Brexit

Question 1

NIMAR

Answer 1

Norther Ireland MHRA Authorised Route
Introduced to allow supply of PLGB products to NI where there is a medical need for the product that cannot be supplied from the EU.
Only applies POM’s have to be on NIMAR list
Can’t apply to be added

Question 2

Northern Ireland Protocol

Answer 2

Supply of medicines to NI
EU proposal for NI (Dec 2021)
Human medicines made in GB can be exported to NI on basis of GB testing and QP certification provide that:
i. NI MAs will have to apply the full range of EU medicines law
ii. NI MAs will have to contain a legal prohibition of sale (resale) outside its geographical scope i.e NI medicines cannot be legally sold elsewhere in the EU
iii. The EU FMD safety features provisions would have to be applied such that NI packs scanned elsewhere in the EU would not be accepted

Grace period extended to end of 2022 to allow time for the change to made
	i. Medicines that have been tested and QP certified will not be retested and     recertified in NI so medicines can be exported from GB directly to wholesalers,     hospitals
	ii. IMPs can continue to be supplied from GB to NI, providing they have been QP     certified in either GB or the EU
 
Changes to licensing:
	i. Easier to have UK wide PL licence unless the product is CAP in the EU
	ii. EU CAPs will only be able to have GB PLs and the EU CAP will still apply to NI
	iii. New Northern Ireland MHRA Authorisation route (NIMAR) being introduced     to allow supply of PLGB products to NI where there is a medical need for the product that cannot be supplied from the EU. List of NIMAR products will be on MHRAs website
 
Packaging:
	i. Packs that have UK MAs still need to comply with the EU FMD provisions
	ii. PLGB packs are encouraged to at least comply with the tamper evidence part     of     the FMD requirements
	iii. The derogation that packs supplied from EU to GB do not need to be     decommissioned on export from the EU has been extended for another 3 years until     end of 2024.

Question 3

Windsor Agreement

Answer 3

27 February 2023 announcement of the ‘Windsor Framework’
UK rather than EU legislation will apply to Northern Ireland
MHRA will approve medicines for the whole UK market. This means that all product approvals granted by the MHRA will automatically be valid in Northern Ireland
The Falsified Medicines Directive provisions for medicines in NI to have safety features, such as serialisation, will NOT apply anymore. However, packs exported to NI will need to be labelled “for UK only”.
New innovative medicines, which in the EU would have to be assessed under the centralised procedures, will be approved under the UK regulatory system rather than managed by European Medicines Agency.
On 9 June the MHRA published guidance that confirms the implementation date of 1 January 2025 -

This transitional guidance is as follows:
‘UK only’ labels may be placed anywhere on a medicine pack. This label will need to follow MHRA guidance on labelling, which was issued later on 28 July 2023 (see below)
Packs in existing packaging already on the UK market, and within the supply chain, may remain until the date of their expiry.
UK‐based suppliers or distributors of medicines should prepare for different packaging for medicines to be supplied to UK and EU markets from 1 January 2025. Comprehensive guidance
In advance of these new arrangements taking effect, the Northern Ireland MHRA Authorised Route (NIMAR) will continue to function to support the supply of medicines into Northern Ireland.
The introduction of a ‘bridging mechanism’ to allow companies to supply NI with medicines that are subject to the EU Centrally Authorised Procedure for up to 6 months when the MHRA licenses a product before the European Medicines Agency (EMA).  This mechanism is permitted by EU Directive 2022/642
The MHRA will expect anti‐tamper devices to remain on all medicine packaging.
On 28 July 2023 the MHRA published requirements for the ‘UK Only’ labelling:
	 
When using the ‘UK Only’ label on packaging, the following will apply:
‘UK Only’ may be presented anywhere on the outer packaging of the medicine.  The text must be conspicuous and clearly legible, at least 7‐point font and in line with Article 5 of EU Regulation 2023/1182, current MHRA expectations and best practice guidance
 
To provide a single deadline for new packaging requirements, the MHRA will continue to allow manufacturers to supply medicines in legacy EU packaging until 31 December 2024. This extends the previous 31 December 2023 deadline, which required medicines for GB to be presented in GB compliant packaging, by one year.
 
The ‘UK Only’ statement can be applied via a sticker for a limited time period of 6 months, to 30 June 2025. After this date, ‘UK Only’ must be printed directly onto the packaging.
After 1 January 2025 the safety features included for the purposes of compliance with EU FMD requirements may be removed. However, the MHRA say that they “continue to encourage companies to use anti‐tamper packaging” and that MA holders may continue to apply the EU FMD features of the 2D bar code and serialisation if they wish.
 
From 1 January 2025, joint EU/UK packs can no longer enter the supply chain. A joint pack is one that is shared with another European country or countries, and which presents administrative details for both the UK and the other markets sharing the pack.

Question 4

Tell me about UK law for clinical trials

Answer 4

UK Legislation on Clinical Trials.
The UK was a member of the EU at the time Directive 2001/20/EC was implemented and it was transposed into UK law as SI 2004/1031, which came into force on 1 May 2004. The UK continues to follow EU GMP for both commercial and investigational medicinal products.

As the UK had departed from the EU by the time that the CT Regulation 536/2014 was implemented it did not apply in the UK and SI 2004/1031, as amended for Brexit by SI 2019/744, remains the current UK CT legislation.

As the UK has left the EU, separate CTA applications will be required in the EU and GB to conduct CTs and GB IMP manufacturing sites will need a UK MIA(IMP). IMP exported from GB to the EU will need to be QP certified at a site holding an MIA(IMP) in the EU.

The UK will continue to recognise both regulatory and ethics approvals that were made before the end of 2020 and there is be no need to re‐apply. With regards to safety reporting the UK will require sponsors to submit all UK relevant suspected unexpected serious adverse reactions (SUSAR) reports to the MHRA and these are now submitted via UK‐based IT systems (as the option to report via EMA systems will no longer exist).

The approach to QP certification of is similar to that for licensed medicines but here the list of approved countries does not include the seven countries where the EU currently has an operational MRA or ACCA. The QP of the MIA(IMP) importing an IMP into the UK from an approved country will need evidence that the IMP has been QP certified in the approved country.

There should be written agreements which describe the assigned responsibilities and provision of
relevant information between the organisations. These include agreements between:
* Sponsor and the UK MIA(IMP) holder responsible for the oversight of import from the listed country
* Sponsor and the listed country MIA(IMP) holder
* UK MIA(IMP) holder and Great Britain storage and distribution hub (if applicable)
* Sponsor and Great Britain storage and distribution hub (if applicable)

The QA system must be overseen by a QP, however the IMPs would not require recertification. The routine tasks relating to verification of QP certification in a listed country may be delegated by the QP named on the UK MIA(IMP) to appropriate personnel operating within their MIA(IMP) quality system.

IMPs that have been QP certified in the EU/EEA do NOT need to be re‐certified on imported into GB but a QP named on a UK MIA(IMP) must verify the certification by the EU QP. The QP named on the UK MIA(IMP) that is responsible for this verification process may be resident in the UK or the EU/EEA.

Any manufacturing activity or importation from a non‐listed country must be certified by a QP who is resident in the UK.

The QP named on the UK MIA(IMP)should have the following documentation available as part of the
oversight process for import of IMP to Great Britain from listed countries:
* Details of the manufacturing and distribution supply chain
* The UK Clinical Trial Application form, plus amendments. This should be used to confirm the site responsible for final certification of the finished IMP
* The UK Clinical Trial Application and any amendment approval records (including any post approval commitment requirements)
* Evidence that the certifying site in the listed country is appropriately licensed and holds a current GMP certificate for the IMP dosage form(s) and associated activities (e.g. manufacture, packaging, testing and / or import from a third country)
* Details of the approved Great Britain trial sites from the ethics application, plus any updates or amendments
* Details of each shipment of IMP to Great Britain including the addressees’ information. This should be verified against the ethics approvals
* Details of any excursions from the stated storage conditions during shipment, along with any decisions taken by the Sponsor and certifying QP, and the rationale for those decisions
* Details of the responsibilities described in the written agreement between the Sponsor and the listed country MIA(IMP) holder

The MHRA guidance says: “There are two routes for IMPs to be received into the UK from a listed country for use in UK clinical trials following QP certification by the listed country MIA(IMP) holder:
* Direct to the clinical trial site
* Via a UK storage and distribution ‘hub’. Both require the oversight of a UK MIA(IMP) holder and QP, with systems in place to ensure that:
* IMPs are not made available for use in the trial until appropriate QP certification in a listed country has been verified by the UK QP
* IMPs are only shipped to appropriate trial sites detailed within the UK trial/ethics application
* Up‐to‐date information and documentation relating to the clinical trial and associated Product Specification File are made available to the UK QP by the Sponsor
* In addition to QP certification in the listed country, the clinical trial is authorised by the MHRA before IMP is made available to the Investigator

There should be written agreements which describe the assigned responsibilities and provision of relevant information between the organisations. These include agreements between:
* Sponsor and the UK MIA(IMP) holder responsible for the oversight of import from the listed country
* Sponsor and the listed country MIA(IMP) holder
* UK MIA(IMP) holder and UK storage and distribution hub (if applicable)
* Sponsor and UK storage and distribution hub (if applicable)”

The guidance goes on to give requirements for:
* What constitutes acceptable evidence of QP certification
* The documentation that needs to be available to the GB QP
* The supply of IMP to a GB clinical trial site
* Using a GB storage and distribution ‘hub’
* Reference and retention samples, and
* Importing non‐investigational medicinal products for use in a clinical trial

The UK knew that it would be outside of the EU before Regulation 536/2014 was implemented so they started to build their own systems and process to mimic, as far as possible, the changes introduce by the EU Regulation. A UK on‐line application system, called the Integrated Research Application System (IRAS) was launched to provide similar application functionality to the EU’s CTIS.

Future of UK Clinical Trials Legislation
On 17 January 2022 the MHRA launched an 8‐week public consultation, due to end 14 March 2020, on proposals for legislative changes for clinical trials. The legal basis for making these changes is Section 2 of the Medicines and Medical Devices Act 2021. This consultation specifically relates to clinical trials and Investigational Medicinal Products (IMPs).

The aim is to update and strengthen the current UK clinical trial legislation to:
* Promote public health and ensure protection of participants remains at the heart of legislation
* Remove obstacles to innovation, whilst maintaining robust oversight of the safety of trials
* Streamline the regulation of clinical trials and reduce unnecessary burden to those running trials by embedding risk proportionality into the framework
* Facilitate the evaluation and development of new or better medicines to reduce the burden of disease on patients and society
* Ensure the legislation builds international interoperability so that the UK remains a preferred site to conduct multi‐national trials

The specific proposals being consulted on are as follows:
* Patient and public involvement
 Involvement of people with relevant lived experience in the design, management, conduct and dissemination of a trial
* Research transparency
 A requirement to publish a summary of results within 12 months of the end of the trial unless a deferral has been agreed,
 A requirement to share trial findings with participants
* Clinical trial approval processes
 A combined MHRA and ethics review, with an initial decision given on the application (i.e. approval or a request for further information) within a maximum timeline of 30 days from validation,
 A sponsor‐driven timeline to respond to any requests for further information (nominally 60 days but with flexible extension),
 A combined MHRA and ethics final decision on a trial of a maximum of 10 days, following receipt of any Requests for Further Information (RFI) responses,
 The ability for the regulators to extend the timeframe for medicinal products or trials where the risks involved may be greater so that independent expert advice can be sought,
 A clinical trial approval to lapse after a specified time limit if no participants have been recruited,
 The details of what should be submitted in CT applications to be in the form of guidance rather than legislation,
 A trial sponsor to have sight of RFIs when they are ready, rather than issued when the final part of the assessment
 The ability to receive an RFI during the review of a substantial amendment,
 A notification scheme for low‐intervention trials,
* Proposals for Research Ethics Reviews and composition of Research Ethics Committees (RECs),
* Informed consent in cluster trials
 Flexibility on consent provisions where the trial is considered to have lower risk
* Safety Reporting
 To remove the requirement for individual SUSARs to be reported to all investigators,
 To remove the requirement to report SUSARs and annual safety reports to RECs,
 Where justified and approved by the regulatory authority, SUSARs can be reported in an aggregate manner
* GCP
* Sanctions and corrective measures
 Regulators to be permitted to take into account information on serious and ongoing non‐compliance that would impact participant safety they hold when considering an application for a new study
 To enable regulatory action to be taken against specific part of a trial rather than the trial as a whole
* Manufacturing and assembly
 To introduce the term ‘non‐investigational medicinal product’ into legislation to provide assurance on the quality and safety of these products
 Where a medicine is labelled according to its marketing authorisation (and is used in its approved packaging) that specific clinical trial labelling may not be required
 Radio pharmaceuticals used in a trial to be able to be exempted from the need to hold a Manufacturers Authorisation for IMPs
* Definitions and other terminologies

Question 5

What can you tell me about the RPI?

Answer 5

RESPONSIBLE PERSON – IMPORT (RPi)
* Post‐Brexit role where wholesalers are importing product from EU/EEA
* No need for re‐testing; can accept EU/EEA QP certification
* RPi duty to:
○ Perform duties of the RP, plus
○ Check that product has been QP certified
* MHRA to establish RPi register
* To be an RPi will need to:
* a) Hold a formal qualification in pharmacy, chemistry, medicine, biology or a related life‐science
* b) Be a member of a professional body with a published code of conduct
* c) Have 2 years’ experience as an RP or equivalent

MHRA Guidance First Published September 2020
* Equivalent qualifications acceptable for Rpi candidates include:
○ Level 5 qualifications from Chartered Institute of Logistics and Transport
○ A Quality Management System Lead Auditor or Pharmaceutical GMP Lead Auditor qualification awarded by Chartered Quality Institute
○ Other qualifications may also be acceptable
* Check with MHRA