All ICSR reporting by marketing authorisation holders (MAHs) should be by electronic transmission through E2B. The MHRA no longer accepts paper Council for International Organizations of Medical Sciences (CIOMS) forms from registered MAHs. If you are not reporting to the MHRA electronically please follow the registration instructions below.
All MAHs are required to successfully test electronic transmission with the MHRA prior to switching from paper to electronic reporting. Testing will be conducted with test reports in a dedicated testing environment at the MHRA.
Paper reporting of real reports in fulfillment of reporting obligations should continue in parallel during the testing period. Once testing has been completed to the satisfaction of the MHRA and the MAH, paper reporting can stop and electronic reporting of real reports can begin. It is not intended to have a transition period of parallel paper and electronic reporting of real reports.
Where to find information on the electronic reporting standards
The electronic reporting format that should be used is defined by the International Conference on Harmonisation (ICH) in the ICH E2B(M) standard (external link).
In addition to this standard format, the Medical Dictionary for Regulatory Affairs (MedDRA) medical terminology (external link) must be used to code reports.
EU regulators and the European Medicines Agency (EMA) have collaborated in the creation of a data processing network and management system called EudraVigilance to support the transmission of electronic Individual Case Safety Reports (ICSRs).
Within the UK, MAHs are expected to submit reports to the MHRA using this network. The network can be considered as a hub and spoke system with the EudraVigilance Gateway as the hub and all EU regulators and MAHs as spokes. Electronic ICSR are routed through the hub to the desired spoke in an automated and secure manner.
To use the network, MAHs will need to register with the EudraVigilance gateway and install one of the many software packages that support secure data exchange. The gateway is supported by the EMA and information on registering and using the gateway can be found at on the EudraVigilance website (external link). This site also contains extensive information on the ICH-E2B(M) standard, the EudraVigilance system and links to numerous EU guidance documents on electronic reporting.
MHRA specific validation rules
The MHRA has incorporated further UK specific validation checks in addition to those in the ICH standard. As a result of the changes to Sentinel as outlined above, these additional validations have been updated and are detailed below:
|E2B element||E2B field name||Validation|
|A1.1||primarysourcecountry||Mandatory field for all cases|
|A.2.1.4||qualification||At least one required for each case|
|B1.2.2a||patientonsetage||Age cannot be greater than 120 years|
|B.1.3||patientweight||Not to be greater than 500kg|
|B.1.4||patientheight||Not to be greater than 300 cm|
|B.1.7.1c||patientmedicalstartdate||Date is not greater than today’s/report’s date|
|B.1.7.1f||patientmedicalenddate||Date is not greater than today’s/report’s date|
|B.1.8c||patientdrugstartdate||Date is not greater than today’s/report’s date|
|B.1.8e||patientdrugenddate||Date is not greater than today’s/report’s date|
|B.2.i.8||reactionoutcome||All outcomes should be populated. If the outcome is unknown this field should be populated with 'unknown' and not left blank|
|B.3.1b||testdate||Date is not greater than today’s/report’s date|
|N/A||All dates||All dates must be less than today’s date – future dates will be rejected|
|B.2.i.4b||reactionstartdate||The reaction start date must be greater than the suspect drug start dates|
|B.4.k.7||drugdosageform||The pharmaceutical form can be reported using both the text and code format. However the terms / codes will need to be selected from the table available on the MHRA website only (47Kb)|
|B.4.k.18.1b||drugreactionassess||The MedDRA code used in this field should be an exact match of those populated in the reactionmeddrallt field|
|All numerical fields||For every numerical field that is completed the unit field must also be populated. For example, if the dosage field is completed the dosage unit field must also be populated. The only exception to this rule is with regards to the test fields (ie test results do not have to accompanied by units (however should be when available)|
All other data elements not specified in the table are as defined in the ICH E2B(M) standard.
Implementation of regulations for small or medium enterprises
The MHRA will not be able to provide an adverse drug reaction (ADR) ‘conversion’ service, converting paper company ADRs into the electronic format and forwarding this to the EMA database.
Such companies should use the EMA EVWEB tool to submit their reports electronically, details of which can be found at on the EudraVigilance website (external link). EVWEB supports the full range of two-way electronic communications between regulators and the MAH.
Registering for testing
Please note if you have already registered for testing, the MHRA will be in contact shortly regarding your testing slot. Please do not complete a second registration form unless your company details have changed.
If your company has not yet registered for E2B testing with the MHRA please complete the following information:
- company name and address
- company names and company numbers (eg XYZ Pharma Ltd, 12345 PL 12345/0001 – the company number is 12345 PL = Product Licence); please also include the stem number of any clinical trials licences (CTAs) or centralised licences
- business contact (including name, position, phone, fax and email details)
- technical contact (including name, position, phone, fax and email details)
- EudraVigilance Gateway ID (testing and production)
- please provide the name of your database system and version
- earliest date when available to begin testing
- preferred date to begin testing
- do you have access to EVWEB
- if yes, what is your EVWEB User ID (testing and production)
- once testing has been completed the aim is to switch to production as soon as possible - do you envisage any further delays once testing is complete for both inbound and outbound?
Please complete this information in the E2B testing registration form (653Kb) and email to ICSRtesting@mhra.gsi.gov.uk We will contact you to agree a slot in the testing schedule and a testing plan in due course. Until testing is completed, paper reporting should continue in line with reporting obligations.
While you are waiting for certification to allow electronic reporting all reports eligible to be expedited should be emailed as PDF CIOMS forms to ICSRSubmissions@mhra.gsi.gov.uk.
The testing process requires your company to submit 10 test cases, the criteria for which are listed below:
|1||An ICSR including details of other drugs, medical history, drug history, narrative (B.5.1) and tests:|
|- sender must demonstrate that both the structured medical (B.1.7.1a-1g and B.1.7.2), and drug (B.1.8 – B.1.8g.2) history can be provided for the reports|
|- the reports must also contain examples of correctly structured tests (B.3 - B.3.1.3 and B.3.2) and show the Pharmaceutical forms (B.4.k.7) have been incorporated correctly.|
|2||A fatal ICSR including cause of death and post mortem details:|
|- seriousness death flag must be yes|
|- reaction outcome must be fatal|
|- patient death date should be provided (B.1.9.1(a+b))|
|- reported cause of death should be provided (B.1.9.2(a+b))|
|- autopsy flag (B.1.9.3) should be set to ‘yes’|
|- autopsy cause of death should be provided (B.1.9.4 (a+b)).|
|3||A nullification ICSR:|
|- the nullification flag must be set to Yes|
|- the nullification reason must be provided and it must be valid reason to nullify a case.|
|4||A parent-child ICSR:|
|- the child/foetus must be encoded as the patient|
|- the parent's details must be provided in the parent's section|
|- it is essential that:|
|i) the child (patient) route is entered in B.4.k.8. The drug route of administration must be Transmammary, Transplacental, or Other (if parent is male)|
|ii) the parent route is entered in B.4.k.9|
|iii) that section B.1.10 contains validating parent details (ie initials, age, sex, weight) as well as any relevant parent history/ other details available.|
|5||A follow-up ICSR to an initial ICSR which has previously been sent:|
|- initial report should have the same receive (A.1.6(a+b)) and receipt (A.1.7(a+b)) dates|
|- follow-up report must have the same receive date as the initial but the receipt date must be changed to reflect when the follow-up information was received|
|- the worldwide case ID must be identical in both the initial and follow-up reports.|
|6||A follow-up ICSR to an initial ICSR which has previously been sent from an alternative sender (i.e. alternative company or competent authority):|
|- this should be a test loading of a case received electronically|
|- the worldwide case ID (A.1.10) must be preserved by the sender when retransmitting a report to another receiver, however may be assigned a different company reference number (A.1.10.2).|
|7*||An ICSR from a study:|
|- report type must be ’Report from studies’ (A.1.4)|
|- study type must be ‘Other studies’ (A.2.3.3)|
|- study name and number should be provided (A.2.3.1 and A.2.3.2).|
|8||An ICSR based on a literature article:|
|- literature reference must be provided in Vancouver style|
|9||An ICSR with duplicate details completed (A.1.11.1 and A.1.11.2):|
|1. to capture all the safety report IDs that has been used in the past to transmit a case between different organisations|
|2. to capture all previous paper numbers that have been used in the past, this is to enable the detection of duplicates if a case had previously been sent on paper. eg old Yellow Card numbers and company CIOMS MFR numbers.|
|- report type must be ’Report from studies’|
|- study type must be ‘Clinical trials’|
|- study name must include an example EudraCT number in the correct format e.g. 2138383-01#Name of study...|
|- patient ID must be provided (B.1.1.1d).|
|receiverstreetaddress||3.O, 151 Buckingham Palace Road|
|receivertel||0203 080 6039|
|receiverfax||0208 8754 3960|
We envisage that the testing procedure should not take more than one week, providing your company is available for regular communication with the MHRA. The MHRA aim to give rapid feedback to the cases that are received (within one working day of receipt).
The following guidance is issued in accordance with the EMA's guidance document EMA/321386/2012 Rev 8: EMA’s guidance document (external link)
In the transitional phase, or interim period, the MHRA have the following reporting requirements:
Mandatory Reporting Requirements
Serious UK ADR Reports:
Within 15 Days
Serious third country (Non EU) HCP ADR Reports:
Within 15 Days
Optional Reporting Requirements
In addition to the above mandatory reporting requirements during the transitional period the MHRA would also like to request:
- Serious non-UK EU ADR reports for products on the additional monitoring list or where the UK is the Rapp or RMS
- Serious third country (Non EU) Consumer ADR Reports.
Please note these requirements are optional and are to enable the MHRA to carry out signal detection activities in our own database whilst the full functionality of EV is being developed.
Please note the MHRA’s policy on SUSAR reporting:
The MHRA do not accept any study reports until the study medication has been unblinded. Any SUSARs received that contain blinded study medications will be invalidated and an invalid letter sent to you. This includes instances where there is a known comparator listed as a co-suspect medication. These cases should not be expedited until the study medication has been unblinded so that a thorough causality assessment can be made.
What is the process for contacting the MHRA concerning E2B reporting?
In the first instance all enquiries should be submitted via email to the following email addresses:
- ICSRtesting@mhra.gsi.gov.uk to register for E2B testing with the MHRA
- E2B.Support@mhra.gsi.gov.uk for enquires regarding submission of production cases and receipt of automated acknowledgements
- firstname.lastname@example.org for enquiries specifically regarding ASPRs.
Portal helpdesk for general queries regarding the portal, such as workspaces, user login or permission problems, email@example.com
To escalate an E2B related issue, the following named individuals can also be contacted if you require to speak to a member of the E2B team in person:
Rebecca Owen, 020 3080 6022, firstname.lastname@example.org
Tahira Jan, 020 3080 6191, email@example.com
For further information regarding E2B reporting please see our frequently asked questions.
The MHRA is currently updating its E2B MAH contact list. This list is used to contact MAHs in instances of technical problems with E2B submission of ICSRs. MAHs who wish to receive these updates from the MHRA please provide a relevant contact name and email address to E2B.Support@mhra.gsi.gov.uk.