Pharmacovigilance Procedures UK No-Deal Guidance

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MedicinesUK Post-Deal Published Guidance
Guidance

Guidance on pharmacovigilance procedures

Published 31 December 2020

1. 1. General Approach to the operation of pharmacovigilance

The MHRA retain 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 we will publish a guidance note on the exceptions and modifications to the EU guidance on good vigilance practices in due course.

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.

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

2. 2. Actions for submitting and receiving ICSRs

We will require submission of all UK (including NI) 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 to your systems. Registrations should be made as early as possible.

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

For products placed on the market in Northern Ireland you will need to 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. This will require a technical change and we expect the EMA to provide information on this in due course. 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 the 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 the 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.

3. 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. 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).

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. 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.

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. 5. Periodic Safety Update Reports (PSURs)

5.1 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 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 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, where appropriate.

We have developed our own submission portal for PSURs. 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) 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 should be made by a Type IA variation.

For products authorised in the UK your PSUR should be submitted to the MHRA system.

Where the product is authorised for sale and supply in Northern Ireland, you should additionally submit your PSUR in line with EU requirements to the EMA via the EU PSUR repository. The outcomes from the EU procedure should be implemented.

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

5.2 5.2 PSURs submitted before 1 January 2021

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 UK MAs where this applies (also see section 10).

6. 6. Post Authorisation Safety Studies (PASS)

6.1 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 applies in Northern Ireland 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 applies in Northern Ireland the study report should also be submitted to the Pharmacovigilance Risk Assessment Committee (unless the study was only conducted in the UK).

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. This is the case where the study is to be conducted only in the UK or is subject to a Great Britain-only MA. In all other cases the fee is £734.

The reduced fee also applies where the MA has been granted via the unfettered access route and the same protocol/final study report has been submitted to the EU or Northern Ireland MA. Both protocols and final study reports should be submitted to us using either the Type II complex variation route (classification C.I.13) where the higher fee is applicable or via the Type II route in all other cases with the corresponding fee.

6.2 6.2 Ongoing issues regarding PASS protocols after 1 January 2021

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, 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 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. 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 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).

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 will include UK products in respect of Northern Ireland. You should implement the outcome where your MA covers Northern Ireland.

8. 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. 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. 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 was no EU decision before 1 January 2021, we will conclude the procedure and the outcome will be published together with advice on implementation.

If you hold an MA which applies in Northern Ireland you should continue to monitor the EMA website and implement the outcomes from EU decisions as appropriate. Where the UK has additional requirements, we will publish this on our own website shortly after the EU decision is published and give advice on how safety updates should be implemented with the aim of not creating a conflict with the EU decision.

11. 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. In order 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 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 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.

12. 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: