EMA detailed guidelines on validity and coding of ICSR in context of COVID 19

On 30-October-2020, EMA had released detailed guidance on ICSRs in the context of COVID 19 – validity and coding of ICSRs.

This detailed guidance document provides recommendations relevant to the processing and submission of Individual Case Safety Reports (ICSRs) associated with medicinal products used for the treatment or prevention of COVID-19 infection, taking into account:
• the Notice to stakeholders published by the European Commission
• the guidance regarding COVID-19 related terms published by the MedDRA MSSO; and
• the introduction of COVID-19 related terms since the updated MedDRA version 23.0.

Important points from document:

• 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;
• Reports should not be submitted for the misuse of non-medicinal products which may contain substances also present in medicinal products, such as swimming pool cleaner containing chloroquine phosphate;
• Reports of off-label use with no associated suspected adverse reactions (this includes reports of unexpected therapeutic benefit) should not be reported to EudraVigilance; they should be discussed in the Periodic Safety Update Report and/or addressed in the product Risk Management Plan.
• If a medicinal product is being used in accordance with its authorisation to prevent or treat COVID-19 infection and a lack of therapeutic efficacy is reported with no associated suspected adverse reaction, then, because COVID-19 is a potentially life-threatening disease, this should be submitted within 15 days to EudraVigilance as an ICSR,
• If a medicinal product is being used off-label to prevent or treat COVID-19 infection and a lack of therapeutic efficacy is reported without an associated ADR, then this should not be submitted as an ICSR. It should instead be discussed in the Periodic Safety Update Report and/or addressed in the product Risk Management plan,
• Reports with a valid Adverse Drug Reaction which also have of lack of therapeutic efficacy reported should be submitted as ICSRs, regardless of whether the medicinal product was used off-label or not;
• ICSRs of compassionate use and named patient use programs should be considered as solicited reports if active collection of adverse events occurring, if the active collection of adverse events occurring in these programmes is not required, then any ICSRs should be considered as spontaneous reports;
• Since the number of publications relating to COVID19 increasing significantly marketing authorisation holders shall not create duplicates in EudraVigilance by submitting ICSRs which should be submitted by the Medical Literature Monitoring service.
• In addition, the following points should be taken into consideration: The exclusion criteria provided below should be followed. Particular attention should be paid to exclusion criteria d to f, which concern literature which:
• d. refers to data from publicly available databases (e.g. poison control centres) and where the cases are presented in aggregate tables or line listings. The submission requirement remains for valid cases described individually,
• e. presents the results from post-authorisation studies, meta-analyses, or literature reviews,
• f. describes suspected adverse reactions in a group of patients with a designated medicinal product and the patients cannot be identified individually for creating valid ICSRs,
• One case should be created for each single identifiable patient while respecting the exclusion criteria provided in GBP module VI.C.2.2.3.2. ICSRs based on information from the medical literature, lay press or other media should have as complete as possible patient and reporter information to aid in the detection and management of duplicates;
• Marketing authorisation holders (MAHs) should regularly screen the internet or digital media under their management or responsibility, for potential reports of suspected adverse reactions. MAHs are not expected to search non-company sponsored digital media for potential reports of suspected adverse reactions where their product is being used in COVID-19 infection; however, if a MAH becomes aware of a report of suspected adverse reaction described in any of these sources, the report should be assessed to determine whether it qualifies for submission as ICSR.
• Specific COVID-19 terms have been included in MedDRA since version 23.0. Stakeholders should ensure that they select the relevant precise COVID-19 related term when coding ICSRs in accordance with the MedDRA term selection Points to Consider.
• In line with the MedDRA MSSO Best Practices document the decision to re-code historical data is left to the discretion of each individual organisation. Amended versions of the ICSRs should be submitted when the re-coding significantly impacts on the medical evaluation of cases already submitted to EudraVigilance.
• From MedDRA version 23.1 a new COVID-19 SMQ (Special MedDRA Query) was released. The MedDRA MSSO has advised to apply this SMQ not only in Reaction(s)/Event(s) data elements, but also in other relevant data elements such as those for medical history, indications, laboratory tests, etc. Furthermore, since this SMQ has been designed to be specific to COVID-19, users are advised to consider applying other SMQs in combination to perform a more comprehensive search of the various clinical manifestations of the infection if desired.
• The indication for which the suspected medicinal product was administered should not be included in the ICH-E2B section ‘Reactions/Events’ unless aggravation of the medical condition occurs.
• If a patient experiences an aggravation or exacerbation of their condition, then usually the ‘Reaction (MedDRA)’ field should be populated with either the MedDRA LLT “COVID-19 aggravated” (LLT Code 10084657) or MedDRA LLT “COVID-19 pneumonia aggravated” (LLT Code 10084658).
• If neither of those terms is sufficiently precise, then, in accordance with the principles of MedDRA term selection: Points to Consider, two reactions should be entered:
• • The most precise COVID-19 related LLT and “Condition aggravated” (LLT code 10010264)
• If a suspected adverse reaction occurs in the setting of off label use, the guidance provided in GVP Module VI chapter VI.C.6.2.3.3. should be followed for the provision of the information in the ICSR.
• Each medicinal product used to treat confirmed or suspected COVID-19 infection should have an indication (ICH E2B(R2)B.4.k.10/(R3)G.k.7.r.2b) populated with the most precise COVID-19 related MedDRA LLT.
• If the medicine is used as prophylaxis against COVID-19 infection, the indication should be populated with the MedDRA LLT “COVID-19 prophylaxis” (LLT code 10084458).
• If the medicine is used as immunisation against COVID-19 infection, the indication should be populated with the most precise MedDRA LLT under the PT “COVID-19 immunisation”.
• If the medicine is used as treatment for COVID-19 infection, the indication should be populated with the most precise MedDRA LLT under the PT “COVID-19 treatment”, unless a more precise term is available.
• The data elements for medical history should also be used to capture concurrent conditions. This is particularly relevant for ICSRs concerning COVID-19 patients, for which the suspected medicinal product was not used for the treatment and/or prevention of the COVID-19 infection.
• If a patient has confirmed COVID-19 infection, then the ICH-E2B data elements patient medical history (ICH E2B(R2)B.1.7.1a.2/(R3)D.7.1.r.1b) should be populated with the most precise COVID-19 related MedDRA LLT.
• For ICSRs where the suspected medicinal product was not used for the treatment of COVID-19 infection and where it is explicitly reported that the patient has known exposure to COVID-19 without developing infection (e.g. healthcare workers), the most precise MedDRA LLT under the PTs “Exposure to SARS-CoV-2” or “Occupational exposure to SARS-CoV-2” should be entered.
• The two paragraphs above also apply to parent medical history.
• MedDRA LLTs such as “Coronavirus test positive” (LLT Code 10070255) or “SARS-CoV-2 test negative” (LLT Code 10084273) reflect test results and should not be used in the ICH-E2B data elements for test name (ICH E2B(R2)B.3.1c/(R3)F.r.2.2b). The data element for the test name should be populated with the most precise MedDRA LLT under the PTs “Coronavirus test”, “SARS-CoV-2 test” or “SARS-CoV-2 antibody test” as applicable.

Reference: EMA guidance