19 Mar Day Zero in Local Literature Screening

The interpretation of day 0 in local literature screening historically encountered challenges, particularly regarding hard copy journals. In January 2023 European Medicines Agency (EMA) posted an interesting view of the Pharmacovigilance Inspectors Working Group regarding Day 0 in the context of Individual Case Safety Reports (ICSRs) found in physical/hard copy local medical journals:

“For ICSRs, described in the medical literature containing the minimum criteria, the clock starts (day zero) on the day when the physical/hard copy local journal is received by the organisation/Marketing authorisation holder (MAH), and this should be considered equal to performing a literature search in an electronic database.”

Before that, the understanding was “Day 0 at awareness”, i.e. when the assessment of an article comes to a result. Such awareness supposes that the articles were read, matched with the selected search terms, assessment was carried out and evaluation was made about the presence of an ICSR. Hence, the mere receipt of the physical copies was not considered as the point of awareness of the minimum criteria.

It was clear that EMA aimed at making sure that MAH’s organisation does not allow for delays between the point of having available literature hard copies and their respective processing. However, there were some practical implications related to paper literature: the unpredictable arrival date and volume of hard copy medical journals. For MAHs that meant maintaining significant stand-by resources in order to do the processing as soon as possible upon arrival. It was questionable what the actual impact on patient safety would be, considering that at the time we read a paper article the case in such local literature or reference databases is already at least three-months old.

In March 2024 EMA reconsidered their position regarding day zero for ICSRs described in hard copy medical literature. According to the updated Q&A:

“For ICSRs identified in relevant published abstracts from meetings and draft manuscripts as well as publications in local medical journals (i.e., all mandatory medical literature monitoring activities with the exception of weekly literature searching in reference databases), the regulatory time clock for reporting starts (day zero) as soon as MAH identifies sufficient information to determine that the minimum criteria for a valid ICSR reporting are met. The marketing authorisation holders should review the received information without delay to identify and manage potential cases of suspected adverse reactions. This should be done within a week of the date of receipt.”

In essence, this combines “Day 0 at awareness” approach with a 7-day deadline for processing hard copy journals upon receipt.

This interpretation is in line with the Guideline on good pharmacovigilance practices (GVP), Module VI. According to GVP (VI.B.7.) for ICSRs described in medical literature, the clock starts (day zero) with awareness of a publication containing the minimum criteria. According to GVP VI.App.2.7. day zero is the date on which an organisation becomes aware of a publication containing the minimum information for an ICSR to qualify for submission. Awareness of a publication includes any personnel of that organisation, or third parties with contractual arrangements with the organisation. For articles that have been ordered as a result of literature search results, day zero is the date when the minimum information for an ICSR to be valid is available. Organisations should take appropriate measures to obtain articles promptly in order to confirm the validity of a case.