The definitions provided in Article 1 of Directive 2001/83/EC shall be applied for the purpose of this Module; of particular relevance are those provided in this Section. Some general principles presented in ICH-E2A and ICH-E2D (see GVP Annex IV) should also be adhered to; they are included as well in this Section (see GVP Annex I for all definitions applicable to GVP).

VI.A.1.1. Adverse reaction, causality

Adverse reaction: A response to a medicinal product which is noxious and unintended [DIR Art 1 (11)]. Adverse reactions may arise from use of the product within or outside the terms of the marketing authorisation or from occupational exposure [DIR Art 101(1)]. Use outside the marketing authorisation includes off-label use, overdose, misuse, abuse and medication errors.

Causality: In accordance with ICH-E2A (see GVP Annex IV), the definition of an adverse reaction implies at least a reasonable possibility of a causal relationship between a suspected medicinal product and an adverse event1 . An adverse reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship between a medicinal product and an occurrence is suspected. For regulatory reporting purposes, as detailed in ICH-E2D (see GVP Annex IV), if an event is spontaneously reported, even if the relationship is unknown or unstated, it meets the definition of an adverse reaction. Therefore all spontaneous reports notified by healthcare professionals or consumers are considered suspected adverse reactions, since they convey the suspicions of the primary sources 2 , unless the reporters specifically state that they believe the events to be unrelated or that a causal relationship can be excluded.

VI.A.1.2. Overdose, off-label use, misuse, abuse, occupational exposure, medication error, falsified medicinal product

Overdose: This refers to the administration of a quantity of a medicinal product given per administration or cumulatively, which is above the maximum recommended dose according to the authorised product information. Clinical judgement should always be applied.

Off-label use: This relates to situations where the medicinal product is intentionally used for a medical purpose not in accordance with the terms of the marketing authorisation.

Misuse: This refers to situations where the medicinal product is intentionally and inappropriately used not in accordance with the terms of the marketing authorisation.

Abuse: This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is accompanied by harmful physical or psychological effects [DIR Art 1(16)].

Occupational exposure: This refers to the exposure to a medicinal product (see definition in VI.A.1.3.), as a result of one’s professional or non-professional occupation. It does not include the exposure to one of the ingredients during the manufacturing process before the release as finished product.

Medication error: This is an unintended failure in the drug treatment process that leads to, or has the potential to lead to harm to the patient3 .

Falsified medicinal product: This relates to any medicinal product with a false representation of:

  • its identity, including its packaging and labelling, its name or its composition as regards any of the ingredients including excipients and the strength of those ingredients;
  • its source, including its manufacturer, its country of manufacturing, its country of origin or its marketing authorisation holder; or
  • its history, including the records and documents relating to the distribution channels used.

This definition does not include unintentional quality defects and is without prejudice to infringements of intellectual property rights [DIR Art 1(33)].

VI.A.1.3. Active substance, excipient, medicinal product

Active substance: Any substance or mixture of substances intended to be used in the manufacture of a medicinal product and that, when used in its production, becomes an active ingredient of that product intended to exert a pharmacological, immunological or metabolic action with a view to restoring, correcting or modifying physiological functions or to make a medical diagnosis [DIR Art 1(3a)].

Excipient: Any constituent of a medicinal product other than the active substance and the packaging material [DIR Art 1(3b)]; E.g. colouring matter, preservatives, adjuvant, stabilisers, thickeners, emulsifiers, flavouring and aromatic substances [DIR Annex I].

Medicinal product: A medicinal product is characterised by any substance or combination of substances,

  • presented as having properties for treating or preventing disease in human beings; or
  • which may be used in, or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis [DIR Art 1(2)].

VI.A.1.4. Primary source, healthcare professional, consumer

In accordance with ICH-E2B, the primary source of the information is the person who reports the facts about an ICSR. Several primary sources, such as healthcare professionals and/or consumers, may provide information on the same case. In this situation, all the primary sources’ details, including the qualifications, should be provided in the ICSR and the “Primary source(s)” section should be repeated as necessary in line with ICH-E2B (see VI.B.2. for ICSRs validation based on the primary source identifiability).

In accordance with the ICH-E2D (see GVP Annex IV),

  • a healthcare professional is defined as a medically-qualified person such as a physician, dentist, pharmacist, nurse , coroner or as otherwise specified by local regulations;
  • a consumer is defined as a person who is not a healthcare professional such as a patient, lawyer, friend, relative of a patient or carer.

The “Primary Source for Regulatory Purposes” is defined in ICH-E2B(R3)4 and is not applicable for the electronic submission of ICSRs under the ICH-E2B(R2) format. This data element refers to the person who first reported the facts. In case of multiple primary sources from different countries, this data element identifies the country for the ICH-E2B data element “worldwide unique case identification number”.

Where the patient experienced a suspected adverse reaction in another country than the one of the primary source, this information should be captured in the ICH-E2B data element “Identification of the Country Where the Reaction / Event Occurred”, e.g. a male patient from Ireland is reporting experiencing an anaphylactic reaction with drug X while travelling in Spain, in this instance the primary source country is Ireland and the occurrence country is Spain. Guidance about the automatic rerouting of the ICSR to the competent authority of the EU Member State where the reaction occurred is provided in VI.C.4.

VI.A.1.5. Medical confirmation

A consumer may provide medical documentations (e.g. laboratory or other test data) that support the occurrence of a suspected adverse reaction and which indicate that an identifiable healthcare professional suspects a causal relationship between a medicinal product and the reported adverse reaction. Similarly, a report may be notified by a medically qualified patient, friend, relative or carer of the patient. In these situations, the reported information is considered medically confirmed. In the same way, where one or more suspected adverse reactions initially reported by a consumer are subsequently confirmed by a healthcare professional, the ICSR should be considered medically confirmed.

It should be updated at case level in line with ICH-E2B(R2), or at adverse reaction level in accordance with ICH-E2B(R3) for each subsequently medically confirmed suspected adverse reaction.

VI.A.1.6. Seriousness

As described in ICH-E2A (see GVP Annex IV), a serious adverse reaction corresponds to any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect.

The characteristics/consequences should be considered at the time of the reaction to determine the seriousness. For example, life-threatening refers to a reaction in which the patient was at risk of death at the time of the reaction; it does not refer to a reaction that hypothetically might have caused death if more severe.

Medical judgement should be exercised in deciding whether other situations should be considered serious. Some medical events may jeopardise the patient or may require an intervention to prevent one of the above characteristics/consequences. Such important medical events should be considered serious5 . The EudraVigilance Expert Working Group has co-ordinated the development of an important medical event (IME) terms list based on the Medical Dictionary for Regulatory Activities (MedDRA) (see GVP Annex IV). This IME list aims to facilitate the classification of suspected adverse reactions, the analysis of aggregated data and the assessment of ICSRs in the framework of the day-to-day pharmacovigilance activities. The IME list is intended for guidance purposes only and is available on the Agency website6 to stakeholders who wish to use it for their pharmacovigilance activities. It is regularly updated in line with the latest version of MedDRA.

Where one or more serious suspected adverse reactions are reported in an ICSR, the information on the seriousness should be documented at case level in line with ICH-E2B(R2) or for each suspected adverse reaction in accordance with ICH-E2B(R3), depending on the ICH-E2B format used for the ICSR electronic submission.

VI.A.1.7. Individual case safety report (ICSR)

This refers to the format and content for the submission of an individual report of suspected adverse reactions in relation to a medicinal product that occur in a single patient at a specific point of time [IR Art 27]. A valid ICSR should include at least one identifiable reporter, one single identifiable patient, at least one suspect adverse reaction, and at least one suspect medicinal product (see VI.B.2. for ICSRs validation).

VI.A.1.8 nullFlavors

The nullFlavors are a collection of codes specifying why a valid value is not present in an ICSR. They are available with the ICH-E2B(R3) format and not with ICH-E2B(R2). They refer to instances, where for example a proper value is applicable, but not known (e.g. age of the patient is unknown: code UNK), or where the information is available to a sender of an ICSR but it is masked because it cannot be provided due to security, privacy or other reasons (e.g. date of birth of the patient cannot be shared due to local data protection laws: code MSK). ICH-E2B(R3) uses the nullFlavor code sets from the HL7 Messaging Standard primarily to classify the set of source data situations that may give rise to a missing value. For examples how a nullFlavors can be used to code values in the ICSR, refer to the ICH Implementation Guide for Electronic Transmission of Individual Case Safety Reports (ICSRs) E2B(R3) Data Elements and Message Specification7 . Additional EU guidance on the use of the nullFlavor in some specific situations is also provided in the EU Individual Case Safety Report (ICSR) Implementation Guide8 .