Brexit and Pharmacovigilance Where may pharmaceutical companies go?

UK left the EU on 31 January 2020 with an agreed transitional period until 31 December 2020.

Philipp Hofmann, MD, Head of Pharmacovigilance and QPPV, Navitas Life Sciences (a TAKE Solutions Enterprise) explores the potential impact of Brexit to Pharmacovigilance (PV) in both the UK and the EU.

Hard Brexit was not to be

The ghost of a hard Brexit, one in which “no deal” between the UK and EU could be reached, luckily disappeared.

According to a study in the Lancet 2019, a “no deal” Brexit would have an adverse impact on health in the UK under every scenario, and that “no deal” would have the worst impact. In total, a “no deal” Brexit could have cost the UK GBP 90 billion .

The transition period, published on 19 March 2018, gave pharmaceutical companies time to prepare for Brexit, to continue with the current PV system to ensure patients’ safety .

The current situation: Soft Brexit

As of December 2020, the negotiators in the UK and the EU reached an agreement on the regulation. Many details still need to be agreed upon in specialist working groups to cover all aspects of daily life.

So far it seems clear that the Medicines and Healthcare products Regulatory Agency (MHRA) will not continue to be part of the European PV system, including the PV Risk Assessment Committee (PRAC) or EudraVigilance. This will have a tremendous impact for both the involved Health Authorities and pharmaceutical companies.

This approach will require double efforts in PV in order to satisfy the needs of Health Authorities in the UK and the EU, and could leave room for certain conjectures.

Consequences for Marketing Authorisations

With this in mind, just what are the consequences for Marketing Authorisations (MA), and how can supply with Centrally Authorised Products (CAP) be ensured in the UK and in the EU?

After 31 December 2020, a pharmaceutical company solely located in the UK will no longer be able to hold an EU MA. On the other hand, an EU pharmaceutical company can continue to hold a UK MA for a period of time after 31 December 2020, but they will have had to establish a contact person based in the UK.

The MHRA has issued a businesscontinuity plan for more than 370 CAPs to rapporteurs and co-rapporteurs, which are registered within the EU. All MAs need to be converted to national licenses. The plan is that CAPs will automatically be converted to UK MAs on the day of Brexit. Mutual recognition and decentralised MAs will be unaffected since they already hold national UK MAs.

Additionally, MAs, which are only held in the UK, will need to be transferred to an entity or affiliate which is located within the EU.

Submission of Individual Case Study Reports (ICSR) and Aggregate Reports

Post Brexit on 31 December 2020, the UK requires submission of all UK ICSRs (serious and non-serious) and serious ICSRs from other countries via the new MHRA Gateway and/or ICSR Submissions portal which have been developed. Obligatory registrations should have been made prior to Brexit.

The MHRA may, at some point, issue a new list of UK-specific reference dates for Periodic Safety Update Reports (PSURs) potentially resulting in the submission of PSURs at different times in the UK and the EU. In the meantime, the European Union Reference Dates (EURD) should be followed and, from 01 January 2021, PSURs should be submitted in parallel to the UK and EU. The Authorities may require joint signatories for both the UK and the EU.

Owing to a separate deal known as the Northern Ireland protocol, Northern Ireland’s ICSRs, Risk Management Plans (RMPs), and PSURs for products being marketed in the Northern Ireland region will remain aligned with EU requirements, while the rest of the UK will follow national procedures. For products placed on the market in Northern Ireland signals should be additionally reported to the European Medicines Agency (EMA).

Signals and safety management

In addition to the current practices for the EMA, the MHRA requests notifying of signals arising from any data source/ emerging safety issues within three working days if they have not already been notified to them. After Brexit, this also includes standalone signal notifications submitted to the EMA as well as signals raised by the EMA. The MHRA will carry out assessment of signals and issue UK decisions for both signals identified by the MHRA and those highlighted internationally.

Risk Management Plans (RMPs)

The MHRA will continue to accept EU versions of the RMP, but where the UK has made a specific request for information to be included; this may need to be provided in a UK specific annex. For centrally approved products the current approved version of the RMP should be included in the initiating sequence as part of the conversion process.

PV System Master File (PSMF)

According to EU legislation , the PSMF must be housed within a member state of the European Economic Area. Post Brexit, the Marketing Authorisation Holder (MAH) will need to change the location of the PSMF to a Member State within the European Economic Area (EEA). Typically, the PSMF is electronically accessible from any location in the world. The MHRA is, therefore, unlikely to ask for a separate UK PSMF. However, there may need to be UK-specific annexes. MHRA says the format and content requirements for the UK PSMF are “equivalent to that of the EU PSMF.” On the other hand, the MHRA says that each UK PSMF must have a unique identification number.

After 31 December 2020, a pharmaceutical company solely located in the UK is no longer able to hold an EU MA. On the other hand, an EU pharmaceutical company can continue to hold a UK MA for a period of time after 31 December 2020, but they will have had to establish a contact person based in the UK.

EU QPPV and UK QPPV

According to Article 8 of Directive 2001/83/EC and Article 74 of Directive 2001/82/EC, the Qualified Person responsible for PV (QPPV) must reside and carry out their tasks in a Member State of the EEA. The QPPV will, therefore, need to change his/her place of residence and carry out his/her tasks in the EEA, or a new QPPV residing and carrying out his/her tasks in the Union (EEA) will need to be appointed.

Based on information by the MHRA, “the role and responsibilities of the UK QPPV are equivalent to that of the EU/EEA QPPV,” but require that the QPPV be based in the UK. Comparable to the EU QPPV for products in the EEA, the UK QPPV will be responsible for establishing and maintaining a PV system for all UK authorized products. This includes oversight of what is happening at all times and visibility of the global safety database. However, the MHRA also notes that it will allow MAHs an exemption to the requirement that the QPPV be based in the UK for a short period of time in order to transition.

Pharmaceutical companies need to prepare a plan after the transition period. This will most likely reference having in place an EU QPPV as well as a UK QPPV to have direct points of contacts in place for the Authorities.

What are the most likely next steps?

The UK and the EU will continue to independently negotiate on the detailed terms of Brexit to ensure the continuous provision of medicinal products and medical devices. There are still some areas in PV post Brexit, which will be defined in specialised working groups by the authorities. Pharmaceutical companies are advised to be ready for upcoming changes, which will be published in due course on an independent system for PV, PSMF and QPPV. The outcome of the detailed discussions between the involved parties is so far unclear. Our QPPV office will continue to closely monitor and keep abreast of any further developments. We will ensure that, as an end-to-end PV Service partner, our QPPV services remain uninterrupted. References are available at www.pharmafocusaia.com

AUTHOR BIO

Upon gaining his MD with the Philipp’s University of Marburg, Germany, Philipp Hofmann started his career as a medical writer in the pharmaceutical industry, responsible for Annual Safety Reports. This very first position was soon followed by a continuous professional development from Medical Manager Vigilance, Safety Officer, Deputy EU QPPV, Director Global Safety to Head of Pharmacovigilance and EU QPPV prior to joining Navitas Life Sciences. Philipp, with his specialization in Pharmaceutical Medicine, is now heading the pharmacovigilance department of Navitas Life Sciences and the QPPV office.

FPS Reactors and Process Vessels Charging Isolators

Tailor made solutions for your needs

Stefano Butti, Sales Director, FPS, Italy

FPS is an Italian company specialised in the design and manufacture of containment & isolation systems and micronisation solutions for the handling and production of active and sterile pharmaceutical ingredients; it is mainly addressed to pharmaceutical, chemical and cosmetic companies all over the world.

With almost 100 employees, more than 1,300 systems in operation worldwide for handling pharmaceutical substances, FPS presents itself on the market as an international company, extremely flexible and able to adapt to different customer's needs.

During the past years the necessity to have a safe loading system for process vessels became more and more actual due to the increased activity of product to be handled and also to the updated requirement from REACH regulation. Based on this FPS has designed a full range of containment systems suitable to load process vessels in a fast, safe and ergonomic way. Always starting from the process evaluation and from a risk assessment we have realised more than 100 systems for this specific topic. They are almost all different one from the other due to the specific requirement and need of our customer.

The project definition always starts from on-site supervision to check installation areas and discuss with the end user about specific needs. In function of possible physical constraint first evaluation is about the possibility to use gravity discharge or to evaluate alternative systems like Vacuum Transport System (VTS).

First of all, a preliminary design is realised and once the real project starts an ergonomic study on a 1:1 scale mock-up is performed to check real activities to be performed. Once this critical step is completed the final manufacturing of the system is started.

FPS propose different configurations:

• Single chamber mobile reactor loading system for small quantities of product handling, up to OEB4 category (CPT down to 1mg/m3). • Single chamber reactor charging system for larger quantity of product handling, up to OEB4 category (CPT down to 1mg/m3). • Double chamber reactor charging system for larger quantity of product handling, up to OEB5/OEB6 category (CPT down to 0.1 and 0.01 mg/m3). • Double chamber reactor charging system for larger quantity of product handling, up to OEB5 category (CPT down to 0.1mg/m3). For more information contact: sales@fps-pharma.com

AUTHOR BIO

Stefano Butti has studied Mechanical Enineering at university of Milan and graduated in 2000. ISPE member since 2002, he participated as speaker to different congress and seminar on Containment and Micronisation topic both for HPAPI and Sterile application as well as published different articles in technical newspapers. He Joined FPS company in 2008 starting as Technical Sales Manager and he is now head of the Sales group for the company Containment and Micronisation system provided worldwide.

EMPLOYING REAL-WORLD EVIDENCE TO IMPROVE CLINICAL TRIAL STRATEGIES

There are many advantages to studying a drug’s performance under everyday conditions that cannot be matched in clinical trials, which are essentially controlled experiments. A traditional, Randomised Controlled Trial (RCT), which has a specific design with established inclusion and exclusion criteria, cannot anticipate all the real-world situations that can occur when external factors come into play. Those factors can include behavioural patterns, other therapeutic interventions, and health system effects, such as whether a drug is reimbursed in that country and the treatment protocols in that region or hospital. External factors can be global, local, or specific to the individual patient.