VI.B.7. Submission of individual case safety reports (ICSRs)

Only valid ICSRs (see VI.B.2. for ICSRs validation) should be submitted. The clock for the submission of a valid ICSR starts as soon as the information containing the minimum criteria has been brought to the attention of the national or regional pharmacovigilance centre of a competent authority or of any personnel of the marketing authorisation holder, including medical representatives and contractors. This date should be considered as day zero. It is the first day when a notified competent authority or marketing authorisation holder gets knowledge of a valid ICSR, irrespective of whether the information is received during a weekend or public holiday. The timelines for submission are based on calendar days.

Where the marketing authorisation holder has set up contractual arrangements with a person or an organisation, explicit procedures and detailed agreements should exist between the marketing authorisation holder and the person/organisation to ensure that the marketing authorisation holder can comply with the submission of valid ICSRs within the appropriate time frames. These procedures should in particular specify the processes for the exchange of safety information, including the timelines and responsibilities for the regulatory submission of valid ICSRs. They should be organised in order to avoid the submission of duplicate ICSRs to the competent authorities.

For ICSRs described in the medical literature (see VI.B.1.1.2. for guidance on the management of medical literature reports), the clock starts (day zero) with awareness of a publication containing the minimum criteria (see VI.B.2. for ICSRs validation, and VI.App.2.7. for guidance on day zero estimation for medical literature reports). Where contractual arrangements are made with a person/organisation to perform literature searches and/or submit valid ICSRs, detailed agreements should exist to ensure that the marketing authorisation holder can comply with its regulatory submission obligations.

When additional significant information is received for a previously submitted case, the clock for the submission of a follow-up report starts again from the date of receipt of the relevant follow-up information. For the purpose of submission of ICSRs, significant follow-up information corresponds to new medical or administrative information that could impact on the assessment or management of a case, or could change its seriousness criteria; non-significant information includes updated comments on the case assessment, or corrections of typographical errors in the previous case version. See also VI.C.6.2.2.7. regarding the distinction between significant and non-significant follow-up information for the submission of ICSRs in the EU.

VI.B.7.1. Submission time frames of ICSRs

In general, the submission of serious valid ICSRs is required as soon as possible, but in no case later than 15 calendar days after initial receipt of the information by the national or regional pharmacovigilance centre of a competent authority or by any personnel of the marketing authorisation holder, including medical representatives and contractors. This applies to initial and follow-up information. Where a case initially sent as serious becomes non-serious based on new follow-up information, this information should still be submitted within 15 days; the submission time frame for non-serious reports should then be applied for the subsequent follow-up reports. Information as regards the submission time frame of non-serious valid ICSRs in the EU is provided in VI.C.3.. ICH-E2B provides a mechanism to the sender to indicate whether the case fulfils the local expedited requirements. Further EU guidance on this aspect is provided in VI.C.3.

VI.B.7.2. Report nullification

The nullification of a report should be used to indicate that a previously transmitted ICSR is considered completely void (nullified), for example when the whole case was found to be erroneous. EU guidance on ICSRs nullification in line with ICH-E2B is provided in VI.C.6.2.2.9.

VI.B.7.3. Report amendment

There may be instances, where an ICSR which has already been submitted may need to be amended for example when, after an internal review or according to an expert opinion some items have been corrected (such as adverse event/reaction terms, seriousness, seriousness criteria or causality assessment) but without receipt of new information that would warrant submission of a follow-up report. The same would apply where documentations mentioned in an ICSR, translations or literature articles are requested by competent authorities and are further sent as attachments in line with ICH E2B(R3).These submissions are considered as amendment reports. Further EU guidance on the amendment of ICSRs in line with ICH-E2B is provided in VI.C.6.2.2.8.