VI.C.1. Management of individual safety reports for clinical trials, postauthorisation studies, compassionate use and named patient use in the EU

In line with Article 3(3) and 107(1) of Directive 2001/83/EC, the pharmacovigilance rules laid down in Directive 2001/83/EC and Regulation (EC) No 726/2004 do not apply to medicinal products intended for research and development trials conducted in accordance with Directive 2001/20/EC.

In the EU, post-authorisation safety or efficacy studies can be imposed by competent authorities in Member States or the Agency during the evaluation of the initial marketing authorisation application in accordance with Article 21a(b)(f) of Directive 2001/83/EC and Article 9(4)(cb)(cc) of Regulation (EC) No 726/2004, or they can be requested during the post-authorisation phase in line with Article 22a(1)(a)(b) of Directive 2001/83/EC and Article 10a(1)(a)(b) of Regulation (EC) No 726/2004. They can also be conducted voluntarily by the marketing authorisation holders.

As shown in Figure VI.1., post-authorisation studies can either be clinical trials or non-interventional post-authorisation studies and the management of individual safety reports falls therefore either

• under the scope of Directive 2001/20/EC for any clinical trials; or
• under the provisions set out in Directive 2001/83/EC and Regulation (EC) No 726/2004 for any non-interventional post-authorisation studies.

Reports of suspected adverse reactions should not be submitted under both legislations that are Directive 2001/20/EC as well as Regulation (EC) No 726/2004 and Directive 2001/83/EC since this creates duplicate reports.

Further guidance on post-authorisation safety studies is provided in GVP Module VIII.

Figure VI.1. illustrates the different types of clinical trials and post-authorisation studies which can be conducted in the EU. The management of individual safety reports for clinical trials designated by sections A, B, and C follows the requirements of Directive 2001/20/EC, whereas individual safety reports for non-interventional post-authorisation studies corresponding to section D and E follows the requirements of Directive 2001/83/EC and Regulation (EC) No 726/2004.

The rules for the submission of valid ICSRs to the appropriate EudraVigilance database modules depend on the types of organised collection systems where the suspected adverse reactions occurred and the guidance provided in VI.C.6.2.1. should be followed.

VI.C.1.1. Management of individual safety reports for clinical trials

A suspected adverse reaction to an investigational medicinal product (IMP) occurring in a clinical trial falls under the scope of Directive 2001/20/EC. It is only to be addressed by the sponsor based on the requirements detailed in that Directive. It is therefore excluded from the scope of this Module, even if the clinical trial where the suspected adverse reaction occurred is a post-authorisation safety or efficacy clinical trial imposed in line with Article 21a of Directive 2001/83/EC and Article 9(4) of Regulation (EC) No 726/2004, requested in accordance with Article 22a of Directive 2001/83/EC and Article 10a of Regulation (EC) No 726/2004, or if it is conducted voluntarily by a marketing authorisation holder.

If a clinical trial, conducted under the scope of Directive 2001/20/EC, yields safety concerns which impact on the risk-benefit balance of an authorised medicinal product, the competent authorities in the Member States where the medicinal product is authorised and the Agency should be notified immediately in accordance with the modalities detailed in VI.C.2.2.6.. This applies as well if a safety concern arises from a clinical trial conducted exclusively outside the EU.

The safety data from clinical trials to be presented in the relevant sections of the periodic safety update report of the authorised medicinal product are detailed in GVP Module VII.

Where an untoward and unintended response from a clinical trial conducted in accordance with Directive 2001/20/EC is suspected to be related only to a medicinal product other than the IMP and does not result from a possible interaction with the IMP, it should be managed in line with the requirements provided in Art 107(3) and 107a(4) of Directive 2001/83/EC. The same applies when the adverse reaction is suspected to be related only to an authorised non-investigational medicinal product (NIMP)17 . In this context, the investigator or the sponsor is encouraged to report the case to the competent authority in the Member State where the reaction occurred or to the marketing authorisation holder of the suspected medicinal product, but not to both to avoid duplicate ICSRs submission18. Where made aware of such case, the competent authority or the marketing authorisation holder should apply the time frames and modalities described in VI.C.3., VI.C.4. and VI.C.6.. The report should be managed, classified and submitted as spontaneous and the guidance detailed in VI.C.6.2.3.7. Subsection 3 should be followed with regard to the electronic submission of ICSRs.

VI.C.1.2. Management of individual safety reports for non-interventional post-authorisation studies, compassionate use and named patient use

This chapter applies to non-interventional post-authorisation studies, compassionate use and named patient use. For these organised data collection schemes, a system should be put in place to record and document complete and comprehensive case information on solicited adverse events (see ICH-E2D and GVP Annex I for definition) which need to be collected as specified in VI.C.1.2.1. and in VI.C.1.2.2.

In line with ICH-E2D (see GVP Annex IV), these collected adverse events should be systematically assessed to determine whether they are possibly related to the studied (or supplied) medicinal products. A method of causality assessment should be applied for assessing the causal role of the studied (or supplied) medicinal products in the occurrence of the solicited adverse events (for example, the WHO-UMC System for Standardised Case Causality Assessment19). An adverse event should be classified as an adverse reaction, if there is at least a reasonable possibility of causal relationship with the product.

Reports of adverse reactions, suspected to be related to the studied (or supplied) medicinal product by the primary source or by the notified organisation, should be classified and submitted in accordance with the guidance provided in VI.C.1.2.1. VI.C.1.2.2. and VI.C.6.2.3.7. Depending on the seriousness and country of origin of the suspected reaction, the submission time frames and modalities detailed in VI.C.3. and VI.C.4. should be applied. Other reports of adverse events should be summarised as part of any interim safety analysis and in the final study report, where applicable.

In situations where an adverse reaction is suspected to be related to a medicinal product other than the studied (or supplied) medicine and does not result from a possible interaction with it, the report should be managed, classified and submitted as spontaneous ICSR. It should be notified by the primary source (healthcare professional or consumer) to the competent authority in the Member State where the reaction occurred or to the marketing authorisation holder of the suspected medicinal product, but not to both to avoid duplicate ICSRs submission.

Where made aware, in the frame of these organised data collection schemes, of events which affect the known risk-benefit balance of the studied (or supplied) medicinal product and/or impact on public health, the marketing authorisation holder should notify the concerned competent authorities and the Agency in accordance with the modalities detailed in VI.C.2.2.6.

Further guidance on post-authorisation studies conducted by marketing authorisation holders is provided in VI.C.2.2.2.

The requirements provided in this Module do not apply to non-interventional post-authorisation studies conducted by organisations such as academia, medical research charities or research organisations in the public sector. These organisations should follow the local requirements as regards the submission of cases of suspected adverse reactions to the competent authority in the Member State where the reaction occurred. However, where a study conducted by one of these organisations is directly initiated, managed, or financed by a marketing authorisation holder, or where its design is controlled by a marketing authorisation holder (voluntarily or pursuant to obligations imposed in accordance with Article 21a and 22a of Directive 2001/83/EC, or Article 9(4) and 10a of Regulation (EC) No 726/2004), the requirements provided in this Module are applicable20. In this context, contractual agreements should be in place to clearly define the role and responsibilities of each party for implementing these requirements (see GVP Module I).

VI.C.1.2.1. Non-interventional post-authorisation studies

Non-interventional post-authorisation studies (see GVP Annex I) should be distinguished between

• studies with a design based on primary data collection directly from healthcare professionals or consumers (i.e. where the events of interest are collected as they occur specifically for the study), and
• studies with a design based on secondary use of data (i.e. where the events of interest have already occurred and have been collected for another purpose).

Depending on the study design, the requirements provided hereafter in VI.C.1.2.1.1. and VI.C.1.2.1.2. apply.

For combined studies with a design based on both primary data collection and secondary use of data, the submission of ICSRs is required exclusively for the data obtained through primary data collection and the guidance provided hereafter in VI.C.1.2.1.1. should be followed. For the events identified through secondary use of data, the guidance in VI.C.1.2.1.2. applies. All adverse events/reactions collected as part of this type of studies should be recorded and summarised in the interim safety analysis and in the final study report.

In case of doubt, the management of individual safety reports should be clarified with the concerned competent authority in the Member State.

National legislation should be followed as applicable regarding the obligations towards local ethics committees.

VI.C.1.2.1.1. Non-interventional post-authorisation studies with a design based on primary data collection

Information on all adverse events should be collected and recorded from healthcare professionals or consumers in the course of the study unless the protocol provides with a due justification for not collecting certain adverse events. Any reference to adverse events that are not collected should be made using the appropriate level of the MedDRA classification (see GVP Module VIII).

For all collected adverse events, comprehensive and high quality information should be sought in a manner which allow for valid ICSRs to be submitted within the appropriate time frames. Cases of adverse reactions, which are suspected to be related to the studied medicinal product by the primary source or the notified organisation, should be recorded in the pharmacovigilance database and submitted as ICSRs in accordance with the time frames and modalities provided in VI.C.3. and VI.C.4.. They should be classified as solicited reports (see summary in Table VI.1., and VI.6.2.3.7 Subsection 1 for guidance on the electronic submission of these ICSRs).

All fatal outcomes should be considered as adverse events which should be collected. In certain circumstances, suspected adverse reactions with fatal outcome may not be subject to submission as ICSRs, for example because they refer to study outcomes (efficacy end points), because the patients included in the study have a disease with high mortality, or because the fatal outcomes have no relation to the objective of the study. For these particular situations, the rationale for not submitting as ICSRs certain adverse reactions with fatal outcome should be clearly described in the protocol together with a list using the appropriate level of the MedDRA classification (see GVP Module VIII). All adverse events collected during the study should be summarised in the interim safety analysis and in the final study report. For adverse events specified in the study protocol which are not systematically collected, healthcare professionals and consumers should be informed in the protocol (or other study documents) of the possibility to report adverse reactions (for which they suspect a causal role of a medicine) to the marketing authorisation holder of the suspected medicinal product (studied or not) or to the concerned competent authority via the national spontaneous reporting system (see summary in Table VI.1.).The resulting valid ICSRs should be managed, classified and submitted as spontaneous by the notified competent authority or marketing authorisation holder (see VI.6.2.3.7 Subsection 2 for guidance on the electronic submission of these ICSRs). Where made aware of them, these reports should also be summarised in the relevant study reports by the marketing authorisation holder sponsoring the study.

VI.C.1.2.1.2. Non-interventional post-authorisation studies with a design based on secondary use of data

The design of such studies is characterised by secondary use of data previously collected from consumers or healthcare professionals for other purposes. Examples include medical chart reviews (including following-up on data with healthcare professionals), analysis of electronic healthcare records, systematic reviews, meta-analyses. For these studies, the submission of suspected adverse reactions in the form of ICSRs is not required. All adverse events/reactions collected for the study should be recorded and summarised in the interim safety analysis and in the final study report unless the protocol provides for different reporting with a due justification (see GVP Module VIII).

VI.C.1.2.2. Compassionate use and named patient use

The guidance provided in this Module applies to medicinal products supplied in the context of compassionate use as defined in Article 83(2) of Regulation (EC) No 726/2004, subject to and without prejudice to the applicable national laws in EU Member States. As the case may be, this guidance may also apply to named patient use as defined under Article 5(1) of Directive 2001/83/EC. Local requirements should be followed as applicable.

Where an organisation21 or a healthcare professional, supplying a medicinal product under compassionate use or named patient use, is notified or becomes aware of an adverse event, it should be managed as follows depending on the requirements in the concerned Member State:

• for compassionate use and named patient use conducted in Member States (or in countries outside the EU) where the active collection of adverse events occurring in these programmes is required, the reports of adverse reactions, suspected to be related to the supplied medicinal product by the primary source or the notified organisation, should be submitted as ICSRs in line with the time frames and modalities provided in VI.C.3. and VI.C.4.. They should be considered as solicited reports (see VI.6.2.3.7 Subsection 1 for guidance on the electronic submission of these ICSRs).
• for compassionate use and named patient use conducted in Member States (or in countries outside the EU) where the active collection of adverse events occurring in these programmes is not required, any notified noxious or unintended response to the supplied medicinal product should be submitted as ICSR in accordance with the time frames and modalities provided in VI.C.3. and VI.C.4.. It should be considered as a spontaneous report of suspected adverse reaction (see VI.6.2.3.7 Subsection 2 for guidance on the electronic submission of these ICSRs).