VI.C.2. Collection of individual safety reports

VI.C.2.1. Responsibilities of Member States

Each Member State shall have in place a system for the collection and recording of unsolicited and solicited reports of suspected adverse reactions that occur in its territory and which are brought to its attention by healthcare professionals, consumers, or marketing authorisation holders 22 [DIR Art 101(1) and 107a(1)]. In this context, the competent authority in a Member State shall establish procedures for collecting and recording all reports of suspected adverse reactions that occur in its territory [IR Art 15 (2)]. The definitions and general principles detailed in VI.A.1. and Section VI.B., together with the time frames and modalities presented in VI.C.3., VI.C.4. and VI.C.6. should be applied with regard to their submission as ICSRs to the EudraVigilance database.

Each Member State shall take all appropriate measures to encourage healthcare professionals and consumers in their territory to report suspected adverse reactions to their competent authority. In addition, the competent authority in a Member State may impose specific obligations on healthcare professionals. To this end, the competent authority in a Member State shall facilitate in its territory the reporting of suspected adverse reactions by means of alternative straightforward reporting systems, accessible to healthcare professionals and consumers, in addition to web-based formats [DIR Art 102].

Information on the different ways of reporting suspected adverse reactions related to medicinal products shall be made publicly available, including by means of national medicines web-based portals [DIR 106(e)]. To increase awareness of the reporting systems, organisations representing consumers and healthcare professionals may be involved as appropriate [DIR Art 102]. In line with Article 25 of Regulation (EC) No 726/2004, standard web-based structured forms for the reporting of suspected adverse reactions by healthcare professionals and consumers have been developed by the Member States in collaboration with the Agency in order to collect across the EU harmonised information relevant for the evaluation of suspected adverse reactions, including errors associated with the use of medicinal products.

The reports of suspected adverse reactions received from healthcare professionals and consumers should be acknowledged where appropriate and further information should be provided to the reporters as requested and when available.

Member States shall involve patients and healthcare professionals, as appropriate, in the follow-up of any reports they receive in order to comply with Article 102(c) and (e) of Directive 2001/83/EC [DIR Art 107a(1)]. Furthermore, for reports submitted by a marketing authorisation holder, Member States on whose territory the suspected adverse reaction occurred may involve the marketing authorisation holder in the follow-up of the reports [DIR Art 107a(2)]. The criteria upon which a marketing authorisation holder may be involved include situations where:

• important additional information is necessary for case evaluation or reconciliation,
• clarifications is needed regarding inconsistent data within ICSRs,
• there is a need to obtain further information in the context of the validation of a signal, the evaluation of a safety issue, the assessment of a periodic safety update report, or the confirmation of a safety concern in a risk management plan.

In support of the operation of these follow-up procedures, business process maps and process descriptions are provided in VI.App.1.1. and VI.App.1.2.. Further guidance on the follow-up of ICSRs is provided in VI.B.3. and in VI.C.6.2.2.7.

Member States shall ensure that the reports of suspected adverse reactions arising from an error associated with the use of a medicinal product (see VI.A.1.2. for medication error definition) that are brought to their attention are made available to the EudraVigilance database and to any authorities, bodies, organisations and/or institutions, responsible for patient safety within that Member State. They shall also ensure that the authorities responsible for medicinal products within that Member State are informed of any suspected adverse reactions brought to the attention of any other authority within that Member State. These reports shall be appropriately identified in the standard web-based structured forms referred to in Article 25 of Regulation (EC) No 726/2004, developed for the reporting of suspected adverse reactions by healthcare professionals and patients [DIR Art 107a(5)]. To facilitate such reporting, it may be necessary to implement data exchange agreements or other arrangements, as appropriate. Further guidance concerning the management and assessment of reports of medication errors is provided in the Good Practice Guide on Recording, Coding, Reporting and Assessment of Medication Errors23 .

Pharmacovigilance data and documents relating to individual authorised medicinal products shall be retained by the national competent authorities in Member States and the Agency as long as the product is authorised and for at least 10 years after the marketing authorisation has expired. However, the documents shall be retained for a longer period where Union law or national law so requires [IR Art 16(2)] (see VI.C.6.2.4. and GVP Module I for guidance on ICSRs data quality).

Unless there are justifiable grounds resulting from pharmacovigilance activities, individual Member States shall not impose any additional obligations on marketing authorisation holders for the reporting of suspected adverse reactions [DIR Art 107a(6)].

VI.C.2.2. Responsibilities of the marketing authorisation holder in the EU

Each marketing authorisation holder shall have in place a system for the collection and recording of all reports of suspected adverse reactions in the EU or in third countries which are brought to its attention, whether reported spontaneously by healthcare professionals or consumers or occurring in the context of a post-authorisation study [DIR Art 104(1), Art 107(1)].

The marketing authorisation holder shall not refuse to consider reports of suspected adverse reactions received electronically or by any other appropriate means from patients and healthcare professionals [DIR Art 107(2)].

The marketing authorisation holder shall establish procedures in order to obtain accurate and verifiable data for the scientific evaluation of suspected adverse reaction reports [Dir Art 107(4)]. They shall also collect follow-up information on these reports and submit the updates to the EudraVigilance database [Dir Art 107(4)]. The marketing authorisation holder shall establish mechanisms enabling the traceability and follow-up of adverse reaction reports while complying with the data protection legislation [IR Art 12 (1)]. In support of the operation of the follow-up procedures, business process maps and process descriptions are provided in VI.App.1.1. and VI.App.1.2.. Further guidance on the follow-up of ICSRs is provided in VI.B.3. and in VI.C.6.2.2.7.

For the ICSRs made accessible to a marketing authorisation holder from the EudraVigilance database in accordance with Article 24(2) of Regulation (EC) No 726/2004 and in line with the EudraVigilance Access Policy for Medicines for Human Use24, the routine request for follow-up by the marketing authorisation holder is not foreseen. If the follow-up of an ICSR is necessary for a specific situation, a justification should be provided with the request, which should be addressed directly to the sender organisation of the ICSR.

Pharmacovigilance data and documents relating to individual authorised medicinal products shall be retained by the marketing authorisation holder as long as the product is authorised and for at least 10 years after the marketing authorisation has ceased to exist. However, the documents shall be retained for a longer period where Union law or national law so requires [IR Art 12 (2)] (see VI.C.6.2.4. and GVP Module I for guidance on ICSRs data quality).

With regard to the collection and recording of reports of suspected adverse reactions, the marketing authorisation holder responsibilities apply to reports related to medicinal products for which ownership cannot be excluded on the basis of one the following criteria: medicinal product name, active substance name, pharmaceutical form, batch number or route of administration (see also the introduction to Section VI.C. for the type of medicinal products concerned by EU requirements). Exclusion based on the primary source country or country of origin of the adverse reaction is possible if the marketing authorisation holder can demonstrate that the suspected medicinal product has never been supplied or placed on the market in that territory or that the product is not a travel medicine (e.g. anti-malarial medicinal product).

The marketing authorisation holder shall ensure that any information on adverse reactions, suspected to be related to at least one of the active substances of its medicinal products authorised in the EU, is brought to its attention by any company outside the EU belonging to the same mother company (or group of companies) 25 . The same applies to the marketing authorisation holder when having concluded a commercial agreement with a company outside the EU for one of its medicinal product authorised in the EU. Pursuant to Article 107(1) of Directive 2001/83/EC, the marketing authorisation holder shall record those reports of suspected adverse reactions and shall ensure that they are accessible at a single point within the EU. The source data or an image should be easily accessible in order to be made available to competent authorities in Member States upon request (see VI.B.5. for guidance on quality management). The clock for the submission (see VI.B.7. for day zero definition) starts when a valid ICSR is first received by one of these companies outside the EU.

In addition to the requirements presented in this chapter, the definitions and general principles detailed in VI.A.1. and Section VI.B., together with the time frames and modalities presented in VI.C.3., VI.C.4. and VI.C.6. should be applied by the marketing authorisation holder to all reports of suspected adverse reactions.

VI.C.2.2.1. Spontaneous reports

The marketing authorisation holder shall record all reports of suspected adverse reactions originating from within or outside the EU, which are brought to its attention spontaneously by healthcare professionals or consumers. This includes reports of suspected adverse reactions received electronically or by any other appropriate means [DIR Art 107(1), Art 107(2)]. In this context, the marketing authorisation holder may consider utilising its websites to facilitate the collection of reports of suspected adverse reactions by providing adverse reactions forms for reporting, or appropriate contact details for direct communication (see VI.B.1.1.4. for guidance on ICSRs management from the internet or digital media).

VI.C.2.2.2. Solicited reports

In accordance with Article 107(1) of Directive 2001/83/EC, the marketing authorisation holder shall record all reports of suspected adverse reactions originating from within or outside the EU, which occur in post-authorisation studies, initiated, managed, or financed by that organisation26 . For noninterventional post-authorisation studies, this requirement applies to study designs based on primary data collection and the guidance provided in VI.C.1.2.1.1. should be followed.

For all solicited reports (see VI.B.1.2. for definition), the marketing authorisation holder should have mechanisms in place to record and document complete and comprehensive case information and to evaluate that information, in order to allow the meaningful assessment of individual cases and the submission of valid ICSRs (see VI.B.2. for ICSRs validation) related to the studied (or supplied) medicinal product. The marketing authorisation holder should therefore exercise due diligence in establishing such system, in following-up those reports (see VI.B.3. for follow-up guidance) and in seeking the view of the primary source as regards the causal role of the studied (or supplied) medicinal product on the notified adverse event. Where this opinion is missing, the marketing authorisation holder should exercise its own judgement to perform a causality assessment based on the information available in order to decide whether the report is a valid ICSR, which should be submitted in accordance with the time frames and modalities presented in VI.C.3., VI.C.4. and VI.C.6.. This requirement does not apply to study designs based on secondary use of data since the submission of ICSRs is not required (see VI.C.1.2.1.2. for guidance on this type of studies). Safety data from solicited reports to be presented in the relevant sections of the periodic safety update report of the authorised medicinal product are detailed in GVP Module VII.

VI.C.2.2.3. Case reports published in the medical literature

General principles in relation to the monitoring for individual cases of suspected adverse reactions described in the medical literature are provided in VI.B.1.1.2.. Detailed guidance on the monitoring of the medical literature is provided in VI.App.2.. Electronic submission guidance for ICSRs published in the medical literature is provided in VI.C.6.2.3.2.

With regard to the screening of the medical literature, the requirements provided in this Module are part of the marketing authorisation holder obligations in relation to (i) the submission of individual cases of suspected adverse reactions, and to (ii) the wider literature searches which need to be conducted for periodic safety update reports (see GVP Module VII).

VI.C.2.2.3.1 Monitoring of the medical literature by the European Medicines Agency

In line with Article 27 of Regulation (EC) No 726/2004, the Agency monitors selected medical literature for reports of suspected adverse reactions to medicinal products containing certain active substances. It publishes a list of active substances being monitored and the medical literature subject to this monitoring. The Agency enters into the EudraVigilance database relevant information from the selected medical literature. The Agency, in consultation with the European Commission, Member States and interested parties, draws up a detailed guide regarding the monitoring of medical literature and the entry of relevant information into the EudraVigilance database.

The medical literature and the active substances subject to the monitoring by the Agency are published on a dedicated webpage27 of the Agency’s website together with supporting documents. Further information is also provided in the Detailed Guide Regarding the Monitoring of Medical Literature and the Entry of Relevant Information into the EudraVigilance Database by the European Medicines Agency28 , which defines the different steps of the medical literature monitoring (MLM) business processes.

ICSRs resulting from the MLM service performed by the Agency can be accessed from the EudraVigilance database by the marketing authorisation holder concerned. They are also made available for download in XML format. This refers to ICSRs of serious suspected adverse reactions occurring within and outside the EU, and to ICSRs of non-serious suspected adverse reactions from within the EU.

In accordance with Article 107(3) of Directive 2001/83/EC and to avoid the submission of duplicate ICSRs, the marketing authorisation holder shall only submit those ICSRs described in the medical literature which is not reviewed by the Agency, for all medicinal products containing active substances which are not included in the list monitored by the Agency pursuant to Article 27 of Regulation (EC) No 726/2004.

VI.C.2.2.3.2 Exclusion criteria for the submission of ICSRs published in the medical literature

The following exclusion criteria for the submission of ICSRs to the EudraVigilance database by a marketing authorisation holder may be applied for cases published in the medical literature:

a. where ownership of the suspected medicinal product by the marketing authorisation holder can be excluded on the basis of the medicinal product name, active substance name, pharmaceutical form, batch number or route of administration;

b. which originates in a country where a company holds a marketing authorisation but has never commercialised the medicinal product;

c. which is based on an analysis from a competent authority database within the EU. However, the submission requirements remain for those ICSRs which are based on the analysis from a competent authority database outside the EU;

d. which refers to data from publicly available databases (e.g. poison control centres) and where the cases are presented in aggregate tables or line listings. The submission requirement remains for valid cases described individually;

e. which presents the results from post-authorisation studies, meta-analyses, or literature reviews;

f. which describes suspected adverse reactions in a group of patients with a designated medicinal product and the patients cannot be identified individually for creating valid ICSRs (see VI.B.2. for ICSRs validation).

For points d to f, this type of literature aims at identifying or quantifying a safety hazard related to a medicinal product. The main objective is to detect/evaluate specific risks that could affect the overall risk-benefit balance of a medicinal product.

New and significant safety findings presented in these articles, for which the submission of ICSRs is not required, should however be discussed in the relevant sections of the concerned periodic safety update report (see GVP Module VII) and analysed as regards their overall impact on the medicinal product risk-benefit profile. In addition, any new safety information, which may impact on the risk-benefit profile of a medicinal product, should be notified immediately to the competent authorities in Member States where the medicinal product is authorised and to the Agency in accordance with the guidance provided in VI.C.2.2.6.

VI.C.2.2.4. Suspected adverse reactions related to quality defect or falsified medicinal products

When a report of suspected adverse reactions is associated with a suspected or confirmed falsified medicinal product29 or with a quality defect of a medicinal product, a valid ICSR should be submitted. The seriousness of the ICSR is linked to the seriousness of the reported suspected adverse reactions in accordance with the definitions provided in VI.A.1.6. The guidance on the electronic submission of ICSRs provided in VI.C.6.2.3.5. should be followed.

In addition in order to protect public health, it may become necessary to implement urgent measures such as the recall of one or more defective batch(es) of a medicinal product from the market. Therefore, the marketing authorisation holder should have a system in place to ensure that reports of suspected adverse reactions related to falsified medicinal products or to quality defects of a medicinal products are investigated in a timely fashion and that confirmed quality defects are notified separately to the manufacturer and to the competent authorities in Member States in accordance with the provisions described in Article 13 of Directive 2003/94/EC.

VI.C.2.2.5. Suspected transmission via a medicinal product of an infectious agent

Any suspected transmission of an infectious agent via a medicinal product should be considered as a serious adverse reaction and such cases should be submitted within 15 days in accordance with the requirements outlined in VI.C.4. and the electronic submission guidance detailed in VI.C.6.2.3.6. If no other criterion is applicable, the seriousness of this ICSR should be considered as important medical event (see VI.A.1.6. for seriousness definition). This also applies to vaccines.

In the case of medicinal products derived from human blood or human plasma, haemovigilance procedures may also apply in accordance with Directive 2002/98/EC. Therefore the marketing authorisation holder should have a system in place to communicate any suspected transmission of an infectious agent via a medicinal product to the manufacturer, the relevant blood establishment(s) and national competent authorities in Member States.

Any organism, virus or infectious particle (e.g. prion protein transmitting transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.

A transmission of an infectious agent may be suspected from clinical signs or symptoms, or laboratory findings indicating an infection in a patient exposed to a medicinal product.

Emphasis should be on the detection of infections/infectious agents known to be potentially transmitted via a medicinal product, but the occurrence of unknown agents should also always be considered.

In the context of evaluating a suspected transmission of an infectious agent via a medicinal product, care should be taken to discriminate, whenever possible, between the cause (e.g. injection/ administration) and the source (e.g. contamination) of the infection and the clinical conditions of the patient at the time of the infection (immuno-suppressed /vaccinated).

Confirmation of contamination (including inadequate inactivation/attenuation of infectious agents as active substances) of the concerned medicinal product increases the evidence for transmission of an infectious agent and may therefore be suggestive of a quality defect for which the procedures detailed in VI.C.2.2.4. should be applied.

Medicinal products should comply with the recommendations provided in the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Products30 . For advanced therapy medicinal products, Article 14(5) of Regulation (EC) No 1394/2007 and the Guideline on Safety and Efficacy Follow-up – Risk Management of Advanced Therapy Medicinal Products31, should also be followed as appropriate.

VI.C.2.2.6. Emerging safety issues

Events/observations may occur in relation to an authorised medicinal product, which may have major impacts on the risk-benefit balance of the product and/or on patients or public health. They may require urgent attention of the competent authority and could warrant prompt regulatory action and communication to patients and healthcare professionals. These important new evidences should be considered as emerging safety issues (see GVP Annex I). They should be notified to the competent authorities and the Agency in accordance with the requirements provided in GVP Module IX. This is in addition to the ICSR submission requirements detailed in VI.C.3. and VI.C.4., when the emerging safety issue refers to a single case of suspected adverse reactions (see VI.C.6.2.2.1. for general guidance on ICSRs preparation).

VI.C.2.2.7. Period between the submission of the marketing authorisation application and the granting of the marketing authorisation

In the period between the submission of the marketing authorisation application and the granting of the marketing authorisation, information (quality, non-clinical, clinical) that could impact on the riskbenefit balance of the medicinal product under evaluation may become available to the applicant32. It is the responsibility of the applicant to ensure that this information is immediately submitted in accordance with the modalities described in VI.C.2.2.6. to the competent authorities in the Member States where the application is under assessment (including Reference Member State and all concerned Member States for products assessed under the mutual recognition or decentralised procedures) and to the Agency. For applications under the centralised procedure, the information should also be provided to the (Co-) Rapporteur.

In the situation where a medicinal product application is under evaluation in the EU while it has already been authorised in a third country, valid ICSRs from outside the EU, originating from unsolicited reports (see VI.B.1.1. for definition) or solicited reports (see VI.B.1.2. for definition), should be submitted in accordance with the time frames and modalities provided in VI.C.3., VI.C.4. and VI.C.6.

VI.C.2.2.8. Period after suspension, revocation or withdrawal of marketing authorisation

The marketing authorisation holder shall continue to collect any reports of suspected adverse reactions related to the concerned medicinal product following the suspension of a marketing authorisation. The time frames and submission requirements outlined in VI.C.3., VI.C.4. and VI.C.6. remain for valid ICSRs. Where a marketing authorisation is withdrawn or revoked, the former marketing authorisation holder is encouraged to continue to collect spontaneous reports of suspected adverse reactions originating within the EU to, for example, facilitate the review of delayed onset adverse reactions or of retrospectively notified cases.

VI.C.2.2.9. Period during a public health emergency

A public health emergency is a public health threat duly recognised either by the World Health Organization (WHO) or the Community in the framework of Decision No. 2119/98/EC as amended of the European Parliament and of the Council. In the event of a public health emergency, regular submission requirements may be amended. Such arrangements will be considered on a case-by-case basis and will be appropriately notified on the Agency website.

VI.C.2.2.10. Reports from class action lawsuits

Stimulated reports arising from class action lawsuits should be managed as spontaneous reports. Valid ICSRs should describe suspected adverse reactions related to the concerned medicinal product. They should be submitted in accordance with the time frames and modalities described in VI.C.3., VI.C.4. and VI.C.6.

Where large batches of potential ICSRs are received, the marketing authorisation holder may request, in exceptional circumstances, for an exemption in order to submit serious cases of suspected adverse reactions within 30 days from their date of receipt instead of 15 days. The 90 days submission time frame for non-serious ICSRs remains unchanged. The request should be made to the Agency’s pharmacovigilance department.

VI.C.2.2.11. Reports from patient support programmes and market research programmes

A patient support programme is an organised system where a marketing authorisation holder receives and collects information relating to the use of its medicinal products. Examples are post-authorisation patient support and disease management programmes, surveys of patients and healthcare professionals, information gathering on patient compliance, or compensation/re-imbursement schemes.

A market research programme refers to the systematic collection, recording and analysis by a marketing authorisation holder of data and findings about its medicinal products, relevant for marketing and business development.

Safety reports originating from those programmes should be considered as solicited reports. The marketing authorisation holder should have the same mechanisms in place as for all other solicited reports (see VI.C.2.2.2. for marketing authorisation holders responsibilities on solicited reports) to manage that information and to submit, in line with the time frames and modalities outlined in VI.C.3. and VI.C.4., valid cases of adverse reactions which are suspected to be related to the concerned medicinal product.

Valid ICSRs should be submitted as solicited in accordance with the guidance provided in VI.6.2.3.7 Subsection 1.

VI.C.2.2.12. Reporting of off-label use

The off-label use of a medicinal product may occur for various reasons (see definition in VI.A.1.2. and GVP Annex I). Examples include the intentional use of a product in situations other than the ones described in the authorised product information, such as:

• a different indication in term of medical condition;
• a different group of patients;
• a different route or method of administration;
• a different posology.

With regard to the management of individual reports referring to the off-label use of a product, the responsibilities of the marketing authorisation holder can be summarised as follows, depending if the off-label use results in the patient’s harm:

a. The off-label use of a medicinal product results in patient’s harm with occurrence of a suspected adverse reaction In line with Article 107(1), 107(3) and 107(4) of Directive 2001/83/EC, the marketing authorisation holder shall collect individual reports of suspected adverse reactions when becoming aware of them.

The reports shall be routinely followed-up to ensure that the information is as complete as possible (see VI.C.2.2. for marketing authorisation holders’ responsibilities on ICSRs). Valid ICSRs shall be submitted to the EudraVigilance database in accordance with the time frames, and modalities provided in VI.C.3., VI.C.4., and VI.C.6.2.3.3.

Where relevant and appropriate, the benefit-risk analysis evaluation presented in the periodic safety update report should take into account the clinical importance of a risk in relation to the off-label use of the concerned medicinal product (see GVP Module VII).

In line with the guidance provided in GVP Module V, where there is a scientific rationale that an adverse clinical outcome might be associated with the off-label use of the product, the adverse reaction should be considered a potential risk, and if deemed important, should be included in the list of safety concerns of the risk management plan as an important potential risk. This is particularly relevant, when differences in safety concerns between the target and the off-label population are anticipated. Important potential risks included in the risk management plan would usually require further evaluation as part of the pharmacovigilance plan.

b. The off-label use of a medicinal product does not result in patient’s harm and occurrence of a suspected adverse reaction

The potential obligations regarding the collection of data on the off-label use of a medicinal product are set out in Article 23(2) of Directive 2001/83/EC, which requires the marketing authorisation holder to report to competent authorities in Member States any other new information which might influence the evaluation of the benefits and risks of the medicinal product, including data on the use of the product where such use is outside the terms of the marketing authorisation.

Under this condition, the most appropriate way to deliver a planned and risk proportionate approach to enable the monitoring of the use of a specific medicinal product in routine clinical settings is through the risk management plan. Where the potential for off-label use has been identified for a product and such use could raise a safety concern (i.e. because there is a justified supposition that an important potential risk might be associated with the off-label use of the product) the risk management plan should discuss the need of pharmacovigilance activities in terms of:

• • specific follow-up questionnaires for suspected adverse reactions derived from the off-label use;
  • other required forms of routine pharmacovigilance activities for the targeted collection and follow-up of individual reports of off-label use not associated with suspected adverse reactions;
  • additional structured investigations (such as drug utilisation studies, searches in databases).

If collected in the frame of the routine pharmacovigilance activities, individual reports of off-label use with no suspected adverse reaction should not be submitted to the EudraVigilance database since the minimum criteria for ICSRs validation are incomplete (see VI.B.2. for ICSRs validation).

As part of risk management planning, the monitoring of the off-label use should focus on collection and assessment of information which might influence the evaluation of the benefits and risks of the concerned medicinal product.

For products without a risk management plan, the marketing authorisation holder and the competent authority should consider whether the off-label use of the product constitutes a safety concern. If it does, then consideration should be given to requiring a risk management plan or a post-authorisation safety study.

Some Member States may already have put in place specific requirements at national level regarding the collection and submission by marketing authorisation holders of information on the off-label use of their products. The guidance presented in this chapter should not be interpreted as preventing the fulfilment of those local obligations.