Responding to the MHRA’s requirement for a UK Pharmacovigilance System Master File (PSMF): Strategy, planning, execution, and delivery

RESPONDING TO THE MHRA’S REQUIREMENT FOR A UK PHARMACOVIGILANCE SYSTEM MASTER FILE (PSMF):

Strategy, planning, execution and delivery

By Vasavi Kalyani Garlapalli, John Verheul, and Amisha Sandhu

The pharmacovigilance system master file (PSMF) is a detailed description of the pharmacovigilance system used by the marketing authorisation holder (MAH) for their authorised medicinal products. In fact, it was the European Medicines Agency (EMA), in July 2012, who first formalised the concept of the PSMF via the Good Vigilance Practice (GVP) Module II guideline. With the United Kingdom’s (UK) departure from the European Union (EU), the Medicines & Healthcare products Regulatory Agency (MHRA) mandated an independent UKPSMF for MAHs. This article focuses on measures taken to strategise, plan, implement and publish a new UK PSMF during the rapidly evolving regulatory situation following the withdrawal of the UK from the EU.

In 2020, Novartis initiated preparatory actions, having anticipated that the new requirements should be implemented by the end of the Brexit transition period (early 2021). Several potential UK PSMF models were considered as options to meet the evolving requirements: 1. An integrated EU and UK PSMF 2. Pharmacovigilance Sub-System File (PSSF) 3. Standalone PSMF

In terms of PSMF requirements, it was apparent early on that the MHRA would follow a similar approach to the EMA. However, the exact scope was clear only after the publication of new guidance from the MHRA on 1 Jan 2021. The scope of the UK PSMF was to describe the pharmacovigilance system for UK nationally authorised products, and was required to include the details of the UK Qualified Person for Pharmacovigilance QPPV. The annexes must be specific to UK nationally authorised products, including those in respect of Northern Ireland, and should represent the global availability of safety data for those products.

(reference: II.B.4. Information to be contained in the pharmacovigilance system master file- Paragraphs 1 and 2 of Exceptions and modifications to the EU guidance on good pharmacovigilance practices that apply to UK marketing authorisation holders and the licensing authority. GVP Module II – Pharmacovigilance system master file (Rev 2)) At this stage, due to the precise clarification of the scope of the UK PSMF (required to reflect only the PV system for the UK nationally authorised products*) and the representation of the global availability of safety data for those products, models 1 and 2 were excluded.

*Novartis has no Northern Ireland (NI) only licenses. Due to the limited execution period, the strategy was to implement the stand-alone UK PSMF in two stages, which also enabled us to dovetail with the company’s ongoing EU-PSMF review cycle. This approach also provided an opportunity to assess how we could develop a UK PSMF

that reflected the global availability of safety data, where applicable:

Step 1:

Register UK PSMF and reflect the UK content within the EU PSMF.

Novartis operates a single pharmacovigilance system with one named QPPV for both the EU and the UK; as a consequence, the content of the core PSMF remained broadly consistent with the EU. Exceptions to this were:

i) Addition of the UK PSMF registration code on the cover page, ii) Identification of a National Contact Person for

Pharmacovigilance (NCPPV) details under the QPPV back-up section and, iii) Details specific to the UK licensing authority. For the annexes, the UK-specific information (productspecific listings) was included. This was the optimal solution in January 2021 considering the evolving regulatory situation.

Step 2:

Separate the UK content from the EU PSMF, thereby creating a stand-alone UK PSMF. The production of a stand-alone UK PSMF took place as follows:

UK Stand-alone PSMF planning and execution

Planning Phase

1 2 1

Execution Phase

Identified the stakeholders

Built-in a communication plan

Developed a local procedure

Exception to the Global procedure

Onboarding and Training

Compilation of input and Review

Release of the UK PSMF

Impact Assessment on legislations

3

Gap Assessment on EU PSMF Comparison of relevant legislations

4

Templates for UK PSMF 2 3 4 5 6

The 4 key exercises that brought forth UK PSMF model(refer figure 2)

7

i) Planning Phase: Key activities were performed during this phase that helped Novartis to design a hybrid model (union of local and global content) for the UK PSMF: 1. Impact Assessment was conducted both at a local and global level on relevant legislation including The

Human Medicines Regulations (HMR) Schedule 12A and Exceptions and modifications to the EU guidance (GVP Module II) on good pharmacovigilance practices that apply to UK MAHs and the MHRA. 2. Comparison between HMR schedule 12A vs

Exceptions and Modifications to the EU guidance on good pharmacovigilance practices that apply to UK

MAHs, the licensing authority, and GVP module II. 3. Gap Assessment on the EU PSMF to assess the content that could be used for the UK PSMF.

4. Templates were created for the main body and annexes utilising the existing EU PSMF structure.

How does the model work?

Main Body:

Soon after the release of the EU PSMF, the main body was divided into modules aligned with GVP II. These global modules were inserted into the main body of the UK PSMF as applicable, according to the model below. The modules which required only local information were drafted by the UK affiliate. Where a module required both global and local content, the local team added local content to the global module.

PSMF CORE MODEL - EXCECUTED

Company’s EU PSMF

Divided into modules

EU-PSMF

Module 1:

Module 2:

Module 3:

Module 4:

Module 5:

Module 6:

Module 7:

Module 8:

UK Local PSMF

Section 1: Local Content

Section 2: Local Content

Section 3: Local Content Global module 2 (attachment)

Section 4: Global module 4 (as attachment)

Section 5: Local content Global module 5 (attachment)

Section 6: Local Content

Section: Local Content Global module 6 (attachment)

Global module 7 (attachment)

Section 8: Local plus Global Content* *Consolidated list added for the easy linking of annexes

• Hybrid model with global and local content. • Local content worded in the body of the UK PSMF • Where the PV system for UK and EU authorised products is the same, the EU PSMF modules are inserted into UK PSMF

As the scope of the UK annexes must reflect the global availability of safety data for UK MAHs, similar to the EU PSMF requirements for EU MAHs, the majority of the annexes were taken directly from the EU PSMF. Some of the annexes were prepared using local content originating from the UK as indicated below.

ii) Execution Phase:

A team was formed comprising local and global experts. This project team played a crucial role in ensuring that the following milestones were met to implement the UK PSMF:

• Identifying local contributors to collect the information

• Setting up a clear communication plan • Developing a Standard Operating Procedure specific to the UK for QPPV/NCPPV and PSMF processes • Creating an exception from the global procedure to extend its scope in terms of global support to the

UK PSMF

• On-boarding the contributors on the new procedure and exceptions • Compiling, aligning, and reviewing inputs from the local and global contributors • Final release of the UK PSMF

Annex Category Local Content Global Content Notes

A-Annexes ✔ UK QPPV and NCPPV content

B-Annexes

C-Annexes

D-Annexes

E-Annexes

F-Annexes

G-Annexes

H-Annexes ✔ ✔ • Local agreements listings were organised into UK and Non-UK. • Listing of global vendors supporting PV activities was added.

✔ Global studies and programmes listed without reference to EU/UK MAs (same approach as EU-PSMF)

✔ No UK-specific databases exist within Novartis

✔ ✔ • Global listings cover the procedures for whole PV system. • Additional list of dedicated Standard Operating Procedures (SOPs) which were introduced to cover UK activities consequent to exit from the EU

✔ ✔ • Global Key Performance Indicators (KPIs) were added with an extension to local only information (for example: submissions to MHRA) • KPIs of local vendors that support the UK organisation were included • Safety Label changes for UK nationally- authorised products

✔ Audits and deviations are process-specific and the processes are applicable to one PV system. Hence, global listings were included.

✔ Listings are product-specific, UK annexes introduced

Figure 3: UK PSMF Annex Model

Challenge

Resource challenge

Lack of awareness among the PSMF contributors

Tight timelines

Mitigation

• Global team extended their support to the UK and colloborated intensively providing expertise gained from compiling the EU PSMF • Securing dedicated UK resources

• Directed meetings to local and global contributors clarifying the scope and timelines of EU and UK PSMF releases • Clear correspondence and explanation of the method adopted for compiling the UK PSMF

• Created a detailed, time-based, project plan • Created templates based on the EU PSMF to help local contributors include the required data

Figure 4: Challenges and Mitigations

First MHRA inspection of the UK PSMF:

The first version of the UK PSMF was released in the last week of April 2021 and in the first week of May, a notification of inspection was received from the MHRA Inspectorate. The first version of the PSMF went through the inspection and no relevant findings or observations were included in the Inspection Report.

Conclusions:

The key factors that played an important role in the implementation of the UK PSMF in the rapidly evolving situation were:

• Strategic planning and early initiation of the project • Good collaboration between local and global teams • Clear communication and prior alignment on the expected inputs required from all of the stakeholders • Early identification of the challenges and prompt mitigation of issues identified The company’s UK PSMF fulfils the overall requirements as per the UK regulation. However, there is room for continuous improvement based on the following factors: • Inclusion of any future MAs specific for Northern Ireland (if any) • Responding to feedback from future inspections and audits • Adapting content of the Annexes to reflect only information specific to UK MAs in the PSMF (where applicable)

• Any alternative approaches to the existing model based on the EU PSMF to facilitate the interchange of modules between EU and UK PSMF (for example: writing the EU PSMF as modules)

References

1. Exceptions and modifications to the EU guidance on good pharmacovigilance practices that apply to UK marketing authorisation holders and the licensing authority.

GVP Module II – Pharmacovigilance system master file (Rev 2) 2. HMR Schedule 12A (part 1)

Vasavi Kalyani Garlapalli

Manager, QPPV office Novartis

John Verheul

Lead Operations and Strategy, QPPV office Novartis

Amisha Sandhu

Patient Safety Group Manager Novartis