Marketing Authorisations in the post-Brexit world

New MHRA Brexit guidance was released on 1 September 2020 (and further supplemented in October 2020), after the previous UK Government guidance in relation to pharmaceuticals was withdrawn in January 2020.  The guidance confirms the regulatory steps required for grandfathering of centralised marketing authorisations to ensure that they are replaced by the UK marketing authorisations (UK MAs) at the end of the transition period (referred to as “exit day” or “implementation period completion day – IP completion day”).

In summary, the granted marketing authorisations issued centrally by the European Medicines Agency (EMA) will automatically convert to UK MAs, following which some further supporting data will need to be submitted, unless the holders opt out of the scheme. Pending applications which have already been submitted to EMA by the end of the transition period will either be determined in parallel by the Medicines and Healthcare products Regulatory Agency (MHRA) or will be put “on hold” until the EMA’s Commission for Medicinal Products for Human Use (CHMP) issues a positive decision which can be relied upon by MHRA. From 1 January 2021 any new applications for UK MAs based on an abridged procedure will need to rely on “eligible” Reference Medicinal Product, as explained further below.

Market Authorisations (MAs)

From 1 January 2021, the MHRA will be the only medicines and medical devices regulator in relation to products being marketed in the UK, taking over the EMA’s previous functions.

An MA is required in order to market pharmaceuticals within the EU. MAs are currently obtained either nationally (whether by a national authorisation procedure or via the European authorisation routes, the decentralised procedure (DCP) or mutual recognition procedure (MRP), that involve the Heads of Medicines Agencies (HMA) or using the centralised procedure. The centralised procedure gives the granting authority, the European Commission, the power to grant a single marketing authorisation (in the guidance referred to as either centralised Marketing Authorisations or Community Marketing Authorisations) (CMAs) for the whole of the European Union, Iceland, Norway and Lichtenstein. This is in contrast to the other procedures that result in individual member states authorising the medicines for use in their own territory. Products which obtain authorisation via centralised procedure are referred to as Centrally Authorised Products (CAPs). The centralised procedure is optional for some medicines but compulsory for others (such as medicines derived from biotechnology processes). The EMA is the European body responsible for the scientific evaluation of CMAs. Following a positive recommendation from the EMA, which is usually followed by the European Commission, it takes around two months for the European Commission to approve a medicine.

Grandfathering of Centrally Authorised Products (CAPs)

At the end of transition period, any existing CMA will automatically (without a fee) convert to a national UK MA and be issued with a UK MA number. This is termed "grandfathering" and such MAs are referred to in the guidance as “converted EU MAs”. The MA holder (MAH) is not compelled to accept the converted EU MA and can opt out by notifying the MHRA in writing by the end of 21 January 2021. However, to support the ongoing regulation of these converted EU MAs, the MHRA requires certain "baseline data" to be submitted by the MAH within a year of the end of transition. The detailed list of information which the MAH must submit for each converted EU MA in accordance with the applicable regulatory provisions and guidance on how to submit the application is available here.

On 26 October 2020 the MHRA issued a further guidance in the form of a letter to industry setting out the actions each MAH ought to take to ensure the grandfathering process runs smoothly, which include reviewing the list of currently authorised CAPs and advising of any errors or omissions, advising the MHRA on any CAPs that the MAH does not want to be converted and advising of the marketing status of each product.

Reference Medicinal Products (RMPs)

A RMP is a medicinal product which has been granted an MA (either via procedures resulting in a national MA or via the centralised route) on the basis of a complete dossier (with the submission of the quality, pre-clinical and clinical data as required by the Directive 2001/83/EC). A generic or a biosimilar can apply for an MA without submitting such a full suite of information but by submitting a so-called “abridged application” instead which can be a faster and cheaper route. If the MAH seeks authorisation using an abridged application, they will have to identify in their application form the RMP which has been authorised in the EEA and is used as a comparator in the abridged application.

A difficult issue is what happens to granted MAs and pending MA applications (MAAs) for generic or biosimilar medicines which are based on the data from a RMP where that RMP was not granted by the UK national route or where the UK was not the Reference Member State (RMS). In this situation, the underlying data for the RMP will be held by the EMA or other relevant non-UK authority that was used as the RMS and will no longer be available to the MHRA after 31 December 2020.

The MHRA guidance confirms that granted MAs (whether obtained nationally or via the centralised procedure) for products which are based on a RMP authorised in the EU remain valid after 31 December 2021 (and, for CMAs, they will convert to converted EU MAs, as described above). The guidance also states that pending MAAs based on a RMP authorised in the EU will remain valid (and will be dealt with in accordance with the guidance for pending applications as described below).

From 1 January 2021 any applicant that would like to apply to the MHRA for an MA using an abridged procedure (ie, based on RMP) will be able to do so if it falls within the definition in regulation 48 of the Human Medicines Regulations 2012, as amended by the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019, that is an RMP which:

(i) has been authorised under Regulation 49(1)(a) of the Human Medicines Regulations 2012 (the provision which governs the grant of UK MAs), or

(ii) had a CMA prior to 31 December 2020 but where the MAH opted out of the conversion to a UK MA.

It is worth noting, if the “eligible RMP” is a converted EU MA, the MAH has 12 months to submit the baseline data to the MHRA which could, arguably, cause delays when assessing an MAA using an abridged procedure which relies on that “eligible RMP”. Schedule 7 of the Human Medicines (Amendment etc.) (EU Exit) Regulations 2019 gives the MHRA the power to request the MAH of a converted EU MA to submit the baseline data before the 12-month deadline.

Where there is no eligible RMP (for example, the RMP has a national MA from another EU Member State), generic and biosimilar companies will need to file a complete set of regulatory data to the MHRA in order to obtain a new MA.

Pending applications for Centrally Authorised Products

Applications under the EMA’s centralised procedure which are still pending on 1 January 2021 will be determined by the regulatory route chosen by the MAH and the stage of the procedure the application was at on that day. Essentially, the applicant has two options:

(1) to apply to the MHRA for what the guidance describes as an “in-flight assessment” in parallel with the application for a CMA. In that case the applicant submits the same application to the MHRA as has been submitted to the EMA. The MHRA will take into account any assessment that has already been reported on or before 1 January 2021 and the MHRA will tailor its assessment to any outstanding issues and reach a decision as soon as practicable (the guidance suggests a 60-day process); or

(2) to wait for the positive opinion of the CHMP and to apply to the MHRA using the new reliance route (which is not further described in the MHRA Brexit guidance). The application will then be determined when the decision by the European Commission regarding CMA has been confirmed.

In both cases, the applicant will need to submit an application and supporting dossier to the MHRA accompanied by all iterations of the CHMP assessment report, since the MHRA does not hold the supporting data for applications made to the EMA. Procedures that have been completed with a positive opinion from the CHMP and are awaiting a European Commission decision will be determined "as soon as practicable" by the MHRA; in other cases, the MHRA will need to make an assessment, the timetable of which will vary depending on the stage the EMA assessment has reached. More detailed guidance dependant on the stage of the assessment before the EMA is available here.

Renewals and variations

Converted EU MAs will be treated as if they were granted on the date the corresponding CMA was granted. The renewal date will stay the same. If renewals were submitted through the MRP or DCP and no decision was rendered before 1 January 2021, the MHRA will ensure the renewal process is concluded and processed appropriately, and there will be no need to resubmit the application. From 1 January 2021 the requirements for renewal submissions remain the same as currently required by the EMA and the MAH should continue to submit renewal applications to the MHRA 9 months before they expire (or 6 months in relation to conditional MAs).

In relation to variations to converted EU MAs, the general rule is that MHRA will not consider variations until the MAH submits at least a “minimal initiating sequence” and related documentation. The date on which these are received is referred to as the “data submission date”. The MHRA will consider the variation before the data submission date only in limited circumstances. These include: (1) if a variation is necessary on urgent safety grounds, or (2) if it is necessary to maintain supplies of a particular medicinal products to patients in Great Britain (England, Wales and Scotland); or (3) if there are other reasons to consider the variation in such timeframe. The approach to assessing the variations in the regular timeframe (ie, after the data submission date) depends on the type of variation (whether it is a minor Type IA or IB variation or a major Type II variation) and the stage the application (ie, whether the application to vary was submitted before or after 1 January 2021 and whether the variation had reached positive CHMP opinion by then).

A handy guide of MHRA’s approach to handling variations to converted EU MAs which were pending as at 1 January 2021 can be accessed here.

The procedures applicable to variations to purely national MAs, detailed under Chapter IIa of Variations Regulation (EC) No 1234/2008, will become incorporated into UK law at the end of the transition period and will apply to pending and new applications to purely national UK MAs. They can be found in the new regulation 65C and Schedule 10A to the Human Medicines Regulations 2012. Detailed guidance on how the MHRA will assess variations to national MAs is available here.

Conditional MAs

The MHRA will introduce a national Conditional Marketing Authorisation scheme for new medicinal products from 1 January 2021. The scheme will have the same eligibility criteria as the EU scheme and is intended for medicinal products that fulfil an unmet medical need, such as where the medicine is for serious and life-threatening diseases where no satisfactory treatment methods are available or where the product offers a major therapeutic advantage. Conditional MAs may be granted where comprehensive clinical data is not yet complete, provided sufficient evidence of safety and efficacy is submitted to the MHRA to conclude that the risk-benefit balance of the medicinal product is positive. Conditional MAs will be valid for one year and will be renewable annually.

Prioritising Access to New Medicines and new assessment routes

The MHRA is introducing changes designed to streamline the assessment procedures and reduce the time needed for the approval of a novel medicine. In the newly published guidance dated 27 October 2020, the MHRA foreshadows a new interactive toolkit which will use the expertise of the MHRA and other partners in the wider UK healthcare system, such as NICE, with further information to be published by December.

Additionally, the MHRA plans on introducing an accelerated procedure and reach its opinion on MAAs within 150 days of filing an application. The accelerated assessment will be available for good quality new MAAs for both new and existing active substances as well as orphan designations. Interested applicants should contact the MHRA in advance of submitting the application.

The assessment process will run in two phases totalling 150 days and MHRA will provide an opinion on approvability of the product by day 150.

The Rolling Review is a new route for MAAs based on on-going regulatory input and feedback to ensure the applications can be approved as efficiently as possible. Applications for any new active substances based on a submission of a “full dossier”, including biological applications, are eligible for a rolling review. If any questions are raised during assessment, the applicant will be given the opportunity to update the modules prior to final submission.

MAA referrals under Article 29 of Directive 2001/83/EC

Article 29 referrals are triggered on the grounds of a potential serious risk to public health when a consensus cannot be reached between Member States on the outcome for an MAA which has been evaluated using either the MRP or DCP. In cases of such disagreement, the RMS may refer the matter to the EMA. Under an Article 29 referral, the CHMP would normally issue an opinion on the issue referred within 60 days of the start of the procedure. This opinion is then usually adopted by the EMA and sent to the European Commission that issues a binding decision. In relation to Article 29 referrals that remain pending on 1 January 2021, the MHRA guidance states that if either a positive or negative opinion has been issued by the CHMP but no final decision was issued by that date, the MHRA will either grant or refuse the application with regard to that opinion. If no opinion has been reached by 1 January 2021, the MHRA will complete the assessment as a national procedure.

Active Substance Master Files (ASMFs) and Certificates of Suitability (CEPs)

An ASMF is a set of documents that protects the valuable confidential intellectual property of the manufacturer. It must contain all the scientific information relating to the active substance of the medicine in question and is submitted to support a MAA or a MA variation. A CEP certifies compliance of the active pharmaceutical ingredient (API) with the requirements laid down in the relevant monograph of the European Pharmacopoeia.

The MHRA will continue to accept ASMFs and CEPs from 1 January 2021 in both new national initial MAAs and in MA variation applications, with the guidance suggesting that an ASMF ought to be prepared in accordance with the CHMP guidelines. However, the UK will no longer participate in ASMF worksharing procedures with EU Member States, so the EU/ASMF/XXXXX reference numbers won’t be applicable to UK national applications from 1 January 2021.

CEPs are not affected by the UK leaving the EU as they are issued by the European Directorate for the Quality of Medicines and Healthcare and there will be no change to the relevant procedures.

Steps to be taken once you have been issued a converted EU MA

Once an MAH has been issued with a new converted EU MA, they will have 24 months from 1 January 2021 to establish and register a Great Britain presence for the converted EU MA, which includes submitting:

(i) the name and address of the MAH or their representative;

(ii) the Great Britain MA number; and

(iii) the name and address of the product manufacturer for batch release.

A change of MAH from a company out of the UK to one established in the UK requires submission of a Change of Ownership application. Before one is submitted, the MHRA will ask MAH for details of a UK contact.

The MAH will then have further 12 months to ensure all stock released to market is in compliant packaging, which may require the labelling and/or patient information leaflet (PIL) to be amended to take account of this new information. Some changes, such as changing the name and address of the MAH and/or the manufacturer for batch release, will be suitable for self-certification under the Better Regulation of Medicines Initiative (BROMI) scheme. If changes are more extensive (eg, new changes to the pack design), then the MAH will need to submit the artwork for full assessment to the Product Information Quality Unit.

Multi-country packs are medicinal products that are labelled to allow their placing on the market in several Member States with the same packaging. The MHRA will continue to allow multi-country packs, provided that the entirety of the information is UK-compliant.

Recognition of EC decisions for 2 years from 1 January 2021

The guidance published on 27 October 2020 states that the UK will adopt decisions taken by the European Commission in relation to the approval of new MAs in the centralised procedure for two years from 1 January 2021. The MAH should provide to the MHRA all information that was provided to the EMA during the licensing procedure, including all iterations of the CHMP report and the final CHMP opinion. The UK will also have the power to take into account MA decisions of EU Member States when considering applications for MAs for products that have been approved in decentralised or mutual recognition procedures. Similarly, the MAH should provide to the MHRA all information that was submitted to the RMS, including the RMS assessment report and end of procedure notification.

For more of our Brexit coverage click here.