VI.C.6. Electronic exchange of safety information in the EU
Chapter VI.C.6. highlights the requirements, as defined in Article 24(1) and 24(3) of Regulation (EC) No 726/2004, for the establishment and maintenance of the European database and data processing network (the EudraVigilance database) in order to collate and share pharmacovigilance information electronically between competent authorities in Member States, marketing authorisation holders and the Agency, in ways which ensure the quality and integrity of the data collected. The information provided here is relevant for the electronic exchange of ICSRs in the EU between all stakeholders and for the electronic submission of information on medicinal products to the Agency.
VI.C.6.1. Applicable guidelines, definitions, international formats, standards and terminologies
For the classification, retrieval, presentation, risk-benefit evaluation and assessment, electronic exchange and communication of pharmacovigilance and medicinal product information, Member States, marketing authorisation holders and the Agency shall adhere to the legal requirements provided in Chapter IV and V of the Commission Implementing Regulation (EU) No 520/2012. In addition the following guidelines should be applied:
- the ICH Guidelines detailed in VI.B.8.;
- the guidelines applicable for the ICH-E2B(R2) and ICH-E2B(R3) formats:
| Reference | Guidelines |
| ICH-E2B(R2) | Note for guidance – EudraVigilance Human – Processing of Safety Messages and Individual Case Safety Reports (ICSRs) (EMA/H/20665/04/Final Rev. 2) (also referred as EudraVigilance Business Rules); |
| ICH-E2B(R3) | EU Individual Case Safety Report (ICSR) Implementation Guide 37; EU ICSR Implementation Guide Business Rules Spreadsheet38; EU Backwards Forwards Conversion Element Mapping Spreadsheet38; EU E2B(R3) code lists38; EU reference instances38; EU example instances38 . |
The latest version of these documents should always be taken into account.
VI.C.6.2. Electronic submission of individual case safety reports
The submission of valid ICSRs electronically, by competent authorities in Member States and marketing authorisation holders, is mandatory for all medicinal products authorised in the EU [DIR Art 107(3), Art 107a(4)]. Non-adherence to this requirement constitutes a non-compliance with EU legislation.
The responsibilities in case of communication failure (including adherence to compliance for submission of ICSRs) are detailed in the EU Individual Case Safety Report (ICSR) Implementation Guide 39 .
Technical tools (EVWEB) have been made available by the Agency to interested electronic data interchange partners, including small and medium-sized enterprises, to facilitate compliance with the electronic submission requirements of ICSRs as defined in EU legislation. Information is available on the EudraVigilance webpage40 , together with some guidance on the access by stakeholders to the data submitted to the EudraVigilance database41 .
VI.C.6.2.1. EudraVigilance Database Modules
Two modules are available in the EudraVigilance database to address the collection of reports of suspected adverse reactions related to medicinal products for human use in accordance with EU legislation:
- the EudraVigilance Post-Authorisation Module (EVPM), implemented based on the requirements defined in Regulation (EC) No 726/2004 and Directive 2001/83/EC; and
- the EudraVigilance Clinical Trial Module (EVCTM), implemented based on the requirements defined in Directive 2001/20/EC.
VI.C.6.2.1.1. Adverse reaction data collected in the EudraVigilance Post-Authorisation Module
The adverse reaction reports collected in the EudraVigilance Post-Authorisation Module (EVPM) refer to unsolicited reports and solicited reports which do not fall under the scope of the Clinical Trials Directive 2001/20/EC (see VI.C.1.2. for ICSRs management in non-interventional studies, compassionate and named patient use).
In line with ICH-E2B the ICSRs should be submitted to EVPM with the following value:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | EVHUMAN’ in the data element M.1.6 ‘Message receiver identifier’ (ICH M2). |
| ICH-E2B(R3)) | EVHUMAN’ in the data elements N.1.4 ‘Batch Receiver Identifier’ and ‘N.2.r.3 Message Receiver Identifier’. |
Depending on their type, these ICSRs should be classified based on one of the following options in line with ICH-E2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Data element A.1.4 ‘Type of report’: – spontaneous report; – other; – not available to sender (unknown); or – report from study. · When the value of the data element A.1.4 is ‘Report from study’, the data element A.2.3.3 ‘Study type in which the reaction(s)/event(s) were observed’ should be populated with: – individual patient use, e.g. compassionate use or named-patient basis; or – other studies, e.g. pharmacoepidemiology, pharmacoeconomics, intensive monitoring, post-authorisation study. |
| ICH-E2B(R3) | · Data element C.1.3 ‘Type of report’: – spontaneous report; – other; – not available to sender (unknown); or – report from study. · When the value of the data element C.1.3 is ‘Report from study’, the data element C.5.4 ‘Study type in which the reaction(s)/event(s) were observed’ should be populated with: – individual patient use, e.g. compassionate use or named-patient basis; or – other studies, e.g. pharmacoepidemiology, pharmacoeconomics, intensive monitoring, post-authorisation study. |
VI.C.6.2.1.2. Adverse reaction data collected in the EudraVigilance Clinical Trial Module
Only cases of suspected unexpected serious adverse reactions (SUSARs), related to investigational medicinal products (IMPs) studied in clinical trials which fall under the scope of Directive 2001/20/EC (see VI.C.1.1. for ICSRs management in clinical trials), should be submitted by the sponsor to the EudraVigilance Clinical Trial Module (EVCTM). The requirements provided in chapter II of EudraLex Volume 10 of The Rules Governing Medicinal Products in the European Union42 should be applied with regard to the collection, verification and presentation of adverse event/reaction reports arising from clinical trials.
The ICSRs should be submitted to EVCTM with the following value in line with ICH-E2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | EVCTMPROD’ in the data element M.1.6 ‘Message receiver identifier’ (ICH M2). |
| ICH-E2B(R3) | EVCTMPROD’ in the data elements N.1.4 ‘Batch Receiver Identifier’ and ‘N.2.r.3 Message Receiver Identifier’. |
These ICSRs should be classified as follows in line with ICH-E2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Data element A.1.4 ‘Type of report’: – report from study. · When the value of the data element A.1.4 is ‘Report from study’, the data element A.2.3.3 ‘Study type in which the reaction(s)/event(s) were observed’ should be populated with: – clinical trials. |
| ICH-E2B(R3) | · Data element C.1.3 ‘Type of report’: – report from study. · When the value of the data element C.1.3 is ‘Report from study’, the data element C.5.4 ‘Study type in which the reaction(s)/event(s) were observed’ should be populated with: – clinical trials. |
VI.C.6.2.2. Preparation of individual case safety reports
VI.C.6.2.2.1. General principles
The content of each valid ICSR transmitted electronically between all stakeholders should comply with the legal requirements and guidelines detailed in the Commission Implementing Regulation (EU) No 520/2012 and in VI.C.6.1., particularly:
- the requirements provided in Chapters IV and V of the Commission Implementing Regulation (EU) No 520/2012;
- the latest version of the MedDRA Term Selection: Points to Consider43 (see GVP Annex IV);
- the EudraVigilance business rules or the EU Individual Case Safety Report (ICSR) Implementation Guide as referred to in VI.C.6.1., depending on the ICH-E2B format applied.
It is recognised that it is often difficult to obtain all the details on a specific case. However, the complete information (medical and administrative data) for a valid ICSR that is available to the sender should be submitted in a structured manner in the relevant ICH-E2B data elements (which should be repeated as necessary when multiple information is available) and in the narrative section for serious cases (see VI.C.6.2.2.4. for guidance on case narrative). This applies to all types of ICSRs, such as reports with initial information on the case, follow-up information and cases highlighted for amendment44 or nullification45.
In the situation where it is evident that the sender has not transmitted the complete information available on the case, the receiver may request the sender to re-transmit the ICSR within 24 hours with the complete case information in electronic format in accordance with the requirements applicable for the electronic submission of ICSRs. This should be seen in the light of the qualitative signal detection and evaluation activity, where it is important for the receiver to have all the available information on a case to perform the medical assessment (see VI.C.6.2.4. for guidance on ICSRs data quality).
Where the suspected adverse reactions reported in a single ICSR have a major impact on the riskbenefit balance of the medicinal product, this should be considered as an emerging safety issue and notified accordingly (see VI.C.2.2.6. and GVP Module IX for guidance on emerging safety issue). This is in addition to the ICSR submission requirements detailed in VI.C.3. and VI.C.4. A summary of the points of concerns and the action proposed should be recorded in the ICSR in the data element ‘Sender’s comments’ in line with ICH-E2B.
VI.C.6.2.2.2. Information on suspect, interacting and concomitant medicinal products
a. General guidance
Information on the active substances/invented names for the reported medicinal products (suspect, interacting, concomitant) should be provided in accordance with the requirements provided in Article 28 (3) (g) to (i) of the Commission Implementing Regulation (EU) No 520/2012. Depending on the ICH E2B format used, the guidance detailed in the Note for guidance – EudraVigilance Human – Processing of safety messages and individual case safety reports (ICSRs)46 and in the EU Individual Case Safety Report (ICSR)
Implementation Guide47 should also be followed. The characterisation of the medicinal products as suspect, interacting or concomitant is based on the information provided by the primary source. Where the notified competent authority or marketing authorisation holder disagrees with the primary source characterisation, this should be indicated in the data element ‘Sender’s comments’ in line with ICH-E2B while respecting the reporter description.
For medicinal products, which contain more than one active substance, the following applies in line with ICH-E2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | In addition to the information included in the data element B.4.k.2.1 ‘Proprietary medicinal product name’, each active substance needs to be reflected individually in the data element B.4.k.2.2 ‘Active substance name(s)’, which should be repeated for each active substance contained in the medicinal product. |
| ICH-E2B(R3) | In addition to the information included in the mandatory data element G.k.2.2 ‘Medicinal Product Name as Reported by the Primary Source’, each active substance needs to be reflected individually in the section G.k.2.3.r. ‘Substance / Specified Substance Identifier and Strength’, which should be repeated for each active substance contained in the medicinal product. This applies where there is no Medicinal Product Identifier (MPID), Pharmaceutical Product Identifier (PhPID) or where no Substance/Specified Substance TermID is available as referred to in the EU Individual Case Safety Report (ICSR) Implementation Guide48. |
1.When the primary source reports a suspect or interacting branded/proprietary medicinal product name without indicating the active substance(s) of the medicinal product and where the proprietary medicinal product can be one of two or more possible generics, which have different compositions depending on the country where the medicinal product is marketed, the ICSR should be populated as follows in line with ICH-E2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Data element B.4.k.2.1 ‘Proprietary medicinal product name’ should be populated with the proprietary/branded medicinal product name as reported by the primary source. · Data element B.4.k.2.2 ‘Active substance name(s)’ should be completed with the active substance(s) that correspond(s) to the composition of the proprietary/branded medicinal product of the country where the reaction/event occurred. · Where there is more than one active substance contained in the medicinal product, data element B.4.k.2.2 ‘Active substance name(s)’ should be repeated accordingly. |
| ICH-E2B(R3) | · Data element G.k.2.2 ‘Medicinal Product Name as Reported by the Primary Source’ should be populated with the proprietary/branded medicinal product name as reported by the primary source. · Data element G.k.2.3.r.1 ‘Substance/Specified Substance Name’ should be completed with the active substance(s) that correspond(s) to the composition of the proprietary/branded medicinal product of the country where the reaction/event occurred. · Where there is more than one active substance contained in the medicinal product, section G.k.2.3.r ‘Substance/Specified Substance Identifier and Strength’ should be repeated accordingly. |
However, the composition with regard the active substance(s) of the suspected or interacting proprietary medicinal product name should be provided accordingly if information is also available on the following ICH-E2B data elements for the reported product:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Data element B.4.k.2.3 ‘Identification of the country where the drug was obtained’, · Data element B.4.k.4.1 ‘Authorization/application number’, · Data element B.4.k.4.2 ‘Country of authorization/application’, and/or · Data element B.4.k.3 ‘Batch/lot number’. |
| ICH-E2B(R3) | · Data element G.k.2.4 ‘Identification of the Country Where the Drug Was Obtained’, · Data element G.k.3.1 ‘Authorization/application number’, · Data element G.k.3.2 ‘Country of Authorisation/Application’, and/or · Data element G.k.4.r.7 ‘Batch/lot number’. |
2. Where the primary source reports a suspect or interacting branded/proprietary medicinal product name without indicating the pharmaceutical form/presentation of the product and where the proprietary/branded medicinal product can be one of two or more possible pharmaceutical forms/presentations, which have different compositions in a country, the ICSR should be populated as follows in line with ICH-E2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Data element B.4.k.2.1’Proprietary medicinal product name’ should be populated with the proprietary/branded medicinal product name as reported by the primary source. · Data element B.4.k.2.2 ‘Active substance name(s)’ should be completed with those active substances, which are in common to all pharmaceutical forms/presentations in the country of authorisation. · Where there is more than one active substance contained in the medicinal product, data element B.4.k.2.2 ‘Active substance name(s)’ should be repeated accordingly. |
| ICH-E2B(R3) | · Data element G.k.2.2 ‘Medicinal Product Name as Reported by the Primary Source’ should be populated with the proprietary/branded medicinal product name as reported by the primary source. · Data element G.k.2.3.r.1 ‘Substance/Specified Substance Name’ should be completed with the active substances which are in common to all pharmaceutical forms/presentations in the country of authorisation. · Where there is more than one active substance contained in the medicinal product, section G.k.2.3.r ‘Substance/Specified Substance Identifier and Strength’ should be repeated accordingly. |
c. Suspicion of a therapeutic class of medicinal products
Where the medicinal product cannot be described on the basis of the active substances or the invented names, for example when only the therapeutic class is reported by the primary source, or in case of other administered therapies that cannot be structured, this information should only be reflected in the case narrative. The information should not be included in the structured data elements of the medicinal product name or the active substance name(s). The same applies if a suspected food interaction is reported (e.g. to grapefruit juice).
Where a case of adverse reactions is suspected to be related only to a therapeutic class, it is considered incomplete and does not qualify for submission as ICSR (see VI.B.2. for ICSRs validation). Efforts should be made to follow-up the case in order to collect the missing information regarding the suspected medicinal product (see VI.B.3. for follow-up guidance).
d. Suspicion of drug interactions
For reports of drug interactions, which concern drug/drug (including biological products), drug/food, drug/device, and drug/alcohol interactions, the coding of the suspected interaction along with the resulting adverse reactions should be performed in the following ICH-E2B section in line with the appropriate recommendations provided in the latest version of the Guide for MedDRA Users – MedDRA Term Selection: Points to Consider (see GVP Annex IV).
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Section B.2 ‘Reactions/Events’ |
| ICH-E2B(R3) | Section E.i.1’Reaction/Events’ |
In addition, the following applies for the suspected interacting medicinal products in line with ICHE2B:
1.For drug/drug interactions
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Section B.4 ‘Drug information’ should be completed with information reported by the primary source on the active substances/proprietary medicinal products concerned. · Data element B.4.k.1 ‘Characterisation of drug role’ is to be completed as ‘interacting’ for all suspected interacting medicines. |
| ICH-E2B(R3) | · Section G.k ‘Drug(s) Information’ should be completed with information reported by the primary source on the active substances/proprietary medicinal products concerned. · Data element G.k.1 ‘Characterisation of Drug Role’ is to be completed as ‘interacting’ for all suspected interacting medicines. |
2. For drug/ food interactions or interactions with other non-drug compounds
The information on the suspected interacting medicine should be included in ICH E2B section ‘Drug information’, however the information concerning the interacting food or other nondrug compounds should be provided in the case narrative.
e. Suspicion of one of the excipients
If the primary source suspects a possible causal role of one of the excipients (e.g. colouring matter, preservatives, adjuvant, stabilisers, thickeners, emulsifiers, flavouring and aromatic substances, see VI.A.1.3. for definition) of the suspected medicinal product, this information should be provided in line with ICH-E2B as follows:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · In the section B.4 ‘Drug information’: as a separate entry specifying the suspected excipient, in addition to the information given regarding the suspected medicinal product. This should also be specified in the case narrative. · If available, tests results (positive or negative) in relation to the causal role of the suspected excipient should be included in the section B.3 ‘Results of tests and procedures relevant to the investigation of the patient’. |
| ICH-E2B(R3) | · In the section G.k ‘Drug(s) Information’: as a separate entry specifying the suspected excipient, in addition to the information given regarding the suspected medicinal product. This should also be specified in the case narrative. · If available, tests results (positive or negative) in relation to the causal role of the suspected excipient should be included in the section F.r ‘Results of tests and procedures relevant to the investigation of the patient’. |
f. Additional information on the medicinal product
Often, additional information on the medicine(s) is provided in individual cases, which is important for the purpose of data analysis and case review; for example in the context of counterfeit, overdose, drug taken by father, drug taken beyond expiry date, batch and lot tested and found within specifications, batch and lot tested and found not within specifications, medication error, misuse, abuse, occupational exposure and off label use. In line with ICH-E2B, the following applies to capture this information for the respective suspected medicinal products, along with the guidance provided
- in section VI.C.6.2.3.3. for the provision of information on the suspected adverse reactions associated to overdose, abuse, off-label use, misuse, medication error or occupational exposure, and
- in section VI C.6.2.3.5. for the provision of information on suspected adverse reactions associated to quality defect or falsified medicinal product
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · As a general principle, additional characteristics related to the medicines that cannot be structured in one of the data elements of section B.4 ‘Drug(s) information’ and which are pertinent to the case should be provided in free text. · Data element B.4.k.19 ‘Additional information on drug’ should be used to specify any additional information (e.g. beyond expiration date, batch and lot tested and found to be within specifications). Additional information concerning the indication for the drug, which cannot be described in data element B.4.k.11 ‘Indication for use in the case’ should also be provided as applicable in the data element B.4.k.19. · Along with the resulting suspected adverse reactions, an appropriate MedDRA term should be provided in section B.2 ‘Reactions/events’ where applicable in line with the latest version of the Guide for MedDRA Users, MedDRA Term Selection: Points to Consider49. · Data elements B.5.3 ‘Sender’s diagnosis/syndrome and/or reclassification of reaction/event’ can also be used to combine reported signs and symptoms into a succinct diagnosis, or to provide the sender’s assessment of the drug role, with a reasoning included in the data element B.5.4 ‘Sender’s comments’. |
| ICH-E2B(R3) | · As a general principle, additional characteristics related to the medicines and pertinent to the case should be coded and further information provided in free text. · Data element G.k.10.r ‘Additional Information on Drug (coded)’ should be completed using one or more of the following values as applicable: Counterfeit, Overdose, Drug taken by father, Drug taken beyond expiry date, Batch and lot tested and found within specifications, Batch and lot tested and found not within specifications, Medication error, Misuse, Abuse, Occupational exposure, or Off label use. The value(s) should be used where the primary source has made a clear statement related to the additional characteristics of the drug. · Along with the resulting suspected adverse reactions, an appropriate MedDRA term should be provided in section E.i ‘Reaction(s)/Event(s)’ (where applicable in line with the latest version of the Guide for MedDRA Users, MedDRA Term Selection: Points to Consider49. · Section H.3.r ‘Sender’s Diagnosis’ can also be used to combine reported signs and symptoms into a succinct diagnosis, or to provide the sender’s assessment of the drug role, with a reasoning included in the data element H.4 ‘Sender’s comments’. If the primary source did not provide an explicit statement about the drug characterisation which would clearly transpose into a MedDRA term in the reaction section but there is an indication in the context of the clinical course description, the sender may also choose the most applicable value(s) of G.k.10.r ‘Additional Information on Drug (coded)’ at their discretion. The case should be followed-up to obtain further information. · Data element G.k.11 ‘Additional Information on Drug (free text)’ should be used to capture any additional drug information in free text format not described in G.k.10.r, e.g. expiry date for the lot number. |
| Reference | E2B(R2)/(R3) requirements | |
| Definitions for data element G.k.10.r ‘Additional Information on Drug (coded)’. Note: for overdose, off-label use, misuse, abuse, occupational exposure, medication error, the definitions in VI.A.1.2. should be applied. | ||
| Counterfeit50 | This is to indicate that the medicine was suspected or confirmed to be a falsified medicinal product in line with the definition provided in Article 1(33) of Directive 2001/83/EC. | |
| Drug taken beyond expiry date | This is to indicate that the medicine administered to or taken by the patient was beyond its expiry date as indicated in the product information or on the packaging of the medicine. | |
| Batch and lot tested and found within specifications | This is to indicate that a batch or lot of a medicine was tested and found within the specifications of the marketing authorisation. | |
| Batch and lot tested and found not within specifications | This is to indicate that a batch or lot of a medicine was tested and found outside the specifications of the marketing authorisation. | |
| Drug taken by father | This is to indicate that suspect drug was taken by the father for cases describing miscarriage, stillbirth or early spontaneous abortion. In this situation only a mother report is applicable and the data elements in Section D ‘Patient Characteristics’ apply to the mother (see VI.C.6.2.3.1. for guidance on the electronic submission of pregnancy ICSRs). | |
VI.C.6.2.2.3. Suspected adverse reactions
In line with Article 28(3)(j) of the Commission Implementing Regulation (EU) No 520/2012, all available information on the reported suspected adverse reactions shall be provided for each individual case. Examples of relevant information include: the start and end date or duration, seriousness, outcome at the time of last observation, time intervals between the suspect medicinal product administration and the start of the reactions, the original reporter’s words or short phrases used to describe the reactions, the country of occurrence of the reactions.
The coding of diagnoses and provisional diagnoses with signs and symptoms should be performed with the supported versions51 of the MedDRA dictionary used at the lowest level term (LLT) level and in line with the applicable recommendations provided in the latest version of the Guide for MedDRA Users, MedDRA Term Selection: Points to Consider (see GVP Annex IV).
In practice, if a diagnosis is reported with characteristic signs and symptoms, the preferred option is to select a term for the diagnosis only and to MedDRA code it. If no diagnosis is provided, all reported signs and symptoms should be listed and MedDRA-coded. If these signs and symptoms are typically part of a diagnosis, the diagnosis can be MedDRA-coded in addition in the ICSR by the competent authority in the Member State or by the marketing authorisation holder as part of the sender’s diagnosis and sender’s comment.
If in the narrative other events have been reported, which are not typically signs or symptoms of the primary source’s diagnosis or provisional diagnosis, and those events are suspected to be adverse reactions, they should also be listed and MedDRA-coded.
Where a competent authority in a Member State or a marketing authorisation holder disagrees with the diagnosis reported by the primary source, an alternative diagnosis can be provided in addition as part of the sender’s diagnosis. In this situation, reasoning should be included as sender’s comment (see VI.C.6.2.2.4. for guidance on the provision of comments in ICSRs).
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Section B.2 ‘Reaction(s)/event(s)’ should be completed in line with the EudraVigilance Business Rules52, including the data element B.2.i.1 ‘Reaction/event in MedDRA terminology (Lowest Level Term)’. · Data element B.5.3 ‘Sender’s diagnosis/syndrome and/or reclassification of reaction/event’ should be used where the sender would like to combine reported signs and symptoms into a succinct diagnosis. Reasoning should be included in the data element B.5.4 ‘Sender’s comments’. · Data element B.5.3 ‘Sender’s diagnosis/syndrome and/or reclassification of reaction/event’ should also be used, if there is disagreement with the diagnosis reported by the primary source and to provide an alternative diagnosis. Reasoning should be included in the in the data element B.5.4 ‘Sender’s comments’. |
| ICH-E2B(R3) | · Section E.i ‘Reaction(s)/Event(s)’ should be completed in line with the EU Individual Case Safety Report (ICSR) Implementation Guide53, including the data element E.i.2.1b ‘Reaction/Event (MedDRA code)’. · Section H.3.r ‘Sender’s Diagnosis’ should be used where the sender would like to combine reported signs and symptoms into a succinct diagnosis. Reasoning should be included in the data element H.4 ‘Sender’s Comments’. · Section H.3.r ‘Sender’s Diagnosis’ should also be used, if there is disagreement with the diagnosis reported by the primary source and to provide an alternative diagnosis. Reasoning should be included in the in the data element H.4 ‘Sender’s Comments’. |
In the event of death of the patient, the date, cause of death including autopsy-determined causes shall be provided as available [IR 28 (3) (l)]. The recommendation provided in the EudraVigilance Business Rules54 and the EU Individual Case Safety Report (ICSR) Implementation Guide55 should be followed with regard to the provision in the ICSR of information on the patient’s death. If the death is unrelated to the reported suspected adverse reaction(s) and is linked for example to disease progression, the seriousness criterion should not be considered as fatal.
VI.C.6.2.2.4. Case narrative, comments and causality assessment
a. Case narrative
In accordance with Article 28 (3)(m) of the Commission Implementing Regulation (EU) No 520/2012, a case narrative shall be provided, where possible56 , for all cases with the exception of non-serious cases. The information shall be presented in a logical time sequence, in the chronology of the patient’s experience including clinical course, therapeutic measures, outcome and follow-up information obtained. Any relevant autopsy or post-mortem findings shall also be summarised.
The narrative should be presented in line with the recommendations detailed in ICH-E2D (see GVP Annex IV).It should serve as a comprehensive, stand-alone “medical report” containing all known relevant clinical and related information, including patient characteristics, therapy details, medical history, clinical course of the events, diagnoses, adverse reactions and their outcomes, relevant laboratory evidence (including normal ranges) and any other information that supports or refutes the suspected adverse reactions (see VI.C.6.2.2.11. for EU guidance on languages management in ICSRs). With regard to the identifiability of the patient, information should be provided in accordance with local data protection laws (see VI.C.6.2.2.10. for guidance on the processing of personal data in the EU). Case narratives should not include information that could lead to the identification of the patient, including references to healthcare professionals or treatment centres.
An example of a standard narrative template is available in the Report of the CIOMS Working Group V57 .
The information provided in the narrative should be consistent with the data appropriately reflected in all the other relevant ICH-E2B data elements of the ICSR. In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Section B.5 ‘Narrative case summary and further information’ should be used and the data element B.5.1 ‘Case narrative including clinical course, therapeutic measures, outcome and additional relevant information’ completed. |
| ICH-E2B(R3) | Section H ‘Narrative Case Summary and Further Information’ should be used and the data element H.1 ‘Case Narrative Including Clinical Course, Therapeutic Measures, Outcome and Additional Relevant Information’ completed. |
b. Comments
Where available, comments from the primary source should be provided on the diagnosis, the causality assessment, or on other relevant issues in the following ICH-E2B data elements:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Data element B.5.2 ‘Reporter’s comments’. |
| ICH-E2B(R3) | Data element H.2 ‘Reporter’s Comments’. |
The competent authority in a Member State and the marketing authorisation holder may provide an assessment of the case and describe a disagreement with, and/or alternatives to the diagnoses given by the primary source (see VI.C.6.2.2.3. for guidance on the processing of suspected adverse reactions in ICSRs). Discrepancies or confusions in the information notified by the primary source may also be highlighted. Where applicable, a summary of the points of concerns and the actions proposed should also be included in the ICSR when it leads to the notification of an emerging safety issue (see VI.C.2.2.6. for guidance on emerging safety issue). In line with ICHE2B this information should be provided in the following data elements:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Data element B.5.4 ‘Sender’s comments’. |
| ICH-E2B(R3) | Data element H.4 ‘Sender’s Comments’. |
c. Causality assessment
The degree of suspected relatedness of each medicinal product to each reported adverse reaction can be presented in a structured manner in the ICSR. It can be expressed for multiple sources (reporters, competent authorities, marketing authorisation holders) while using multiple methods of causality assessment. In line with ICH-E2B this information should be provided in the following sections:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Section B.4.k.18 ‘Relatedness of drug to reaction(s)/event(s)’. The data elements of this section should be repeated as applicable to provide the assessment of relatedness of each drug-reaction pair expressed by multiple sources and with multiple methods of assessment. |
| ICH-E2B(R3) | Section G.k.9.i ‘Drug-reaction(s)/Event(s) Matrix’. The data elements of this section should be repeated as applicable to provide the assessment of relatedness of each drug-reaction pair expressed by multiple sources and with multiple methods of assessment. |
VI.C.6.2.2.5. Test results
In accordance with the requirements provided in Article 28(3)(k) of the Commission Implementing Regulation (EU) No 520/2012, information on the results of tests and procedures relevant to the investigation of the patient shall be provided in the ICSR. This includes tests and procedures performed to diagnose or confirm the reaction/event, including those tests done to investigate (exclude) a nondrug cause, (e.g. serologic tests for infectious hepatitis in suspected drug-induced hepatitis). Both positive and negative results should be included in the ICSR.
The coding of investigations should be performed in line with the latest version of the Guide for MedDRA Users, MedDRA Term Selection: Points to Consider (see GVP Annex IV). If it is not possible to provide information on tests and test results in a structured manner, provisions have been made to allow for the presentation of the information in free text.
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Section B.3 ‘Results of tests and procedures relevant to the investigation of the patient’ should be completed and the data elements repeated as applicable. · Data element B.3.1 ‘Structured information’ should be used to structure the information on the test, the result and unit, the date the test was performed, and the normal low and high range. Where several tests or procedures were performed, the data element should be repeated as necessary. · Data element B.3.2 ‘Results of tests and procedures relevant to the investigation’ should be used to provide information on tests and procedures, which cannot be captured in data element B.3.1. |
| ICH-E2B(R3) | · Section F.r ‘Results of tests and procedures relevant to the investigation of the patient’ should be used to structure the information on the date the test was performed (data element F.r.1 ‘Test date’), the test (section F.r.2 ‘Test name’), the outcome (section F.r.3 ‘Test result’) and the normal low (data element F.r.4 ‘Normal low value’) and normal high (data element F.r.5 ‘Normal high value’). · Data element F.r.2.1 ‘Test Name (free text)’ should be used for the description of a test when an appropriate MedDRA code is unavailable for use in data element F.r.2.2b ‘Test Name (MedDRA code)’. · Data element F.r.3.4 ‘Result Unstructured Data (free text)’ should be used when the data elements F.r.3.1 ‘Test results (code)’, F.r.3.2 ‘Test results (value / qualifier) and F.r.3.3 ‘Test result (unit)’ cannot be used (often because a Unified Code for Units of Measure (UCUM) code is not available for the test unit). · Data elements F.r.4 ‘Normal low value’ and F.r.5 ‘Normal high value’ should be used to capture the lowest and highest values in the normal range for the test. The same units as used in F.r.3.3 are implied. · Data element F.r.6 ‘Comments (free text)’ should be used to capture any relevant comments made by the reporter about the test result. · A separate block (r) should be used for each test/procedure. |
VI.C.6.2.2.6. Supplementary records/information
Key information from supplementary records should be provided in the relevant section of the ICSR, and their availability should be mentioned in the E2B section ‘Additional Available Documents Held by Sender’. Provision has been made in ICH-E2B(R3) format for the electronic submission of documents as attachments to the ICSR message itself. This option is not available in ICH-E2B(R2) and requested documents should be sent separately as specified in the request.
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Section A.1.8 ‘Additional available documents held by sender’ should be completed as applicable. |
| ICH-E2B(R3) | · Data element C.1.6.1 ‘Are Additional Documents Available’ should be completed. · Section C.1.6.1.r ‘Documents Held by Sender’ should be completed as applicable, where the data element C.1.6.1.r.1 ‘Documents Held by Sender’ should provide a description of the nature of documents (e.g. clinical records, hospital records, autopsy reports) and C.1.6.1.r.2 ‘Included Documents’ should contain the actual attached document, if the sender chooses to send the document or is required to do so. The processing of personal data should be done in accordance with local data protection law (see VI.C.6.2.2.10. for guidance on the processing of personal data in the EU). |
Other known case identifiers relevant for the detection of duplicates should be presented systematically in ICSRs in the following section in line with ICH-E2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Section A.1.11 ‘Other case identifiers in previous transmissions’. |
| ICH-E2B(R3) | Section C.1.9.1 ‘Other case identifiers in previous transmissions’. |
VI.C.6.2.2.7. Follow-up information
In addition to the general principles provided in VI.B.3., the following guidance should be followed concerning the management of follow-up information on ICSRs.
ICSRs are sent at different times to multiple receivers. Therefore the initial/follow-up status for a report is dependent upon the receiver. For this reason an item to capture follow-up status is not included in ICH-E2B. However, the date of receipt of the most recent information taken together with the worldwide unique case identification number and the sender’s identifier provide a mechanism for each receiver to identify whether the report being transmitted is an initial or a follow-up report. These items are therefore considered critical for each submission and a precise date should always be used (i.e. day, month, year).
In this context, the date of receipt of the most recent information should always be updated each time follow-up information is received by a competent authority or a marketing authorisation holder, irrespective whether the follow-up information is significant enough to be submitted. The worldwide unique case identification number of the initial ICSR should be maintained and the date the report was first received from a reporter should remain unchanged to the date the competent authority or the marketing authorisation holder became aware of the initial report.
When an organisation (competent authority or marketing authorisation holder) is receiving follow-up information on a case initially received and submitted to the EudraVigilance database by a different organisation, the worldwide unique case identification number of the initial report submitted by the first organisation should be preserved in the subsequent submissions of the ICSR. In line with ICH E2B, the sender’s (case) safety report unique identifier and the sender’s identifier should be updated with the new organisation’s own unique identifiers.
New follow-up information should always be clearly identifiable in the case narrative (required for serious reports of suspected adverse reactions) and should also be captured in structured format as applicable.
In line with ICH-E2B the following data elements/sections should always be completed for follow-up ICSRs submission:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Data element A.1.0.1 ‘Sender’s (case) safety report unique identifier’. · Data element A.1.6 ‘Date report was first received from source’ (which should remain unchanged). · Data element A.1.7 ‘Date of receipt of the most recent information for this report’. · Data element A.1.10 ‘Worldwide unique case identification number’ (which should remain unchanged). · Data element A.3.1.2 ‘Sender identifier’. · Data element B.5.1 ‘Case narrative including clinical course, therapeutic measures, outcome and additional relevant information’ (for serious reports of suspected adverse reactions). |
| ICH-E2B(R3) | · Data element C.1.1 ‘Sender’s (case) Safety Report Unique Identifier’. · Data element C.1.4 ‘Date Report Was First Received from Source’ (which should remain unchanged). · Data element C.1.5 ‘Date of Most Recent Information for this Report’. · Section C.1.8 ‘Worldwide Unique Case Identification’ (which should remain unchanged). · Data element C.3.2 ‘Sender’s organisation’. · Data element H.1 ‘Case narrative including clinical course, therapeutic measures, outcome and additional relevant information’ (for serious reports of suspected adverse reactions). |
a. Significant information
Competent authorities in Member States or marketing authorisation holders should submit followup ICSRs if significant new medical information has been received. Significant new information relates to, for example, a new suspected adverse reaction, a change in the causality assessment, and any new or updated information on a case that impacts on its medical interpretation. Medical judgement should therefore be applied for the identification of significant new information requiring to be submitted as follow-up ICSR.
Situations where the seriousness criteria and/or the causality assessment are downgraded (e.g. the follow-up information leads to a change of the seriousness criteria from serious to non-serious, or the causality assessment is changed from related to non-related) should also be considered as significant changes and thus submitted as ICSR (see VI.C.3. for ICSRs submission time frames).
In addition, the competent authority in a Member State or the marketing authorisation holder should also submit a new version of an ICSR, when new administrative information is available, that could impact on the case management. For example, if new case identifiers have become known to the sender, which may have been used in previous submissions. This information may be specifically relevant to manage potential duplicates. In this context, the following sections should be completed in line with ICH-E2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Section A.1.11 ‘Other case identifiers in previous transmissions’. |
| ICH-E2B(R3) | Section C.1.9.1 ‘Other case identifiers in previous transmissions’. |
Another example refers to additional documents held by sender, whereby new documents that have become available to the sender may be relevant for the medical assessment of the case. In this regard, the following sections should be completed in line with ICH-E2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Section A.1.8 ‘Additional available documents held by sender’. |
| ICH-E2B(R3) | Section C.1.6 ‘Additional Available Documents Held by Sender’. |
b. Non-significant information
In contrast, a follow-up report which contains non-significant information does not require to be submitted as ICSR. This may refer, for example, to minor changes to some dates with no implication for the evaluation or submission of the case, or to some corrections of typographical errors in the previous case version. Medical judgement should be applied since a change to the birth date may constitute a significant modification (e.g. with implications on the age information of the patient). Similarly, a change of the status of a MedDRA code/term from current to noncurrent, due to a version change of MedDRA, can be considered as a non-significant change as long as this change has no impact on the medical content of a case.
VI.C.6.2.2.8. Amendment of cases
General guidance is provided in VI.B.7.3.. Serious and non-serious cases which have already been submitted to EudraVigilance may need to be amended when, after an internal review or according to an expert opinion some items have been corrected, without receipt of new information that would warrant for the submission of a follow-up report.
Where the amendment significantly impacts on the medical evaluation of the case, an ICSR should be resubmitted and information on the amendment should be explained in the case narrative. For example, an amendment of the MedDRA coding due to a change in the interpretation of a previously submitted ICSR may constitute a significant change and therefore should be resubmitted as amendment report (see VI.C.6.2.2.7. Subsection a and b for examples of significant and nonsignificant information).
Additionally, for reports for which cases translations should be provided by a marketing authorisation holder when requested by the Agency or another Member State (see VI.C.6.2.2.11. for EU guidance on anguages management in ICSRs), the translations should be submitted in the form of amendment reports. The same applies where documentations or articles mentioned in the ICSRs are requested by the Agency or another Member State and are further sent as attachments in data element ICH E2B(R3) C.4.r.2 ‘Included documents’ (the attachment of document is not available under the ICH E2B(R2) format).
New received information (significant or non-significant) should be considered as follow-up report and not as amendment report and in this context, the guidance provided in VI.C.6.2.2.7. should be followed.
In line with ICH-E2B the following applies for the submission of amendment ICSRs:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | The possibility of flagging an ICSR as amendment report is not supported under the ICH-E2B(R2) format. Where the amendment of an ICSR is necessary, the same principles as for a follow-up report should be applied as follows: · Data element A.1.0.1 ‘Sender’s (case) Safety Report Unique Identifier’ should remain unchanged. · Data element A.1.6 ‘Date report was first received from source’ should remain unchanged. · Data element A.1.7 ‘Date of receipt of the most recent information for this report’ should remain unchanged. · Data element A.1.10 ‘Worldwide Unique Case Identification Number’ should remain unchanged. · Data element A.3.1.2 ‘Sender identifier’ should remain unchanged. · Information on the amendment should be identifiable in the case narrative (data element B.5.1). It should be noted that amendment ICSRs submitted in the ICH-E2B(R2) format will appear as “late reports” in the compliance monitoring performed by the Agency (see VI.C.6.2.4. for guidance on ICSRs data quality) if they are submitted beyond the 15 or 90 days submission time frames since the date of receipt of the most recent information should remain unchanged. |
| ICH-E2B(R3) | · Data element C.1.1 ‘Sender’s (case) Safety Report Unique Identifier’ should remain unchanged. · Data element C.1.4 ‘Date Report Was First Received from Source’ should remain unchanged. · Data element C.1.5 ‘Date of Most Recent Information for This Report’ should remain unchanged. · Section C.1.8 ‘Worldwide Unique Identifier’ should remain unchanged. · Data element C.1.11.1 ‘Report Nullification/Amendment’ should be set to ‘Amendment’. · Data element C.1.11.2 ‘Reason for Nullification/Amendment’ should be completed to indicate the reason why a previously transmitted ICSR is amended. · Data element C.3.2 ‘Sender’s organisation’ should remain unchanged. · Information on the amendment should be identifiable in the case narrative (data element H.1). ICSRs set as amendment reports in the ICH-E2B(R3) format are not considered in the compliance monitoring performed by the Agency. They will be however monitored as part of the regular review of the ICSRs quality and integrity conducted by the Agency (see VI.C.6.2.4. for guidance on ICSRs data quality). This is to ensure that they have not been misclassified by the sending organisation as amendment reports instead of follow-up reports which should be taken into account in the compliance monitoring. |
VI.C.6.2.2.9. Nullification of cases
In line with ICH-E2B (see GVP Annex IV), the nullification of individual cases should be used to indicate that a previously transmitted report should be considered completely void (nullified), for example when the whole case was found to be erroneous or in case of duplicate reports.
The following principles should be followed:
- The nullification reason should be clear and concise to explain why this case is no longer considered to be a valid report. For example a nullification reason stating, ‘the report no longer meets the criteria for submission’ or ‘report sent previously in error’ are not detailed enough explanations;
- An individual case can only be nullified by the original sending organisation;
- Once an individual case has been nullified, the case cannot be reactivated;
- Individual versions (i.e. follow-up reports) of a case cannot be nullified, only the entire individual case to which they refer;
- A nullified case is one that should no longer be considered for scientific evaluation. The process of the nullification of a case is by means of a notification by the sender to the receiver that this is no longer a valid case. However, the case should be retained in the sender’s and receiver’s pharmacovigilance database for auditing purposes.
In line with ICH-E2B the following applies for nullified ICSRs submission:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Data element A.1.0.1 ‘Sender’s (case) Safety Report Unique Identifier’ should remain unchanged. · Data element A.1.6 ‘Date report was first received from source’ should remain unchanged. · Data element A.1.7 ‘Date of receipt of the most recent information for this report’ should either reflect the date when information was received that warrants the nullification of the report or otherwise should remain unchanged. · Data element A.1.10 ‘Worldwide unique case identification number’ should remain unchanged. · Data element A.1.13 ‘Report nullification’ should be set to “Yes”. · Data element A.1.13.1 ‘Reason for nullification’ should be completed to indicate the reason why a previously transmitted ICSR is considered completely void. · Data element A.3.1.2 ‘Sender identifier’ should remain unchanged. |
| ICH-E2B(R3) | · Data element C.1.1 ‘Sender’s (case) Safety Report Unique Identifier’ (should remain unchanged. · Data element C.1.4 ‘Date Report Was First Received from Source’ should remain unchanged. · The data element C.1.5 ‘Date of Most Recent Information for This Report’ should either reflect the date when information was received that warrants the nullification of the report or otherwise should remain unchanged. · Data element C.1.8 ‘Worldwide Unique Identifier’ should remain unchanged. · Data element C.1.11.1 ‘Report Nullification/Amendment’ should be set to ‘Nullification’. · Data element C.1.11.2 ‘Reason for Nullification/Amendment’ should be completed to indicate the reason why a previously transmitted ICSR is considered completely void. · Data element C.3.2 ‘Sender’s organisation’ should remain unchanged. |
Examples of scenarios for which ICSRs should be nullified are provided in VI.App.5.
If it becomes necessary to resubmit the case that has been previously nullified the following should be considered in line with ICH-E2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | A new ‘Sender’s (case) safety report unique identifier’ (data element A.1.0.1) and a new ‘Worldwide unique case identification number’ (data element A.1.10) should be assigned. |
| ICH-E2B(R3) | A new ‘Sender’s (Case) Safety Report Unique Identifier’ (data element C.1.1) and a new ‘Worldwide Unique Case Identification’ (Section C.1.8) should be assigned. |
VI.C.6.2.2.10. Data protection laws
To detect, assess, understand and prevent adverse reactions and to identify, and take actions to reduce the risks of, and increase the benefits from medicinal products for the purpose of safeguarding public health, the processing of personal data concerning the patient or the primary source within the EudraVigilance database is possible while respecting EU legislation in relation to data protection (Directive 95/46/EC, and Regulation (EC) No 45/2001).
Where in accordance with the applicable national legislation, the patient’s direct identifiers cannot be transferred to the EudraVigilance database, pseudonymisation may be applied by the competent authority in the Member State and by the marketing authorisation holder, thereby replacing identifiable personal data such as name and address with pseudonyms or key codes, for example in accordance with the ISO Technical Specification DD ISO/TS 25237:2008, Health informatics – Pseudonymization [IR Recital 17]. The application of pseudonymisation will facilitate the ability of the EudraVigilance system to adequately support case processing and detect duplicates. Alternatively where pseudonymisation is not feasible, the following may be applied in line with ICH-E2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | In certain data elements which can identify an individual such as in the reporter’s name, initials, address, or in the patient’s name, initials, medical record number, where the information cannot be transmitted for data protection reasons, the data element should be populated with the value ‘PRIVACY’, in line with the EudraVigilance business rules detailed in the Note for guidance – EudraVigilance Human – Processing of Safety Messages and Individual Case Safety Reports (ICSRs) (EMA/H/20665/04/Final Rev. 2). |
| ICH-E2B(R3) | The nullFlavor ‘MSK’ (see VI.A.1.8. for definition of nullFlavor) should be used if personal information is available but cannot be provided by the sender due to local protection legislation. It informs the receiver that the information does exist without providing personal details such as birth date or name. See EU Individual Case Safety Report (ICSR) Implementation Guide (EMA/51938/2013) for ICH-E2B(R3) sections/data elements where the use of the nullFlavor ‘MSK’ is not permitted. |
Pseudonymisation or the use of the nullFlavor ‘MSK’ should be applied without impairing the information flow in the EudraVigilance database and the interpretation and evaluation of safety data relevant for the protection of public health; given the high-level nature of the information, data elements such as patient’s age, age group and gender should in principle be kept un-redacted/visible.
VI.C.6.2.2.11. Handling of languages
The electronic submission of ICSRs is based on the fact that structured and coded information is used for data outputs of pharmacovigilance systems (e.g. listings) and for signal detection. However, for scientific case assessment and signal evaluation a medical summary is normally required (see VI.6.2.2.4. for guidance on case narrative).
Where suspected adverse reactions are reported by the primary source in narrative and textual descriptions in an official language of the Union other than English, the original verbatim text and the summary thereof in English shall be provided by the marketing authorisation holder [IR 28 (4)]. In practice, the original verbatim text reported by the primary source in an official language of the Union other than English should be included in the ICSR, if it is requested by the Member State where the reaction occurred or by the Agency. The ICSR should be completed and submitted in English if not otherwise requested.
Member States may report case narratives in their official language(s). For those reports, case translations shall be provided when requested by the Agency or other Member States for the evaluation of potential signals. For suspected adverse reactions originating outside the EU, English shall be used in the ICSR [IR 28 (4)].
Additional documents held by the sender, which may be only available in a local language, should only be translated if requested by the receiver.
When requested by a Member State or the Agency, the following applies in line with ICH-E2B for the provision of the original verbatim text in an official language of the Union other than English for the suspected adverse reaction and the additional description of the case:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Data element B.5.1 ‘Case narrative including clinical course, therapeutic measures, outcome and additional relevant information’ should be used to capture – the original verbatim text for the suspected adverse reactions, – the reporter’s description and comments for the case in the original language (if provided), – the English summary of the case. |
| ICH-E2B(R3) | · Data element E.i.1.1a ‘Reaction / Event as reported by the primary source in Native Language’ should be completed with the original verbatim text for the suspected adverse reactions. · Data element E.i.1.1b ‘Reaction / event as reported by the primary source language’ should provide information on the language used in E.i.1.1a. · Data element E.i.1.2 ‘Reaction / event as reported by the primary source for translation’ should provide the translation in English of the original reporter’s words used to describe the suspected adverse reactions. · Data element H.1 ‘Case narrative including clinical course, therapeutic measures, outcome and additional relevant information’ should be used to provide the English summary of the case. · Section H.5.r ‘Case Summary and Reporter’s Comments in Native Language (repeat as necessary)’ should be used to capture the reporter’s description and comments for the case in the original verbatim text (if provided). |
VI.C.6.2.3. Special situations
VI.C.6.2.3.1. Use of a medicinal product during pregnancy or breastfeeding
General principles provided in VI.B.6.1. should be followed.
With regard to the electronic submission of parent-child/foetus cases, the following should be adhered to for the creation of ICSRs depending on the situation. This is in addition to the recommendations included in the latest version of the Guide for MedDRA Users, MedDRA Term Selection: Points to Consider for the provision of the appropriate reaction/event terms in line with ICH-E2B.
a. The child/foetus experiences suspected adverse reactions other than early spontaneous abortion/foetal demise:
When the child or foetus, exposed to one or several medicinal products through the parent, experiences one or more suspected adverse reactions other than early spontaneous abortion/foetal demise, information on both the parent and the child/foetus should be provided in the same report. This case is referred to as a parent-child/foetus report. The information provided for the patient’s characteristics applies only to the child/foetus. The characteristics concerning the mother or father, who was the source of exposure to the suspect medicinal product, should be captured as part of the information concerning the parent. If both parents are the source of the suspect drug(s), the structured parent information in the case should reflect the mother’s characteristics; information regarding the father should be provided in the narrative together with all other relevant information.
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Section B.1 ‘Patient characteristics’ should be completed for the child/foetus. · Section B.1.10 ‘For a parent-child/foetus report, information concerning the parent’ should be completed for the mother or the father as applicable. · Data element B.5.1 ‘Case narrative including clinical course, therapeutic measures, outcome and additional relevant information’ should be used to provide the medical summary for the entire case and where both parents are the source of the suspected drug(s), the father’s characteristics should be also reflected here. |
| ICH-E2B(R3) | · Section D ‘Patient Characteristics’ should be completed for the child/foetus. · Section D.10 ‘For a Parent-child/Foetus Report, Information Concerning the Parent’ should be completed for the mother or the father as applicable. · Data element H.1 ‘Case Narrative Including Clinical Course, Therapeutic Measures, Outcome and Additional Relevant Information’ should be used to provide the medical summary for the entire case and where both parents are the source of the suspected drug(s), the father’s characteristics should be also reflected here. |
b. Both the parent and child/foetus experience suspected adverse reactions:
When the parent and the exposed child/ foetus experience suspected adverse reactions other than early spontaneous abortion/foetal demise, two separate reports, i.e. one for the parent (mother or father) and one for the child/foetus, should be created. Both reports should be linked to identify cases that warrant being evaluated together by using the following data element in line with ICHE2B:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Data element A.1.12 ‘Identification number of the report which is linked to this report’. |
| ICH-E2B(R3) | Data element C.1.10.r ‘Identification Number of the Report Linked to this Report (repeat as necessary)’. |
c. No reaction is affecting the child/foetus:
When no reaction is reported for the exposed child/foetus, the parent-child/foetus report does not apply. Only a parent report should be created to describe the child exposure to the medicinal product. The patient characteristics refer only to the parent (mother or father) who may as well experience adverse reactions with the suspected medicinal product. Reports with no reaction should not be submitted as ICSRs (see VI.B.6.1. for general guidance on the management of these reports).
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Section B.1 ‘Patient characteristics’ should be completed for the mother or father as applicable. |
| ICH-E2B(R3) | Section D ‘Patient Characteristics’ should be completed for the mother or father as applicable. |
d. Miscarriage or early spontaneous abortion is reported:
When miscarriage or early spontaneous abortion is reported, only a parent report is applicable with the patient’s characteristics to be provided for the mother. However, if the suspect medicinal product was taken by the father, this information should also be recorded.
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Section B.1 ‘Patient characteristics’ should be completed for the characteristics of the mother. · The data element B.4.k.19 ‘Additional information on drug’ should be completed if suspect drug(s) were taken by the father. |
| ICH-E2B(R3) | · Section D ‘Patient Characteristics’ should be completed for the characteristics of the mother. · Data element G.k.10.r ‘Additional Information on Drug (coded)’ should be completed if the suspect drug was taken by the father. The value to be selected is ‘Drug taken by father’. Guidance on the use of data element G.k.10.r is provided in VI.C.6.2.2.2. Subsection f. |
VI.C.6.2.3.2. Suspected adverse reaction reports published in the medical literature
EU requirements in relation to the monitoring of suspected adverse reactions reported in the medical literature are provided in VI.C.2.2.3.1.. With regard to the electronic submission of ICSRs published in the medical literature, the following should be followed:
The literature references shall be provided in the Vancouver Convention (known as “Vancouver style”), developed by the International Committee of Medical Journal Editors [IR Art 28 (3) (b)]58 .
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · The data element A.2.2 ‘Literature reference(s)’ should be populated with the literature reference. The Digital Object Identifier (DOI) for the article should be included where available, e.g.: “International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. N Engl J Med 1997; 336:309-15. doi:10.1056/NEJM199701233360422” |
| ICH-E2B(R3) | · Data element C.4.r.1 ‘Literature Reference(s)’ should be populated with the literature reference. The Digital Object Identifier (DOI) for the article should be included where available e.g.:” International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. N Engl J Med 1997; 336:309-15. doi:10.1056/NEJM199701233360422” |
In accordance with Article 28(3) (b) of the Commission Implementing Regulation (EU) No 520/2012, a comprehensive English summary of the article shall be provided in the following ICH-E2B data element/section:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Data element B.5.1 ‘Case narrative including clinical course, therapeutic measures, outcome and additional relevant information’. |
| ICH-E2B(R3) | Data element H.1 ‘Case narrative including clinical course, therapeutic measures, outcome and additional relevant information’. |
Upon request of the Agency, for specific safety review, a full translation in English and a copy of the relevant literature article shall be provided by the marketing authorisation holder that transmitted the initial report, taking into account copyright restrictions [IR 28(3)].
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | The guidance detailed in VI.App2.10, regarding the mailing of the literature article, should be adhered to. |
| ICH-E2B(R3) | The electronic version of the document (i.e. the journal article and a copy of the translation where applicable) should be attached to the ICSR in data element C.4.r.2 ‘Included Documents’. · If the article and/or translation are not provided at the time of the ICSR submission, attachments can be transmitted separately. In this situation, the original ICSR along with all the same medical information captured in the E2B(R3) data elements should be retransmitted as an ‘amendment’ report (see VI.C.6.2.2.8. for guidance on amendment reports). However if new additional information is provided, then the ICSR with the attachment should be submitted as a follow-up report. |
Guidance presented in VI.App2.10., for the submission of several individual cases when they are presented in the same literature article, should be followed.
VI.C.6.2.3.3. Suspected adverse reactions related to overdose, abuse, off-label use, misuse, medication error or occupational exposure
General principles detailed in VI.B.6.3. should be followed. Further guidance on the management of individual reports of off-label use is provided in VI.C.2.2.12.
Along with the resulting suspected adverse reactions, an appropriate MedDRA LLT term corresponding most closely to the description of the reported overdose, abuse, off-label use, misuse, medication error or occupational exposure should be specified in the ICH-E2B section ‘Reactions/Events’. This should be done in accordance with the applicable recommendations given in the latest version of the Guide for MedDRA Users, MedDRA Term Selection: Points to Consider, while respecting the definitions provided in VI.A.1.2.
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements | |
| ICH-E2B(R2) | · As a general principle, additional characteristics related to the medicines and pertinent to the case should be coded and further information provided in free text. · Data element B.4.k.2.1 ‘Proprietary medicinal product name’ and/or B.4.k.2.2 ‘Active substance name(s)’ should be completed in accordance with the information reported by the primary source (see VI.C.6.2.2.2. for guidance on suspect, interacting and concomitant medicinal products). · Data element B.4.k.19 ‘Additional information on drug’ can be used to specify any additional information pertinent to the case (e.g. overdose, medication error, misuse, abuse, occupational exposure, off-label use). This data element can also be used to provide additional information concerning the indication for the drug not covered in data element B.4.k.11 ‘Indication for use in the case’. · An appropriate MedDRA terms should be provided for the drug characterisation in the data element B.2.i.1 ‘Reaction/event in MedDRA terminology (Lowest Level Term)’ along with the resulting suspected adverse reaction. If applicable, the data element B.5.3 ‘Sender’s diagnosis/syndrome and/or reclassification of reaction/event’ should be completed with a reasoning provided in the data element B.5.4 ‘Sender’s comments’. · If the primary source did not provide an explicit statement about the overdose, medication error, misuse, abuse, occupational exposure or off-label use, which would clearly transpose into a MedDRA term in the data element B.2.i.1 ‘Reaction/event in MedDRA terminology (Lowest Level Term)’, but there is an suggestion in the context of the clinical course description, the sender may provide that information in the data element B.5.3 ‘Sender’s diagnosis/syndrome and/or reclassification of reaction/event’ with a reasoning provided in the data element B.5.4 ‘Sender’s comments’. The case should be followed up to obtain further information. |
|
| ICH-E2B(R3) | · As a general principle, additional characteristics related to the medicines and pertinent to the case should be coded and further information provided in free text. · In addition to the mandatory data element G.k.2.2 ‘Medicinal Product Name as Reported by the Primary Source’, section G.k ‘Drug(s) Information’ should be completed in accordance with the information reported by the primary source (see VI.C.6.2.2.2. for guidance on suspect, interacting and concomitant medicinal products). · Data element G.k.10.r ‘Additional Information on Drug (coded)’ should be completed using one or more of the following values as applicable: overdose, medication error, misuse, abuse, occupational exposure, off label use. The value(s) should be used where the primary source has made a clear statement related to the additional characteristics of the drug. · An appropriate MedDRA terms should be provided for the drug characterisation in the data element E.i.2.1b ‘Reaction/Event (MedDRA code)’ along with the resulting suspected adverse reaction. If applicable, the section H.3.r ‘Sender’s Diagnosis’ should be completed with a reasoning provided in the data element H.4 ‘Sender’s comments’. · If the primary source did not provide an explicit statement about the overdose, medication error, misuse, abuse, occupational exposure or off label use, which would clearly transpose into a MedDRA term in the data element E.i.2.1b ‘Reaction/Event (MedDRA code)’, but there is an suggestion in the context of the clinical course description, the sender may choose the most applicable value(s) of G.k.10.r ‘Additional Information on Drug (coded)’. The case should be followed up to obtain further information. · Data element G.k.11 ‘Additional Information on Drug (free text)’ should be used to capture any additional drug information in free text format not described in G.k.10.r. · The data element G.k.1 ‘Characterisation of Drug Role’ should be populated with the value ‘Drug not administered’ for reports of medication error where the patient did not receive the actual prescribed drug but a different one, based on the information provided. There is no equivalent in ICH-E2B(R2). Sections G ‘Drug(s) Information’ should be completed with the information about the prescribed drug (including the fact that it was not administered), as well as the information on the dispensed drug as the ‘suspect’ drug. |
|
| Definitions for data element G.k.10.r ‘Additional Information on Drug (coded)’. | ||
| Overdose | This is to indicate that the medicine may have been subject to an overdose as defined in VI.A.1.2. | |
| Medication error | This is to indicate that the medicine may have been associated with a medication error as defined in VI.A.1.2. | |
| Misuse | This is to indicate that the medicine may have been associated with misuse as defined in VI.A.1.2. | |
| Abuse | This is to indicate that the medicine may have been associated with abuse as defined in VI.A.1.2. | |
| Occupational exposure | This is to indicate that the medicine may have been associated with occupational exposure as defined in VI.A.1.2. | |
| Off label use | This is to indicate that the medicine may have been associated with off label use as defined in VI.A.1.2. | |
VI.C.6.2.3.4. Lack of therapeutic efficacy
General principles are provided in VI.B.6.4.
If the primary source suspects a lack of therapeutic efficacy, the MedDRA LLT term, corresponding most closely to the description of the reported lack of therapeutic efficacy, should be specified in the ICSR in accordance with the recommendations given in the latest version of the Guide for MedDRA Users, MedDRA Term Selection: Points to Consider (see GVP Annex IV). In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | The appropriate MedDRA term should be provided in the data element B.2.i.1 ‘Reaction/event in MedDRA terminology (Lowest Level Term)’. |
| ICH-E2B(R3) | The appropriate MedDRA term should be provided in the data element E.i.2.1b ‘Reaction/Event (MedDRA code)’. |
Unless aggravation of the medical condition occurs, the indication for which the suspected medicinal product was administered should not be included in the ICH-E2B section ‘Reactions/Events’.
When the lack of therapeutic efficacy is reported with no suspected adverse reaction, the same submission modalities as for serious ICSRs (see VI.C.4. for ICSRs submission modalities in EU) should be applied for cases related to medicinal products detailed in VI.B.6.4., for which ISCRs submission is required (e.g. medicinal products used in critical conditions or for the treatment of life-threatening diseases, vaccines, contraceptives). The ISCRs should be submitted within a 15-day time frame even if no seriousness criterion is specified.
VI.C.6.2.3.5. Suspected adverse reactions related to quality defect or falsified medicinal products
EU requirements are provided in VI.C.2.2.4.. In order to be able to clearly identify cases related to quality defect or falsified medicinal products (see GVP Annex I) when they are exchanged between stakeholders, the following guidance should be applied:
a. Quality defect
Where a report of suspected adverse reactions is associated with a suspected or confirmed quality defect of a medicinal product, the MedDRA LLT term corresponding most closely to the product quality issue, should be added to the observed suspected adverse reaction(s) in accordance with the applicable recommendations given in the latest version of the Guide for MedDRA Users, MedDRA Term Selection: Points to Consider. In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements | |
| ICH-E2B(R2) | · As a general principle, additional characteristics related to the medicines and pertinent to the case should be coded and further information related to the quality defect provided in free text. · Data element B.4.k.2.1 ‘Proprietary medicinal product name’ and/or B.4.k.2.2 ‘Active substance name(s)’ should be populated in accordance with the information reported by the primary source (see VI.C.6.2.2.2. for guidance on suspect, interacting and concomitant medicinal products). · Data element B.4.k.19 ‘Additional information on drug’ should be used to specify any additional information pertinent to the case (e.g. beyond expiration date, batch and lot tested and found to be within/not within specifications). This data element can also be used to provide additional information concerning the indication for the drug not covered in data element B.4.k.11 ‘Indication for use in the case’. · An appropriate MedDRA term should be provided for the drug characterisation in the data element B.2.i.1 ‘Reaction/event in MedDRA terminology (Lowest Level Term)’ along with the resulting suspected adverse reaction. If applicable, the data element B.5.3 ‘Sender’s diagnosis/syndrome and/or reclassification of reaction/event’ should be completed with a reasoning provided in the data element B.5.4 ‘Sender’s comments’. |
|
| ICH-E2B(R3) | · As a general principle, additional characteristics related to the medicines and pertinent to the case should be coded and further information related to the quality defect provided in free text. · In addition to the mandatory data element G.k.2.2 ‘Medicinal Product Name as Reported by the Primary Source’, section G.k ‘Drug(s) Information’ should be completed in accordance with the information reported by the primary source (see VI.C.6.2.2.2. for guidance on suspect, interacting and concomitant medicinal products). · Data element G.k.10.r ‘Additional Information on Drug (coded)’ should be completed using one or more of the following values as applicable: drug taken beyond expiry date, batch and lot tested and found within specifications, batch and lot tested and found not within specifications. These values should be used where the primary source has made a clear statement related to the additional characteristics of the drug. · An appropriate MedDRA term should be provided for the drug characterisation in the data element E.i.2.1b ‘Reaction/Event (MedDRA code)’ along with the resulting suspected adverse reaction. If applicable, the section H.3.r ‘Sender’s Diagnosis’ should also be completed with a reasoning provided in the data element H.4 ‘Sender’s comments’. · Data element G.k.11 ‘Additional Information on Drug (free text)’ should be used to capture any additional drug information in free text format not described in G.k.10.r. |
|
| Definitions for data element ‘G.k.10.r Additional Information on Drug (coded)’ | ||
| Drug taken beyon dexpiry date | This is to indicate that the medicine administered to or taken by the patient was beyond its expiry date as indicated in the product information or on the packaging of the medicine. | |
| Batch and lot tested and found within specifications | This is to indicate that a batch or lot of a medicine was tested and found within the specifications of the marketing authorisation. | |
| Batch and lot tested and found not within specifications | This is to indicate that a batch or lot of a medicine was tested and was found outside the specifications of the marketing authorisation | |
b. Falsified medicinal products
Where a report of suspected adverse reactions is associated with a suspected or confirmed falsified excipient, active substance or medicinal product, the MedDRA LLT term corresponding most closely to the reported information should be added to the observed suspected adverse reaction(s) in accordance with the applicable recommendations given in the latest version of the Guide for MedDRA Users, MedDRA Term Selection: Points to Consider. Information on the suspected medicinal product, active substance(s) or excipient(s) should be also provided in line with the guidance in VI.C.6.2.2.2.
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements | |
| ICH-E2B(R2) | · As a general principle, additional characteristics related to the medicines and pertinent to the case should be coded and further information related to the falsified medicinal product provided in free text. · Data element B.4.k.2.1 ‘Proprietary medicinal product name’ and/or B.4.k.2.2 ‘Active substance name(s)’ should be populated in accordance with the information reported by the primary source (see VI.C.6.2.2.2. for guidance on suspect, interacting and concomitant medicinal products). · Data element B.4.k.19 ‘Additional information on drug’ should be used to specify any additional information pertinent to the case (e.g. falsified medicine, medicine purchased over the internet). This data element can also be used to provide additional information concerning the indication for the drug not covered in data element B.4.k.11 ‘Indication for use in the case’. · An appropriate MedDRA term should be provided for the drug characterisation in the data element B.2.i.1 ‘Reaction/event in MedDRA terminology (Lowest Level Term)’ along with the resulting suspected adverse reaction. If applicable, the data element B.5.3 ‘Sender’s diagnosis/syndrome and/or reclassification of reaction/event’ should be completed with a reasoning provided in the data element B.5.4 ‘Sender’s comments’. · If new information is received to confirm the product is not a counterfeit, the data element B.4.k.19 should be changed appropriately in a follow-up. If the product is confirmed as a counterfeit, the appropriate MedDRA code should be used in the data element ‘B.5.3 ‘Sender’s diagnosis/syndrome and/or reclassification of reaction/event’ with a reasoning provided in the data element B.5.4 ‘Sender’s comments’ and information should be provided in the case narrative. |
|
| ICH-E2B(R3) | · As a general principle, additional characteristics related to the medicines and pertinent to the case should be coded and further information related to the falsified medicinal product provided in free text. · In addition to the mandatory data element G.k.2.2 ‘Medicinal Product Name as Reported by the Primary Source’, section G.k ‘Drug(s) Information’ should be completed in accordance with the information reported by the primary source (see VI.C.6.2.2.2. for guidance on suspect, interacting and concomitant medicinal products). · Data element G.k.10.r ‘Additional Information on Drug (coded)’ should be completed using the following value ‘Counterfeit’ 59. The value should be used where the medicine is suspected or confirmed to be a falsified medicinal product. · An appropriate MedDRA term should be provided for the drug characterisation in the data element E.i.2.1b ‘Reaction/Event (MedDRA code)’ along with the resulting suspected adverse reaction. If applicable, the section H.3.r ‘Sender’s Diagnosis’ should be completed with a reasoning provided in the data element H.4 ‘Sender’s comments’. · If new information is received to confirm the product is not a counterfeit, the data element G.k.10.r should be changed appropriately in a follow-up. If the product is confirmed as a counterfeit, the appropriate MedDRA code should be used in the section H.3.r ‘Sender’s Diagnosis’ with a reasoning provided in the data element H.4 ‘Sender’s comments’ and information should be provided in the case narrative. · Data element G.k.11 ‘Additional Information on Drug (free text)’ should be used to capture any additional drug information in free text format not described in G.k.10.r (e.g. medicine purchased over the internet). |
|
| Definitions for data element G.k.10.r ‘Additional Information on Drug (coded)’ | ||
| Counterfeit59 | This is to indicate that the medicine was suspected or confirmed to be a falsified medicinal product in line with the definition provided in Article 1(33) of Directive 2001/83/EC. | |
VI.C.6.2.3.6. Suspected transmission via a medicinal product of an infectious agent
General guidance on the management of this type of reports in the EU is provided in VI.C.2.2.5.
The coding of a suspected transmission of an infectious agent via a medicinal product should be performed in line with the latest version of the Guide for MedDRA Users, MedDRA Term Selection: Points to Consider.
In addition, if the infectious agent is specified in the report, the MedDRA LLT term corresponding most closely to the infectious agent should also be included in the ICSR.
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | The appropriate MedDRA term should be provided in the data element B.2.i.1 ‘Reaction/event in MedDRA terminology (Lowest Level Term)’. |
| ICH-E2B(R3) | The appropriate MedDRA term should be provided in the data element E.i.2.1b ‘Reaction/Event (MedDRA code)’. |
VI.C.6.2.3.7. Reports of suspected adverse reactions originating from organised data collection systems and other systems
General guidance about the management of individual safety reports in the EU for post-authorisation studies (interventional clinical trials and non-interventional studies) is provided in VI.C.1. Individual reports originating from those studies shall contain information on study type, study name and the sponsor’s study number or study registration number [IR Art 28 (3)(c)]. This should be provided in the following ICH E2B section:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Section A.2.3 ‘Study identification. |
| ICH-E2B(R3) | Section C.5 ‘Study Identification’. |
Guidance concerning the management of individual safety reports for patient support programmes or market research programmes is provided in VI.C.2.2.11.
All ICSRs reportable to the EudraVigilance database and which originate from organised data collection systems and other systems which do not fall under the scope of the clinical trials Directive 2001/20/EC, should be submitted to EVPM (see VI.C.6.2.1. for guidance on EudraVigilance database modules). The same applies to cases of adverse reactions originating from clinical trials if they are suspected to be related to a medicinal product other than the IMP and do not result from a possible interaction with the IMP.
The following submission rules for ICSRs should be applied based on (i) the type of data collection system and (ii) whether the suspected medicinal product is part of the scope of the data collection system.
1. For suspected adverse reactions (i) in relation to those adverse events for which the protocol of non-interventional post-authorisation studies requires their systematic collection (see VI.C.1.2.1.1.), (ii) originating from compassionate use or named patient use conducted in Member States where the active collection of adverse events occurring in these programmes is required (see VI.C.1.2.2.), or (iii) originating from patient support programmes, or market research programmes (see VI.C.2.2.11.):
a. Where the adverse reaction is suspected to be related at least to the studied (or supplied) medicinal product:
-
-
- the report should be considered solicited;
- in line with ICH-E2B the following applies:
-
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Data element A.1.4 ‘Type of report’ should be populated with the value ‘Report from study’. · Data element A.2.3.3 ‘Study type in which the reaction(s)/event(s) were observed’ should be populated with the value ‘Other studies’ or ‘Individual patient use’. |
| ICH-E2B(R3) | · Data element C.1.3 ‘Type of report’ should be populated with the value ‘Report from study’. · Data element C.5.4 ‘Study type where reaction(s)/event(s) were observed’ should be populated with the value ‘Other studies’ or ‘Individual patient use’. |
b. Where the adverse reaction is only suspected to be related to a medicinal product which is not subject to the scope of the organised data collection system and there is no interaction with the studied (or supplied) medicinal product:
-
-
- the report should be considered spontaneous; as such it conveys the suspicion of the primary source;
- in line with ICH-E2B the following applies:
-
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Data element A.1.4 ‘Type of report’ should be populated with the value ‘Spontaneous’. |
| ICH-E2B(R3) | Data element C.1.3 ‘Type of report’ should be populated with the value ‘Spontaneous’. |
2. For suspected adverse reactions (i) in relation to those specified adverse events for which the protocol of non-interventional post-authorisation studies does not require their systematic collection (see VI.C.1.2.1.1.), or (ii) originating from compassionate use or named patient use conducted in Member States where the active collection of adverse events occurring in these programmes is not required (see VI.C.1.2.2.):
-
-
- the report should be considered spontaneous; as such it conveys the suspicion of the primary source;
- in line with ICH-E2B the following applies:
-
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Data element A.1.4 ‘Type of report’ should be populated with the value ‘Spontaneous’. |
| ICH-E2B(R3) | Data element C.1.3 ‘Type of report’ should be populated with the value ‘Spontaneous’. |
3. For clinical trials conducted in accordance with Directive 2001/20/EC where the adverse reaction is only suspected to be related to a medicinal product other than the IMP and does not result from a possible interaction with the IMP (see VI.C.1.1.):
-
-
- the report should be considered spontaneous; as such it conveys the suspicion of the primary source;
- in line with ICH-E2B the following applies:
-
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | Data element A.1.4 ‘Type of report’ should be populated with the value ‘Spontaneous’. |
| ICH-E2B(R3) | Data element C.1.3 ‘Type of report’ should be populated with the value ‘Spontaneous’. |
VI.C.6.2.3.8. Receipt of missing minimum information
When missing minimum information (see VI.B.2. for ICSRs validation) has been obtained about a nonvalid ICSR, the following rules should be applied:
- the date where the report was first received from the reporter should reflect the date of receipt of the initial non-valid ICSR;
- the date of receipt of the most recent information should reflect the date when the minimum criteria required for ICSR validation have become available;
- clarification should be provided in the case narrative that some of the four elements were missing in the initial report;
- as for any submitted cases, compliance monitoring is performed against the date of receipt of the most recent information for this report.
In line with ICH-E2B the following applies:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Data element A.1.6 ‘Date report was first received from source’ should capture the date of receipt of the initial non-valid ICSR. · Data element A.1.7 ‘Date of receipt of the most recent information for this report’ should capture the date when the minimum criteria required for ICSR validation have become available. · Clarification should be provided in the data element B.5.1 ‘Case narrative including clinical course, therapeutic measures, outcome and additional relevant information’ that some of the four elements were missing in the initial report. |
| ICH-E2B(R3) | · Data element C.1.4 ‘Date Report Was First Received from Source’ should capture the date of receipt of the initial non-valid ICSR. · Data element C.1.5 ‘Date of Most Recent Information for This Report’ should capture the date when the minimum criteria required for ICSR validation have become available. · Clarification should be provided in the data element H.1 ‘Case Narrative Including Clinical Course, Therapeutic Measures, Outcome and Additional Relevant Information’ that some of the four elements were missing in the initial report. |
VI.C.6.2.4. Data quality of individual case safety reports transmitted electronically and duplicate management
The EudraVigilance database should contain all cases of suspected adverse reactions that are reportable according to Directive 2001/83/EC and Regulation (EC) No 726/2004 to support pharmacovigilance activities. This applies to all medicinal products authorised in the EU independent of their authorisation procedure.
The EudraVigilance database should also be based on the highest internationally recognised data quality standards.
To achieve these objectives, the competent authority in a Member State and the marketing authorisation holder should adhere to:
- the electronic submission requirements as defined in EU legislation;
- the concepts of data structuring, coding and submission in line with the EU legislation, guidelines, standards and principles referred to in VI.C.6.1.
This is a pre-requisite to maintain a properly functioning EudraVigilance database intended to fully support the protection of public health.
In addition, the Agency in collaboration with stakeholders that submit ICSRs, are responsible to contribute to the quality and integrity of the data. This is reflected in the legislation as follows:
- The Agency shall, in collaboration with the marketing authorisation holder or with the competent authority in Member State that submitted an ICSR to the EudraVigilance database, be responsible for operating procedures that ensure the highest quality and full integrity of the information collected in the EudraVigilance database [REG Art 24(3)].
- This includes as well the monitoring of use of the terminologies referred to in Chapter IV of the Commission Implementing Regulation (EU) No 520/2012, either systematically or by regular random evaluation [IR Art 25(3)].
Specific quality system procedures and processes shall be in place in order to ensure:
- the submission of accurate and verifiable data on serious and non-serious suspected adverse reactions to the EudraVigilance database within the 15 or 90-day time frame [IR Art 11 (1) (c)].;
- the quality, integrity and completeness of the ICSRs submitted, which should also be entire and undiminished in their structure, format and content [IR Art 11 (1) (d) and Art 15 (1) (a)];
- the detection of duplicates of suspected adverse reactions reports in collaboration with the Agency [DIR Art 107(5) and Art 107a (3)].
To confirm that the quality system enables for the detection and management of duplicate ICSRs and the submission to the EudraVigilance database of ICSRs of the highest quality within the correct time frames, the marketing authorisation holder and the competent authority in a Member State shall perform risk-based audits of the quality system at regular interval [IR Art 13(1) and Art 17(1)]. Corrective action, including a follow-up audit of deficiencies shall be taken where necessary. The dates and results of audits and follow-up audits shall be documented [IR Art 13 (2) and Art 17(2)].
For the purpose of a systematic approach towards quality in accordance with the quality cycle as outlined in GVP Module I, the marketing authorisation holder, the competent authority in Member States and the Agency shall have sufficient and appropriately qualified and trained personnel for the performance of pharmacovigilance activities [IR Art 10(1) and 14(1)]. All personnel involved in the performance of pharmacovigilance activities shall receive initial and continued training in relation to their role and responsibilities. Stakeholders shall keep training plans and records for documenting, maintaining and developing the competences of personnel based on an assessment of the training needs and make them available for audit or inspection [IR Art 10 (3) and Art 14 (2)].
To assist the training of personnel for pharmacovigilance, the Agency has made available a detailed training plan and catalogue based on a modular training approach focusing on the management of individual safety reports, signals management and EudraVigilance. It is accessible on the EudraVigilance training webpage60 to stakeholders who wish to use it for their pharmacovigilance activities. In support of the operation of the procedures that ensure the highest quality and full integrity of the information collected in the EudraVigilance database as well as the monitoring of use of the terminologies for the submission of ICSRs, business process maps and process descriptions in relation to the quality review of ICSRs are provided in VI.App.6.
A review of the ICSRs quality, integrity and compliance with the submission time frames is performed by the Agency at regular intervals for all organisations submitting ICSRs to the EudraVigilance database in line with the Agency’s SOPs. Parameters upon which the review of organisations may be initiated, refer for example to the volume of reports being submitted to the EudraVigilance database, major changes to pharmacovigilance databases, quality issues identified as part of the signal management, requests from pharmacovigilance inspectors, or the time interval since the last review. The outcome of the review of the ICSRs quality and integrity is provided to the organisations on the basis of a report, which includes the need for corrective measures where applicable and the time frames for these measures to be applied. The time frames and the method for corrective measures depend on the quality issues identified (e.g. corrections of the MedDRA coding of ICSRs to be performed by means of amendment reports).
For the purpose of the monitoring of the compliance with the 15 or 90 days submission time frames, the Agency also provides the competent authority in a Member State and the marketing authorisation holder with monthly compliance reports, which apply to both initial and follow-up ICSRs. Specific rules on the compliance monitoring for amendment reports are detailed in VI.C.6.2.2.8.
With regard to the monitoring by the Agency of selected medical literature for reports of suspected adverse reactions to medicinal products containing certain active substances (see VI.C.2.2.3.1. for EU guidance on medical literature monitoring), and the entering of these reports in the EudraVigilance database in accordance with Article 27 of Regulation (EC) No 726/2004, two-yearly audits are planned to ensure the quality and integrity of the reports. SOPs and WINs for the routine quality review process are published on the Agency’s dedicated medical literature monitoring webpage61.
In support of the operation of procedures that ensure detection and management of duplicate ICSRs, business process maps and process descriptions are provided in VI.App.7. taking into account various scenarios acknowledging that duplicates may be detected at various stages of the processing of ICSRs by numerous stakeholders . The collaboration between the Agency, the competent authority in a Member State and the marketing authorisation holder is required to ensure that potential duplicates of reports of suspected adverse reactions are reviewed, confirmed and processed as necessary. Guidance on the detection of duplicate ICSRs is also provided in GVP Module VI Addendum I – Duplicate management of adverse reaction reports.
VI.C.6.2.5. Electronic re-transmission of ICSRs between multiple senders and receivers
The electronic re-transmission of cases refers to the electronic exchange of ICSRs between multiple senders and receivers, for example where in case of contractual agreement, a third country ICSR is first submitted by a marketing authorisation holder outside the EU to another marketing authorisation holder in the EU and from there to the Agency.
During this re-transmission process, information on the case should not in principle be omitted or changed if no new information on the case is available to the re-transmitting sender. Exceptions apply to the following ICH-E2B data elements or sections:
| Reference | E2B(R2)/(R3) requirements |
| ICH-E2B(R2) | · Data element A.1.0.1 ‘Sender’s (case) safety report unique identifier’. · Data element A.1.3 ‘Date of this transmission’. · Data element A.1.6 ‘Date report was first received from source’, for initial reports. · Data element A.1.7 ‘Date of receipt of the most recent information for this report’. · Section A.3 ‘Information on sender and receiver of case safety report’. · Section B.4.k.18 ‘Relatedness of drug to reaction(s)/event(s)’. · Data element B.5.3 ‘Sender’s diagnosis/syndrome and/or reclassification of reaction/event’. · Data element B.5.4 ‘Sender’s comments’. |
| ICH-E2B(R3) | · Data element C.1.1 ‘Sender’s (case) Safety Report Unique Identifier’. · Data element C.1.2 ‘Date of creation’. · Data element C.1.4 ‘Date Report Was First Received from Source, for initial reports’. · Data element C.1.5 ‘Date of Most Recent Information for This Report’. · Section C.3 ‘Information on Sender of Case Safety Report’. · Section G.k.9.i.2.r ‘Assessment of Relatedness of Drug to Reaction(s)/Event(s)’. · Section H.3.r ‘Sender’s Diagnosis (MedDRA code)’. · Data element H.4 ‘Sender’s Comments’ |
In the interest of improving data quality, in case of errors or inconsistencies in the report, the retransmitters should go back to the originator of the report to correct the case accordingly. However, if this cannot be done within normal submission time frames, the re-transmitter can correct information that has been incorrectly structured.
In addition, any electronic data interchange partner should adhere to the ICH-E2B rules regarding the provision of follow-up information, in accordance with the principles set out in VI.C.6.2.2.7.. Nonadherence to these administrative requirements endangers the electronic case management and leads to the potential for unnecessary duplication of reports in the receiver’s database
VI.C.6.2.6. Electronic submission of ICSRs through the headquarter of a marketing authorisation holder
If a marketing authorisation holder decides to centralise the electronic submission of ICSRs (e.g. by submitting through the company’s global or EU headquarter), the following should be taken into account:
- the central submitting arrangement should be clearly specified in the marketing authorisation holder’s pharmacovigilance system master file and in the internal standard operating procedures;
- the company’s headquarter designated for submitting the ICSRs should be registered with EudraVigilance.
VI.C.6.3. Electronic submission of information on medicinal products
To support the objectives of Directive 2001/83/EC and Regulation (EC) No 726/2004, the provisions provided in second sub-paragraph of Article 57(2) of Regulation (EC) No 726/2004, regarding the electronic submission and update of information on medicinal products for human use authorised or registered in the EU, shall be followed by the marketing authorisation holder. With regard to this, the marketing authorisation holder shall apply the internationally agreed formats and terminologies described in Chapter IV of the Commission Implementing Regulation (EU) No 520/2012. Guidance related to the electronic submission of information on medicines is provided on the Agency’s website62 .