Implementation of the new EU IVD regulation - urgent initiatives are needed to avert impending crisis.

Laboratory medicine in the European Union is at the dawn of a regulatory revolution as it reaches the end of the transition from IVDD 98/79/EC (https://eur-lex.eur-opa.eu/legal-content/EN/TXT/?uri=CELEX%3A31998L0079&qid=1628781352814) to IVDR 2017/746 https://eur-lex.europa.eu/eli/reg/2017/746. Without amendments and contingency plans, implementation of the IVDR in May 2022 will lead the healthcare sector into uncharted waters due to unpreparedness of the EU regulatory infrastructure. Prospective risk analyses were not made by the European Commission, and if nothing happens it can be anticipated that the consequences will impact all stakeholders of the medical test pipeline, may seriously harm patients and may prevent caregivers from making appropriate clinical decisions due to non-availability of medical tests. Finally, it also may discourage manufacturers and academia from developing specialty tests, thereby hampering innovation in medical diagnostic care. We hereby inform laboratory professionals about the imminent diagnostic collapse using testimonies from representative stakeholders of the diagnostic supply chain and from academia developing innovative in-house tests in domains of unmet clinical needs. Steps taken by the EFLM Task Force on European Regulatory Affairs, under the umbrella of the Biomedical Alliance in Europe, will be highlighted, as well as the search for solutions through dialogue with the European Commission. Although we recognize that the IVDR promotes positive goals such as increased clinical evidence, surveillance, and transparency, we need to ensure that the capabilities of the diagnostic sector are not damaged by infrastructural unpreparedness, while at the same time being forced to submit to a growing bureaucratic and unsupportive structure that will not support its "droit d'exister".

Signals from the Dutch national spontaneous reporting system: Characteristics and regulatory actions.

PURPOSE: The aim of the study is to characterise safety signals based on the Dutch spontaneous reporting system (SRS) and to investigate the association between signal characteristics and Product Information (PI) update stratified by approval type: centrally authorised products (CAPs) versus nationally and decentralised authorised products (NAPs). METHODS: This study evaluates the full cohort of signals disseminated from the Dutch SRS in the period from 2008 to 2017. Each retrieved signal was characterised on a number of aspects. The signal management process from signal generation to a potential PI update was analysed in four steps: (1) signal characterisation; (2) proposed actions by the Dutch national competent authority (NCA) for the signals; (3) presence of PI update (yes/no) and association with signal characteristics; (4) timing from the moment the signal was issued to PI update. For step 1-3 we stratified products in CAPs and NAPs. RESULTS: Of all signals, 88.7% led to a proposed regulatory action by the NCA. Signals from the Dutch SRS for CAPs versus NAPs more often concerned biologicals, important medical events, class effects and shorter periods since marketing authorization. We detected PI updates for 26.2% of CAP signals and 61.3% of NAP signals. CONCLUSIONS: The Dutch SRSs remains an important source of signals. There are some notable differences in the characteristics of signals for CAPs versus NAPs. Signals for NAPs more frequently led to PI updates.

Organ transplantation and the European Union, 2009-2015 developments.

This article provides a high-level picture of the developments in organ transplantation in the European Union (EU) between 2009 and 2015. This was the period during which the European Commission and EU 28 member states developed an EU Action Plan on organ donation and transplantation. This plan was adopted by the European Commission in 2008, following calls for policy action to increase transplant numbers. It set out priority actions for member states and European Commission to address. This article describes the three main approaches used by the European Commission and National Competent Authorities to develop this action plan. We also present a quantitative comparison of 2015 and 2008 transplant data, based on the Newsletter Transplant by the Council of Europe (CoE) and the Spanish National Transplant Agency (ONT). This comparison shows contributions of different EU Member States, as well as of different donation and transplant programs to the overall increase of 4597 transplants per year (+16.4%). While another evaluation study of the action plan reported a strong positive impact of the action plan, it is beyond the remit of this publication to demonstrate a causal relationship between the EU Action Plan and the increase in number of organ transplants.

[Implementation status of Regulation EU 536/2014 in the member states]. / Vorbereitungsstand zur EU Verordnung 536/2014 in den Mitgliedstaaten.

The upcoming Regulation EU 536/2014 for clinical trials of medicinal products for human use requires multinational cooperation in the assessment of clinical trial applications by the member states concerned as well as one single decision per member state concerned, supported by the new EU Portal and database system. The implementation makes national reorganisation of the processes necessary, especially coordination and cooperation between the national competent authorities and the ethics committees, necessary.A brief overview of implementation status with regard to national law adaptations, (re-) organisation, information technology systems as well as national or multinational pilot projects in 7 of 28 member states is given.Within these member states some national laws have been adapted already, while others will be soon. The national reorganisation covers mostly administrative organisation and coordination especially within the ethics committees. Overall, it is foreseen that a reduced number of ethics committees will be involved in the approval of clinical trials on medicinal products within the member states.Most of the seven member states expect that in addition to the new EU Portal/database system a national IT system for national cooperation and interaction will be necessary. Therefore, an interface within the EU system for national systems is essential.In order to test the new processes some member states are running national pilot projects or are planning them. In addition, almost all participate in the voluntary multinational assessment of clinical trials on medicinal products, which had existed since 2009, a few also in cooperation with their ethics committees.The member states are confident that all national processes will be in place when the EU regulation becomes applicable.

Microbiological and Chemical Analysis of Food Collected Under Official Control in the Emilia-Romagna Region of Northern Italy, 2014-2019.

This study analyzed data from 6 years (2014-2019) of official controls in the Emilia-Romagna region (northern Italy) to investigate the frequencies of human pathogens and chemical hazards in foods during production and distribution. Campylobacter spp. was the most prevalent pathogen, isolated in 4.4% of the 1,078 food samples examined, followed by Salmonella spp. (2.8%), Shiga toxin-producing Escherichia coli (STEC) (1.9%), and Listeria monocytogenes (0.9%). Salmonella serotyping showed that the isolates belonged to the serotypes most commonly isolated from humans in Emilia-Romagna. These serotypes were as follows: S. Infantis (34.8%), mostly isolated from chicken, monophasic S. Typhimurium (1,4, [5],12:i:-) (12.6%), S. Bredeney (8.9%), and S. Derby (8.6%). No Clostridium botulinum, Yersinia spp., and Shigella spp. were isolated. No positivity was detected for hepatitis A virus, while 5.1% of samples taken in the production phase of the food chain were found to be contaminated with norovirus. The chemical analyses identified environmental contaminants within legal limits (heavy metals, 0.6% positive overall; mycotoxins, 0.4% positive overall), analytes subjected to monitoring (perfluoro-alkyl substances (PFASs), 6.2% positive overall; inorganic arsenic, no positives overall) and process contaminants and additives within legal limits (acrylamide, 9.6% positive overall; permitted or nonpermitted additives, 0.9% positive overall). Only one sample showed dioxins and polychlorinated biphenyls (PCBs) at levels higher than the legal limits. The monitoring by competent authorities (CA) of food contamination can generate useful data that can be used as a basis for estimating the exposure to different food contaminants over time and for evaluating the effects of control measures on the contamination of food.

Authorization of COVID-19 clinical trials: lessons from 2 years of experience of a national competent authority.

The COVID-19 pandemic was immediately marked by strong clinical research activity. The French national competent authority presents the data on request for authorization during the first 2 years of COVID-19 pandemic to inform discussions on future clinical research issues. Applications for authorization of interventional COVID-19 trials submitted between March 2020 and February 2022 were analysed. Trials on medicinal products were classified according to market authorization status, mechanism of action of the investigational product, target population and clinical context. In 2 years, 208 clinical trials were submitted. 75% were authorized, 3% refused, 22% withdrawn by the sponsor. Among medicinal products trials, 6% were adaptative, 28% included outpatients and 2% were focused on post COVID-19 symptoms. Vaccines were evaluated in 9% of trials, antivirals in 38% and immunomodulators in 35%; 63% of antiviral and 60% of immunomodulation trials included a drug with a marketing authorization in another indication. The dynamics of authorization prove the involvement of stakeholders but also illustrates the risk of dispersion of research efforts and the risk of decorrelation between trials and the epidemic evolution. The high rate of withdrawal of applications could be explained by changes in the sanitary context and by the dropping of some therapeutic approaches. Most of clinical trials evaluate drugs authorized in another indication and assessment procedures by authorities have to mitigate between the knowledge of safety profile of those drugs and the uncertainty in a new clinical context with rapidly evolving knowledge. COVID-19 experience should now support future evolution in clinical research practices.

The European system for the control of the safety of food-contact materials needs restructuring: a review and outlook for discussion.

The present European system to assure the safety of migrates from food-contact materials (FCMs) needs improvement. It is proposed to implement better the self-control by the producers through improved official control and more attractive listing of approved substances and materials (the latter being subject of another discussion paper). The initial concept of a positive list for the substances used, a limit for the overall migration and regulation of compliance testing was recognised as insufficient long ago, as it does not properly cover reaction products (including oligomers) and impurities. It also turned out to be unrealistic to cover all 17 types of FCMs owing to lack of resources by the authorities. Therefore, European Union legislation shifted the focus to the compliance work carried out by the business operators (in-house documentation and declaration of compliance). However, this approach has not been properly implemented. This is partly due to lack or unsuccessful control by authorities. A suitable structure of this control still needs to be built. It is proposed that specialised document-collection centres working with dedicated tools harmonised throughout Europe be created. Further, since most migrating substances are not listed, the toxicological evaluation reported by industry must be checked by risk-assessment authorities. Finally, effective and harmonised measures are needed to react in case of non-compliance. The currently large gap between the legal requirements and reality must be bridged by introducing flexibility: authorised work plans by industry are proposed. It is also proposed to encourage certified private institutes to approve compliance work, driven by the attractive listing of approved materials and exploiting market forces. In the long run, the focus of the authorities might change from evaluating the substances used and regulating migration testing to the evaluation of the compliance work performed by industry, which means moving from legislation supporting industry towards checking self-control.

Navigating the maze of requirements for obtaining approval of non-interventional studies (NIS) in the European Union.

OBJECTIVE: The purpose of this article is to give an overview of the complexities and unexpected regulatory requirements for obtaining approval of multinational and multicentre non-interventional studies (NIS) in the European Union (EU). METHODS: The websites of national competent authorities (CAs), ethics committees (ECs) and data protection (DP) authorities were consulted to find regulations and guidance information related to the authorisation of NIS in various member states of the EU. RESULTS: Many additional hurdles, neither disclosed nor clear in the various regulations/guidances for NIS, were identified. Although approval from the CA is not needed for NIS, in many countries request of CA opinion is nevertheless recommended, prior to submission to the EC, to obtain confirmation that the planned NIS does not fall in the interventional trial category. Clinical trial insurance was required in some countries. In countries like Belgium and Italy, the multicentre NIS required the approval from a central EC and local ECs as a single central EC opinion was not considered sufficient. The EC document requirements for submission and the fees were extremely variable among all member states. Additional approvals from data protection authorities and insurance companies were required in some countries. CONCLUSIONS: The process of obtaining approval for multicentre and multinational NIS is time consuming due to lack of transparency and the different regulatory requirements among member states. The EU pharmacovigilance legislation and clinical trial regulation No 536/2014 is a step forward in providing a regulatory framework for PASS (post-authorisation safety studies) and low intervention clinical trials, but since regulation No 536/2014 excludes NIS, it will be difficult to enforce harmonization of requirements for approval of NIS among member states.