Updated guidance on pharmacovigilance procedures in the event the UK leaves the EU without a deal
Updated 9 October 2019
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1. General Approach to the operation of pharmacovigilance
This document outlines the submission requirements for pharmacovigilance data in a no-deal Brexit. The Medicines and Healthcare products Regulatory Agency (MHRA) has primary responsibility for the conduct and oversight of all pharmacovigilance activities in relation to UK Marketing Authorisations (MAs), certificates of registration and traditional herbal registrations.
Sharing of common systems, and formal exchange and recognition of data submitted for regulatory activities between the UK and EU countries will cease.
From Brexit, for medicines authorised in the UK, you, as a MA Holder (MAHs), will be required to submit pharmacovigilance data to the MHRA, including:
- UK and non-UK Individual Case Safety Reports (ICSRs)
- Periodic Safety Update Reports (PSURs)
- Risk Management Plans (RMPs)
- Post-Authorisation Safety Studies (PASS)
These will be assessed taking into account all relevant information and decisions will be made reflecting UK clinical practice to best support UK public health.
The Good Vigilance Practices (GVP) modules will remain in force but we will publish a guidance note on the exceptions and modifications to the EU guidance on good vigilance practices that apply to you shortly after Brexit.
Further guidance on the conversion of Centrally Authorised Products (CAPs) to UK MAs in the event of a no-deal Brexit is available on our website. Any conditions or restrictions subject to which the CAP was granted immediately before Brexit will apply to the converted MA, as will any post-authorisation obligations prior to Brexit.
In general, submission of historical data will not be required but we may request this where it is needed for assessment purposes. Where a request is made, the data must be supplied to us within the specified time period. MHRA already holds its own database of ICSRs, so will not require historical information from you.
More information on specific areas, including transitional measures is given below:
2. Actions for submitting and receiving ICSRs
We will require submission of all UK ICSRs (serious and non-serious) and serious ICSRs from other countries via the new MHRA Gateway or/ICSR Submissions portal which have been developed.
You can register on the MHRA-Gateway and/or ICSR Submissions portal to enable configuration for their systems prior to Brexit. Registrations should be made as early as possible.
3. Signal detection
In line with current requirements, your signal detection systems will need to enable them to meet their requirements for cumulative signal detection across all available data sources. We will not require you to conduct signal detection against our own database, as we will make relevant UK data available for inclusion in your systems.
You are reminded that they are obliged to notify us of signals arising from any data source if they haven’t already notified us of the signal. After Brexit this also includes standalone signal notifications submitted to the EMA as well as signals raised by the EMA.
After Brexit the MHRA will carry out assessment of signals and issue UK decisions for both signals identified by the MHRA and those highlighted internationally.
You are also reminded that they are obliged to notify us of emerging safety issues within 3 working days.
4. Risk Management Plans (RMPs)
The MHRA will continue to accept EU versions of the RMP, but where the UK has made a specific request for information to be included this may need to be provided in a UK specific annex. For CAPs the current approved version of the RMP should be included in the initiating sequence as part of the conversion process.
RMPs for authorised products should continue to be submitted to us via a Type II variation procedure and updates to the approved RMP submitted via a Type IB procedure.
5. Periodic Safety Update Reports (PSURs)
5.1 PSURs submitted after Brexit
The MHRA will continue to accept EU versions of the PSUR, but where the MHRA has made a specific request for information or where there is UK-specific information relevant to the benefit/ risk assessment this should be included in a specific annex. We may develop our own submission requirements and develop a list of UK reference dates, but until this happens the EU reference date (EURD) list should be followed and PSURs, with submission dates after Brexit, should be submitted to the UK at the same time as submission to the EU.
We will assess all PSURs, for products authorised in the UK with the same active/combination as part of the same procedure. The content and format will be the same as that required in the EU, and the expectation is that the same PSUR will be submitted to the UK as to the EU. You will not be required to re-submit PSURs previously submitted to the EU PSUR repository, but we may request this in some circumstances. PSURs for actives/combinations not currently on the EURD list should be submitted to us, unless specified differently on the authorisation, at least six monthly during the first 2 years following placing on the market, once a year for the following 2 years and every 3 years after that.
We will issue the outcomes of our assessments shortly after publication of the EU assessment, at the latest, in order to maintain harmonisation with the EURD submission requirements, where appropriate.
We have developed our own submission portal for PSURs which will be ready for use after Brexit. More detailed requirements for submission will be issued but PSURs can be submitted to the portal in PDF or word or as part of a zip file format. PSUR submissions will not be required as part of the CTD lifecycle in the UK and should not be submitted as part of the initiating sequence in the conversion process for centrally authorised to UK MAs.
A fee of £890 will be payable for the assessment of PSURs for actives/ combinations currently listed on the EURD (or future UK reference date list) but there will be a reduction to £445 for each PSUR where more than one PSUR is involved in the procedure. Following assessment, we will publish the outcome of PSUR assessment procedures. No further fee will be payable for the amendment of the product information as a result of the UK assessment which will generally be made by a Type IA variation.
5.2 PSURs submitted before Brexit
Where a PSUR has been submitted before Brexit but the EU single-assessment procedure has not been concluded, we will assess the PSUR considering any relevant information, including any EU decision and may request further information, where appropriate, in order to conclude the assessment.
Where the assessment has been concluded but the outcome not implemented before Brexit, the MHRA will take the necessary steps to implement the outcome. Where this involves a variation to the MA, the application should be submitted taking into account the guidance on converting CAPs to UK MAs in the event of a no deal scenario where this applies (also see section 10).
6. Post Authorisation Safety Studies (PASS)
6.1 PASS protocols and results submitted after Brexit
Where a study is a condition of the UK MA, the protocol and final study reports should be submitted to the MHRA and will be assessed in line with usual practices. Studies that are conditions of the UK are equivalent to category 1 and 2 studies at EU level (imposed studies). For category 3 studies, which are required through the RMP but are not imposed studies and hence are not conditions of the MA, we do not require submission of the study protocol for assessment. We will continue to accept the EU format for PASS protocols and final study reports.
We anticipate that in most circumstances the UK and EU assessment of protocols will be aligned, and we will take into account all information available to us from the EU procedure in the UK assessment. However, we will need to conduct our own assessment and take into account the UK clinical perspective.
Final study reports (for category 1,2 and 3 studies) should also be submitted to the MHRA.
The final study report should be submitted within 12 months of the end of data collection. The fee for assessment of PASS protocols or final study reports is £8,309. Both protocols and final study reports should be submitted to us using the Type II complex variation route (classification C.I.13) with the corresponding fee.
6.2 Ongoing issues regarding PASS protocols after Brexit
For products authorised in the UK where the EU PRAC (Pharmacovigilance Risk Assessment Committee) has either endorsed a draft study protocol or made a substantial amendment to a draft protocol before Brexit, we will accept the draft or the amended draft study protocol but may request that further information is submitted to us within a specified time.
Where a non-interventional PASS has been proposed or imposed but the draft protocol has not been endorsed prior to Brexit, any information required by the PRAC, together with any information required by the MHRA regarding the protocol, must be submitted directly to the MHRA.
This must happen even if the information was submitted via the EU procedure prior to Brexit. The MHRA will then assess the information in line with usual procedures.
6.3 Ongoing issues with PASS final study reports after Brexit
For products authorised in the UK, where a final study report was submitted to the EMA before Brexit but no recommendation was made before Brexit, it may be required that the study report and abstract of the study report are submitted to the MHRA together with any further information relating to the study. In any event tyou should evaluate the impact of the results on the authorisation and submit a variation application as necessary.
Where PRAC made a recommendation prior to Brexit, the MHRA will implement the agreed measures in line with the agreed timetable. You should submit any variation to us (for CAPs please refer to the guidance on our website and we will determine the application within the usual timeframes).
7. Safety Referrals
For procedures started but not concluded before Brexit, the MHRA will complete the assessment and make a decision on the procedure based upon the information we have before Brexit, including any decision made prior to Brexit. We may request further information regarding the procedure on a case-by-case basis where deemed appropriate and take the necessary steps to implement the decision.
Where the referral has been concluded but the decision not implemented before Brexit, the MHRA we will take the necessary steps to implement the final decision (see section 10).
8. Major Safety Reviews
Following Brexit, where there are significant concerns regarding the benefit-risk of a medicine or class of medicines, the MHRA may conduct a major safety review to resolve the issues. In these circumstances we will announce the initiation of the review, outlining the reasons for the review. You will be requested to submit information as necessary. The outcome of the review will be published.
A major safety review will incur the following fees for assessment:
- £51,286 where one or two active ingredients or combinations of active ingredients are included
- £59,595, where three active ingredients, or combinations of active ingredients, are included
- £67,904, where four active ingredients, or combinations of active ingredients, are included
- £76,213, where five or more active ingredients, or combinations of active ingredients, are included
Where the review relates to 2 or more authorisations, the fee will be divided by the number of authorisations forming part of the review and you will pay that reduced fee for each relevant authorisation it holds.
9. Post-authorisation Measures (PAMs)
Post-authorisation obligations, including specific obligations, Annex II conditions, additional pharmacovigilance activities in the RMP (MEA), legally binding measures (LEG) or recommendations, in place at the time of Brexit will remain in place and will need to be submitted to us. We recommend that you use the current application forms for PAMs and submit the information to us as a post-authorisation commitment, following the same principles for submission as for variations in the CAPs conversion guidance.
Where data relating to a PAM has been submitted before Brexit but the assessment has not been concluded we will conclude the assessment. For converted EU MAs a copy of the application should be included in the data submission package.
Where your evaluation of data supporting a MEA or LEG suggests that an update to the product information is required this should be submitted via a Type II variation application.
10. Implementation of outcomes of referrals and procedures concerning PSURs, PASS, signal assessments and PAMs
Where an amendment to the product information is required as a result of the above procedures, this will be implemented via a variation procedure. Where the procedure has been concluded before Brexit, but the variation has not been submitted, the outcome will be implemented by the same procedure as for the EU (Type IA, Type IB or Type II).
Where the variation has been submitted, but not finally processed in the UK before Brexit, the UK will conclude the variation in line with the outcome of the procedure.
Where there has been no EU decision before Brexit, we will carry out our own assessment and the outcomes of assessments will be published together with advice on implementation. The UK outcome should be followed and where a variation is required you will be notified regarding the type of variation required.