Selection of the safety assessing Member State
1. A safety assessing Member State shall be selected for each active substance that is used in clinical trials authorised in the Union in accordance with Regulation (EU) No 536/2014, in each of the following situations:
(a)
the sponsor submits to more than one Member State in accordance with Article 5 or 11 of Regulation (EU) No 536/2014 an application dossier for the authorisation of a clinical trial with a new active substance for safety cooperation and at least two Member States authorise that clinical trial in accordance with Article 8 of that Regulation;
(b)
a substantial modification adding a new active substance for safety cooperation to a clinical trial is authorised in at least two Member States concerned in accordance with Articles 19 and 23, respectively, of Regulation (EU) No 536/2014;
(c)
a mono-national active substance becomes a multi-national active substance.
2. In the situations described in paragraph 1, points (a) and (b), any Member State, whether or not it received the application referred to in those points, may express interest, through the IT tools as described in Article 11, to become the safety assessing Member State, within 7 days after the authorisation of the clinical trial or of the substantial modification in the second Member State concerned. If more than one Member State expresses interest, the reporting Member State selects the safety assessing Member State within 5 days from the end of the 7 days period referred to in the first sentence, taking into account the existing expertise of the Member States relating to the active substance and the fair division of workload between Member States. If no Member State expresses interest, the reporting Member State, within 12 days after the authorisation of the clinical trial or of the substantial modification in the second Member State concerned, shall appoint the safety assessing Member State from among the Member States concerned, taking into account the fair division of workload between them.
3. When the authorisation of a clinical trial or of a substantial modification adding an active substance to a clinical trial concerns an active substance for which a safety assessing Member State has already been appointed, that safety assessing Member State shall also be appointed as the safety assessing Member State for the new or modified clinical trial, irrespective of whether the application has been submitted by the same or a different sponsor. This shall also apply where the existing safety assessing Member State (i) is not a Member State concerned for the clinical trial, (ii) refused the clinical trial application, and (iii) received an application limited only to aspects covered by Part I of the assessment report referred to in Article 11 of Regulation (EU) No 536/2014, as well as (iv) when the clinical trial is no longer ongoing in its territory.
4. When an active substance, which is not used in any ongoing clinical trials in the Union, but had a safety assessing Member State in the past, is reintroduced through the authorisation of a new clinical trial or a substantial modification of a clinical trial, that safety assessing Member State shall be appointed as the safety assessing Member State for this active substance in the new or modified clinical trial.
5. The reporting Member State of the clinical trial shall verify if there is an existing safety assessing Member State for any active substance used in investigational medicinal products in the clinical trial based on information provided in accordance with Article 11(3), point (b). If a safety assessing Member State has already been selected for that active substance, the reporting Member State shall inform it about that clinical trial immediately after the authorisation of that clinical trial by at least one Member State concerned in accordance with Article 8 of Regulation (EU) No 536/2014.
6. In the situation described in paragraph 1, point (c), when necessary, the new reporting Member State shall notify the original reporting Member State. The original reporting Member State shall launch and apply the selection procedure for determining the safety assessing Member State in accordance with paragraph 2 without undue delay after the clinical trial in the second Member State has been authorised.
7. When a clinical trial involves the use of several investigational medicinal products with different new active substances for safety cooperation, the reporting Member State shall ensure that a safety assessing Member State is appointed for each new active substance for safety cooperation in that clinical trial.
8. The safety assessing Member State shall be assigned to the active substance and the identity of the safety assessing Member State shall be recorded by the reporting Member State no later than 12 days after the authorisation of a clinical trial involving a new active substance for safety cooperation has been notified in the second Member State.
Changing the Safety Assessing Member State
1. When the safety assessing Member State of an active substance is no longer a Member State concerned in any clinical trial involving the use of that active substance, or where a safety assessing Member State has a disproportionate workload in comparison to other Member States, that safety assessing Member State may initiate the procedure for the selection of a new safety assessing Member State in accordance with Article 3(2). That procedure shall, if possible, be launched after the submission by the safety assessing Member State of the final assessment report of the annual safety report.
The safety assessing Member State initiating the procedure referred to in the first subparagraph shall fulfil the tasks assigned to the reporting Member State in Article 3(2).
2. Any Member State can volunteer at any time to take over the role of the safety assessing Member State, provided that the original safety assessing Member State agrees.
3. When a new safety assessing Member State is appointed pursuant to paragraph 1 or 2, the original safety assessing Member State shall record its identity in the information systems referred to in Article 11 for each relevant clinical trial without undue delay.
4. In the situations referred to in paragraphs 1 and 2, the original safety assessing Member State shall continue carrying out its tasks until all final safety assessment reports and records, including the assessment report of the last annual safety report, have been submitted and the new safety assessing Member State has been recorded in the information systems referred to in Article 11 in accordance with paragraph 3.
5. By way of derogation to paragraph 4, the original safety assessing Member State shall be able to resign immediately without finalising the ongoing assessments and without submitting the corresponding assessment reports and records, provided that the new safety assessing Member State agrees.
Role and tasks of the safety assessing Member State
1. The safety assessing Member State shall have the following tasks as regards the assigned active substance contained in investigational medicinal products that are used in clinical trials authorised in the Union:
(a)
to screen and assess information about all suspected unexpected serious adverse reactions reported in the EudraVigilance database in accordance with Article 42 of Regulation (EU) No 536/2014, regardless of whether they occurred in Member States or in third countries, as well as information contained in annual safety reports, in accordance with Articles 6 and 7 following a risk based approach;
(b)
to identify safety concerns in relation to the active substance and the investigational medicinal product, based on the assessments referred to in point (a);
(c)
to support, upon request of the reporting Member State, the assessment of aspects related to the reference safety information in the initial application referred to in Articles 5 and 11 of Regulation (EU) No 536/2014 or in an application for substantial modification referred to in Article 16 of that Regulation;
(d)
to request missing or further information from sponsors, which is necessary for the assessments or for the cooperation in the safety assessment;
(e)
to submit assessment reports and other records related to the safety assessment in accordance with Articles 6, 7 and 11 in order to ensure that all reporting Member States and Member States concerned receive appropriate information on clinical trials using the same active substance;
(f)
to prepare and submit recommendations to the reporting Member States and Member States concerned related to the safety of the active substance, so that corrective measures and other actions for safety oversight related to the active substance can be taken if necessary, in accordance with Article 8;
(g)
to provide assistance on any additional safety matter related to the particular active substance when requested by the reporting Member States or the Member States concerned.
2. The safety assessing Member State shall carry out its tasks until three months after the end of the last clinical trial with the active substance in all Member States concerned. It shall submit the final assessment report of the last annual safety report for the active substance without undue delay.
3. The responsible ethics committees shall be involved in the safety assessments performed by the safety assessing Member State, when such involvement is provided for in the national law of the safety assessing Member State.
Screening and assessment of suspected unexpected serious adverse reactions
1. The screening of the EudraVigilance database referred to in Article 5(1), point (a), shall take place at least once every 15 calendar days.
2. For investigational medicinal products with a marketing authorisation in the Union, the safety assessing Member State may decide to decrease the screening frequency referred to in paragraph 1 to at least once every 30 calendar days.
3. When the state of knowledge about the safety profile of the active substance or the degree of deviation in the use of the active substance from normal clinical practice so requires, the safety assessing Member State shall apply a higher screening frequency than that set out in paragraphs 1 and 2. The safety assessing Member State shall record the outcome and the date of the screening in the information systems referred to in Article 11.
4. In case concerns regarding the safety of the active substance arise from the screening of reported suspected unexpected serious adverse reactions, the safety assessing Member State shall:
(a)
assess the information about the suspected unexpected serious adverse reactions and submit an initial assessment as soon as possible but no later than 15 days after the screening;
(b)
update the initial assessment as soon as possible after additional information from the sponsor has become available in accordance with Article 42(2) of Regulation (EU) No 536/2014 or in accordance with Article 5(1), point (d), of this Regulation;
(c)
notify without undue delay the identified safety concerns in relation to an investigational medicinal product to all reporting Member States and Member States concerned by clinical trials involving the active substance in question.
The submission and sharing of the assessment referred to in points (a) and (b) and the notification referred to in point (c) shall be done through the information systems referred to in Article 11.
5. The safety assessing Member State shall increase the extent and shorten the timelines of the assessment referred to in paragraph 4 if the risk to safety of participants in a clinical trial so requires.
6. If additional information is requested pursuant to Article 5(1), point (d), in the context of the assessment of suspected unexpected serious adverse reactions, and the sponsor does not acknowledge receipt of the request for information by (i) the deadline set by the safety assessing Member State or (ii) 7 days after the request was sent, whichever is the later, the safety assessing Member State shall notify all reporting Member States and Member States concerned by a clinical trial using the active substance to consider taking corrective measures in accordance with Article 77 of Regulation (EU) No 536/2014.
7. Where the safety assessing Member State considers it necessary, based on its assessment(s), it shall submit general recommendations related to the safety of the active substance to the reporting Member States and the Member States concerned enabling them to take corrective measures and other actions for safety oversight related to the active substance.
The assessment of the annual safety reports
1. When assessing annual safety reports, the safety assessing Member State shall:
(a)
assess the information in all annual safety reports relating to the use of the active substance in clinical trials authorised in the Union, regardless of the pharmaceutical form and strength or indication investigated and regardless of whether the active substance is used in several clinical trials managed by different sponsors;
(b)
request additional information pursuant to Article 5(1), point (d), from sponsors and assess their responses. If a sponsor does not provide the information within the deadline set in the request, the safety assessing Member State shall inform relevant reporting Member States and Member States concerned to consider taking corrective measures in accordance with Article 77 of Regulation (EU) No 536/2014;
(c)
submit the final assessment report in the information systems referred to in Article 11 within 42 days after the submission of the latest annual safety report or within a maximum of 84 days from the submission of the latest annual safety report if additional information is requested pursuant to point (b);
(d)
when necessary, address any safety concerns identified during the assessment, develop recommendations for corrective measures and other actions for safety oversight related to the active substance, and communicate them to the reporting Member States and to the Member States concerned.
2. The safety assessing Member State may increase the extent and shorten the timelines of the assessment referred to in paragraph 1 if the risk to safety of participants in a clinical trial so requires. In this assessment, the safety assessing Member State shall take into account the marketing authorisation status of the investigational medicinal product or active substance, the state of knowledge about the safety profile of the active substance and the degree of deviation in the use of the active substance from normal clinical practice.
3. By way of derogation from paragraph 1, when the sponsor submits a single annual safety report specific to a single clinical trial involving several investigational medicinal products pursuant to Article 43(2) of Regulation (EU) No 536/2014, this annual safety report shall be assessed by the reporting Member State of this particular clinical trial. Upon request of the reporting Member State, the safety assessing Member States for the active substances included in these investigational medicinal products shall support the reporting Member State with this assessment. The reporting Member State shall submit a final assessment report to the information systems referred to in Article 11, and, where necessary, notify safety concerns to the Member States concerned and to every responsible safety assessing Member State for the active substance(s) included in the investigational medicinal products concerned.
Recommendations of corrective measures and other actions for safety oversight related to the active substance
1. If the safety assessing Member State identifies safety concerns related to the active substance from sources other than the screening and assessment referred to in Articles 6 and 7, it may submit recommendations for corrective measures and other risk mitigating actions for safety oversight to the reporting Member States and Member States concerned.
2. Following a recommendation pursuant to Article 6(7), Article 7(1), point (d), or paragraph 1 of this Article, the reporting Member States of the clinical trials in which the active substance is used should coordinate the action to be taken for these clinical trials with the Member States concerned.
3. Member States concerned may at any time take corrective measures and other actions for safety oversight related to the active substance in their territory in accordance with Article 77 of Regulation (EU) No 536/2014.
The role of the Member States concerned and the reporting Member States in the coordinated safety assessment
1. The reporting Member States and the Member States concerned shall:
(a)
support the safety assessing Member State in the coordinated safety assessment and have the possibility to comment and raise queries on the assessments;
(b)
take due account of safety concerns in relation to an investigational medicinal product and recommendations by the safety assessing Member State, referred to in Article 8(2), in the context of clinical trial(s) authorised in their territory;
(c)
communicate to the safety assessing Member State any relevant safety concerns related to the active substance.
2. The reporting Member State(s):
(a)
shall inform existing safety assessing Member States about the authorisation of a new clinical trial involving the same active substance;
(b)
shall verify if there is an existing safety assessing Member State for any active substance used in a clinical trial and, if that is not the case, launch and conduct a selection procedure in accordance with Article 3(2). In order to ensure continuity in safety assessment at any time, the reporting Member State shall carry out the tasks of the safety assessing Member State during the selection process;
(c)
may request support from the safety assessing Member State for the assessment of changes to the reference safety information when the safety assessing Member State is not a Member State concerned with the clinical trial, in accordance with article 5(1), point (c).
3. Member States shall jointly develop a good practice guidance describing detailed procedures for safety cooperation including corresponding timelines and the content of the assessment reports.
4. Member States may coordinate and facilitate safety surveillance and oversight, related to the active substance, across clinical trials.
Lead safety assessing Member State
1. When the safety assessment involves the participation of several safety assessing Member States, they may appoint a lead safety assessing Member State by consensus.
2. The lead safety assessing Member State shall be responsible for the coordination of the safety assessments performed by the safety assessing Member States for an active substance or a pharmacologic class of active substances. Coordinated safety assessment by several safety assessing Member States shall follow the standard screening and assessment timelines as set out in Articles 6 and 7.
Source: EUR-Lex (Publications Office of the EU), © European Union, reuse permitted under Commission Decision 2011/833/EU.
