1. General Approach to the operation of pharmacovigilance
This document outlines the submission requirements for pharmacovigilance data from 1 January 2021.
The MHRA will retain responsibility for Pharmacovigilance across the UK from 1 January 2021. There will be some different requirements for products placed on the market in the UK with respect to Great Britain and Northern Ireland. Great Britain is England, Wales and Scotland. Products placed on the market in Northern Ireland will need to be in line with EU legislation and follow EU requirements. More details will follow in due course.
From 1 January 2021, for medicines authorised in Great Britain, you, as a Marketing Authorisation Holder (MAH), will be required to submit pharmacovigilance data to the MHRA, according to GB requirements, including:
- UK and non-UK Individual Case Safety Reports (ICSRs)
- Periodic Safety Update Reports (PSURs)
- Risk Management Plans (RMPs)
- Post-Authorisation Safety Studies (PASS) protocols and final study reports
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 in due course.
For medicines authorised to be sold or supplied in Northern Ireland information will need to be submitted according to EU requirements. .
For medicines which are the subject of a UK MA covering both Great Britain and Northern Ireland, information will need to be submitted in accordance with requirements for both Great Britain and the EU, as appropriate.
Further guidance on the conversion of Centrally Authorised Products (CAPs) to UK MAs is available on our website. Any conditions or restrictions subject to which the CAP was granted immediately before 1 January 2021 will apply to the converted MA, as will any post-authorisation obligations prior to that date.
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 1 January 2021. Registrations should be made as early as possible.
For products placed on the market in Northern Ireland you will need to submit ICSRs according to EU requirements to the Eudravigilance database.
3. Signal detection
In line with current requirements, your signal detection systems will need to enable you to meet your requirements for cumulative signal detection across all available data sources. MHRA 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 you are obliged to notify the MHRA of signals arising from any data source if you haven’t already notified the MHRA of the signal. From 1 January 2021 this also includes standalone signal notifications submitted by you to the EMA that are relevant to your products as well as signals raised by the EMA.
For products placed on the NI market, you are additionally required to report to the EMA those safety signals that are considered to meet the definition of an emerging safety issue (see GVP-Module IX Signal Management).
From 1 January 2021 the MHRA will carry out assessment of signals and issue decisions for both signals identified by the MHRA and those highlighted internationally.
You are obliged to notify the MHRA of emerging safety issues within 3 working days after establishing that a signal or a safety issue from any source meets the definition of an emerging safety issue.
4. Risk Management Plans (RMPs)
The MHRA will continue to accept EU versions of the RMP, but where we have made a specific request for information to be included this may need to be provided in a 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 and updates to RMPs for products authorised to be sold or supplied in the UK should be submitted to the MHRA, via the appropriate variation procedure.
5. Periodic Safety Update Reports (PSURs)
5.1 PSURs submitted after 1 January 2021
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 1 January 2021, should be submitted to the UK at the same time as submission to the EU.
All PSURs, for products which are the subject of a UK MA, with the same active/combination, should be submitted as part of the same procedure. The content and format will remain the same as currently required in the EU, and the expectation is that the same PSUR will be submitted to the MHRA as to the EU. In general, you will not be required to re-submit PSURs submitted to the EU PSUR repository prior to 1 January 2021, but we may request this in some circumstances.
Unless the marketing authorisation specifies differently, PSURs for actives/combinations not currently on the EURD list and therefore not subject to the single assessment process should be submitted to the MHRA, 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 submission requirements on the EURD list. submission requirements, where appropriate.
We have developed our own submission portal for PSURs which will be ready for use from 1 January 2021. 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 Great Britain 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) which are submitted to the MHRA. 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 including any amendments to the SPC and PL wording. 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.
For Great Britain-only MAs the PSUR should be submitted to the MHRA system.
For products authorised to be sold or supplied in Northern Ireland, PSURs should be submitted in line with EU requirements and submitted to the EMA via the EU PSUR repository. The outcomes from the EU procedure should be implemented.
PSURs for UK MAs covering both Great Britain and Northern Ireland will need to be submitted to both the MHRA and EMA.
5.2 PSURs submitted before 1 January 2021
For Great Britain-only MAs where a PSUR has been submitted before 1 January 2021 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 PSUR is for a product authorised by a UK MA, in respect to both Great Britain and Northern Ireland the procedure will continue in line with the single-assessment procedure.
Where the assessment has been concluded but the outcome not implemented before 1 January 2021, 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 Great Britain MAs where this applies (also see section 10).
6. Post Authorisation Safety Studies (PASS)
6.1 PASS protocols and results submitted after 1 January 2021
For PASS where the study is a condition of the UK MA, prior to the start of the study the draft protocol should be submitted to the MHRA and will be assessed in line with usual practices. Where the MA extends to Northern Ireland or is an Northern Ireland only MA the draft study protocol should also be submitted to the Pharmacovigilance Risk Assessment Committee (unless the study is only to be conducted in the UK at the request of the MHRA).
For all PASSs that are non-interventional, that are either voluntary or a condition of the MA and that involve collection of safety data from patients/healthcare professionals you should send the final study reports to the MHRA for assessment
You should submit the final study report (and abstract of study results) to the MHRA. Where the MA extends to Northern Ireland or is a Northern Ireland only MA the study report should also be submitted to the Pharmacovigilance Risk Assessment Committee (unless the study was only conducted in the UK at the request of 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 1 January 2021
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 1 January 2021, 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 1 January 2021, 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 1 January 2021. The MHRA will then assess the information in line with usual procedures.
6.3 Ongoing issues with PASS final study reports after 1 January 2021
For products authorised in the UK, where a final study report was submitted to the EMA before 1 January 2021 but no recommendation was made before that date, 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 you should evaluate the impact of the results on the authorisation and submit a variation application as necessary.
Where PRAC made a recommendation prior to 1 January 2021, the MHRA will implement the agreed measures in line with the agreed timetable. You should submit any variation to us (for converted 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 1 January 2021, such as where a CHMP/CMDh opinion had not been reached the MHRA will complete the assessment, where appropriate, and make a decision on the procedure based upon the information we have, including any decision made at EU level prior to 1 January 2021. 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 1 January 2021, the MHRA we will take the necessary steps to implement the final decision (see section 10).
8. Major Safety Reviews
From 1 January 2021, where there are concerns regarding a medicine or class of medicines that are authorised in the UK, the MHRA may conduct a major safety review to review the available data and consider what regulatory action may be needed.
In these circumstances we will publicly announce the initiation of the review, outlining the reasons for the review, the list of affected active substances and products, and the timescales for the review.
Where you hold a MA for an affected product, you will be notified of the start of and reasons for the review. You will also be provided with a list of questions that should be addressed by all MAHs along with the deadline by which the requested information should be submitted.
In the first instance, this correspondence will be done via the Qualified Person for Pharmacovigilance (QPPV) but a different or additional contact for future correspondence can be nominated. The outcome of the review will be published. Where the recommendations include proposals for regulatory action the details of the measures to be taken including any changes to the product information 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 on 1 January 2021 will remain in place. For converted EU MAs 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 1 January 2021 but the assessment has not been concluded we will conclude the assessment where appropriate. 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 1 January 2021, 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 before 1 January 2021, the variation will be concluded in line with the outcome of the procedure.
Where there has been no EU decision before 1 January 2021, we will carry out our own assessment where appropriate and the outcomes of assessments will be published together with advice on implementation