1. General Approach to the operation of pharmacovigilance

The MHRA retains responsibility for Pharmacovigilance across the UK.

There are 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. For products authorised for sale or supply in Northern Ireland EU pharmacovigilance requirements will continue to apply in addition to UK requirements as indicated below:

For medicines which are authorised nationally in the UK, you as a Marketing Authorisation Holder (MAH), will be required to submit pharmacovigilance data to the MHRA, according to UK 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 patient safety in the UK.

The Good Vigilance Practices (GVP) modules will remain in force but a guidance note on the exceptions and modifications to the EU guidance on good vigilance practices has been published.

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 before 1 January 2021 and have not been fulfilled 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.

More information on specific areas, including transitional measures, is given below.

2. Actions for submitting and receiving ICSRs

We require submission of all UK (including Northern Ireland) ICSRs (serious and non-serious) and serious ICSRs from other countries via the new MHRA Gateway and/or ICSR Submissions portal which have been developed.

You can register on the MHRA-Gateway and/or ICSR Submissions portal to enable configuration to your systems.

If you have already registered, you do not need to complete this process again.

For products placed on the market in Northern Ireland you should continue to submit ICSRs according to EU requirements to the Eudravigilance database including all serious reports from the UK and other countries and non-serious reports that occur in the EEA or in Northern Ireland. These cases should be identified by using the country code “XI” in the field primary source country for regulatory purposes. Organisations have the option to use either the country code “XI” or “GB” as the first two characters of the worldwide case ID and the safety report ID.

For UK cases that relate to Northern Ireland which were initially submitted before 1 January 2021, the worldwide case ID should not be changed, however, in line with GVP module VI guidance when sending follow-up reports organisations can change the safety report case ID if needed.

The country code “GB” should be used for all reportable SUSARs occurring in the UK. Although it is possible for organisations to use the country code “XI” for SUSAR reporting, it will not be a requirement as reporting requirements between Northern Ireland and the rest of UK for clinical trial cases will not differ.

A list of reports received via the EMA from 28 December to 31 December

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. The 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. 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.

We request that PRAC signal assessment reports are shared with us once the PRAC recommendation is available. Signal assessment reports should be submitted to safetyprojects@mhra.gov.uk.

A new or changed risk that requires a change to the terms of the marketing authorisation should in principle be the subject of an application for variation of the terms of marketing authorisation, unless the marketing authorisation holder considers that further analysis by the licensing authority is warranted. Further analysis by the MHRA may be sought on signals in the case of validated signals that cannot be refuted nor confirmed as new or changed risks by the marketing authorisation holder based on their assessment. If a PSUR is due to be submitted within 6-months of the completion of the MA holder’s assessment of the signal, the signal should be reported in the PSUR and a separate standalone signal notification is not required unless advised otherwise by the MHRA. However, if the PSUR includes a signal that corresponds to an important risk (see GVP Annex 1), you should notify us at signalmanagement@mhra.gov.uk at the time of submission of the PSUR. Refuted signals need only be reported in PSURs.

The same principles apply where the MAH has been requested to assess a signal by another regulatory authority. Further analysis by the MHRA may be sought using the standalone signal notification form, otherwise, a variation should be submittedor the signal reported in the PSUR asdetailed above . In these circumstances, if the signal is included within the PSUR, you should additionally notify us at the time of PSUR submission.

For products placed on the Northern Ireland 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 ).

The MHRA will carry out assessment of signals and issue decisions for signals identified by the MHRA as well as 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.

You can notify the MHRA at signalmanagement@mhra.gov.uk.

4. Risk Management Plans (RMPs)

The MHRA continues 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 UK-specific annex using this format.

The current approved version of the RMP should be included in the initiating sequence as part of the conversion process for EU MAs.

Conversion of Centrally Authorised Products (CAPs) to UK MAs.

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 for products authorised in Great Britain only, but until this happens the EU reference date (EURD) list should be followed for .PSUR submissions to the MHRA. PSURs should therefore be submitted to the MHRA at the same time as to the EU.

The content and format for all PSURs will remain the same as currently required in the EU, and the expectation is that where a PSUR is required to be submitted to both the MHRA and EU, the same PSUR will be submitted to the MHRA as to the EU. In general, you will not be required to re-submit to the MHRA PSURs that have been submitted to the EU PSUR repository,prior to 1 January 2021 but we may need to request a copy 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 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.

Where the EU assessment results in an amendment to the product information, we request that you notify us of the PRAC recommendation as soon as possible and submit a copy of the CMDh Decision or CHMP opinion as soon as available. This information should be submitted by e-mail to safetyprojects@mhra.gov.uk. This will allow us to take the EU recommendation into account in our assessment of anyproduct information updates to avoid any unnecessary divergence. Provided that this information is submitted to us in a timely manner we will inform MAHs if, following our assessment, we have any additional requirements to the EU. This will be communicated before or shortly after (within 14 days) the publication of the EU outcome but otherwise the EU outcome should be implemented. A delay in the providing the necessary information the MHRA may result in additional requests being made outside this timeframe.

We have developed our own submission portal for PSURs. More detailed requirements for submission can be found here but PSURs can be submitted to the portal in PDF or Word format or as part of a zip file format. Submissions will not be required as part of the eCTD 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 -only MAs. Please note that RMPs cannot be submitted via the PSUR submission portal and must be submitted via a separate variation submission.

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 and submitted to the MHRA. .No further fee will be payable for the amendment of the product information as a result of the UK assessment which should be made by a Type IA variation.

PSURs for products authorised in the UK should be submitted to the MHRA via the submission portal.Where the product is authorised in Northern Ireland, you should also submit your PSUR to the EMA via the EU PSUR repository.

As stated above, in the future we may amend reporting requirements for PSURs for products authorised by Great Britain-only MAs. However, for the time being you should continue to submit according to the timelines set out in the EURD list.

PSURs for actives authorised via an EU MA (centralised authorisation) which will apply directly in Northern Ireland need only be submitted to the EU PSUR repository.

You should continue to submit information regarding the informal PSUSA follow-up procedure to us via the usual procedure (i.e. via CESP not the MHRA submission portal). Outcomes should be implemented via the same type of variation procedure as in the EU and where the MHRA have additional requirements we will inform you.

5.2 PSURs submitted before 1 January 2021

Where the PSUR is for a product authorised by a UK MA, with respect to both Great Britain and Northern Ireland the procedure will continue in line with the single-assessment procedure.

Where the assessment was 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 UK 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

PASS Protocols

For non-interventional PASS where the study is a condition of the UK MA, the draft protocol should be submitted to the MHRA prior to the start of the study. Where the MA applies in Northern Ireland, the draft study protocol should also be submitted to the Pharmacovigilance Risk Assessment Committee (PRAC); with the exception of a study that is only to be conducted in the UK at the request of the MHRA in which case the protocol should only be submitted to the MHRA. For studies that are a condition of a GB MA or a UK MA, where the study is to be conducted in the UK at the request of the MHRA, the MHRA will assess the protocol and contact you within 60 days.

Where the PASS is a condition of the MA, any significant amendments to the draft protocol should also be submitted to the MHRA and where the MA applies in Northern Ireland additionally to the PRAC unless the study is only being conducted in the UK at the request of the MHRA. The definition of significant amendment is in line with that provided in Good Vigilance Practice Module VIII.

There is no specific requirement to submit draft protocols for PASS which are not a condition of the MA but are a requirement of the RMP (category 3). However, we may request submission where we consider that an assessment is required, in this case the protocol should be submitted as Type II (standard) variation.

PASS Results

Final study reports for non-interventional PASS (either voluntary or a condition of the MA). that involve collection of safety data from patients/healthcare professionals should be submitted to the MHRA.

The final study report should be submitted within 12-months of the end of data collection.

Interim reports for PASS which are a condition of the UK MA should also be submitted to the MHRA.Interim reports for PASS which are a condition of the MA and all final study report for non-interventional PASS, where the MA applies in Northern Ireland the study report should also be submitted to the Pharmacovigilance Risk Assessment Committee (PRAC) (unless the study was only conducted in the UK and not at the request of PRAC)

Interim reports for category 3 studies are generally not required, but where we require interim reports for these PASS, we will inform you.

6.1.2 Submission and fees

Imposed PASS that are conditions of the MA(category 1 and 2 studies)

Protocol and Final Study reports

Protocol and final study reports which are submitted to the PRAC as Article 107 procedures should be submitted to the MHRA as standalone PASS submissions using a variation procedure as detailed below:

Where protocols and final study reports are also submitted to the PRAC, the MHRA will refer to the EU decision and the relevant EU documentation (assessment report, CHMP opinion etc.) should be included in the submission. The protocol and final study report should be submitted to the MHRA using a Type II (standard) variation procedure (classification C.I.13) with the corresponding fee of £734.

Where the PASS is to be conducted only in the UK, or relates to a product authorised only in Great Britain and the protocol and final study report have not been submitted to the PRAC, the protocol and final study reports should be submitted to the MHRA via a Type II (complex) variation procedure (classification C.I.13) with the corresponding fee of £8,309.

Significant amendments and interim study reports

Significant amendments to study protocols and interim study reports for category 1 and 2 PASS should be submitted to the MHRA as post authorisation measures/ commitments via the information update route and will not incur a fee (please section 9). It should be clearly stated in the cover letter that the amendment or interim report relates to a category 1 or 2 PASS.

Non-imposed PASS (category 3 studies)

Where draft protocols are requested, they should be submitted via the Type II (standard) variation route Final study reports for category 3 studies should be submitted as a Type II (standard) variation.

Where protocols and final study reports are also submitted to the PRAC, the MHRA will refer to the EU decision and the relevant EU documentation (assessment report, CHMP opinion etc.) should be included in the submission

Where interim reports are required these should be submitted to us as post authorisation measures/ commitments via the information update route and will not incur a fee (please see section 9)

6.1.3 Updates to product information to reflect study results

Where the results of any PASS study affect the product information, the amendments should be submitted via a separate type II variation. The reliance procedure can be used where you wish to make the same amendments to the product information as those agreed for the corresponding EU MA (see section 10).

6.2 Ongoing issues regarding PASS protocols after 1 January 2021

Where the EU PRAC (Pharmacovigilance Risk Assessment Committee) 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 was proposed or imposed but the draft protocol was not endorsed prior to 1 January 2021, the assessment will be concluded by the PRAC but any information required by the PRAC, together with any information required by the MHRA regarding the protocol, should be submitted directly to the MHRA.

This must happen even if the information was submitted via the EU procedure prior to 1 January 2021.

6.3 Ongoing issues with PASS final study reports after 1 January 2021

Where a final study report was submitted to the PRAC before 1 January 2021 but no recommendation was made before that date, we will accept the conclusion made by the PRAC but may request 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, the procedure will follow the usual process, but all information should be submitted to the MHRA. We will then implement the outcome of the procedure.

Where the referral was concluded but the decision not implemented before 1 January 2021, the MHRA will take the necessary steps to implement the final decision (see section 10).

From 1 January 2021 UK products will continue be part of Union referral procedures in respect of Northern Ireland. The scientific opinion and Commission Decisions or CMDh Decisions will include UK products in respect of Northern Ireland. You should implement the outcome via the relevant variation procedure where your MA covers Northern Ireland.

Where you hold a Great Britain-only MA and the outcome of an EU referral is to be reflected in your MA you should submit a Type II variation application together with all relevant documentation regarding the referral. This will be assessed by the MHRA, taking into account the EU decision, to determine the necessary updates to the product information.

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 you hold.

9. Post-authorisation Measures (PAMs)

Post-authorisation measures and commitments 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 until considered fulfilled. For MAs granted via the reliance route after 1 January 2021 all post- authorisation measures and commitments agreed for the EU MA will also apply. Standalone PAMs should be submitted as a post-authorisation commitment via the MHRA portal using the information update route. The nature of the PAM should be clearly stated in the cover letter. We will take into account the EU decision on any PAM, providing the relevant EU documentation (CHMP opinion, AR assessment report etc.) is submitted, once available, via the MHRA portal. In most circumstances the MHRA will not issue a separate approval for PAMs unless we have additional requirements, or the PAM is at the request of the MHRA.

Where data relating to a PAM was submitted before 1 January 2021, a copy of the application should be included in the data submission package for converted EU MAs.

Where your evaluation of data supporting a MEA or LEG recommends that an update to the product information is required this should be submitted via a Type II variation application.

10. Implementation of outcomes of EU referrals and procedures concerning PSURs, PASS, signal assessments and PAMs

MAs should continue to monitor the EMA website and implement the outcomes from EU decisions as appropriate. Where you hold a UK MA which covers Northern Ireland, the EU outcome must be implemented and the same type of variation procedure as recommended in the EU procedure should be used to implement the change for the UK MA.

For Great Britain-only MAs, the expectation is that you will follow EU outcomes and make the same changes to the Great Britain-only MA that are made to the corresponding EU MA. In order to do so you will need to submit the corresponding procedure to the MHRA.Where the outcome for the corresponding centrally-authorised product is implemented as part of the EC Decision without a separate variation . , a Type IAIN variation should be submitted to implement the same outcome for the Great Britain-only MA, unless you are advised otherwise. Where we have UK specific requirements for submission of procedures these are detailed in the relevant sections of this guidance.

Unless otherwise stated in this guidance (please see specific advice regarding PASS and referrals) the reliance route can be used to implement the outcome for the corresponding EU procedure for Great Britain- only MA. In this case you must provide all relevant EU documentation (CHMP opinion, assessment report and, where applicable, the EC decision). However, the reliance route is not a substitute for MAH obligations to submit pharmacovigilance data and information to the MHRA and to keep the MA up to date with current scientific knowledge. Information regarding safety, including that in the EU documentation, may be required earlier than the CHMP opinion stage. In particular, where there is information which affects the benefit: risk balance of the product or potentially impacts the clinical management of patients, including where proactive communications to healthcare professionals may be required, we would expect to receive the information as soon as available and submission should not be delayed until the CHMP opinion is available. There may be other circumstances where the MHRA may request that you provide information regarding the EU assessment prior to the CHMP opinion.

Where the MHRA assessment results in additional UK-specific requirements we will contact MAHs directly before or shortly after (within 14 days) the publication of the EU outcome. However, where necessary data, as outlined above, has not been provided this may lead to a delay in us contacting you regarding UK specific requests.

11. Requirements for MAs granted via the Unfettered Access route

Where you have a Great Britain-only MA granted via the unfettered access route, all pharmacovigilance obligations continue to apply. To ensure the safety of patients in Great Britain you must provide any new information that may impact on the terms of the MA and/ or impact on the balance of benefits and risk of the product. This includes information from clinical trials and data on the use of the product outside the terms of the MA. Unless otherwise stated, the same data/submission as that provided to the EU should be submitted to the MHRA. Other requirements are set out below

11.1 Submitting ICSRS

You should submit to the MHRA reports of all serious suspected adverse reactions that occur in the UK and other countries, and all non-serious suspected adverse reactions that occur in the UK via the MHRA Gateway and/or ICSR submissions portal.

11.2 Provision of other Pharmacovigilance data

You should submit copies of the Periodic Safety Update Reports (PSURs) to the MHRA portal. We will accept copies of the PSUR submitted to the EU in line with the frequency set by the EU.

All other pharmacovigilance data submitted to the EU, including RMPs, PASS protocols and final study reports etc. should also be submitted to the MHRA, and we will accept copies of the same information submitted to the EU.

Contact

For further information, please email our Customer Services Centre at info@mhra.gov.uk or call 020 3080 6000. You can also email pharmacovigilanceservice@mhra.gov.uk with urgent questions. Alternatively, contact your Trade Association by emailing:

• Association of the British Pharmaceutical Industry (ABPI): regulatory@abpi.org.uk
• British Generic Manufacturers Association (BGMA): info@britishgenerics.co.uk
• BioIndustry Association (BIA): regulatory@bioindustry.org
• Clinical & Contract Research Association (CCRA): mail@ccra.org.uk
• Ethical Medicines Industry Group (EMIG): info@emig.org.uk
• Health Food Manufacturers’ Association (HFMA): pennyviner@btconnect.com
• The National Pharmacy Association (NPA): independentsvoice@npa.co.uk
• Proprietary Association of Great Britain (PAGB): regulatory@pagb.co.uk