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ICSRs Handling (Module VI) EMEA Guidance
Q: Is it mandatory to submit Non-serious cases also to EU Agency (EMEA)?
A: Yes, it is Mandate. As per the applicable legal requirements, MAH must ensure the submission of individual reports of suspected adverse reactions (serious and non-serious) associated with medicinal products for human use authorised in the European Union (EU).
Q: Is it required to submit the special scenario ICSRs (individual reports of events which do not result in suspected adverse reactions (e.g. Drug exposure during pregnancy or breastfeeding, overdose, abuse, misuse, Off-label use, medication error or occupational exposure, Lack of therapeutic efficacy) and which are not required to be submitted as individual case safety reports (ICSRs).
A: Not required to submit as ICSRs. However, must be collected and presented in PSURs/PBRERs. If any other consequences happened with these scenarios, then those events need to be treated as per their seriousness criteria.
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Q: What is an Adverse Event?
A: A response to a medicinal product which is noxious and unintended. Adverse reactions may arise from use of the product within or outside the terms of the marketing authorisation or from occupational exposure. Use outside the marketing authorisation includes off-label use, overdose, misuse, abuse and medication errors.
Q: What is Adverse reaction?
A: Definition of an adverse reaction implies at least a reasonable possibility of a causal relationship between a suspected medicinal product and an adverse event.
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Q: What will be causality of Spontaneous case report?
A: 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.
Q: What is overdose?
A: Administration of a quantity of a medicinal product, which is above the maximum recommended dose according to the authorised product information.
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Q: What is Off-Label use?
A: The usage of medicinal product is intentionally for a medical purpose not in accordance with the terms of the marketing authorisation. Examples of Off-label scenarios like
- different indication in term of medical condition;
- a different group of patients;
- a different route or method of administration;
- a different posology
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Q: What is Misuse?
A: Usage of medicinal product intentionally and inappropriately used not in accordance with the terms of the marketing authorisation. Eg: For recreational purposes, to facilitate assault.
Q: What is Abuse?
A: This corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is accompanied by harmful physical or psychological effects. Eg: Usage of medicine for getting euphoria.
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Q: What is Occupational exposure?
A: This refers to the exposure to a medicinal product 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
Q: What is Medication error?
A: This is an unintended failure in the drug treatment process that leads to harm to the patient. Eg: Child took grandmother’s tablets
Q: What is Primary reporter?
A: The primary source of the information is the person who reports the facts about an ICSR.
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Q: What is Primary country?
A: The country where the patient experienced a suspected adverse reaction. Clause: The patient experienced a suspected adverse reaction in another country than the primary source, then the Country Where the Reaction / Event Occurred need to be considered as Primary country. 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.
Q: What is seriousness of case report?
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.
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Q: What is IME, DME List?
A: 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). This IME list aims to facilitate the classification of suspected adverse reactions. The IME list is intended for guidance purposes only and is available on the Agency website.
Q: What is Individual Case Safety Report (ICSR)?
A: Occurrence of adverse reactions in relation to a medicinal product in a single patient at a specific point of time is call ICSR.
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Q: What is a valid ICSR?
A: 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.
Q: What are Unsolicited reports?
A: A case report from any healthcare professional or a consumer or a literature source or lay press or any other media or internet or digital media that describes one or more suspected adverse reactions in a patient who was given one or more medicinal products is called as unsolicited report
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Q: What are Solicited reports?
A: Solicited reports of suspected adverse reactions are those derived from organised data collection systems, which include clinical trials, non-interventional studies, registries, post-approval named patient use programmes, other patient support and disease management programmes, surveys of patients or healthcare professionals, compassionate use or name patient use, or information gathering on efficacy or patient compliance. Reports of suspected adverse reactions obtained from any of these data collection systems should not be considered spontaneous
Q: Why to do Global and Local literature search?
A: Marketing authorisation holders are expected to maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g. Medline, Excerpta Medica or Embase) no less frequently than once a week. In addition, marketing authorisation holders should have procedures in place to monitor scientific and medical publications in local journals in countries where medicinal products have a marketing authorisation.
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Q: Why to do follow up for the case report?
A: Every attempt should be made to follow-up the case to obtain the minimum information that constitutes a valid ICSR.
Clause: For some cases, it may not always be possible to perform follow-up activities taking into account that the reporter information may have been anonymised. These cases should be considered valid for submission as ICSRs, providing that the notified organisation was able to confirm them directly with the primary sources and that the other minimum criteria for reports validation are satisfied.
Q: Why to monitor non-medical sources?
A: Marketing authorisation holder should manage reports of suspected adverse reactions originating from a non-medical source (the lay press or other media) as a spontaneous report
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Q: Why to monitor internet or digital media?
A: Marketing authorisation holders should regularly screen the internet or digital media for potential reports of suspected adverse reactions. For this, a digital medium is considered to be company sponsored (whether it is paid or owned).
Marketing authorisation holders may also consider utilising their websites to facilitate the collection of reports of suspected adverse reactions.
If a marketing authorisation holder becomes aware of a report of suspected adverse reaction described in any non-company sponsored digital medium, the report should be assessed to determine whether it qualifies for submission as ICSR.
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Q: What is four minimum criteria?
A: one or more identifiable reporter, one single identifiable patient, one or more suspected substance/medicinal product, one or more suspected adverse reaction.
Q: What is identifiable patient?
A: Single identifiable patient is characterised by at least one of the qualifying descriptors as initials, medical record number (from general practitioner, specialist, hospital, or investigation), date of birth, age, age group, gestation period, or gender.
Q: Sudden death is a valid case report?
A: A report of sudden death would usually need to be considered as a case of suspected adverse reaction and the valid ICSR should be submitted.
Q: If there is no suspected adverse reaction, then the validity is incomplete?
A: Yes, if there is no suspected adverse reaction, then that case is not to be considered as valid case.
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Q: Can any report from consumer be downgraded to non-relevant?
A: No. A valid case of suspected adverse reaction initially notified by a consumer cannot be downgraded to a report of non-related adverse event even healthcare professional (nominated by the consumer for follow-up information) or competent authority or marketing authorisation holder subsequently disagrees with the consumer’s opinion. The opinions of both the consumer and the healthcare professional should be detailed in the narrative section of the ICSR.
Q: Batch number request has been done in the follow-up attempt. Is this information need to be mentioned in Case narrative?
A: Yes. All appropriate measures should be taken to clearly identify the names of the products and their batch numbers. With respect to this, it is recommended to specify in the case narrative if information on the batch number has been requested.
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Q: Is it required to maintain confidentiality of case details?
A: Yes. Confidentiality of patients’ records including personal identifiers, if provided, should always be maintained. Identifiable personal details of reporting healthcare professionals should be kept in confidence, protected from unauthorised access. Case report information should be transmitted between stakeholders (marketing authorisation holders or competent authorities) in accordance with local data protection laws.
Q: Is it required to check the duplicates of a case?
A: Yes. Procedure should be in place to account for identification and management of duplicate cases at data entry.
Q: Is it required to maintain Quality management system in Pharmacovigilance?
A: Yes. Marketing authorisation holders should have a quality management system in place to ensure compliance with the necessary quality standards at every stage of case documentation, such as data collection, data transfer, data management, data coding, case validation, case evaluation, case follow-up, ICSR submission and case archiving.
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Q: Who all are need to be trained on pharmacovigilance activities?
A: Staff directly performing pharmacovigilance activities should be appropriately trained in applicable pharmacovigilance legislation and guidelines. Other personnel who may receive or process safety reports (e.g. clinical development, sales, medical information, legal, quality control) should be trained in adverse events/reactions collection and submission to the pharmacovigilance department in accordance with internal policies and procedures.
Q: What are special scenario reports?
A: Drug exposure during pregnancy or breastfeeding, overdose, abuse, misuse, Off-label use, medication error or occupational exposure, Lack of therapeutic efficacy.
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Q: Is it required to report Lack of efficacy cases?
A: Reports of lack of therapeutic efficacy should be collected and recorded. They should normally not be submitted as ICSRs if there is no associated suspected adverse reaction. Clause: In certain circumstances, reports of lack of therapeutic efficacy with no suspected adverse reactions may require to be submitted within a 15-day time frame. Medicinal products used in critical conditions or for the treatment of life threatening diseases, vaccines, and contraceptives are examples of such cases. This applies unless the reporter has specifically stated that the outcome was due to disease progression and was not related to the medicinal product.
Q: What is day zero?
A: 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. For ICSRs described in the medical literature, the clock starts (day zero) with awareness of a publication containing the minimum criteria.
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Q: What is time frame for ICSR submission?
A: 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. If a case initially sent as serious becomes non-serious based on new follow-up information, this information should still be submitted within 15 days.
Q: What is nullification?
A: 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.
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Q: When a case need to be nullified as per EMEA guidance?
A: 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 things to be followed while doing nullification
- 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.
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Q: What is amendment report?
A: 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. These submissions are considered as amendment reports
Q: How MAH deal with Amendment of cases?
A: 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. Scenarios such as for reports for which cases translations should be provided by a marketing authorisation holder when requested by the Agency or another Member State
- Where the amendment significantly impacts on the medical evaluation of the case
- 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
- For reports for which cases translations should be provided by a marketing authorisation holder when requested by the Agency or another Member State
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Q: Is it required that, MAH need to submit the ICSRs from other countries which are not having Marketing Authorization?
A: Yes. Marketing authorisation holders (MAH) have to submit in addition to information on adverse reactions that occur in the EU, information on serious suspected adverse reactions that occur in third countries. This is valid irrespective of the strengths, pharmaceutical forms, and routes of administration, presentations, authorised indications, or names of the medicinal product.
Clause: With regard to the collection and recording of reports of suspected adverse reactions, the marketing authorisation holder responsibilities apply to reports related to medicinal products for which ownership cannot be excluded on the basis of one the following criteria: medicinal product name, active substance name, pharmaceutical form, batch number or route of administration. Exclusion based on the primary source country or country of origin of the adverse reaction is possible if the marketing authorisation holder can demonstrate that the suspected medicinal product has never been supplied or placed on the market in that territory or that the product is not a travel medicine.
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Q: For what sort of products, MAH need to perform pharmacovigilance activities?
A: MAH which formulates Allopathic, Homeopathic, herbal medicinal products, devices containing active substances also need to perform the pharmacovigilance activities.
Q: What are post-Authorization safety studies?
A: In the European Union, post-authorisation safety or efficacy studies can be imposed by competent authorities in Member States. They can also be conducted voluntarily by the marketing authorisation holders.
Q: How to do Management of adverse events for non-interventional post-authorisation studies?
A: Collect and record comprehensive and high quality information. Perform causality assessment. Summarise all collected adverse events in the interim safety analysis and in the final study report. Valid ICSRs should be managed classified and submitted as solicited report.
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Q: What are designed Non-interventional post-authorisation studies?
A: These studies are characterised by secondary use of data previously collected from consumers or healthcare professionals for other purposes. Examples include medical chart reviews, analysis of electronic healthcare records, systematic reviews, meta-analyses.
For these studies, the submission of suspected adverse reactions in the form of ICSRs is not required. All adverse events/reactions collected for the study should be recorded and summarised in the interim safety analysis and in the final study report
Q: How long any MAH need to maintain the Pharmacovigilance data?
A: Pharmacovigilance data and documents relating to individual authorised medicinal products shall be retained by the marketing authorisation holder as long as the product is authorised and for at least 10 years after the marketing authorisation has ceased to exist.
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Q: What are responsibilities of MAH in collection of reports of suspected adverse reactions?
A: The marketing authorisation holder responsibilities apply to the collection of reports within or outside EU related to medicinal products for which ownership cannot be excluded on the basis of one of the criteria such as medicinal product name, active substance name, pharmaceutical form, batch number or route of administration
Q: How MAH deal with spontaneous cases?
A: The marketing authorisation holder shall record all reports of suspected adverse reactions originating from within or outside the EU, which are brought to its attention spontaneously by healthcare professionals or consumers.
Q: How MAH deal with Solicited reports?
A: The marketing authorisation holder shall record all reports of suspected adverse reactions originating from within or outside the EU, which occur in post-authorisation studies. The marketing authorisation holder should have mechanisms in place to record and document complete and comprehensive case information and to evaluate that information, in order to allow the meaningful assessment of individual cases and the submission of valid ICSRs.
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Q: What is Medical Literature monitoring by the European Union?
A: In line with Article 27 of Regulation (EC) No 726/2004, the Agency monitors selected medical literature for reports of suspected adverse reactions to medicinal products containing certain active substances. It publishes a list of active substances being monitored and the medical literature subject to this monitoring
Q: Since when the MLM service been fully operational?
A: The service has been fully operational since September 2015. The legal basis is Article 27 of Regulation (EC) No 726/2004.
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Q: What data will be monitored and collected by MLM service of EU?
A: ICSRs resulting from the MLM service are made available for download in XML format. This refers to ICSRs of serious suspected adverse reactions occurring within and outside the EU, and to ICSRs of non-serious suspected adverse reactions from within the EU.
Q: How to access the MLM data from EU Agency?
A: This data can be accessed from the EudraVigilance database by the marketing authorisation holder. The marketing authorisation holder shall only submit those ICSRs described in the medical literature which is not reviewed by the Agency
Q: In which scenarios, there is no need of submission of literature cases?
A: As below
- Case which originates in a country where a company holds a marketing authorisation but has never commercialised the medicinal product.
- Cases from aggregate tables or line listings
- Reports on an analysis from a competent authority database within the EU.
- Data from publicly available databases.
- Results from post-authorisation studies, meta-analyses, or literature reviews.
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Q: What is obligation to submit suspected adverse reactions related to quality defect or falsified medicinal products?
A: When a report of suspected adverse reactions is associated with a suspected or confirmed falsified medicinal product or with a quality defect of a medicinal product, a valid ICSR should be submitted.
Q: What is the need to submit reports of quality defect or falsified medicinal products?
A: The marketing authorisation holder should have a system in place to ensure that reports of suspected adverse reactions related to falsified medicinal products or to quality defects of a medicinal products are investigated in a timely fashion and that confirmed quality defects are notified separately to the manufacturer and to the competent authorities
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Q: How to deal with suspected transmission via medicinal product of an infectious agent?
A: Any suspected transmission of an infectious agent via a medicinal product should be considered as a serious adverse reaction and such cases should be submitted within 15 days.
Q: Is it required for MAH to collect the reports in the period between the submission of the marketing authorisation application and the granting of the marketing authorisation?
A: MAH need to collect information (quality, non-clinical, clinical) that could impact on the risk benefit balance of the medicinal product. It is the responsibility of the applicant to ensure that this information is immediately submitted.
Clause: In the situation where a medicinal product application is under evaluation in the EU while it has already been authorised in a third country, valid ICSRs from outside the EU, originating from unsolicited reports or solicited reports should be submitted.
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Q: Is it required for MAH to collect reports after suspension of a marketing authorisation for product?
A: The marketing authorisation holder shall continue to collect any reports of suspected adverse reactions related to the concerned medicinal product following the suspension of a marketing authorisation.
Q: Is it required for MAH to collect reports once the marketing authorisation for product is withdrawn or revoked.
A: Marketing authorisation is withdrawn or revoked, then the marketing authorisation holder is encouraged to continue to collect spontaneous reports of suspected adverse reactions originating within the EU.
Q: How MAH should deal the Reports from class action lawsuits?
A: Stimulated reports arising from class action lawsuits should be managed as spontaneous reports. Where large batches of potential ICSRs are received, the marketing authorisation holder may request for an exemption in order to submit serious cases of suspected adverse reactions within 30 days from their date of receipt instead of 15 days. The 90 days submission time frame for non-serious ICSRs remains unchanged
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Q: How MAH deal with reports of Post-authorization studies such as Reports from patient support programmes and market research programmes?
A: Safety reports originating from those programmes should be considered as solicited reports. The marketing authorisation holder should have the same mechanisms in place as for all other solicited reports
Q: Time Frame for MAH for submission of serious and non-serious cases to EU?
A: Serious valid ICSRs shall be submitted by the competent authority in a Member State or by the marketing authorisation holder within 15 days from the date of receipt of the reports;
The marketing authorisation holder shall submit all serious ICSRs that occur within or outside the EU, including those received from competent authorities outside the EU, to the EudraVigilance database only.
Non-serious valid ICSRs shall be submitted by the competent authority in a Member State or by the marketing authorisation holder within 90 days from the date of receipt of the reports. The marketing authorisation holder shall submit all non-serious ICSRs that occur in the EU to the EudraVigilance database only.
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Q: What is Electronic submission of individual case safety reports?
A: 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. Non-adherence to this requirement constitutes a non-compliance with EU legislation. 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.
Q: What are EudraVigilance Databases?
A: 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.
- The EudraVigilance Post-Authorisation Module (EVPM)
- The EudraVigilance Clinical Trial Module (EVCTM)
Q: What is EudraVigilance Post-Authorisation Module (EVPM)?
A: 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.
Q: What is EudraVigilance Clinical Trial Module (EVCTM)?
A: 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 should be submitted by the sponsor to the EudraVigilance Clinical Trial Module (EVCTM).
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Q: What to collect and what to report as ICSRs?
A: Each marketing authorisation holder shall have in place a system for the collection and recording of all reports of suspected adverse reactions in the EU or in third countries which are brought to its attention, whether reported spontaneously by healthcare professionals or consumers or occurring in the context of a post-authorisation study.
The marketing authorisation holder responsibilities apply to reports related to medicinal products for which ownership cannot be excluded on the basis of one the following criteria: medicinal product name, active substance name, pharmaceutical form, batch number or route of administration.
Exclusion based on the primary source country or country of origin of the adverse reaction is possible if the marketing authorisation holder can demonstrate that the suspected medicinal product has never been supplied or placed on the market in that territory or that the product is not a travel medicine (e.g. anti-malarial medicinal product).
The marketing authorisation holder shall record all spontaneous reports of suspected adverse reactions originating from within or outside the EU, which are brought to its attention spontaneously by healthcare professionals or consumers.
The marketing authorisation holder shall record all solicited reports of suspected adverse reactions originating from within or outside the EU, which occur in post-authorisation studies, initiated, managed, or financed by that organisation.
Any information (quality, clinical, non-clinical) that could impact on the risk-benefit balance of the medicinal product under evaluation may become available to the applicant in the period between the submission of the marketing authorisation application and the granting of the marketing authorisation must be submitted immediately.
In the situation where a medicinal product application is under evaluation in the EU while it has already been authorised in a third country, valid ICSRs from outside the EU, originating from unsolicited reports or solicited reports should be submitted.
The marketing authorisation holder shall continue to collect, submit any reports of suspected adverse reactions related to the concerned medicinal product following the suspension of a marketing authorisation.
Marketing authorisation is withdrawn or revoked, then the marketing authorisation holder is encouraged to continue to collect spontaneous reports of suspected adverse reactions originating within the EU.
Where the suspected adverse reactions reported in a single ICSR have a major impact on the risk-benefit balance of the medicinal product, this should be considered as an emerging safety issue and notified accordingly.
For the submission of valid ICSRs, the MAH need to do meaningful assessment of individual cases. The marketing authorisation holder shall only submit those ICSRs described in the medical literature which is not reviewed by the Agency.
When a report of suspected adverse reactions is associated with a suspected or confirmed falsified medicinal product or with a quality defect of a medicinal product, a valid ICSR should be submitted.
Any suspected transmission of an infectious agent via a medicinal product should be considered as a serious adverse reaction and such cases should be submitted within 15 days.
Literature ICSRs which are based on the analysis from a competent authority database outside the EU must be submitted as per timelines.
Submission of Literature ICSRs can be excluded in the scenarios such as
- If MAH product is not matching with any of the medicinal product name, active substance name, pharmaceutical form, batch number or route of administration.
- Case originates from a country where MAH holds Marketing Authorization but never commercialised the medicinal product.
- A case based on an analysis from a competent authority database within the EU.
- Data from publicly available databases (e.g. poison control centres) and where the cases are presented in aggregate tables or line listings. But, the submission requirement remains for valid cases described individually.
- Results from post-authorisation studies, meta-analyses, or literature reviews.
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Q: Who all are the people have access to the EudraVigilance database?
A: In accordance with Article 24(2) of Regulation (EC) No 726/2004, the data submitted to the EudraVigilance database are made accessible to stakeholders such as competent authorities, healthcare professionals, consumers, as well as marketing authorisation holders and research institutions. Access is provided based on the latest version of the EudraVigilance Access Policy for Medicines for Human Use.
Q: How MAH need to deal with a case received with only the therapeutic class instead of active ingredient?
A: This information should only be reflected in the case narrative. The information should not be included in the structured data. When 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. Efforts should be made to follow-up the case in order to collect the missing information
Q: What must be included in PADERs?
A: Safety data from solicited reports to be presented in the relevant sections of the periodic safety update report of the authorised medicinal product.
New and significant safety findings presented in these articles (Data presented in aggregate tables or line listings, results from post-authorisation studies, meta-analyses, or literature reviews.) for which the submission of ICSRs is not required, however be discussed in the relevant sections of the concerned periodic safety update report
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Q: How MAH need to deal with Suspected adverse reactions related to quality defect or falsified medicinal products?
A: When a report of suspected adverse reactions is associated with a suspected or confirmed falsified medicinal product or with a quality defect of a medicinal product, a valid ICSR should be submitted.
In addition in order to protect public health, it may become necessary to implement urgent measures such as the recall of one or more defective batch (s) of a medicinal product from the market. Therefore, the marketing authorisation holder should have a system in place to ensure that reports of suspected adverse reactions related to falsified medicinal products or to quality defects of a medicinal products are investigated in a timely fashion.
Q: How MAH need to deal with Suspected transmission via a medicinal product of an infectious agent?
A: Any suspected transmission of an infectious agent via a medicinal product should be considered as a serious adverse reaction and such cases should be submitted within 15 days. This also applies to vaccines
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Q: What is to be considered as infectious agent?
A: Any organism, virus or infectious particle (e.g. prion protein transmitting transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious agent.
Q: What are emerging safety issues?
A: Events/observations may occur in relation to an authorised medicinal product, which may have major impacts on the risk-benefit balance of the product and/or on patients or public health. They may require urgent attention of the competent authority and could warrant prompt regulatory action and communication to patients and healthcare professionals. These important new evidences should be considered as emerging safety issues. They should be notified to the competent authorities and the Agency.
Q: How MAH need to deal with the reports of Period between the submission of the marketing authorisation application and the granting of the marketing authorisation?
A: In the period between the submission of the marketing authorisation application and the granting of the marketing authorisation, information (quality, non-clinical, clinical) that could impact on the risk-benefit balance of the medicinal product under evaluation may become available to the applicant. It is the responsibility of the applicant to ensure that this information is immediately submitted in accordance with the modalities.
In the situation where a medicinal product application is under evaluation in the EU while it has already been authorised in a third country, valid ICSRs from outside the EU, originating from unsolicited reports or solicited reports should be submitted in accordance with the time frames.
Q: How MAH deal with Period after suspension, revocation or withdrawal of marketing authorisation?
A: The marketing authorisation holder shall continue to collect any reports of suspected adverse reactions related to the concerned medicinal product following the suspension of a marketing authorisation.
Where a marketing authorisation is withdrawn or revoked, the former marketing authorisation holder is encouraged to continue to collect spontaneous reports of suspected adverse reactions originating within the EU.
Q: How MAH need to deal with Reports from class action lawsuits?
A: Stimulated reports arising from class action lawsuits should be managed as spontaneous reports. Valid ICSRs should be submitted in accordance with the time frames.
Where large batches of potential ICSRs are received, the marketing authorisation holder may request, in exceptional circumstances, for an exemption in order to submit serious cases of suspected adverse reactions within 30 days from their date of receipt instead of 15 days. The 90 days submission time frame for non-serious ICSRs remains unchanged. The request should be made to the Agency’s pharmacovigilance department.
Q: What are patient support programs?
A: A patient support programme is an organised system where a marketing authorisation holder receives and collects information relating to the use of its medicinal products. Examples are post-authorisation patient support and disease management programmes, surveys of patients and healthcare professionals, information gathering on patient compliance, or compensation/re-imbursement schemes.
Q: How MAH need to deal with reports of patient support programs?
A: Safety reports originating from those programmes should be considered as solicited reports. The marketing authorisation holder should have the same mechanisms in place as for all other solicited reports.
Q: Submission time frames for ICSRs in EU?
A: Serious valid ICSRs shall be submitted by the competent authority in a Member State or by the marketing authorisation holder within 15 days from the date of receipt of the reports;
Non-serious valid ICSRs shall be submitted by the competent authority in a Member State or by the marketing authorisation holder within 90 days from the date of receipt of the reports.
Q: How MAH deal with serious ICSRs of EU and out of EU?
A: The marketing authorisation holder shall submit all serious ICSRs that occur within or outside the EU, including those received from competent authorities outside the EU, to the EudraVigilance database only
Q: How MAH deal with Non serious ICSRs of EU and out of EU?
A: The marketing authorisation holder shall submit all non-serious ICSRs that occur in the EU to the EudraVigilance database only
Q: How MAH deal with ICSRs when primary source country and the country of occurrence of the reaction if differ?
A: When the primary source country and the country of occurrence of the reaction differ, the competent authorities of the concerned member states in the EU will be automatically notified about these specific ICSRs.
Q: if death is reported in the case report which is not related to the product. Still ICSR need to be considered as Fatal?
A: 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
Q: What is Case narrative format in ICSR as per EMEA Guideline?
A: In accordance with Article 28 (3)(m) of the Commission Implementing Regulation (EU) No 520/2012, a case narrative shall be provided, where possible, 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.
Narrative 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.
The information provided in the narrative should be consistent with the data appropriately reflected in all the other relevant data elements of the ICSR.
Q: Is it required to determine causality assessment in ICSR?
A: Yes. 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.
Q: What test results need to be included in ICSR?
A: This includes tests and procedures performed to diagnose or confirm the reaction/event, including those tests done to investigate (exclude) a non-drug cause, (e.g. serologic tests for infectious hepatitis in suspected drug-induced hepatitis). Both positive and negative results should be included in the ICSR.
Q: Is it required to attach additional documents in ICSR?
A: Yes. 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 in “Additional Available Documents Held by Sender”.
Q: Patient name can be reported in ICSR?
A: No. In accordance with the applicable national legislation, the patient’s direct identifiers cannot be transferred to the EudraVigilance database. There by replacing identifiable personal data such as name and address with pseudonyms or key codes.
Q: How to handle follow up with significant information?
A: Competent authorities in Member States or marketing authorisation holders should submit follow-up ICSRs if significant new medical information has been received. Significant new information relates to
- a new suspected adverse reaction,
- a change in the causality assessment,
- any new or updated information on a case that impacts on its medical interpretation
- Situations where the seriousness criteria and/or the causality assessment are downgraded
- the causality assessment is changed from related to non-related
Q: How to handle a follow up with non-significant information?
A: Follow-up report which contains non-significant information does not require to be submitted as ICSR such as
- Minor changes to some dates with no implication for the evaluation
- Some corrections of typographical errors in the previous case version.
- 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
Q: How MAH need to deal with drug exposure during pregnancy cases?
A: The following are the scenarios
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.
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.
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).
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.
Q: What font style, MAH need to be with literature case reporting?
A: The literature references shall be provided in the Vancouver Convention (known as “Vancouver style”), developed by the International Committee of Medical Journal Editors
Q: When to start and stop searching in the medical literature?
A: In addition to the submission of serious and non-serious ICSRs or their presentation in periodic safety update reports, the marketing authorisation holder has an obligation to review the worldwide experience with medicinal product in the period between the submission of the marketing authorisation application and the granting of the marketing authorisation.
For the period between submission and granting of a marketing authorisation, literature searching should be conducted to identify published articles that provide information that could impact on the risk-benefit assessment of the product under evaluation.
Literature searches should be conducted for all products with a marketing authorisation, irrespective of commercial status.
It would therefore be expected that literature searching would start on submission of a marketing authorisation application and continue while the authorisation is active.
Q: How and where to look for the literature monitoring?
A: The marketing authorisation holder should establish the most relevant source of published literature for each product.
Medline, Embase and Excerpta Medica are often used for the purpose of identifying ICSRs. These databases have broad medical subject coverage. Other recognised appropriate systems may be used. It is best practice to have selected one or more databases appropriate to a specific product
Q: How literature search need to be conducted in Databases?
A: Searches should be performed to find records for active substances and not for brand names only. This can also include excipients or adjuvants that may have a pharmacological effect.
- Is the active substance an indexed term?
- What spellings might be used by authors (particularly if the active substance is not indexed)?
- What alternative names might apply (numbers or codes used for products newly developed, chemical names, brand names, active metabolites)?
- Is it medically relevant to search only for a particular salt or specific compound for an active substance?
Q: How literature search results need to be archived?
A: It is always good practice to retain a record of the search construction, the database used and the date the search was run. In addition, it may be useful to retain results of the search for an appropriate period of time, particularly in the event of zero results.
Q: When is day zero in literature monitoring?
A: 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.
Q: What are duplicates in Literature monitoring?
A: Consistent with the general requirements for the submission of cases of suspected adverse reactions, literature cases should be checked to prevent the submission of duplicates ICSRs. It is, therefore, expected that ICSRs are checked to identify literature articles that have already been submitted. This should include ICSRs resulting from the Agency’s Medical Literature Monitoring activities.
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