Written Evidence from Medicines and Healthcare Products Regulatory Agency (BRE0087)

 

The Medicines and Healthcare products Regulatory Agency (MHRA) welcomes the opportunity to submit written evidence to the Health Select Committee’s Inquiry on Brexit and health and social care. 

  1.                MHRA regulates medicines, medical devices and blood components for transfusion in the UK.  We are an executive agency of the Department of Health.  The agency has 3 centres:

MHRA’s response to Brexit

  1.                The regulation of medicines and medical devices in the UK is largely governed by EU regulations.  The EU is home to a network of medicines agencies who work together through a cooperation and work-sharing model on the evaluation, supervision and safety monitoring of medicines. Similarly, the assessment of medical devices is undertaken by an EU network of Notified Bodies under the supervision of national competent authorities.  The MHRA is the UK’s competent authority. Therefore Brexit could potentially have a profound impact on the work of MHRA and the regulation of the medicines and medical devices sector in the UK.
  2.                While it is currently unclear what our future relationship with the European Union will be, it is important that we understand the implications of different scenarios in full.  As a result, the MHRA is examining a range of options for the future regulation of medicines and medical devices in the UK.  This of course includes us examining the extent to which we may want an ongoing relationship with the European Medicines Agency after our departure from the EU, where this makes sense on the grounds of public health.  Even when we are outside the EU’s legislative framework for medicines, we may want to retain some ongoing role in their regulatory procedures and continue co-operation whether on clinical trials, scientific assessments or post-market safety work. Similarly, we are looking at options for remaining part of the current EU regime on medical devices, either directly or through some sort of mutual recognition agreement.
  3.                Equally, MHRA is exploring the opportunities presented by Brexit for providing a different, or better, regulatory offer to industry where possible, looking to reduce burdens on industry where this will not compromise public health. We are also examining how the UK regulatory regimes for medicines and medical devices, and consequently the MHRA, might operate in future within a global context.  The MHRA has recently been elected Chair of the International Coalition of Medicines Regulatory Authorities (ICMRA) which affords us an important opportunity to work with international partners to ensure that the UK remains embedded within a global regulatory framework.  
  4.                To assess the impact of Brexit, MHRA has set up a cross-Agency task force with representatives from all divisions of the Agency. MHRA is also leading two parallel reviews with industry representatives to assess the options for the post-Brexit regulation of medicine and medical devices in the UK. This is part of wider work led by a joint industry and government steering group examining the Life Science sector as a whole (established by the Office for Life Sciences).
  5.                While negotiations continue, the UK remains a full and active member of the EU, with all the rights and obligations of EU membership firmly in place. The UK has consistently provided significant, high quality resource to the European Medicines Agency (EMA), the Heads of Medicines Agencies (HMA) network, and the oversight of medical device assessments and will continue to do so for at least as long as the UK remains within the EU.
  6.                There has been much speculation about the future of the EMA.  The EMA has made it publically clear that the implications for its seat and operations depend on the future relationship between the UK and the EU.  While its long-term location - once the UK has exited the EU - is unclear, at present it remains in London and MHRA’s relationship with it is unchanged. 
  7.                Working with our partners, stakeholders and customers, our focus continues to be the protection of public health.  The rest of this submission sets out the work of MHRA in the European context, including the resource we provide to the EMA / HMA network.  This highlights the wide range of issues we need to resolve to establish the post-Brexit regulatory regimes for medicines and medical devices in the UK.

Background to the regulation of Medicines

  1.                Medicines regulation in the UK takes place within the wider context of a European regulatory regime under EU legislation. The system utilises the scientific capacity of MHRA and that of other medicines regulators in a range of activities, including the assessment of applications for marketing authorisations, scientific advice to companies and to perform pharmacovigilance/market surveillance functions. Licensing activities are coordinated by the EMA for the centralised approval procedure and by Member States for decentralised and mutual recognition procedures. The EMA coordinates pharmacovigilance activities for all products (centralised, decentralised or mutual recognition) relying on contribution from national adverse drug reaction monitoring systems and pharmacovigilance functions at Member State level.

 

 

  1.            The EMA coordinates a number of committees and scientific working parties which support the regulatory framework and also coordinates EU activity into the International Conference on Harmonisation (ICH) which is concerned with harmonising technical and scientific requirements for Marketing Authorisation submissions globally.

Clinical Trials

  1.            Clinical trials in the UK are currently regulated by the The Clinical Trials Directive (Directive 2001/20/EC) and ‘The Good Clinical Practice Directives (GCP) (Directive’ 2005/28/EC). This EU legislation requires that clinical trials of medicinal products in human subjects should be authorised by a national regulator in the EU, like MHRA and should also receive a positive opinion from an ethics committee. The Directive will be superseded by the new Clinical Trials Regulation 536/2014, which is due to apply in autumn 2018. MHRA is continued its preparations to implement the new regulations.
  2.            Whilst the Directive has done much to advance the area of Clinical Trials in the EU, the new Clinical Trials Regulation aims to address a number of identified weaknesses within the existing regulatory framework by streamlining the application process, harmonising assessment procedures, introducing a single portal for all EU clinical trials and simplifying reporting procedures (including for multi-Member State trials). Together, this will mean a far more positive regulatory framework which has been widely welcomed by industry. 

Marketing Authorisation

  1.            Marketing authorisations submitted via the EMA’s centralised procedures are granted by the European Commission while marketing authorisations submitted via the decentralised or mutual recognition procedures are granted by national regulators of EU Member States. Marketing authorisations can also be obtained by national procedure which is only valid in the authorising member state. Almost all new active substances are now licensed through the centralised procedure, whereas for the other procedures, older products and generics dominate.
  2.            The centralised procedure is mandatory for certain types of medicines and biotechnology products, but optional for others.  Applications for marketing authorisations under the centralised procedure are made directly to the EMA and, once granted, the Marketing Authorisation is valid simultaneously in all EU Member States (plus the EEA countries). 
  3.            The decentralised procedure enables medicines that are yet to be licensed anywhere in the EU to be simultaneously authorised in multiple EU states. The number of applications submitted in the decentralised procedure is about 20 fold greater than those submitted in the centralised procedure. The mutual recognition procedure means that a market authorisation already granted in one EU state can be recognised in others through an abbreviated process.
  4.            One of the fundamental issues for the future regulation of medicines in the UK post-Brexit is the extent to which we will remain part of these EU regulatory procedures.  This links to related questions about the future status of EU and UK approved medicines in our respective markets and the extent to which the MHRA will work with other regulators – whether in the EU or globally - in undertaking our own assessments of applications for marketing authorisations and/or take into account of assessments they may have already made. We are exploring all of these issues within the MHRA and in partnership with industry representatives.  
  5.            In line with the single market, authorised medicines from the EEA which are the same as the UK product may be licenced for use in the UK under the simplified “Parallel Import” scheme. This scheme relies on the exchange of confidential regulatory information about the product between national regulators and the EU principle of “exhaustion of trademark rights” Once a trademark owner places a product onto the market in any member state they cannot prevent the movement to and sale of the product in any other member state.

Medicines classification, availability and access

  1.            EU legislation defines two classifications of medicines: those subject to medicinal prescription (Prescription Only Medicines, POM), and those not subject to medicinal prescription (Non-Prescription Medicines, NP). For medicines authorised through national and decentralised procedures the classification is a national competence.  Medicines authorised through the centralised procedure must have the same legal classification in all Member States.
  2.            The classification of medicine varies widely through the EU.  There are currently a very limited number of medicines available without prescription across all Members States. The UK Government’s policy is to widen access to medicines through reclassification when it is safe to do so and when it is in the interests of public health. The UK has a well-developed culture of patient empowerment and self-care. It has been at the forefront of moves to reclassify medicines and is recognised as a leader in Europe in this regard.
  3.            Current EU legislation on medicines classification and the different attitudes to reclassification of medicines across Member States present difficulties for the UK in increasing the number of medicines available without prescription.  This is a particular problem for medicines authorised through the centralised procedure where the UK has to accept a majority decision for a medicine to remain available only on prescription even when it is considered to be safe and of benefit to public health if supplied without prescription in the UK.  

Inspection and Supervision

  1.            MHRA is responsible for a number of inspection regimes which ensure that the supply chain for medicines is safe and secure.  Inspections are undertaken across the entire medicines lifecycle, and MHRA’s Inspectorate comprises of Good Manufacturing Practice, Good Distribution Practice, Good Clinical Practice, Good Laboratory Practice and Good Pharmacovigilance Practice units.

 

Good Manufacturing Practice / Good Distribution Practice

  1.            Good Manufacturing Practice (GMP) is the minimum standard that a medicines manufacturer must meet in their production processes.  Products must:

-          be of consistent high quality

-          be appropriate to their intended use

-          meet the requirements of the marketing authorisation or product specification

  1.            Good Distribution Practice (GDP) requires that medicines are obtained from the licensed supply chain and are consistently stored, transported and handled under suitable conditions, as required by the marketing authorisation or product specification. 
  2.            Risk-based inspections have been undertaken by UK Inspectors since 2009 to check if manufacturing and distribution sites comply with the EU Guidance on GMP and/or GDP. GMP inspections of each Member State are ‘mutually recognised’ by other EU countries (meaning they do not ‘re-inspect’ those facilities). 
  3.            GMP inspections are supported by a Heads of Medicines Agencies audit programme called the Joint Audit Programme (JAP) whose organising group is chaired by MHRA.  The EU also has formal Mutual Recognition Agreements of inspections with Australia, Canada, Israel, Japan, New Zealand and Switzerland (with USA under negotiation where MHRA was the first member state to be assessed by FDA).  It will be important that MHRA continues building Mutual Recognition Agreements with such countries post Brexit.
  4.            The UK also operates two Official Medicines Control Laboratories (OMCLs).  The OMCL’s are responsible for carrying out independent official batch release testing of chemical and biological medicines as required by EU law.  Each batch is examined and approved, independently from the manufacturers, and issued with an EU/EEA Official Control Authority Batch Release (OCABR) certificate before being released onto the market.  These activities are mandated by both EU and national legislation, operate within a network of OMCLs and are coordinated under the Council of Europe (part funded by the EU). 
  5.            General OMCL activities are open to all the member and observer states of the European Convention on the Elaboration of a European Pharmacopoeia.  Certain activities involve countries from the European Union (EU) and the European Economic Area (EEA) only and may be affected by the UK leaving the EU.

Good Clinical Practice

  1.            Good Clinical Practice (GCP) is a set of internationally-recognised ethical and scientific quality requirements that must be followed when designing, conducting, recording and reporting clinical trials that involve people. The GCP inspectorate are responsible for conducting GCP inspections to determine if clinical trials authorised by MHRA’s Clinical Trials Unit have been performed in line with GCP requirements. In accordance with GCP inspection policy for centralised procedures the GCP inspectorate performs routine and triggered GCP inspections on behalf of EMA.

Good Laboratory Practice

  1.            Good Laboratory Practice (GLP) is a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived. GLP is governed by OECD Council Decisions - the UK is a signatory.  Implementation of the regulations and the organisation of compliance monitoring programmes are regulated at a national level and do not form part of EU directives. 

Good Pharmacovigilance Practice

  1.            Good Pharmacovigilance Practice (GPvP) is the minimum standard for monitoring the safety of medicines on sale to the public.  MHRA GPvP inspections of Marketing Authorisation Holders (MAHs) (and their contractors), aim to ensure that these organisations have an adequate and effective system for monitoring the safety of the medicines they have licences for (or provide contracted services for).
  2.            National Competent Authorities have a supervisory duty for the medicines that are placed on their markets. Irrespective of the route of authorisation, MHRA GPVP inspectorate will oversee the activities of the authorisation holder(s) according to our risk based inspection programme. The supervisory authority concept for centrally authorised products was put in place in 2012 as a means to co-ordinate inspection activities across Member States (and reduces duplication where possible).

Pharmacovigilance

  1.            New EU pharmacovigilance legislation implemented in 2012 aimed to make best use of resources across the EU to identify and respond to safety issues with medicines in a timely and consistent manner. Member states conduct pharmacovigilance at a national level, operating adverse drug reaction (ADR) reporting systems and detecting signals of new potential safety issues which are then fed into a signal management system coordinated by the EMA.   
  2.            The Pharmacovigilance Risk Assessment Committee (PRAC) which includes two delegates from each member state is responsible for all aspects of pharmacovigilance including the prioritisation, assessment and communication relating to the risk of adverse reactions.  PRAC is chaired by MHRA. Pharmacovigilance activities are carried out by member states under work sharing principles with individual member states taking the lead for particular products. 
  3.            PRAC makes recommendations to either the Committee for Medicinal Products for Human Use (CHMP) if the product concerned has an EU authorisation or the member states’ coordination group (CMDh) if the product has a national, mutual recognition or decentralised authorisation. The CHMP issues an opinion which results in a European Commission Decision binding on all member states. If discussion at CMDh results in consensus among member states on the best course of action then the conclusion would be implemented without reference to the European Commission.

 

 

MHRA as part of the EMA network

  1.            MHRA provides one of the highest levels of support to the EMA of any Member State. Some examples of this include:
  2.            UK was assigned (co)-rapporteurship in 18% of all EMA centralised assessments between 2011 and 2016. This figure is higher than for any other member state.
  3.            In 2015, the UK
    1. led on 164 out of 786 assessments of Periodic Safety Update Reports;
    2. led on 5 out of 18 assessments of Post authorisation safety study protocols;
    3. was rapporteur for 15% and co-rapporteur for 15% of new applications for Pharmacovigilance Risk Assessment Committee rapporteurships (these correspond to overall responsibility for monitoring safety of new products).
    4. performed 52 of the 165 (31.5%) assigned GMP inspections coordinated by the EMA.  For GPvP and GCP there is a similar level of EU inspection contribution.
  4.            Since the new Pharmacovigilance legislation which came into force in 2012 (Directive 2010/84/EU and Regulation (EU) No1235/2010), the UK has led on 36% of referrals considered by the EMA’s Pharmacovigilance Risk Assessment Committee.
  5.            The UK plays an active role in a wide range of EMA Committees, working parties and drafting groups.  For example, MHRA:

-          chairs a number of groups including the Scientific Advice Working Party, the Pharmacovigilance and Risk Assessment Committee and the Pharmacogenomics Working Party;

-          co-chairs a number of groups including the Clinical Trials Facilitation Group, the Quality Working Party and the co-ordinator group for Mutual Recognition and Decentralised Procedures; and

-          is represented on the majority of human scientific working parties.

The regulation of Medical Devices

  1.            Medical devices in the UK are regulated as part of the EU regulatory framework. The EU medical devices regulatory system includes some fundamental differences from the model of regulation for medicines, largely because there are many more devices, the majority of which are of low complexity and low risk.  Medical devices are treated like other devices on the European market and must undergo a conformity assessment. The manufacturer must demonstrate conformity with the essential requirements as laid out in the relevant directive before affixing a CE-mark, enabling them to market their products freely throughout the European Union, a decentralised approach.
  2.            Medical devices are classified into four classes, I, IIa, IIb and III. For higher risk classifications of products, the conformity assessment, and issuing of CE marks is undertaken by a network of around 50 private Notified Bodies across the EU - of which there are 5 in the UK - overseen by the relevant Member State’s competent authority which, in the UK, is MHRA.  Any designated Notified Body within the EU can assess and certify a medical device that, with its CE mark, can then be freely marketed anywhere in the EU. For the lowest-risk devices, class I, companies may self-certify.
  3.            MHRA’s role also includes pre-market approval of clinical investigations, and a range of post-market surveillance and vigilance; investigating reports of incidents and taking appropriate enforcement action. The Agency also heavily influences the current international agenda, as chair of the executive for the Competent Authorities for Medical Devices (CAMD), which includes all EU and some non-EU countries.  MHRA also played a lead role in negotiating the current and future legislative frameworks for medical devices.   As with medicines, the MHRA is currently considering how we might maintain an ongoing relationship with the EU’s regulation of medical devices, in particular the network of Notified Bodies, as well as exploring opportunities to develop new working relationships with other global regulators.
  4.            Currently there are three main Directives for the regulation of medical devices;

-          Directive 90/385/EEC relating to active implantable medical devices;

-          Directive 93/42/EEC concerning medical devices; and

-          Directive 98/79/EC on in-vitro diagnostic medical devices. 

  1.            The three Directives will be replaced by two new Regulations for Medical Devices and in-vitro diagnostic devices respectively which are expected to enter into force in spring 2017. The MHRA is continuing with plans to implement these new regulations in full.

 

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