Bewertung und Überwachung von Medizinprodukten am Beispiel von kardiologischen Implantaten der Hochrisikogruppe

Background and objective The Medical Device Regulation (MDR) was officially adopted on May 5th 2017 and came into force on May 25th 2017. Manufactures had a transition time of 3 years to prepare their products to meet the new requirements until May 26th 2020. As the MDR brings much stricter rules for manufactures of medical devices, more medical devices must be monitored regularly by the regulatory authorities within European Union (EU) and assessed by the Health Technology Assessment (HTA) agencies with regard to their benefit-to-harm ratio. As a bridge between research and health policy, HTA assesses and analyzes medical technologies and their applications on patients from different aspects. HTA assesses the benefits (including efficacy and safety), cost or cost-effectiveness and the ethical and social impact of technologies as important components. However, since medical devices especially high-risk medical devices have their own specificities compared to pharmaceuticals, such like: many medical devices are diagnostic products; medical devices have short life cycles; it is impossible to undertake blinded studies during the design of medical devices. As a result, limited guidance exists specific to medical devices in official HTA guidelines. Scientific research groups and healthcare systems around the world are currently working on improving the methodology and standardizing the evaluation of medical devices. Standardized evaluating these medical devices play a central role on bringing long-term benefits for patients and their safety. Any group of high-risk medical devices bears the risk of inferior products which can bring harms to patients and can cause additional costs to the healthcare system. Manufacturers must ensure patients’ safety in order to bring their medical devices to the market. Before bringing medical devices to the market, the regulatory authorities and the notified bodies need to ensure patients’ safety through authorization and conformity assessment procedure. A notified body is an organization designated by an EU country to assess the conformity of certain products before placed on the market, here means a conformity assessment body designated in accordance with the MDR. The MDR imposes strict demands on medical device manufacturers and notified bodies who in charge of the approval process of medical devices. Manufactures need to conduct more rigorous clinical investigation for class III and implantable medical devices. In addition, currently approved medical devices need to be re-evaluated and re-approved based on the new requirements. However, it is still difficult to know how a medical device will perform over the long term in a real-world setting. Although medical devices have made an important contribution to improve patients’ quality of life, numerous weaknesses in their premarket evaluation and post-market surveillance system have been persistent. An effective post-market surveillance system would reduce risks and harms associated with these devices. In addition, post-market surveillance is a continuous process like the MDR regulated: collecting and assessing information, detecting product faults and safety issues, quickly initiating necessary measures such as recalls. Another approach to monitoring medical devices and evaluating their clinical efficacy and cost effectiveness is medical device registry. Compared to clinical studies, registries can be designed to ensure a long-term follow-up in post-market surveillance system. There is a clear demand from political authorities on changing from efficacy studies under ideal circumstance to effectiveness studies in a ‘real-world’ setting for post-market surveillance. Medical device registry aims to investigate the performance and impact of a medical device in a ‘real-world’ setting. However, there is little information about the specific requirements for the structure and key elements to design and conduct a medical device registry. The objective of this doctoral thesis is to find and summarize international existing Best Practices for evaluation and monitoring of medical devices, using cardiac implants as examples representative medical devices, especially high-risk medical devices. This doctoral thesis has been divided into four systematic reviews: 1) to identify the conditions in pre-market approval process and its challenges as well as opportunities; 2) to investigate post-market surveillance system of medical devices especially on reacting to a recall when adverse events happened; 3) to identify the structure of a medical device registry and summarize key elements of planning and designing a medical device registry; 4) to analysis the performance of medical device registries using the case study of the international Transcatheter Aortic Valve Implantation (TAVI) registries. To achieve the objective of this doctoral thesis, the following research questions have been investigated: • What challenges and opportunities arise from the current experiences of market approval process (taking Chinese market approval process as an example)? • Which different recall systems and recall reasons can be found through an overview of recalls of cardiac implants in the last decade? • What are the structure and key elements to planning and designing a cardiac implant registry? • How is report quality and transparency of the internationally established TAVI registry based on the recommendations of the Valve Academic Research Consortium (VARC)? Methods To answer the above-mentioned questions, this doctoral thesis has been divided into four peer-reviewed publications. Systematic reviews in this doctoral thesis were conducted according to the Center for Reviews and Dissemination York (CRD) guidelines for systematic reviews [16]. The four publications have been performed also in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in different medical research database, like PubMed, Scopus, ScienceDirect/EMBASE and Cochrane Library. Additionally, data were also collected from different regulatory authorities and HTA agencies. Results All results have been published in international peer-reviewed journals. In the first publication (Assessing new developments in the pre-market regulatory process of medical devices in the People’s Republic of China, published in Expert Review of Medical Devices, 2015, Impact Factor: 2.20), 185 articles were potentially relevant. After applying inclusion and exclusion criteria, 17 articles were chosen by the authors for detailed analysis. The result analyzed three most important topics relating to the market approval process in detail: conformity assessment (products technical requirements), safety and performance assessment (type test report) and clinical evaluation. Since the restructuring of the China Food and Drug Administration (CFDA) in 2013, the new Provision for the Supervision and Administration of Medical Devices came into force on June 1st 2014 [18]. The new Provision provided guidance for manufactures to prepare the application documents, but this was at a rather general level, lacking specific examples. As a result of this study, specific recommendations were drawn up. These advocate the establishment of practical guidelines and standards for clinical studies to ensure high quality studies and appropriate guidelines for medical device manufacturers. Furthermore, more medically qualified clinical centers and medical device registries should be built to shorten the waiting time for the whole process. In the second publication (Recalls of cardiac implants in the last decade: what lessons can we learn? published in PLOS ONE, 2015, Impact Factor: 3.05), a total of 103 recall reports from 11 regulatory authorities were included in this study: the USA, Canada, Australia, New Zealand, PR China, China Hong Kong, Great Britain, Germany, Ireland, Switzerland and Saudi Arabia. The 103 recall reports can be classified into six different categories: implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy (CRTs), pacemaker, coronary stent, leads and implantable artificial organs. Of all 103 recall reports, the ratio of categories was as follows: ICDs 40.8%; pacemakers 14.5%; coronary stents 14.5%; as well as CRTs 12.7%; leads 9.7% and implantable artificial organs 7.8%. Regarding different problems causing the recall, 33.0% of the reports were related to problems with the device batteries; 31.1% of devices were recalled due to incorrect therapy delivery; 15.5% devices had software problems; 14.6% devices had connection problems and 5.8% of devices did not deliver correct output data. Out of 103 analyzed recall reports, four reported death. To ensure patients’ safety, providing safety information to the public and relevant stakeholders is a basic requirement. About the recall report, we suggested: take a unique product name from the manufacturing company; highlight the affected product category; include the recall issuing date and the deadline for completing withdrawals; provide recall classifications to highlight the risk level of affected devices; submit clear recall reasons and background information; mark the volume of affected devices distributed and implanted worldwide and in local country; highlight death and injury reports; add the final outcome and completion date. In the third publication (Cardiac implant registries 2006–2016: a systematic review and summary of global experiences, published in BMJ Open, 2018, Impact Factor: 2.49), the following 82 registries were identified: 18 ICD registries, seven CRT registries, five pacemaker registries and six cardiovascular implantable electronic device registries which combined ICD, pacemaker and CRT implantation data; as well as 22 coronary stent registries and 24 TAVI registries. While 71 national or local registries were from a single country, 44 were from European countries and nine were in USA. The following criteria have been summarized from the identified registries, including: registry working group, ethic issues, transparency, research objective, inclusion criteria, compulsory participation, endpoint, sample size, data collection basement, data collection methods, data entry, data validation and statistical analysis. Some recommendations and concerns raised from planning and designing a cardiac implant registry: adverse event reporting system should be considered as a major focal point; medical device changing more rapidly within a shorter time span compared to drug products, hence product brand and specifications model should be recorded in the registry; the release of a free annual report and the accessibility on a website are the most significant strategies for disseminating registries’ results. In the fourth publication (How TAVI registries report clinical outcomes—a systematic review of endpoints based on VARC-2 definitions, published in PLOS ONE, 2017, Impact Factor: 3.05), 466 studies were potentially relevant, and 20 TAVI registries reported VARC-2 definitions involved in our review. Of all 20 registries, an overall sample size of 12,583 patients was involved. 20 TAVI registries used either Logistic EuroSCORE (LES) or Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) or both to record patients’ baseline characteristics and case selection. The 30-day all-cause mortality ranged from zero to 12.7%. From 20 registries, fourteen registries reported the cardiovascular mortality at 30 days and the important one-year all-cause mortality was reported only in 11 registries. About myocardial infarction (MI), a distinction should be made between peri-procedural MI and spontaneous MI. Nine registries reported MI rate based on VARC-2 definitions, and seven registries reported peri-procedural MI rate (<72h). Of all 20 TAVI registries, only six registries provided complete information on the nine complications, and 11 registries omitted one to two complications. Most registries have reported complications such as bleeding, vascular complications and new pacemaker implantation. The author clearly found that the registries followed VARC definition have more structured clinical outcome reporting system. The biggest advantage of uniform and structured reporting system is to help comparing clinical outcome among different registries or study groups. Conclusion The first publication was written in 2013, during the time of restructuring of the CFDA from the State Food and Drug Administration under the supervision of the Chinese Ministry of Health to the independent CFDA. In March 2018, based on the decision made by the State Council, the CFDA has been changed to the National Medical Products Administration under the supervision of the State Administration for Market Regulation. The 2014 Provision for the Supervision and Administration of Medical Devices has been also edited in 2017. There are also some relevant supporting regulations coming into force from 2014 until now. This was in correspondence with the change of the Medical Device Directive (MDD) to the MDR in 2017 in EU. Chinese policy makers are building a more and more standardized regulatory framework for medical devices step by step. Standardized and detailed regulatory framework can help manufactures to prepare their medical devices to the market, the most important consideration is to ensure patients’ safety. Only if under the standardized, organized and transparency regulatory framework, manufactures can take rigorous efforts to bring their products with high-valued quality to medical device market. This is the first step to ensure patients’ safety of using medical devices. The second publication summarized cardiac implant recall reports worldwide in the last decade, identified different recall reasons of each cardiac implant category, and highlighted adverse events causing serious injuries and death. Through the search and data analysis process, the authors found that there are several opportunities for improving the safety system for cardiac implants. Manufactures should avoid adverse events through summarizing and analyzing recall reasons, especially those high ratios recall reasons. Manufactures and regulatory authorities should react to an adverse event immediately. There is an increasing importance of medical device registries especially registries for high-risk implants. Meanwhile registries provide transparent and long-term data for healthcare authorities, payers, researchers and, above all, patients and consumers. It is recommended to implement implant registries in the context of a post-market surveillance system. An implant registry is an overriding tool when it comes to controlling the high incidence of adverse events. The third publication reviewed the existing global cardiac implant registries and their practices as well as experiences. This study introduced the structure and key elements, which can be seen as the basis for designing a cardiac implant registry in the future. Registries provide a ‘real-world’ picture for patients, physicians, manufacturers, payers, decision-makers and other stakeholders. In this context, medical device registries are important for regulatory decisions, concerning the safety and therefore approval issues of medical devices. For payers, medical device registries provide evidence on benefit-risk of medical devices and drive the decision whether the products should be reimbursed or not. For hospitals, medical device registries’ data are important for sound procurement decisions, and last—and of paramount importance—medical device registries help patients and their physicians to make joint decision on which product is the most appropriate. The fourth publication took the further step to examine the report quality and transparency of the internationally established TAVI registries based on the recommendations of the VARC. The author summarized the registries’ reports using the VARC-2 definitions based upon mortality and other major complications. To address and support patients’ safety and procedural quality as demanded by regulatory authorities and HTA agencies, VARC and VARC-2 definitions are more and more widely used in clinical studies as well as in registry studies. However, since their introduction in 2011, VARC definitions are still not systematically reported in TAVI studies. These endpoint definitions warrant a concise and systemic analysis of outcome measures in high-risk patient groups. These standardized endpoint definitions make study result comparisons feasible, providing better insights by differentiating products and approaches, and thus increasing transparency for patients. However, these standardized endpoint definitions need to be updated to fulfill the development of medical technologies and clinical experience. In this doctoral thesis, a total of four systematic reviews were created to illustrate the methods and procedures for evaluating and monitoring medical technology products in order to ensure patients’ safety. Medical devices are indispensable in the whole healthcare system. New medical technologies bring opportunities, but also risks, so patients’ safety should be a continuous topic and highly important concerns by manufactures, regulatory authorities, HTA agencies and all relevant stakeholders. The methods and procedures for the evaluation and monitoring of medical technology products reported in this doctoral thesis correspond to the new MDR. Manufactures should prove the safety and performance of their medical technology products before and after market entry. Manufacturers have the obligation to supervise their products after market access and to report problems as well as to collect and evaluate data during patients’ use. This is exactly what has been analyzed in this doctoral thesis.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.