On the 1st September 2020, the Medicines & Healthcare products Regulatory Agency (MHRA) released a series of guidance documents for industry organisations and professionals within the United Kingdom (UK) to follow, regarding the transition period for Brexit, beginning on 1st January 2021.
In summary of their guidance, the MHRA have addressed a number of key subjects, ranging from QPPVs; clinical trials; medical devices; pharmacovigilance and more.
For the role of the Qualified Person for Pharmacovigilance (QPPV), the MHRA has communicated that all UK marketing authorisation holders (MAH) must have a permanently situated QPPV resident in the UK, who is responsible for all pharmacovigilance systems and activities – including the maintenance of a Pharmacovigilance System Master File (PSMF), with the guidance stating that the PSMF must be located at the main site for UK pharmacovigilance activities, from which the designated QPPV operates, in addition to being accessible in an electronical format, at the location where suspected adverse reactions are reported, and permanently available, upon request, for inspection by the MHRA. The PSMF will describe how the MAH will perform pharmacovigilance for any product that has a UK licence (and any other licences for that product in the rest of the world, including the EU).
Regarding the topic of clinical trials, the MHRA has released guidance on both the registration of and changes made to the correct conducting of clinical trials.
For the registration of new clinical trials, the MHRA has communicated that, from the start of the transition period (1st January 2021), sponsors should continue to use existing and established international registers and display a link to its location within the Integrated Research Application System (IRAS). Registration is to be completed prior to the recruitment of the first participant and must not exceed 6 weeks after the recruitment of the first participant, with any deferral requests within this given period required to be sent to the Integrated Research Application System (IRAS).
Furthermore, for the publishing of results, sponsors have been notified that all result summaries are required to be published to the designated international register for the trial, within the 6 months that follow the conclusion of a paediatric trial and within the following year of concluding a non-paediatric trial (which is in agreement with ICH E3), in addition to submitting a final report to Health Research Authority in the same reporting period.
Further clinical trial information provided by the MHRA includes changes made to procedures for clinical trials – with key considerations for legal representatives, Investigational Medicinal Product (IMP) certification and importation and Research Ethics Committees.
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The MHRA has also provided information for the subject of medical devices, to help with device certifications, conformity marking and device registration within Great Britain (England, Wales and Scotland), Northern Ireland and the European Union (EU).
Within the information provided, the MHRA has provided information on legislation applicable to Great Britain, with existing directives, within the Medical Devices Regulations 2002, to continue to have effect during the transition period, as both the Medical Devices Regulation (MDR) and in vitro Diagnostic Medical Devices Regulation (IVDR) are not to become effective until after the transition period – on 26th May 2021 and 26th May 2022 respectively.
Furthermore, the MHRA has also provided information on the manufacturing and supplying of Medical Devices in the UK, including registration and responsibilities of responsible persons; Conformity Assessments, including the new UK Conformity Assessed (UKCA) Mark and the role of Assessment Bodies; CE Marks and the role of Notified Bodies; Labelling requirements; and post-marketing safety requirements.
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Finally, the MHRA has communicated that it will be retaining oversight and governance for the Pharmacovigilance sector within the UK, expressing that Marketing Authorisation Holders (MAH) will be required to submit all pharmacovigilance data, including Individual Case Safety Reports (ICSRs); Periodic Safety Update Reports (PSURs); Risk Management Plans (RMPs) and Post-Authorisation Safety Studies (PASS), to the MHRA following the transition period.
However, whilst it has been outlined that this will be required to be completed in accordance with any changes made to the UK market, it has also been communicated that the Good Vigilance Practices (GVP) modules will continue to be enforced, with information on exceptions and modifications from the MHRA forthcoming – but not issued yet!
The MHRA has stated that the following will need to ensure that they have gained access to the MHRA Submission portal:
- All pharmaceutical companies involved in making medicines, regulatory submissions and vigilance activities
- All medicines clinical trial sponsors wishing to make clinical trial submissions to the MHRA i.e. initial applications, substantial amendments, end of trial notifications and Developmental Safety Update Reports (DSURs)
- E-cigarette producers
- Brokers of medicinal products
If you have not yet set-up a company MHRA Submission account, PharSafer recommends that you initiate this process as soon as possible. While we are unable to undertake this set-up on your behalf, we are able to provide guidance and support where needed.
Regarding ICSR submissions requirements, as per the updated guidelines on pharmacovigilance procedures, the MHRA has stated that MAHs will be required to submit all serious and non-serious UK ICSRs and serious ICSRs from other countries via the newly developed MHRA Gateway or ICSR Submissions Portal, with MAHs that have not already done needing to register and configure their system prior to the transition period becoming effective. Submission of ICSRs will be required to be made to EudraVigilance for products on the market in Northern Ireland. These submission requirements will commence from 1st January 2020 and include the transmission of follow-up, nullification and down-grade ICSRs that were previously submitted directly to the EMA. The MHRA will send acknowledgments for all ICSRs submitted directly to them via the procedures outlined in this document. Therefore, information on product status in Northern Ireland should be obtained from your regulatory departments in order to assess which products may require confirmation of Great Britain versus Northern Ireland as country of origin to determine applicable expedited submission requirements to the MHRA and/or EMA.
For companies that intend to undertake ICSR submissions using the MHRA gateway, the company must first gain access to the MHRA Submissions portal, after which the company can use the link within the portal to register to send both ICSRs and SUSARs using this method (although the sending of such safety data will not be undertaken via the MHRA Submissions portal). After registration, a connectively test is recommended. Submission acknowledgements undertaken via the MHRA Gateway will be provided by the MHRA within 48 hours of submission. The MHRA will also send copies of UK ICSR’s to MA Holders via the MHRA Gateway.
If you choose not to utilise the MHRA Gateway for the submission of ICSRs and/or SUSAR, the ICSR Submissions portal can be used. There are multiple elements and stages involved in the registration process; including the request of a company account by a company administrator which requires the existing sender ID (if available), provision of additional information to the MHRA i.e. proof of MedDRA licence and then the addition of other users/administrators within the company and third parties (e.g. consultants and Contract Research Organisations (CROs). Therefore, due to the many elements involved with registering before the deadline, the MHRA have made a series of guides available on their website.
Furthermore, as per the guidelines from the MHRA for Centrally Authorised Products (CAP), it has been communicated that existing CAP MAs will be converted into UK MAs, otherwise known as ‘converted EU MAs’, and issued with a UK MA number automatically – effective in Great Britain, following the transition period. Moreover, existing CAPs will remain valid for marketed products in Northern Ireland and MAHs will have the right to opt out of the automatic conversion, with notification of such action required by 21st January 2021, from which UK MA status will be revoked.
Consequently, PharSafer recommends that MAHs maintain close contact with regulatory affairs departments/function, in order to receive prompt information on the changes to the licenses of CAPs, and update all stakeholders on situations where there is responsibility for expedited reporting and other pharmacovigilance activities.
However, for the subject of expedited reporting, the MHRA guidance does not cover what will happen to the UK entries on xEVMPD for a CAP, with the only content available for xEVMPD being that the MHRA will regard the QPPV details registered prior to the transition period as baseline information, in relation to future QPPV changes.
Additionally, the MHRA have stated that further guidance relating to the notification of QPPV and PSMF details to the MHRA will become available in due course.
If you have not yet set-up a company MHRA Gateway or ICSR Submissions account, PharSafer recommends that you initiate this process as soon as possible. For clients that undertake expedited reporting themselves and would like to report using the MHRA Gateway, while we are unable to undertake this set-up on your behalf, we are able to provide guidance and support where needed.
Where PharSafer undertakes expedited ICSR submissions on behalf of clients, we would have already contacted you regarding the setting up of a company ICSR Submission account. For those of you who have not yet completed this task, PharSafer are able to provide guidance and support where needed, alternatively we can undertake this process on behalf of your company. If you wish PharSafer to arrange access to the ICSR Submission portal on your behalf, please contact us and we shall initiate the process.
With regards to PSUR requirements, following the commencement of the transition period, it has been communicated that separate submissions of PSURs to the UK will be required, with products with authorisations in both the UK and European countries requiring two submissions, to the MHRA and European Medicines Agency (EMA) respectively, and PSURs for products in Northern Ireland required to go to the EMA via the repository.
As for timescales associated with PSUR requirements, the MHRA have stated that any PSUR submitted to the EMA, prior to the transition period, will not be required to be re-submitted, but additional information may be requested. Furthermore, the EURD list will be used for submission dates as normal, but an MHRA schedule may be developed in due course. However, for products not in the EURD list, a standard submission schedule will be required, unless the marketing authorisation specifies otherwise – though, it is worth noting that it has not yet been made clear whether exemptions for generic and well-established use-products will still apply.
Furthermore, the information states that a processing fee of £890 is payable, but is reduced to £445 where there is more than one PSUR being submitted for a product – though, it has not yet been made clear whether payment will be required in advance or upon invoice, with the guidance also stating that fees will be payable for products on the EURD list, but not yet clear for whether this will apply to products not on the EURD list.
Additionally, nothing has been said concerning the assessment of the PBRERs/PSURs. At present, the PRAC review and approve all recommendations from PSUR/PBRER for MAHs to implement, with the system now having two separate assessments – one for the EMA and one from the MHRA – and there could be different assessments and requirements for the same product. This has yet to be explained.
For the topic of RMPs, it has been communicated that RMPs and any updates to the RMP, for products sold or supplied in the UK, are to be submitted to the MHRA, in addition to EU versions of the RMP continuing to be accepted following the commencement of the transition period. However, it has also been mentioned that specific information requests may occur and, in these circumstances, should be presented within the documentation’s annex.
Post Authorisation Safety Studies (PASS)
With regards to PASS conducted by a UK MAH, the MHRA has communicated that draft protocols for pending studies are to be submitted to the MHRA as per usual and, for studies undertaken in Northern Ireland or by a Northern Irish only MAH, the draft study protocol is required to be submitted to the Pharmacovigilance Risk Assessment Committee (PRAC).
Moreover, for final study reports and abstract study results, in correlation to the guidelines above, the guidelines state that MAHs are to submit these directly to the MHRA, for UK studies, or the PRAC, for Northern Irish and other European studies, and to be submitted within no later than 12 months following the conclusion of data collection.
Furthermore, the MHRA has provided further guidance on safety referrals; safety reviews; Post-Authorisation Measures (PAMs) and overall implementation.
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PharSafer will continue to monitor the guidance released by the MHRA, regarding the upcoming transition period, and communicate any new information as it becomes available.
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