of cancer. BMJ 2012;345:e4605 11 Smith AJ, Dieppe P, Vernon K, Porter M, Blom AW. Failure rates of stemmed metal-on-metal hip replacements: analysis of data from the National Joint Registry of England and Wales. Lancet 2012;379:1199-1204 12 Smith AJ, Dieppe P, Vernon K, Porter M, Blom AW. Failure rates of stemmed metal-on-metal hip replacements: analysis of data from the National Joint Registry of England and Wales. Lancet 2012;380:1759-1766 13 Croonen H, Maassen H. Dossier metaal-op-metaal heupprotheses (Metal-onmetal hip implants dossier). Medisch Contact 2012;67:1272-1273 14 Dutch Orthopaedic Association. Het gebruik van metaal-op-metaal heupprothese: aangescherpt advies aan de NOV leden (The use of metal-onmetal hip implants: revised advice to NOV members), NOV 17 January 2012 15 Dutch Orthopaedic Association. Work-up van een patiënt met een metaal op metaal (M-o-M) heupprothese (Work-up of patient with a metal-on-metal (M-o-M) hip implant), NOV Hip Committee, 17 January 2012 Page 33 of 35
Health Care Inspectorate 16 Dutch Orthopaedic Association. Uitwerking NOV advies metaal op metaal articulerende implantaten (MoM) (Implementation of NOV advice regarding metal-on-metal articulating implants (MoM)), NOV 3 June 2012 17 Dijkman MA, Vries I de, Mulder-Spijkerboer H, Meulenbelt J. Kobaltvergiftiging door metaal-op-metaalheupprothese (Cobalt poisoning by metal-on-metal prosthetic hip). Ned. Tijdschr. Geneesk. 2012;156:A4983 Page 34 of 34
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities Annex 1 Research report by the National Institute for Public Health and the Environment (RIVM) Page 35 of 35
Metal-on-metal hip implants A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities. Authors: Adrie de Bruijn Arjan van Drongelen Boris Roszek Claudette de Vries Robert Geertsma
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities Contents Summary 5 Introduction 7 Method 9 Discussion and results 11 References 27 Annex I Assessment form 28 Annex II Hazards and contributing factors 32 Annex III Risks and contraindications identified based on literature 35 Annex IV Clinical evaluation MoM hip implants 37 Annex V References in Annex III and IV 38 Annex VI UK Guidances on selection of hip prostheses 40 Annex: page 3 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities Summary Metal-on-metal (MoM) bearings of cobalt-chromium alloy hip implant systems have been re-introduced in the 1990 s, after an initial unsuccessful period of use in the 1960 s. The Dutch Health Care Inspectorate (IGZ) initiated a surveillance project after observing an increase of clinical problems with total MoM hip impants and resurfacing MoM hip implants. Problems include metal wear debris and elevated serum levels of metal ions. More specific for the resurfacing MoM hip implants the risk for femoral neck fracture is high. Moreover, recent publications of national registry data for Australia and England/Wales have indicated higher revision rates of MoM hip implants. As part of the investigation, the IGZ has requested the National Institute for Public Health and the Environment (RIVM) to assess the quality of the (technical) documentation of MoM hip implants, including the post-market surveillance (PMS) procedures and the results of PMS activities. The following findings resulted from the assessment: Results of the assessments of the technical files of MoM hip implants show major shortcomings in a large part of the documentation. The IFUs have incomplete descriptions of risks and contraindications. Additional inadequacies concerned regulatory issues (i.e., non-compliance with the essential requirements) or layout issues of the IFU (e.g. non-acceptable font size of text). In the risk analyses, broadly defined risk categories (i.e., hazards and contributing factors) and specific MoM-related risks are often not fully addressed. Furthermore, in many cases there was a lack of coherence (i.e., addressing warnings, precautions and contraindications as mentioned in the IFU in the risk analysis). In the documentation concerning biocompatibility data, non-european, nonharmonised ASTM a standards were mainly used to fulfil the requirements. Metal wear debris, a major concern regarding MoM implants, is not addressed in these ASTM standards. No initial clinical evaluations, i.e. those used for CE b -marking, were submitted. Manufacturers submitted their current clinical evaluations. The clinical evaluations submitted are most often based on a combination of manufacturers own data with data from other MoM devices. The number of included data and the level of clinical evidence varied per file. For survival rates of MoM hip implants, no generally recognised acceptance criterion was available. Some manufacturers used a NICE c benchmark as acceptance criterion, and other manufacturers just made comparisons with other MoM devices on the market. Criteria to take action and initiate risk management activities as a consequence of PMS findings are hardly described in the PMS procedures. For the analysis of PMS data, a comparison is often made with other MoM devices. Substantiation of actions to be taken, if any, is often limited. Also, none of the manufacturers specified a timeframe when to take actions based on results observed in PMS data. The risk analysis, clinical evaluation and PMS activities are important items, both in the continuous cycle of improvement of medical devices and for establishing the continued safety and performance of the devices. These are items for which major shortcomings were observed and a systematic approach was missing. a b c American Society for Testing and Materials. Conformité Européenne. UK National Institute for Clinical Excellence. Annex: page 5 of 41
National Institute for Public Health and the Environment Resurfacing MoM hip implants are popularly known as sports hips, which suggests that the implants are particularly suitable for patients with an active lifestyle. However, the files assessed do not contain this terminology. Moreover, most instructions for use contain warnings about the limitations related to activities of patients implanted with a resurfacing MoM hip implant. All manufacturers submitted a surgical technique manual, but only a few manufacturers also indicated the option of training for orthopaedic surgeons. Annex: page 6 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities Introduction Metal-on-metal (MoM) bearings of cobalt-chromium alloy hip implant systems were introduced in the 1960 s. These first generation MoM hip implant systems were abandoned due to high failure rates and replaced mainly by implants with metal-onpolyethylene bearings. However, MoM hip implants were re-introduced in the 1990 s [1]. The tribologic d quality of the MoM bearing surfaces has enabled a novel generation of hip implant systems that is considered a stronger and more durable alternative to systems with metal-on-polyethylene bearings. MoM bearings of hip implants are used for total hip arthroplasty or hip resurfacing arthroplasty. In total hip arthroplasty, the femoral head and neck are dissected and replaced by a metal head and stem inserted in the intramedullary shaft of the femur. The acetabulum is replaced by an acetabular component. Hip resurfacing is an alternative to total hip arthroplasty. Instead of femoral head and neck dissection, the femoral head is resurfaced by a cemented metal cap. There are some specific risks/complications of MoM hip implants, including increased serum levels of metal ions (cobalt and chromium), metal wear debris and metal hypersensitivity [2]. In addition to these risks, fracture of the femoral neck is a specific complication of hip resurfacing implants [3]. Moreover, recent publications of national registry data for Australia and England/Wales have indicated higher revision rates of MoM hip implants [4-7]. Furthermore, higher revision rates were already observed in 2008 [8]. This leads to the question why manufacturers of MoM hip implants did not act on these kinds of problems during the past years. The Dutch Health Care Inspectorate (IGZ) observed an increased incidence of clinical problems concerning MoM hip systems (i.e., hip resurfacing systems as well as total hip implants) based on the number of reports of hip revisions in the Netherlands, precautionary advice of medical professional groups and literature, which triggered the IGZ to initiate a surveillance project. An important topic in this project is analyzing the manufacturer s interpretation of the post-market surveillance (PMS) obligation. As part of the investigation, the IGZ has requested the National Institute for Public Health and the Environment (RIVM) to assess the quality of the (technical) documentation of MoM hip implants. d Tribology is the science that deals with the design, friction, wear and lubrication of interacting surfaces in relative motion. Annex: page 7 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities Method MoM hip implants Eleven MoM hip implants were selected by IGZ for the assessment, based on an inventory of the devices on the Dutch market. The devices selected included devices from both large manufacturers and smaller manufacturers. The information was supplied in time to be assessed. The files included hip resurfacing systems as well as device components of total hip implant systems. Within each of these two main groups, some manufacturers market a range of types of MoM implants. In those cases the information of one type was assessed. In most cases, no differentiation for the range of products was found in important file items such as risk assessment and clinical evaluation. One implant was only marketed by the company that was identified as a manufacturer, and was in fact manufactured by another manufacturer. The file that was provided contained little information as they referred to the actual manufacturer for most of the file items. This manufacturer was also included in this study and the file they provided also contained some information on the implant in question. Although the thus composed file was still missing some items, it was decided to include this implant in the study. One of the files assessed was not for a true MoM implant, as the metal surfaces were coated with ceramics. After due deliberation, it was decided that this product would also be included in the assessment. Six files concerned resurfacing hip implants, one file concerned a total hip implant and for four other files, both hip resurfacing and total hip replacement were addressed. Requested documentation Manufacturers were requested to submit the following (technical) documentation items: 1 Instructions for use (IFU); 2 Risk analysis; 3 Biocompatibility data; 4 Clinical evaluation; 5 PMS procedure(s); 6 Summary and analysis of PMS data; 7 Vigilance procedure(s); 8 Information on the training offered and additional instructions; 9 Device description; and 10 Reference to similar devices or previous generations of the device. If items of the documentation were missing, a reminder was sent to the manufacturer. Files with incomplete (technical) documentation were not excluded. Items which were missing were scored as absent. Literature search for MoM-related risks Risks associated with hip implants, especially MoM hip implants, were identified based on a literature search in Scopus (Elsevier BV, the Netherlands). The search was performed on 16 September 2011. No language restrictions and date of publication limitations were applied to the search strategy. In combination with the booleans AND and OR, the following search terms were used: metal on metal, hip resurfacing, arthroplasty, biocompatibility, toxicology, allergy, hypersensitivity, adverse reactions, soft-tissue reactions, pseudotumor, corrosion, loosening, injury, wear, indications, contraindications, complications, survival, osteolysis, surgical, future, progress, risk, chromium, chrome, cobalt. In addition, the boolean AND NOT in combination with the search term cervical was used. Two reviewers Annex: page 9 of 41
National Institute for Public Health and the Environment independently judged the eligibility of the publications by examining titles and abstracts. The hand-searched identification of relevant publications was complemented by perusing reference lists of selected key publications. The outcomes of the literature search were used to create lists of identified risks and clinical evaluation-related points of interest (see Annexes III and IV). A list of references used is included in Annex V. The literature search was however not intended to obtain a comprehensive overview. The lists of identified risks and clinical evaluation-related points of interest were used as a guidance to assess the risk analyses, IFUs and clinical evaluations. Assessment of documentation items A form was developed for the assessment of the documentation. Items 9 and 10 were not assessed, but were used to provide the assessors with background information on that specific device. For the reference to similar devices (item 10), issues were assessed in other file items, mainly the clinical evaluations, if and when relevant. For each of items 1-8, a set of sub-items was listed (see Annex I). In general, the assessment was based on the presence/description of that particular sub-item in the documentation. Sub-items were assigned N (no), P (partial), or Y (yes). For the assessment of addressing specific MoM-related risks and coherence between IFU and risk analysis, cut-off values of <20%, 20-80% and >80% were used. Coherence between the IFU and risk analysis implies that residual risks identified in the risk analysis are mentioned in the IFU and vice versa warnings, precautions and contraindications mentioned in the IFU are addressed in the risk analysis [9]. If a sub-item was not applicable (NA) for a certain device file it was explained why this sub-item was not applicable and it was not used to calculate the score (insufficient, moderate or good). Sub-items that were not received were assigned NR (Not received). In consultation with IGZ, a higher weight and a higher score were given to important sub-items, related to risk and safety aspects. These sub-items are indicated as Major. In Annex I, the details on the score and classification of each sub-item are given. To provide the possibility to comment on assigned scores and to include additional findings in the assessment form, an option was created to give qualifying remarks for every item. This was considered to be a valuable tool to describe the quality of that item more clearly. Quality of documentation items To determine the overall score of documentation items 1-7, the sub-item points were added up. The sum indicated a good, moderate or insufficient score. Documentation items scored good if the sum was maximal, i.e. every sub-item was adequately addressed. The decision was made that missing one major sub-item, or an equivalent number of points missing otherwise, should lead to an overall score insufficient. This assessment system was based on the principle that all essential elements are needed for a good system (compare to a chain with several links) and therefore a good score and if one of these essential elements is missing, the system does not function correctly, i.e. insufficient. Thus, the IFU, risk analysis, biocompatibility data and clinical evaluation scored insufficient if one or more major sub-items were missing or if a combination of other shortcomings resulted in a decrease of four or more points. PMS and vigilance procedure(s) scored insufficient if at least one sub-item was missing or at least two sub-items were partially addressed. Summary and analysis of PMS data scored insufficient if one or more sub-items were missing. A moderate score was assigned if the sum was in between good and insufficient. For item 8 (training) no overall score was given, as several options for training are possible and not all options might be required. This is a rather strict judgement system, in which a limited number of less than optimal scores for sub-items is reason for an insufficient item score. It was, however, considered justified for these assessments. Annex: page 10 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities Discussion and results Availability of documentation Instructions for use Risk analysis Biocompatibility data Clinical evaluation PMS procedure 1 11 11 11 11 10 Summary & analysis of PMS data 3 8 Vigilance procedure Training 1 11 10 absent present 0 1 2 3 4 5 6 7 8 9 10 11 Number of files Figure 1. Availability of documentation items of MoM hip implants. Not all manufacturers submitted documentation on all of the above mentioned items. In total, three files were incomplete (Figure 1). Three documentation items were not always present (Figure 1). Thus, 94% (83/88) of the documentations items were available. One of the MoM hip implants (hip 11) was marketed by manufacturer A, who provided a limited product file, but was actually manufactured by manufacturer B. For the items risk analyses, biocompatibility, clinical evaluation, summary & analysis of PMS data, and the vigilance procedure, the manufacturer A referred to manufacturer B and the provided PMS procedure was of manufacturer C, who later acquired manufacturer B. Also in the product file of manufacturer B, some information of manufacturer A was provided that was also applicable for Hip 11. Although the question remains who officially manufactures and markets hip 11, the available information related to this product was assessed, if applicable. Results of the assessment of the various documentation items are described in the paragraphs below. Assessment of the quality of documentation items In this paragraph, the results for the assessment of all files are given. For the items assessed, the results are presented in figures and text. The figures provide scores, showing to what extent items and their sub-items are addressed in the documentation. In the text, detailed aspects which could not be translated directly into the scores are presented, providing additional insight into the way the manufacturers addressed the file items. Furthermore, the information in the text puts the scores into perspective with regard to their relevance for safety and performance of the devices. Annex: page 11 of 41
National Institute for Public Health and the Environment 1 IFU Table 1 Assessment of the IFUs concerning MoM hip implants. Sub-item Hip 1 Hip 2 Hip 3 Hip 4 Hip 5 Hip 6 Hip 7 Hip 8 Hip 9 Hip 10 Hip 11 1.1 Compliance with ERs P Y P P P P Y P Y P P 1.2 Surgical techniques Y Y Y Y Y Y Y P P Y Y 1.3 Dutch language Y N Y Y Y Y N Y N N Y 1.4 Coherence: residual risks in >80% >80% >80% >80% NA N >80% >80% 20-20- NA IFU 80% 80% 1.5 Indications Y Y Y Y Y Y Y Y Y Y Y 1.6 Risks & contraindications 20-20- 20-20- 20-20- 20-20- 20-20- 20- (Annex III) 80% 80% 80% 80% 80% 80% 80% 80% 80% 80% 80% 1.7 Clearly written Y Y Y P Y P Y Y Y Y Y 1.8 Well structured Y Y Y P Y Y Y Y Y Y Y 1.9 Readability Y N N N N N N N Y Y Y Assessment score M I I I I I I I I I I Gray shaded rows are major sub-items. IFU- instructions for use, ERs- essential requirements. Sub-item scores: Y- Yes, P- Partial, N- No. NA- Not applicable, because the risk analysis was not received and therefore the coherence between IFU and risk analysis could not be assessed. Assessment score per MoM hip implant file: M- Moderate, I- Insufficient. Several IFUs did not comply with the essential requirements 13.6.a 13.6.q in the Medical Devices Directive (Table 1). Missing information were the details strictly necessary to identify the device and information regarding the risks of reciprocal interference posed by the presence of the device during specific investigations or treatment, e.g. magnetic resonance imaging. Most IFUs referred to a surgical technique manual. Two IFUs scored partial because the IFU mentioned that the surgeon must be thoroughly familiar with the implant, instruments and surgical procedure prior to performing surgery, and the surgeon should contact the manufacturer for product specific surgical techniques, but the availability of a surgical technique manual was not mentioned. A substantial part of the IFUs was not in Dutch (4/11). Although not submitted, some manufacturers indicated that a Dutch version of the IFU is available. In most IFUs, 80% or more of the residual risks for which the risk analysis indicated that they were to be addressed in the IFU, were actually mentioned in the IFU. In one IFU, this was only 20% or less of the residual risks. It should be noted that one manufacturer (hip 5, hip 11) did not submit a risk analysis. Therefore, the coherence between residual risks in risk analysis and their wording in the IFU could not be assessed in these cases. Therefore this sub-item was scored as not applicable. Indications for use were always mentioned in the IFU. The IFUs mentioned only a part of the MoM-related risks and contraindications as identified in literature, see textbox 1. Most IFUs were clearly written and well structured. The readability of the IFUs was often difficult, because several IFUs were printed in font size 7 (Times New Roman). The assessors consider a font size of at least size 9 (Times New Roman) acceptable. Annex: page 12 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities Textbox 1 Residual risks in IFUs. Although most manufacturers indicate in the files that they are aware of potential problems that may be related to the release of metal ions and metal wear debris from metal on metal articulating surfaces, they state in the instructions for use that the long term biological effects are presently unknown. This information is provided in an anecdotal manner; it remains unclear how this information can be used in a risk benefit analysis by physicians, so they can make the correct clinical decision and explain this to their patients. Some manufacturers mention that there is no direct evidence linking metal on metal articulating implants with long term medical problems, including cancer. One manufacturer states that the problems with MoM implants and the release of metal wear debris and metal ions may not have a causal relationship. Potential problems may develop into real problems in the future, or they may not. The uncertainty in the development of potential problems shall be weighed against the benefits of hip replacement. No indication is given by the manufacturer to assist the physician in making this risk benefit analysis, especially taking into account the long term. On two issues the manufacturers are particular clear. The use of metal implants is generally contraindicated for pregnant women and women that are breastfeeding. Some manufacturers exclude women of childbearing age all together, because of the unknown effects of elevated levels of metal ions on the foetus. All manufacturers warn against the use of metal implants in patients that have a known sensitivity or allergy to metals and patients with insufficient kidney function. However, only one manufacturer recommends that patients should be tested for metal allergy. Although hip resurfacing implants are popularly known as the sports hip implying that the implant is particular suitable for patients with an active lifestyle, this is certainly not reflected in the IFU. The manufacturers are very clear on the fact that a hip replacement implant is not capable of sustaining the same level of activity as the natural joint for an indefinite period. The manufacturers instructions are clear on this; patients shall be advised against unrealistic functional expectations and be instructed to refrain from excessive physical activities, labour and sports. Not following these instructions may lead to implant failure, implant loosening and excessive wear. Annex: page 13 of 41
National Institute for Public Health and the Environment 2 Risk analysis Table 2 Assessment of the risk analyses concerning MoM hip implants. Sub-item Hip 1 Hip 2 Hip 3 Hip 4 Hip 5 Hip 6 Hip 7 Hip 8 Hip 9 Hip 10 Hip 11 2.1 Date Y Y Y Y N Y Y Y Y Y N 2.2 Risk categories (Annex II) Y P P P N P P Y P P N 2.3 MoM-related risks 20- <20% 20-20- N 20- <20% >80% <20% <20% N (Annex III) 80% 80% 80% 80% 2.4 Risks estimated Y Y Y Y N Y Y Y Y Y N 2.5 Risk control & mitigation 2.6 Acceptability residual risks Y P P P N Y Y Y P P N Y Y N Y N Y Y Y Y N N 2.7 Coherence: WPC >80% <20% <20% <20% N 20- <20% 20-20- <20% N in risk analysis 80% 80% 80% Assessment score M I I I I I I M I I I Gray shaded rows are major sub-items. WPC- warnings, precautions and contraindications. Sub-item scores: Y- Yes, P- Partial, N- No. Assessment score per MoM hip implant file: M- Moderate, I- Insufficient. One manufacturer (of hip 5 and 11) did not submit a risk analysis but only a risk analysis & control summary. None of the sub-items applicable for a risk analysis were described in this document (Table 2). Other manufacturers submitted several types of documents, i.e. (design) failure mode and effects analyses (FMEAs), risk assessments, risk management reports and/or plans. The dates of the documents ranged from 2001 to 2011. Several of these devices were first introduced before 2001, whereas the latest market launch of products included in this investigation was 2006. This means that most of these risk-related documents are not the original documents at the time of market introduction. Moreover, six out of nine documents submitted were at least two years old, indicating that the latest developments were not included. Change histories of the documents were mostly not included. The concept of the continuous cycle of improvement (CCI) of medical devices requires the manufacturer to update the risk analysis on a regular basis, based on experiences gained with that device [10]. Based on these experiences, the device design or the accompanying IFU can be modified to improve the quality and safety of that device. Apparently, the CCI is not functioning and the opportunities to improve the device are not seized. A major part of the risk analyses (7/9) did not address all (general) hazard/risk categories (Annex II). For the MoM-related risks and contraindications as identified in literature, findings were: 4/9 files addressed <20% of these risks and contraindications, whereas another 4/9 files addressed 20%-80% of these risks and contraindications. MoM-related risks were adequately addressed in just one file (>80%); see textbox 2. In only one case >80% warnings, precautions and contraindications as mentioned in the IFU were incorporated into the risk analysis. Risks were always estimated. However, the description of risk control and risk mitigation was often limited (5/9). The criteria for the acceptability of residual risks were not addressed in two risk analyses. Annex: page 14 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities Textbox 2 Risks related to MoM implants and mitigation of these risks. The risk of metal sensitivity is generally mitigated by the use of standard materials that have a long record of application for implants (see also paragraph 3 Biocompatibility data). The fact that the standards to which these materials conform do not address the potential problems related to the release of metal ions and metal wear debris from metal on metal articulating surfaces is not addressed. At best, the manufacturer recognises that the long term effects of metal wear debris and elevated ion concentrations in the patients blood are presently unknown. This is not mitigated, but just given as information to the user by stating this lack of knowledge in the instructions for use. About half of the manufacturers describe the risk of excessive wear, and thus the excessive generation of metal ions and metal wear debris. They emphasise the importance of correct implant selection, correct surgical technique to ensure proper alignment of the implant, full mating of the tapers of hip stem and ball, and thorough instruction of the patient regarding the necessary limitation of physical activities. 3 Biocompatibility data Table 3 Assessment of biocompatibility data concerning MoM hip implants. Sub-item Hip 1 Hip 2 Hip 3 Hip 4 Hip 5 Hip 6 Hip 7 Hip 8 Hip 9 Hip 10 Hip 11 3.1 Literature review N N Y N N N P N N N N 3.2 EN ISO 10993-1 Annex B or equivalent N N Y N N N N P N Y N 3.3 Tests N N N N N Y Y N N Y N 3.4 Appropriateness of tests N N N N N P N N N Y N 3.5 Standards Y Y Y Y Y Y Y Y Y Y Y 3.6 Test protocols N N N N N N N N N N N 3.7 Data analysis N N N N N Y Y N N N N 3.8 Summary N N Y N N Y Y N N Y N Assessment score I I I I I I I I I I I Sub-item scores: Y- Yes, P- Partial, N- No. Assessment score per MoM hip implant file: I- Insufficient. Evaluation of biocompatibility in the context of the European Medical Devices Directives should be carried out as part of the design and development process and be integrated in the risk management process. Manufacturers should always take account of the generally acknowledged state of the art. Furthermore, animal welfare requirements demand that no unnecessary animal testing be performed. For these reasons, a literature review is considered to be the first step to determine biocompatibility issues to be addressed, evaluate any existing data on these issues, and subsequently decide on the need for further biocompatibility testing. This was not performed for 8 devices (Table 3). Annex: page 15 of 41
National Institute for Public Health and the Environment A systematic evaluation using Annex B of EN ISO 10993-1 (harmonised standard in Europe for biological evaluation of medical devices) or an equivalent alternative approach to determine the tests to be carried out was also infrequently used (7/10 missing). Tests conducted, the appropriateness of the tests conducted, analysis of data and a summary were often not included. Tests protocols were never present. Instead of this systematic approach in line with the European directives, most manufacturers indicated that the materials used for the hip implants conform to specifications issued by the ASTM (American Society for Testing and Materials) as ASTM standards. These standards include a paragraph on biocompatibility, indicating that the materials have a history of successful clinical application, leading to an acceptable level of biological response if used in appropriate applications. Furthermore, it is stated that the materials produce well characterised levels of biological response when tested in accordance with another ASTM standard e. This standard, specifically addressing biocompatibility assessment of biomaterials for surgical implants with respect to effects on muscle and bone, requires biocompatibility to be tested using pieces of implants materials to be implanted in muscle or bone, without simulating actual use and related wear symptoms. Fulfilling the specifications in these standards is used as a rationale for not performing other biocompatibility evaluation or testing. For compliance with the Essential Requirements in European directives, the ASTM approach cannot be considered sufficient. Firstly, ASTM standards are not recognised in Europe as harmonised standards, and are thus insufficient reference as such. The brief statements in the material specification standards claiming favourable biocompatibility properties lack substantiation by a literature review and/or overview of test results using the ASTM standard. Moreover, the manufacturers did not provide substantiation of any equivalence to harmonised European standards; the extent by which this methodology is covering European requirements can therefore not be determined. Furthermore, specific issues related to the use of the final products using the specified materials are not covered. For example, effects of size, shape, surface topography, implant site (including consideration of load bearing characteristics), etc. are not taken into account. Also, importantly, the well known problems related to metal wear debris generated during application of the device, such as damage to surrounding tissue and elevated blood levels of metal ions, are not addressed in these standards. Manufacturers need to include such issues in their biological evaluation. e ASTM F981-04 (2010): Standard practice for Assessment of Compatibility of Biomaterials for Surgical Implants with Respect to Effect of Materials on Muscle and Bone. Annex: page 16 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities 4 Clinical evaluation Table 4 Assessment of the clinical evaluation concerning MoM hip implants. Sub-item Hip 1 Hip 2 Hip 3 Hip 4 Hip 5 Hip 6 Hip 7 Hip 8 Hip 9 Hip 10 Hip 11 4.1 Date Y N Y Y N Y Y Y Y Y N 4.2 Rationale for equivalency P NA P NA Y NA NA NA Y NA Y 4.3 Name of device Y Y Y Y Y Y Y Y Y Y Y 4.4 Identification of manufacturer 4.5 Device description & intended use Y Y Y Y Y Y Y Y N Y Y Y Y Y Y Y Y Y Y Y Y Y 4.6 Indications Y Y Y Y Y Y N Y Y Y Y 4.7 Safety & performance claims 4.8 Objective of clinical evaluation 4.9 Choice clinical data type substantiated 4.10 Summary & appraisal clinical data 4.11 Performance & safety analysis P N P P P Y P Y N Y P Y Y Y Y Y N N Y Y Y Y Y N N N N N Y N N Y N Y P Y P Y P N Y P Y Y P P Y P Y Y P Y Y Y Y 4.12 Indications, contraindications, outcomes (Annex IV) 20-80% >80% >80% >80% 20-80% >80% <20% >80% >80% >80% 20-80% 4.13 Conclusions Y Y Y Y Y Y N Y Y Y Y 4.14 Search strategy Y Y Y Y Y P N Y Y Y Y Assessment score I I I I I I I M I I I Gray shaded rows are major sub-items. Sub-item scores: Y- Yes, P- Partial, N- No. NA- not applicable, because the clinical evaluation contained clinical data of manufacturers own product and was not based on equivalency. Assessment score per MoM hip implant file: M- Moderate, I- Insufficient. Clinical evaluation reports were written in 2007 (n=2), 2008 (n=2), 2009 (n=3) and 2011 (n=1). Three clinical evaluation reports had no date (Table 4). It should be noted that initial clinical evaluations used for CE f marking (1996-2006) were not submitted. The clinical evaluation reports submitted were more recent documents which did not specify which clinical data were available at the time of CE-marking. f Conformité Européenne. Annex: page 17 of 41
National Institute for Public Health and the Environment In five clinical evaluation reports the principle of equivalence was used. For the substantiation of equivalence, manufacturers compared features of their device to the features of devices considered equivalent, usually in table format. These five clinical evaluations reports included three reports discussing the impact of differences between the devices for the validity of the equivalence. The two other reports contained a partial rationale for equivalence, i.e. there was no discussion on the impact of differences. In the six other clinical evaluations reports the principle of equivalence was not used. In these cases, the item rationale for equivalency given was scored yes, because this approach is as valid as equivalency with a rationale. All manufacturers used clinical data from their own devices to varying degrees. The level of clinical evidence varied, i.e. data were used from various types of studies, ranging from case studies to observational studies and randomized controlled clinical trials. In addition, manufacturers used data from national joint registries. Most manufacturers using clinical data of their own devices did compare their results to other MoM hip implants in varying degrees. The clinical evaluation reports gave no insight whether clinical data were obtained from manufacturer-sponsored studies or investigator-initiated studies. The data obtained for the clinical evaluation varied between the files. Some investigations focussed on a limited number of publications, whereas other manufacturers elaborately summarized all publications found. Direct comparison between different MoM devices was not always possible and one manufacturer adjusted the data of his own device for demographic variables to allow comparison to other hip implant systems. No insight is given in the exact nature and scientific rationale of these adjustments. Some manufacturers referred to a UK National Institute for Clinical Excellence (NICE) benchmark of 10% revision rate in 10 years time to compare their performance (Annex VI). Other manufacturers did not state acceptance criteria for the performance of their device. Acceptability of performance was evaluated by comparing performance to other MoM devices. If the performance was within the same range, this was generally considered acceptable by the manufacturers. In clinical evaluation reports the name of the hip implant system, its description and the intended use was always mentioned. The identification of the manufacturer was always given, except in one clinical evaluation report mentioning a 3-character code in the header of the report, which gave an indication of the manufacturer of that device. Except for one clinical evaluation, indications for use were always mentioned. The conclusions were also missing once. Safety and performance claims for the device were often partially present (5/10) or absent (2/10), as well as the summary and appraisal of clinical data (partially present 4/10, absent 1/10). The performance and safety analysis was often partially present. Indications, contraindications and outcomes were often addressed in the clinical evaluation report (7/10). The objective of the clinical evaluation was often mentioned, as well as a description of the literature search strategy. A shortcoming often found was the lack of substantiation of the choice of clinical data type used (7/10); the manufacturers did not indicate why they used either literature, clinical data or a combination of literature and clinical data for the clinical evaluation. It was decided to refrain from more extensive assessment of scientific validity of the outcomes of the evaluations at this time, as this requires more in-depth knowledge on the products and their clinical application than currently available among the assessors. Annex: page 18 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities 5 PMS procedures and activities The European Medical Device Directive requires the manufacturer of medical devices to institute and keep up to date a systematic procedure to review experience gained from devices in the post-production phase, including the provisions referred to in Annex X [of the Medical Device Directive], and to implement appropriate means to apply any necessary corrective action. The results of the assessment of the PMS procedures are presented in Table 5 and 6. Table 5 Assessment of the PMS procedure concerning MoM hip implants. Sub-item Hip 1 Hip 2 Hip 3 Hip 4 Hip 5 Hip 6 Hip 7 Hip 8 Hip 9 Hip 10 Hip 11 5.1 Passive procedure Y Y Y Y Y NR NR Y Y Y Y 5.2 Active procedure Y Y Y Y Y NR NR N Y Y Y 5.3 Sources of active procedure >=2 Y Y Y Y Y NR NR N Y Y Y 5.4 CAPA Y Y Y Y Y NR NR Y Y N Y 5.5 5.6 Criteria, including time frame Risk management activities P P P P P NR NR P P N P Y N Y Y Y NR NR Y Y N Y 5.7 Review PMS data Y Y Y Y Y NR NR Y Y Y Y Assessment score M I M M M NR NR I M I M CAPA- corrective and preventive action. Sub-item scores: Y- Yes, P- Partial, N- No, NR- Not received. Assessment score per MoM hip implant file: M- Moderate, I- Insufficient, NR- Not received. Two manufacturers (hip 6, hip 7) did not submit the PMS procedure (Table 5). One of these manufacturers did submit a procedure for (device) monitoring (during a clinical investigation) instead. Although this procedure contained a description for the active collection and review of experiences during a clinical investigation this is not considered a PMS procedure as described in the Medical Device Directive. This procedure was not further assessed. PMS sources used by the manufacturers according to the PMS procedures are: customer complaints, adverse event reports, customer surveys, reviews of national joint implant registries, post-market clinical studies, conferences and literature studies (Table 6). It is noteworthy that of the PMS sources described in most of the PMS procedures (9/11) just a few, i.e. literature study, clinical studies and national joint registries, were actually used (Table 8). One PMS procedure described only complaint handling/reporting without mentioning sources for active collection and review of experiences. In nine PMS procedures planned review activities were described (Table 6), however criteria for the necessity to take actions, including time frame, were absent in the PMS procedures. Apparently, decisions on the necessity to take actions, the content and extent of the actions are made on a case by case basis, taking into consideration the specific aspects of that case. Two PMS procedures did not describe or refer to risk management activities. One procedure did not refer to corrective and preventive action. The concept of the CCI of medical devices requires the manufacturer to feed back results from PMS Annex: page 19 of 41
National Institute for Public Health and the Environment activities into the risk management process and to consider the need for corrective and preventive actions, including changes in design/ifu [10]. If application of this concept is not guaranteed by the PMS procedure, functioning of the CCI concept is not optimally embedded in the manufacturer s organisation. Table 6 PMS sources and planned PMS review activities described in PMS procedures. Active sources Passive sources Review activities Hip 1 Customer surveys, user feedback via Complaints, risk hazard document Analyse of PMS data shall be performed sales, clinical investigations, user from design history file, expected at defined intervals and shall be reactions during training and related performance rate from the design documented in the Design History File. workshops, studies on explants, history file experience with similar devices made by different manufacturers, literature reviews, joint registry reports Hip 2 Post market clinical studies, literature Complaints, adverse events Monthly review: clinical research, joint reviews, joint registry reports reports registry reports, literature, etc Hip 3 Surgeon face to face meetings, Customer complaint, adverse At a minimum of 5 times per year, a educational seminars, competitive event reporting post-market surveillance activity will products analysis, other countries take place by reviewing customer implant registries, literature, post complaints sorting by sales, products, market clinical studies and types of PMS reports. Review period: 6-month, 12-month, other. Hip 4 Surgeon face to face meetings, Customer complaint, adverse At a minimum of 5 times per year, a educational seminars, competitive event reporting post-market surveillance activity will products analysis, other countries take place by reviewing customer implant registries, literature, post complaints sorting by sales, products, market clinical studies, customer and types of PMS reports. Review comments period: 6-month, 12-month, other. Hip 5 Same PMS procedure as Same PMS procedure as Same PMS procedure as manufacturer manufacturer of hip 3 and 4 manufacturer of hip 3 and 4 of hip 3 and 4 Hip 6 PMS procedure not received PMS procedure not received PMS procedure not received Hip 7 PMS procedure not received PMS procedure not received PMS procedure not received Hip 8 No active sources described Customer complaint PMS activities will be performed on each product that is actively sold or distributed in the market at least once every 12 months. For devices no longer actively marketed, PMS will still be performed according to the PMS procedure, but the intervals of the activities will be reduced to once in three years for devices not demonstrating significant issues at last review Hip 9 Expert users groups, customers Customer complaints, adverse Initial PMS review for each of the surveys, clinical trials, literature events reports product family will be conducted after reviews, device tracking/implant the first twelve months of clinical use. registries, users reactions during Subsequent reviews will take place at Annex: page 20 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities training programs, media, etcetera. regular intervals that will be determined from receiving information on product performance through either manufacturers vigilance system or published reports on similar products produced by other companies Hip 10 General PMS SOP. Customer complaints, review of In general PMS SOP: reviews on a Per specific product a PMS plan. repairs, service reports, and regular basis, timeframe not specified. Examples of sources mentioned are: returns, reviews of design history In PMS plans review periods described. literature review, review of relevant and design changes. registries, review of field feedback, post-training complaints. Hip 11 Same PMS procedure as Same PMS procedure as Same PMS procedure as manufacturer manufacturer of hip 3 and 4 manufacturer of hip 3 and 4 of hip 3 and 4 6 Summary & analysis of PMS data In Table 7 and 8 results of the assessment of the summary and analysis of PMS data are shown. Table 7 Assessment of the summary and analysis of PMS data concerning MoM hip implants. Sub-item Hip 1 Hip 2 Hip 3 Hip 4 Hip 5 Hip 6 Hip 7 Hip 8 Hip 9 Hip 10 Hip 11 6.1 PMS sources Y Y Y Y Y NR NR Y Y Y NR 6.2 PMS data summary P Y Y P Y NR NR Y Y P NR 6.3 PMS data analysis Y N Y Y Y NR NR Y Y N NR 6.4 Decision on action Y Y Y N N NR NR Y Y Y NR Assessment score M I G I I NR NR G G I NR Sub-item scores: Y- Yes, P- Partial, N- No, NR- Not received. Assessment score per MoM hip implant file: G- Good, M- Moderate, I- Insufficient, NR- Not received. Annex: page 21 of 41
National Institute for Public Health and the Environment Table 8 Used PMS sources and information on data analyses. Hip 1 Hip 2 Hip 3 Hip 4 PMS data sources used National joint registries, Survival analysis clinical study, Multi-centre clinical study Literature, clinical data, adverse event reports Clinical studies, review activities of the London Implant Retrieval Centre (LIRC) Clinical studies, national joint registries Data analyses by manufacturers Harris Hip score (effectiveness), Kaplan-Meier survivorship (safety), adverse events (safety) Results showed improved function, activity level and reduced pain and stiffness. Combined survivorship of the MoM total hip artoplasty (THA) products of this manufacturer have shown to be within these of other MoM THA hip products. Published data shows a high survivorship for young, active patients treated with hip resurfacing (HR) systems. 93.5% survivorship at 10 years. Most prevalent risk of failure of HR: femoral neck fracture. Risk is greatly reduced by correct patient selection and surgical techniques. In the IFU, risk of femoral neck fracture is described, including warnings regarding to high activity levels which can cause these fractures. Clinical results: 0.22% revised due to metallossis or ALVAL. Other studies 0.08% and 0.3% ARMD cases. Survivorship curve: 93.7% at 5 years. Adverse events data are summarized not analysed. Failure rate is comparable to other MoM hip implants. In 2007 LIRC investigated high incidence of unexplained failures of MoM hips of all types and brands. LIRC retrieved cases from all manufacturers: cause extremely high wear of Mom hip replacement. Associated with excessive inclination and version angles. Evidence from resurfacing data indicates that smaller diameter heads have a higher risk of revision than larger heads. Resurfacing class has a higher risk of revision compared to THR based on registry data due to femoral neck fractures and use of monoblock cups with MoM bearings which are more position sensitive. Females may be more sensitive to metal wear debris. Field Safety Notification in 2010 (FSN): take special care when deciding to use smaller size of implants, examine patients for signs of metal reactions if there are complaints. In IFU risk of femoral neck fracture described, including warnings regarding to high activity levels which can cause these fractures. THA percentage revised (Kaplan-Meier) at 6 years: 3.9% MoM (n= 6557), 2.2% CoC (n= 359), 2.4% MoP (n= 9358), 1.3% CoP (n= 1259), 1.4% CoM (n= 600 at 3 years). No decisions on actions. Hip 5 National joint registries Failures caused by femoral neck fracture (28%), component loosening (12.5%), infection in 4 cases, dislocation in 2 cases and 5 cases wear or soft tissue reaction to wear debris. The manufacturer stated: The incidence and nature of the revision cases identified do not raise any concern around the performance of the hip implant. Fractures of the femoral neck is a recognised risk within resurfacing and there can be a number of causes for such an outcome, including less than optimal bone quality and poor surgical technique. No further actions or analysis of data observed in this document. In IFU risk of femoral neck fracture described, including warnings regarding to high activity levels which can cause these fractures. Hip 6 Not received Not received Hip 7 Not received Not received Annex: page 22 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities Hip 8 Hip 9 Hip 10 Literature review, national joint registries, complaints, adverse events. Complaints, manufacturers own registries, customer surveys, similar competitive products, clinical literature evaluation, media, National joint registries, Maude, MHRA and AFSSAPS databases, failure analysis, CAPA/recalls. Complaints and adverse events history, post-training complaint review, reviews field feedback, literature and registries PMS data are reviewed per source and actions to take, if applicable, are described. In IFU risk of femoral neck fracture described, including warnings regarding to high activity levels which can cause these fractures. PMS data is reviewed per source and action to take are described in the conclusions/recommendations per sub-item, e.g. design control, CAPA process, customer support. Summary per source, no data analyses. Hip 11 Not received Not received Three manufacturers (hip 6, hip 7 and hip 11) did not submit a summary and analysis of PMS data. In the other files, sources used for PMS data were always identified (Table 7). Most summaries and analyses of PMS data were presentations of the manufacturers, reviews of literature, reviews of clinical evaluations and/or reviews of various joint registries (Table 8). Although customer complaints and surveys among users were described in the PMS procedures as sources to collect PMS data, in almost none of the PMS data documents results of these complaints and surveys were described or analysed. This gives the impression that the manufacturers selectively use certain types PMS data for further analysis. From the submitted data it was often unclear what the frequency and timeframe for these analyses were. One manufacturer submitted a limited set of PMS data without further analysis. The manufacturer however concluded, based on PMS data, that no action was required as the risks were already addressed. The data submitted were too limited to judge the justification of the decisions of the manufacturers. Although literature describes problems with the wear debris of (MoM) hip implants the extent of the problem and its causes is not yet clear. Where the survival rate of the implant is reviewed, the survival rate is typically compared with the survival rate of competitors products. If no significant deviation from survival rate was observed no further actions were described. Furthermore, some manufacturers referred to a NICE benchmark of 10% revision rate in 10 years time to compare their performance (Annex VI). Similar recommendations for survival rate of hip implants are introduced in a guideline of the Dutch Orthopaedic Society (NOV [11]). They recommend that the choice for a hip implant must be made on well-documented long-term effectiveness and costs. Well-documented long-term effectiveness in this case means published in peer-reviewed journals with clinical follow-up with a 10-year survival of more than 90%. Another aspect that is important in relation to resurfacing MoM implants is the fact that these are mainly used in relatively young patients, who are likely to have a high level of activity. An analysis made by one of the manufacturers of the data in the Swedish hip register shows that the failure rate drops considerably with increasing patient age. Almost all manufacturers who marketed resurfacing hips observed the most prevalent risk of resurfacing hip implants, femoral neck fracture in their PMS data. Almost all manufacturers mentioned the risk of femoral neck fracture in the IFU, furthermore also precautions, i.e. to moderate the activity level after the implantation to prevent this risk were described in the IFUs. Annex: page 23 of 41
National Institute for Public Health and the Environment It is noted that, although manufacturers are required to take into account the generally acknowledged state of the art, they still have to pursue risk reduction as far as possible. The summary of PMS data was frequently limited without numbers, consequences, etc. Decisions on action to be undertaken were often not described. The concept of the CCI of medical devices requires the manufacturer to feed back results from PMS activities into the risk management process and to consider the need for corrective and preventive actions, including changes in design/ifu [10]. If application of this concept is not executed sufficiently thorough, reducing risks as far as possible is not guaranteed and thus the relevant essential requirements in the European Medical Device Directives will not be fully met. 7 Vigilance procedure(s) Table 9 Assessment of the vigilance procedure concerning MoM hip implants. Sub-item Hip 1 Hip 2 Hip 3 Hip 4 Hip 5 Hip 6 Hip 7 Hip 8 Hip 9 Hip 10 Hip 11 7.1 Incident reporting Y Y Y Y Y Y NR Y Y Y Y 7.2 FSCA Y Y N P P Y NR Y Y Y P 7.3 Corrective action 7.4 Risk management activities P Y N P P Y NR N Y N P P N Y N P N NR N Y N P Assessment score I I I I I I NR I G I I FSCA- field safety corrective action. Sub-item scores: Y- Yes, P- Partial, N- No, NR- Not received. Assessment score per MoM hip implant file: G- Good, I- Insufficient, NR- Not received. One manufacturer did not submit the vigilance procedure. Another manufacturer did send a vigilance procedure of another manufacturer already subject for investigation in this study. All vigilance procedures described incident reporting to competent authorities (Table 9). However, risk management activities were often not (adequately) described or referred to in vigilance procedures (7/9). Corrective actions were only adequately addressed in three procedures. The concept of the CCI of medical devices requires the manufacturer to feedback results from vigilance activities into the risk management process and to consider the need for corrective and preventive actions, including changes in design/ifu [10]. If application of this concept is not guaranteed by the vigilance procedure, functioning of the CCI concept is not optimally embedded in the manufacturer s organisation. It can be concluded that most vigilance procedures are mainly aimed at reporting incidents. The incomplete application of the CCI concept reduces the change of device improvements being made based on experiences gained with the application of the devices. Therefore, it can be concluded that the procedures of the manufacturers do not align with the essence of the medical devices legislation. Annex: page 24 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities 8 Information on the training offered and additional instructions Table 10 Assessment of training concerning MoM hip implants. Sub-item Hip 1 Hip 2 Hip 3 Hip 4 Hip 5 Hip 6 Hip 7 Hip 8 Hip 9 Hip 10 Hip 11 8.1 Submission surgical technique manual 8.2 Skills lab-based training 8.3 Experienced surgeon supervision Y Y Y Y Y Y Y Y Y Y Y N Y N N N N N Y Y N N N Y N N N N N Y Y N N 8.4 Company N Y N N N N N N N N N supervision Sub-item scores: Y- Yes, N- No. Every hip implant system included a surgical technique manual (Table 10). Manufacturers did not often indicate the option of any training for orthopaedic surgeons. For three hip implant systems, manufacturers indicated skills lab-based training or training under supervision of an experienced orthopaedic surgeon. For one hip implant system, the manufacturer offered training under supervision of a company representative. Information about the amount of training given to surgeons or the number of visits to the skills labs was not available in the submitted technical files. Overall quality of documentation Table 11 Overall quality score of MoM hip implants technical documentation items. Number sub-items Hip 1 Hip 2 Hip 3 Hip 4 Hip 5 Hip 6 Hip 7 Hip 8 Hip 9 Hip 10 Hip 11 Score Insufficient 3 7 5 6 6 5 4 4 4 6 5 Score Moderate 4 0 1 1 1 0 0 2 1 0 1 Score Good 0 0 1 0 0 0 0 1 2 1 0 Not received 0 0 0 0 0 2 3 0 0 0 1 All documentation items that were assigned overall scores, i.e. items 1-7, had major shortcomings. As explained above, three documentation items were not present in all files. Overall, the assessment revealed that 71% (55/77) of all assessed items scored insufficient, 14% (11/77) moderate, 6% (5/77) good and 8% (6/77) could not be assessed because incorrect information or no information was received (Table 11). It should be noted that the assessment scores were based on the principle that all essential elements are needed for a good system (compare to a chain with several links) and therefore a good score. Manufacturers may score positive on a substantial number of sub items, but the overall score will still be insufficient. If one essential element is missing, the system can not function Annex: page 25 of 41
National Institute for Public Health and the Environment adequately. The majority of documentation items including IFU, risk analysis, biocompatibility data and PMS procedure never scored good. It should be noted that the IFU, risk analysis and PMS procedure are key elements in the CCI of medical devices. The concept of the CCI requires the manufacturer to feed back results from PMS activities into the risk management process and to consider the need for corrective and preventive actions, including changes in design/ifu [10]. If application of this concept is not executed sufficiently thorough, reducing risks as far as possible is not guaranteed and thus the relevant essential requirements in the European Medical Device Directive will not be fully met. When looking at the results per file (hip 1 hip 11, see Table 11), slight differences can be observed with regard to the number of good, moderate or insufficient items. Only for a limited number of files the documentation items clinical evaluation, summary and analysis of PMS data and vigilance procedure scored good. In this context, it should be noted that it was decided not to perform more extensive scientific assessment at this time with regard to several important sub items of clinical evaluation and summary and analysis of PMS data. These sub items are i) the validity of the criteria for equivalence and the application of these criteria as part of the clinical evaluation, and ii) the validity of the conclusions that no actions needed to be taken on the basis of the summary and analysis of PMS data, because this requires more in-depth knowledge on the products and their clinical application than currently available among the assessors. To perform a more extensive assessment of the PMS data, it is recommended to consult clinical experts, i.e. orthopaedic surgeons. Shortcomings in the submitted technical documentation do not necessarily mean that the quality and safety of the devices is insufficient. However, the regulatory system depends to a large extent on the quality of the technical documentation. Shortcomings in that documentation could imply that product safety and safe use of the device are insufficiently guaranteed. Annex: page 26 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities References 1. Neumann, D.R., et al., Long-term results of a contemporary metal-on-metal total hip arthroplasty: a 10-year follow-up study. J Arthroplasty, 2010. 25(5): p. 700-8. 2. Macpherson, G.J. and S.J. Breusch, Metal-on-metal hip resurfacing: a critical review. Arch Orthop Trauma Surg, 2011. 131(1): p. 101-10. 3. Lachiewicz, P.F., Metal-on-metal hip resurfacing: a skeptic's view. Clin Orthop Relat Res, 2007. 465: p. 86-91. 4. NJR, National Joint Registry of England and Wales. 8th annual report. 2011. 5. Australia NJRR, Hip and Knee Arthroplasty. Annual report 2010. 2010. 6. Smith, A.J., et al., Failure rates of stemmed metal-on-metal hip replacements: Analysis of data from the National Joint Registry of England and Wales. The Lancet, 2012. 7. Sedrakyan, A., Metal-on-metal failures in science, regulation, and policy. The Lancet, 2012. 379(9822): p. 1174-1176. 8. Heneghan, C., D. Langton, and M. Thompson, Ongoing problems with metalon-metal hip implants. BMJ, 2012. 344. 9. De Bruijn, A., et al., Coherence between risk analysis and instructions for use in the EU. Regulatory Affairs Medtech 2011. March/April, 8-9. 10. Van Drongelen, A., et al., Assessing how widespread the continuous cycle of improvement of medical devices is in the EU. Regulatory Affairs Medtech 2011. July/August, 20-22. 11. Nederlandse Orthopaedische Vereniging, Diagnostiek en behandeling van heupen knieartrose. 2007. 12. NHS NICE, Technology Appraisals Guidance No.2 Guidance on the selection of Prostheses for Primary Total Hip Replacement. 2000 (http://publications.nice.org.uk/guidance-on-the-selection-of-prostheses-forprimary-total-hip-replacement-ta2). NHS NICE, Technology Appraisals Guidance No.44 The clinical effectiveness and cost effectiveness of metal on metal hip resurfacing, 2002 (http://publications.nice.org.uk/guidance-on-the-use-of-metal-on-metal-hipresurfacing-arthroplasty-ta44). Annex: page 27 of 41
National Institute for Public Health and the Environment Annex I Assessment form Manufacturer: Major Product: (M) Documentation item Options Score options Score 1. IFU 1 IFU complies with the ERs 13.6.a 13.6.q No, partially, fully 0, 1, 2 M 2 IFU contains or refers to a document describing the surgical techniques 3 IFU is in Dutch or IFU is not in Dutch, but an exemption for this language requirement is granted M 4 Coherence: residual risks from the risk analysis, for which the risk analysis indicated that they are to be addressed in the IFU, are present in the IFU No, partially, yes 0, 2, 4 No, yes 0, 2 <20%, 20-80%, >80% 0, 2, 4 5 Indications for use No, yes 0, 2 M 6 Risks and contraindications of MoM prostheses, as identified based on literature, are clearly mentioned in the IFU (see Annex III) No, partially, fully 0, 2, 4 7 IFU is clearly written No, partially, yes 0, 1, 2 8 IFU is well structured No, partially, yes 0, 1, 2 9 Readability (font size) of IFU is sufficient No, yes 0, 2 Total 24 Good 24 Moderate 21-23 Insufficient <21 Qualifying remarks 2. Risk analysis 1 Dated/version number Date: No, yes 0, 2 M 2 All risk categories addressed (see Annex II) None, partially, all 0, 2, 4 M 3 MoM-related risks addressed (see Annex III) <20%, 20-80%, >80% 0, 2, 4 4 Risks estimated No, yes 0, 2 M 5 Risk control/mitigation adequately described No, partially, yes 0, 2, 4 6 Acceptability of residual risks addressed No, yes 0, 2 M 7 Coherence: warnings, precautions and contraindications mentioned <20%, 20-80%, >80% 0, 2, 4 Annex: page 28 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities in the IFU, are addressed in the risk analysis Total 22 Good 22 Moderate 19-21 Insufficient <19 Qualifying remarks 3. Biocompatibility 1 A literature review is done as the first step for the biocompatibility investigations 2 Systematic evaluation using Annex B of ISO 10993-1 to identify the test to be carried out No, partially, yes 0, 1, 2 No, partially, yes 0, 1, 2 3 Tests conducted No, yes 0, 2 4 Appropriateness of the tests conducted for MoMs No, partially, yes 0, 1, 2 5 Standards applied No, yes 0, 2 6 Test protocols No, yes 0, 2 7 Analysis of data No, yes 0, 2 8 Summary of results No, yes 0, 2 Total 16 Good 16 Moderate 13-15 Insufficient <13 Qualifying remarks 4. Clinical evaluation 1 Dated/version number Date: No, yes 0, 2 2 If the clinical evaluation report is based on equivalency, is a rationale given to rationalise the equivalency No, partially, yes (or not applicable (NA)) 0, 1, 2 3 Proprietary name of the medical device and any code names assigned during device development No, yes 0, 2 4 Identification of the manufacturer of the medical device No, yes 0, 2 5 Description of the medical device and its intended application No, yes 0, 2 6 Intended therapeutic indications No, partially, yes 0, 1, 2 7 Safety and performance claims made for the medical device No, partially, yes 0, 1, 2 8 Objective of the evaluation No, yes 0, 2 9 Choice of clinical data types (literature, CI or combination) substantiated No, yes 0, 2 Annex: page 29 of 41
National Institute for Public Health and the Environment M 10 Summary of the clinical data and appraisal (considerations leading to conclusions) No, only summary, yes 0, 2, 4 M 11 Performance and safety analysis of the medical device No, partially, yes (including metal wear debris) 0, 2, 4 M 12 Are the relevant topics adequately addressed (see Annex IV) <20%, 20-80%, >80% 0, 2, 4 13 Conclusions No, yes 0, 2 14 Systematic, documented and appropriate literature search strategy (if applicable) No, partially, yes 0, 1, 2 Total 34 Good 34 Moderate 31-33 Insufficient <31 Qualifying remarks 5. PMS procedure 1 Customer or user complaints procedure (passive collection procedure) 2 Principle or procedure for the active collection and review of experiences (explicitly mentioned, not just a reference to another procedure) 3 Sources to actively collect experiences other than (customer / user) complaints 2 No, yes 0, 2 No, yes 0, 2 No, partially, yes 0, 1, 2 4 Corrective and preventive actions will be taken (CAPA) No, only stand-alone reference, yes 5 Criteria for the necessity to take actions, including time frame No, not clearly defined (will be decided ad-hoc), yes (clear criteria) 6 Risk management activities will be undertaken No, only stand alone reference, yes 0, 1, 2 0, 1, 2 0, 1, 2 7 Periodic review of PMS data No, yes 0, 2 Total 14 Good 14 Moderate 13 Insufficient <13 Qualifying remarks 6. Summary and analysis of PMS data 1 PMS sources identified No, yes 0, 2 2 Summary of PMS data No, limited, clear (numbers, consequences, 0, 1, 2 Annex: page 30 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities etc) 3 Analysis of PMS data No, yes 0, 2 4 Decision on action to be undertaken No, yes 0, 2 Total 8 Good 8 Moderate 7 Insufficient <7 Qualifying remarks 7. Vigilance procedure 1 Principle or procedure for incident reporting and the notification duty to competent authorities No, yes 0, 2 2 Principle or procedure for field safety corrective action (FSCA) (formerly known as recall) No, only stand alone reference, yes 0, 1, 2 3 (internal) Corrective actions will be taken No, only stand alone reference, yes 4 Risk management activities will be undertaken No, only stand alone reference, yes 0, 1, 2 0, 1, 2 Total 8 Good 8 Moderate 7 Insufficient <7 Qualifying remarks 8. Training 1 Surgical technique manual submitted No, yes 0, 2 2 Training is offered using skills lab No, yes 0, 2 3 Training under supervision of experienced orthopaedic surgeon No, yes 0, 2 4 Training under supervision of company representative No, yes 0, 2 Qualifying remarks Annex: page 31 of 41
National Institute for Public Health and the Environment Annex II Hazards and contributing factors Annex: page 32 of 41 This appendix provides a selection of categories of risks and is based on hazards described in the standard EN ISO 14971:2000 Medical devices Application of risk management to medical devices 1. Biological and chemical hazards Examples: Bio-contamination - By bacteria or - By viruses or - Inability to maintain hygienic safety Contact with organic material skin/airway Contact with organic material invasive Contact with non-organic material (skin/airway/invasive) Bio-incompatibility - Toxicity - Allergenicity - Mutagenicity - Oncogenicity - Teratogenicity - Carcinogenicity - Re- and/or cross-infection - Pyrogenicity - Substances that produce adverse physiological effects Animal tissue Chemical hazards Examples: - Release/leakage/impurity (substances that should be incorporated)) - Contacts to acids or alkalis - Impurity 2. Hazards related to environment of the implant Examples: Substances that produces adverse physiological effects 3. Hazards related to the information Examples: Inadequate labelling Inadequate operating instructions - Inadequate specifications of accessories to be used with medical device - Inadequate specifications of pre-use checks - Overcomplicated operating instructions Inadequate specification of service and maintenance Insufficient warnings of side effects Inadequate warning of hazards likely with re-use of single use devices Incorrect measurements 4. Design Examples: Material degradation Incompatibility with other devices with which the device is intended to be used Coating quality
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities 5. Manufacturing processes Examples: Change in manufacturing process Insufficient material compatibility information Insufficient control of manufacturing processes Insufficient control of subcontractors 6. Transport and storage Examples: Inadequate packaging Storage conditions Transportation 7. Environmental effects to the device Examples: Corrosion Degradation Biodegradation Electromagnetic fields Susceptibility to electromagnetic interference Temperature, sunlight, humidity, radiation, high-altitude 8. Installation, maintenance and service Examples: Assembly Preparation prior to use Use requires specific training/skills 9. Cleaning, disinfection and sterilisation Examples: Resterilisation 10. Disposal and scrapping 11. Normal operation Examples: Ageing Shelf-life 12. Use errors Examples: Reasonable foreseeable misuse Potential for intentional misuse Insufficient warning of side effects Inadequate warnings of hazards associated with re-use of single-use medical devices Incorrect measurements Incompatibility with consumables/accessories/other medical devices Operation outside prescribed environmental conditions Human factors - Mistakes and judgment errors - Lapses and cognitive recall errors - Slips and blunders - Violation or abbreviation of instructions, procedures, etc. Annex: page 33 of 41
National Institute for Public Health and the Environment Failure modes - Lack of adequate determination of the end of life of the medical device - Loss of /mechanical integrity - Deterioration in function as a result of repeated use - Failure to perform to essential performance requirements Annex: page 34 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities Annex III Risks and contraindications identified based on literature 1. Design and geometry of components Clearance (radial / diametral) Sphericity Surface finish Diameter of the bearing Carbon content of the alloy 2A. Contraindications MoM hip resurfacing Infection of body or blood Skeletal immaturity A patient status than can compromise implant stability Muscular atrophy Neuromuscular disease Vascular insufficiency Inadequate bone quality to support the implant Severe osteopenia or osteoporosis Osteonecrosis with >50% involvement of the femoral head Multiple cysts of the femoral head (>1 cm) Questionable bone stock Women of childbearing age Impaired kidney function Severe obesity Suppressed immune system Known metal sensitivity 2B. Other contraindications Abnormal proximal femoral anatomy / geometry Leg length discrepancy greater than 3 cm Inflammatory arthropathy Large femoral head geodes 3. Complications Metal sensitivity Metallosis Aseptic lymphocytic vasculitis associated lesions (ALVAL) Pseudotumors Adverse reaction to metal debris (ARMD); ARMD is an umbrella term including metallosis, ALVAL, and pseudotumors Adverse local tissue reaction (ALTR): it includes periprosthetic tissue reactions, metal allergy, and metallosis. ALTR was initially termed pseudotumors. Femoral neck fracture Dislocation (Ongoing severe) Pain Avascular necrosis (of the head) Heterotopic ossification Nerve palsy Haematoma dislocation Infection Re-operation within 6 months (related to hip implant) Annex: page 35 of 41
National Institute for Public Health and the Environment Osteolysis Loosening of components Thromboembolic phenomena Stiff joint Neck notching Femoral acetabular impingement Painless clicking of the hip Squeaking Retention of femoral guide pin Superficial wound Iliopsoas tendinopathy 4. Metal wear debris (i.e. particulate metal debris, soluble metal ions, and corrosion products) Cytotoxicity Mutagenicity Carcinogenicity Teratogenicity Metal wear nanoparticles 5. Surgical technique Surgeon s experience Surgical approach Malpositioning of components Fixation and cementing technique Annex: page 36 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities Annex IV Clinical evaluation MoM hip implants It should be checked whether the heading given is addressed, not whether all items are addressed. 1. Indications Osteoarthritis Traumatic arthritis Rheumatic arthritis Avascular necrosis or osteonecrosis Hip dysplasia 2. Contraindications Infection of body or blood Skeletal immaturity A patient status than can compromise implant stability - Muscular atrophy - Neuromuscular disease - Vascular insufficiency Inadequate bone quality to support the implant - Severe osteopenia or osteoporosis - Osteonecrosis with >50% involvement of the femoral head - Multiple cysts of the femoral head (>1 cm) - Questionable bone stock Women of childbearing age Impaired kidney function (requires kidney function testing) Severe obesity Suppressed immune system due to diseases such as AIDS or high doses of corticosteroids and/or immune suppressants Known metal sensitivity 3. Safety Revision surgery Other (secondary) operations Complications, e.g. dislocation, loosening, mechanical failure, fracture, deep vein thrombosis 4. Performance Patient-oriented outcomes, e.g. - Pain - Quality of life - Ability to perform activities of daily living - Implantation success rate Other (surrogate) outcomes, e.g. - Radiographic findings - Range of motion - Bone mineral density measurements - Laboratory tests 5. Survival rates Survival rate of hip resurfacing device comparable to state of the art Follow-up period acceptable Annex: page 37 of 41
National Institute for Public Health and the Environment Annex V References in Annex III and IV Amanatullah, DF, Cheung, Y, and Di Cesare, PE, Hip Resurfacing Arthroplasty: A Review of the Evidence for Surgical Technique, Outcome, and Complications. Orthopedic Clinics of North America, 2010. 41(2): p. 263-272. Amstutz, HC, Present state of metal-on-metal hybrid hip resurfacing. Journal of surgical orthopaedic advances, 2008. 17(1): p. 12-16. Amstutz, HC, Hip resurfacing arthroplasty. Journal of the American Academy of Orthopaedic Surgeons, 2006. 14(8): p. 452-453. Amstutz, HC, et al., Revision of aseptic loose total hip arthroplasties. Clinical Orthopedics 170:21-33, 1982. Clin Orthop Relat Res, 2004(420): p. 2-9. Amstutz, HC, et al., Metal-on-metal hybrid surface arthroplasty: two to six-year follow-up study. J Bone Joint Surg Am, 2004. 86-A(1): p. 28-39. Back, DL, et al., Early results of primary Birmingham hip resurfacings. An independent prospective study of the first 230 hips. J Bone Joint Surg Br, 2005. 87(3): p. 324-9. Baker, RP, et al., A medium-term comparison of hybrid hip replacement and Birmingham hip resurfacing in active young patients. J Bone Joint Surg Br, 2011. 93(2): p. 158-63. Billi, F and Campbell, P, Nanotoxicology of metal wear particles in total joint arthroplasty: A review of current concepts. Journal of Applied Biomaterials and Biomechanics, 2010. 8(1): p. 1-6. Bozic, KJ, et al., Risk of complication and revision total hip arthroplasty among Medicare patients with different bearing surfaces. Clin Orthop Relat Res, 2010. 468(9): p. 2357-62. Engh, CA, Jr., et al., 2008 John Charnley award: metal ion levels after metal-onmetal total hip arthroplasty: a randomized trial. Clin Orthop Relat Res, 2009. 467(1): p. 101-11. Falez, F, et al., Hip resurfacing: why does it fail? Early results and critical analysis of our first 60 cases. Int Orthop, 2008. 32(2): p. 209-16. Garbuz, DS, et al., The John Charnley Award: Metal-on-metal hip resurfacing versus large-diameter head metal-on-metal total hip arthroplasty: a randomized clinical trial. Clin Orthop Relat Res, 2010. 468(2): p. 318-25. Gross, TP, Liu, F, and Webb, LA, Clinical Outcome of the Metal-on-Metal Hybrid Corin Cormet 2000 Hip Resurfacing System An up to 11-Year Follow-Up Study. J Arthroplasty, 2011. Grubl, A, et al., Long-term follow-up of metal-on-metal total hip replacement. J Orthop Res, 2007. 25(7): p. 841-8. Hing, C, Back, D, and Shimmin, A, Hip resurfacing: indications, results, and conclusions. Instructional course lectures, 2007. 56: p. 171-178. Jameson, SS, Langton, DJ, and Nargol, AV, Articular surface replacement of the hip: a prospective single-surgeon series. J Bone Joint Surg Br, 2010. 92(1): p. 28-37. Langton, DJ, et al., Early failure of metal-on-metal bearings in hip resurfacing and large-diameter total hip replacement: A consequence of excess wear. J Bone Joint Surg Br, 2010. 92(1): p. 38-46. Macpherson, GJ and Breusch, SJ, Metal-on-metal hip resurfacing: a critical review. Arch Orthop Trauma Surg, 2011. 131(1): p. 101-10. McBryde, CW, et al., The influence of head size and sex on the outcome of Birmingham hip resurfacing. J Bone Joint Surg Am, 2010. 92(1): p. 105-12. Migaud, H, et al., Cementless metal-on-metal versus ceramic-on-polyethylene hip arthroplasty in patients less than fifty years of age: a comparative study with Annex: page 38 of 41
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities twelve to fourteen-year follow-up. J Bone Joint Surg Am, 2011. 93 Suppl 2: p. 137-42. Moroni, A, et al., Do ion levels in hip resurfacing differ from metal-on-metal THA at midterm? Clin Orthop Relat Res, 2011. 469(1): p. 180-7. Neumann, DR, et al., Long-term results of a contemporary metal-on-metal total hip arthroplasty: a 10-year follow-up study. J Arthroplasty, 2010. 25(5): p. 700-8. Qu, X, Huang, X, and Dai, K, Metal-on-metal or metal-on-polyethylene for total hip arthroplasty: a meta-analysis of prospective randomized studies. Arch Orthop Trauma Surg, 2011. Savarino, L, et al., Serum ion levels after ceramic-on-ceramic and metal-onmetal total hip arthroplasty: 8-year minimum follow-up. J Orthop Res, 2008. 26(12): p. 1569-76. Reininga, IH, et al., Minimally invasive and computer-navigated total hip arthroplasty: a qualitative and systematic review of the literature. BMC Musculoskelet Disord, 2010. 11: p. 92. Shetty, V, et al., Optimal bearing surfaces for total hip replacement in the young patient: a meta-analysis. Int Orthop, 2011. 35(9): p. 1281-7. Smith, TO, et al., The clinical and radiological outcomes of hip resurfacing versus total hip arthroplasty: a meta-analysis and systematic review. Acta Orthop, 2010. 81(6): p. 684-95. Thyssen, JP, et al., The association between metal allergy, total hip arthroplasty, and revision. Acta Orthop, 2009. 80(6): p. 646-52. Treacy, RB, et al., Birmingham hip resurfacing: a minimum follow-up of ten years. J Bone Joint Surg Br, 2011. 93(1): p. 27-33. Annex: page 39 of 41
National Institute for Public Health and the Environment Annex VI UK Guidances on selection of hip prostheses Annex: page 40 of 41 The UK NHS National Institute for Clinical Excellence (NICE) has written two Technical Appraisals Guidances related to hip replacement. Underneath, the major conclusions of these reports are given. TA2 Guidance on the selection of prostheses for primary total hip 1 Using the most recent available evidence of clinical effectiveness, the best prostheses (using long term viability as the determinant) demonstrate a revision rate (the rate at which they need to be replaced) of 10% or less at 10 years. 2 This should be regarded as the current benchmark in the selection of prostheses for primary Total Hip. The evidence used in support of any prosthesis, to establish whether or not it achieves this benchmark, should relate to data on 10 or more years follow up from a number of centres, obtained via adequately sized, well conducted observational studies (preferably with consecutive patients from non-selected populations) or randomised controlled trials. Such evidence should have been published or be available for peer review. 3 The Institute also considers it reasonable to recommend consideration of prostheses with a minimum of 3 years revision rate experience (collected as described in 1.2 above) if their performance is consistent with the benchmark of a 10% revision rate at 10 years. Prostheses that achieve this entry benchmark would then need to be subject to annual review (up to 10 years) to ensure that the revision rate remains consistent with the 10 year benchmark. 4 Prostheses (cemented, uncemented, and hybrid) that have not been shown to achieve either of these benchmarks, should be the subject of comparative clinical evaluation before they can be recommended for routine use in the NHS [12]. TA44 Guidance on the use of metal on metal hip resurfacing arthroplasty 1 Metal on metal (MoM) hip resurfacing arthroplasty is recommended as one option for people with advanced hip disease who would otherwise receive and are likely to outlive a conventional primary total hip replacement. In considering hip resurfacing arthroplasty, it is recommended that surgeons take into account activity levels of potential recipients and bear in mind that the current evidence for the clinical and cost effectiveness of MoM hip resurfacing arthroplasty is principally in individuals less than 65 years of age. 2 When MoM hip resurfacing arthroplasty is considered appropriate, the procedure should be performed only in the context of the ongoing collection of data on both the clinical effectiveness and cost effectiveness of this technology. Ideally, this data collection should form part of a UK national joint registry. 3 This guidance should be read in conjunction with the Institute's guidance on devices for total hip replacement (Guidance on the selection of prostheses for primary total hip replacement: NICE Technology Appraisal Guidance No 2. April 2000). In that guidance, the Institute recommended that the best prostheses (using long-term viability as the determinant) should demonstrate a 'benchmark' revision rate (the rate at which they need to be replaced) of 10% or less at 10 years or, as a minimum, a 3 year revision rate consistent with this 10-year benchmark. Establishing and confirming similar benchmarking criteria will be necessary for MoM hip resurfacing arthroplasty and will be facilitated by a UK national joint registry. In the interim, the 3 year minimum benchmark should apply to MoM hip resurfacing devices. 4 MoM hip resurfacing arthroplasty should be performed only by surgeons who have received training specifically in this technique.
Metal-on-metal hip implants. A critical review of the manufacturers technical documentation items with a specific focus on post-market surveillance activities 5 Surgeons should ensure that patients considering MoM hip resurfacing arthroplasty understand that less is known about the medium- to long-term safety and reliability of these devices or the likely outcome of revision surgery than for conventional total hip replacements. This additional uncertainty should be weighed against the potential benefits claimed for MoM devices [12]. Annex: page 41 of 41