The European Commission, having regard to the Treaty on the Functioning of the European Union, having regard to Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, and in particular Article 44(2) thereof,
(1) Regulation (EU) No 536/2014 lays down the legal framework for the conduct of clinical trials on medicinal products for human use in the Union to ensure that the rights of subjects (‘participants’), their safety and well-being are protected, and that the generated data are reliable and robust. In particular, while the overall responsibility for ensuring participants’ safety lies with the sponsor of the clinical trial, it is reinforced by additional oversight from the Member States including through their cooperation in the assessment of the safety of the investigational medicinal products.
(2) Articles 42 and 43 of Regulation (EU) No 536/2014 provide that the sponsor of a clinical trial is to report suspected unexpected serious adverse reactions to investigational medicinal products used in the clinical trial and to submit annually safety reports to the European Medicines Agency (‘the Agency’) through the database referred to in Article 40(1) of that Regulation. The information reported under those provisions is to be forwarded by the Agency to the Member States concerned, which are to cooperate in the assessment of that information, with the involvement of the responsible ethics committee, where appropriate, in accordance with Article 44 of Regulation (EU) No 536/2014.
(3) Setting out a framework by laying down the rules for the cooperation between Member States in the assessment of information and reports submitted under Articles 42 and 43 of Regulation (EU) No 536/2014 reinforces safety harmonisation and increases scrutiny in safety oversight in the Union. This should strengthen participants’ safety in clinical trials and contribute to improved data robustness regarding the safety profile of investigational medicinal products and their corresponding active substances.
(4) Oversight of the safety of active substances used as investigational medicinal products in clinical trials authorised in only one Member State (mono-national active substances), active substances in investigational medicinal products used as a reference, including as a placebo, and active substances used in auxiliary medicinal products should be outside the scope of this Regulation.
(5) To ensure effective and efficient cooperation between Member States in the assessment of information and reports, submitted under Articles 42 and 43 of Regulation (EU) No 536/2014, for each active substance used in investigational medicinal products, a Member State should be appointed to assess that information and those reports (‘safety assessing Member State’), based on a fair division of workload between Member States and on existing expertise with the given active substance.
(6) Taking into account the considerable attrition of active substances over the development lifecycle and the fact that only a proportion of active substances will be investigated as multi-national active substances in the Union, safety related information for a mono-national active substance should be assessed by the reporting Member State. Those assessments by the reporting Member State should be recorded in a manner that ensures transparency and enables continuity in case an originally mono-national active substance becomes a multi-national active substance, for example through the extension of the clinical trial to another Member State or where another Member State has authorised a clinical trial that involves the same active substance. Once a mono-national active substance becomes multi-national, it should benefit from coordinated safety assessment.
(7) The selection of the first safety assessing Member State for an active substance for the safety cooperation is driven by the reporting Member State, referred to in Article 5 of Regulation (EU) No 536/2014, of the first clinical trial using this active substance in the Union. The reporting Member State should select the safety assessing Member State when more than one Member State, or no Member State at all, expresses interest in becoming the safety assessing Member State for an active substance.
(8) The tasks related to safety assessment should be distributed proportionally between the Member States. The workload associated with the safety oversight of an active substance may depend on, amongst others, existing knowledge with the safety of the active substance and risk adaptations in the screening frequency and the extent of the assessments.
(9) To maintain a proportionate distribution of work between Member States over time, it should be possible, upon request of the original safety assessing Member State, to transfer the role of safety assessing Member State when the original safety assessing Member State is no longer a Member State concerned in any clinical trial involving the use of an active substance or when its workload related to the role of safety assessing Member State becomes disproportionately high in comparison to the workload of the other Member States. However, it is necessary to ensure the continuity of the safety assessment at any time during the re-selection process of the safety assessing Member State.
(10) Safety assessing Member States should assess the information submitted as suspected unexpected serious adverse reactions, and information contained in annual safety reports, referred to in Articles 42 and 43 of Regulation (EU) No 536/2014. When safety concerns arise from those assessments, the safety assessing Member State should prepare general recommendations as regards the safety of the active substance to the reporting Member States and to the Member States concerned by clinical trials involving investigational medicinal products containing that active substance. This enables the relevant reporting Member States and Member States concerned to take appropriate and proportionate corrective measures and other actions for safety oversight related to the active substance, when this is necessary.
(11) In addition, reporting Member States may consider involving the safety assessing Member State in assessing applications for substantial modifications to the reference safety information, submitted in accordance with Article 16 of Regulation (EU) No 536/2014. Substantial modifications to the reference safety information may have implications for the determination of expectedness of serious adverse reactions and, by way of consequence, on the reporting of suspected unexpected serious adverse reactions. To determine the expectedness of serious adverse reactions in relation to an investigational medicinal product, it is therefore appropriate to establish a harmonised approach to safety assessment using, as a basis, a common reference document. The reporting Member State and Member States concerned will remain responsible for the assessment of any substantial modification to the reference safety information.
(12) To further strengthen oversight and harmonisation as well as to avoid that different safety assessing Member States assess different investigational medicinal products using the same active substance, a single safety assessing Member State should, whenever possible, assess the safety of all investigational medicinal products containing the same active substance, regardless of the pharmaceutical form and strength or indication investigated and regardless of whether they are used in several clinical trials managed by the same or different sponsors. Such coordinated approach to the safety assessment based on the active substance rather than on the investigational medicinal product avoids duplication of efforts and at the same time provides the safety assessing Member States with sufficient context for its safety assessments. This approach is also in line with the relevant guideline on Development Safety Update Report of the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH E2F) that recommends a single safety update report for an active substance to promote comprehensive analysis.
(13) A risk-based approach should be taken as regards the frequency of screening of safety information, the extent of its assessment and the timelines of assessment and reporting. Risk adaptations should depend on the knowledge about the safety profile of the active substance. For example, active substances with a marketing authorisation in the Union may be screened less frequently in comparison to unauthorised active substances.
(14) Relevant information systems that are managed by the Agency, including the Clinical Trials Information System, the EudraVigilance Database and the EU Medicinal Product Dictionary, should support Member States’ cooperation in assessing the safety of active substances used as investigational medicinal products in clinical trials. This would enable the integration of information on, and the cooperation in, the safety assessment of clinical trials, which will significantly contribute to strengthening the understanding of the safety of medicinal products that are planned to enter or are already available on the Union market.
(15) The Commission should be able to control whether Member States correctly supervise compliance with the rules set out for the coordinated safety assessment of the information submitted in the reports for suspected unexpected serious adverse reactions and in annual safety reports.
(16) The measures provided for in this Regulation are in accordance with the opinion of the Standing Committee on Medicinal Products for Human Use established by Directive 2001/83/EC of the European Parliament and of the Council.
(17) This Regulation should become applicable at the same time as Regulation (EU) No 536/2014.
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