Teratogenic Medicines Advisory Group: work plan

Overview

Purpose

This paper outlines steps that could be taken in Scotland, both by the Scottish Government and others within the healthcare system, to meet our obligations in relation to the Independent Medicines and Medical Devices Safety Review (IMMDSR), First Do No Harm, as they relate to sodium valproate. Furthermore, it summarises steps that can be taken to prevent wider harm from all medicines with teratogenic potential[1].

In Scotland, progress has been made in relation to reducing exposure to sodium valproate, however it has consistently been noted that the potential of teratogenic harm is wider than one medicine and there is a need to consider other medicines with teratogenic potential. The focus of the work plan initially was on sodium valproate, and then the learnings and experience from sodium valproate were used to explore actions to reduce harm associated with other medicines with teratogenic potential.

This paper was updated by the Scottish Government’s Teratogenic Medicines Advisory Group (TMAG) in October 2024. This paper:

• summarises the policy background around medicines with teratogenic potential
• sets out the relevant data systems and their role in relation to these medicines
• describes actions for the Scottish Government and the TMAG.

Background

Harm caused by medicines with teratogenic potential

Some medicines are known or suspected to cause birth defects and / or developmental disorders when taken during pregnancy: for example, exposure to valproate in pregnancy is associated with physical birth defects in 11% of babies and neurodevelopmental disorders in up to 30-40% of children, which may lead to permanent disability (source: New valproate safety measures apply from 31 January - GOV.UK (www.gov.uk). A Medicines and Healthcare products Regulatory Agency (MHRA) safety review concluded that the use of topiramate during pregnancy is associated with significant harm to the unborn child, including a higher risk of congenital malformation, low birth weight and a potential increased risk of intellectual disability, autistic spectrum disorder and attention deficit hyperactivity disorder in children of mothers taking topiramate during pregnancy (source: Topiramate (Topamax): introduction of new safety measures, including a Pregnancy Prevention Programme - GOV.UK (www.gov.uk)).

It is a priority for the Scottish Government to work with NHS Scotland and other stakeholders to reduce and eliminate harm from medicines with teratogenic potential where possible. While it is for the MHRA as the UK’s independent medicines regulator to investigate any current safety concerns regarding the licensing of medicines, this paper outlines areas where action relevant in a Scottish context can be taken to reduce harm from medicines with teratogenic potential. It is acknowledged that any approaches to reduce the harm from teratogenic medicines will need to be multi-layered and multi-faceted due to the differing levels of harm caused by teratogenic medicines, and as such a ‘one size fits all’ approach is unlikely to be appropriate.

The Independent Medicines and Medical Devices Safety Review (IMMDSR)

The IMMDSR, First Do No Harm, led by Baroness Julia Cumberlege, was published in July 2020. The report was commissioned by the UK Government.

The licensing, regulation and safety of medicines is reserved to the UK Government and is the responsibility of the MHRA. Some of the recommendations of the IMMDSR relate to areas of reserved competence, and the Scottish Government has no powers to implement these.

The IMMDSR was established following many years of campaigning and investigated two medicines, sodium valproate and Primodos, and one surgical intervention (vaginal mesh). The report made several recommendations to make healthcare safer for the future.

On 8 September 2020, the Scottish Government committed to implement all of the recommendations from the report, where they relate to the responsibilities of the Scottish Government and published a Delivery Plan outlining the steps which to be taken in order to implement these recommendations. While the Delivery Plan outlines the steps which are being taken to meet the Scottish Government’s commitments under the IMMDSR, this paper sets out actions in Scotland to build further on those outlined in the Delivery Plan in relation to sodium valproate and other medicines with teratogenic potential, which are within the remit of the Teratogenic Medicines Advisory Group.

Scottish Government Teratogenic Medicines Advisory Group (TMAG)

The Scottish Government established the Teratogenic Medicines Advisory Group (TMAG) in March 2022. The TMAG, formerly known as the Sodium Valproate Advisory Group (SVAG), was originally set up in 2019 by the former Chief Medical Officer, Dr Catherine Calderwood, with a remit to examine steps that could be taken in a Scottish context in addition to the regulatory actions being taken by the MHRA and the European Medicines Agency (EMA) to reduce harm from sodium valproate.

The Chief Pharmaceutical Officer (CPO) chairs the TMAG which includes expert representation from neurologists, psychiatrists, general practitioners, Public Health Scotland (PHS) and Healthcare Improvement Scotland (HIS), with secretariat support provided by the Scottish Government Medicines Policy Unit. In line with the evolving role of the SVAG to encompass other medicines with teratogenic potential, the SVAG was rebranded as the Teratogenic Medicines Advisory Group (TMAG). The full membership of the TMAG is on the group page.

Data systems

The IMMDSR highlighted the importance of collecting patient level data and its role in monitoring the safety of medicines. While Scotland has extensive health data and informatics systems - some of which record indication, drug exposure, clinical modifiers, and resource use and outcome measures - there remain gaps. The need to record the indication in all prescription settings, and an enhanced ability to make linkages between various datasets are important gaps which are being addressed. There is a need to be transparent about current data capabilities and the steps which can be taken to build on and improve the current data landscape, focussing on building on existing infrastructure.

Medicines registries consolidate prescribing data for specific medicines and link data from clinical care and other social administrative databases, enabling the exploration of trends in prescribing patterns and associated patient experiences. Registries also have an important role in improving patient care and patient safety by monitoring the use, benefits, and risks of medicines. The development and maintenance of publicly held medicine registries help ensure that patients prescribed a specific medicine can be identified by health care professionals if necessary and contribute to the evidence base for the use of a specific medicine, which in turn supports patients and their prescribers to make more informed decisions about available treatment options. While the work on UK-wide statutory medicines registries which is led by the MHRA is currently on hold, in Scotland we continue to progress other systems and resources in relation to medicines.

National Medicines in Pregnancy (MiP) surveillance asset

The Scottish Government commissioned PHS to establish a nationalMedicines in Pregnancy (MiP) surveillance asset. The asset supports surveillance (monitoring) and reporting to progress improvements in the safe use of valproate and other teratogenic medicines in Scotland in line with the Scottish Government’s Delivery Plan in response to the IMMDSR.

Work started in April 2023 and its first output, a report which contains equivalent data to the MHRA and NHS England’s registry reports for England, was published on 2 April by PHS. The data closely mirrors the England-only reports from the MHRA’s Medicines and Pregnancy Registry. The first PHS report includes prescribing numbers and trends for anti-seizure medicines including valproate and topiramate and as well as data on exposure in pregnancy. The report covers the period between April 2018 and September 2023 and found that the number of females aged 0-54 prescribed valproate had decreased by 42% during that time. The second PHS report was published on 1 October 2024 and includes data up to March 2024, and a public facing dashboard: Anti-Seizure Medicines in Pregnancy 1 October 2024 - Anti-Seizure Medicines in Pregnancy - Publications - Public Health Scotland

Year two of the MiP work programme, starting in summer 2024, will see further developments to the combined medicines data asset and the linked pregnancy data asset, with automated linkages, and include data for male valproate patients. In addition, a management dashboard with Health Board level data will be complete in year 2.

Scottish Epilepsy Register (SER)

The Scottish Government is funding, through the implementation of the Neurological Care and Support Framework, the development of an epilepsy register which has now been established in NHS Greater Glasgow and Clyde, NHS Tayside and NHS Lanarkshire, with a view to roll out across all Health Boards in Scotland. The Scottish Epilepsy Register (SER) identifies patients with valproate prescriptions as well as any other anti-seizure medicines. Its dashboard allows reports to be generated on women of childbearing age who are dispensed valproate and captures indication for use and contraception status. It also facilitates the annual MHRA review process and generates an alert if a women of childbearing age dispensed valproate becomes pregnant. Discussions took place and outputs were shared with the MHRA which has an England-only Medicines and Pregnancy Registry. It is noted that the SER is not a medicines registry, and sodium valproate and other antiepileptic medicines are prescribed for conditions other than epilepsy, therefore it does not identify all patients.

Hospital Electronic Prescribing and Medicines Administration (HEPMA)

Hospital Electronic Prescribing and Medicines Administration (HEPMA) aims to deliver electronic prescribing and recording/management of medicines administration across secondary care.

The implementation of HEPMA provides an opportunity for NHS Scotland to gather comprehensive data from secondary care at an individual patient level. When added to existing patient data from primary care and hospital-level data on medicines use, this will provide a more complete overview of a patient’s medicines pathway across NHS Scotland, allowing a better understanding of patient response to treatment, supporting national, regional and local data collection and reporting with possibility of comparison, providing opportunities for quality improvements in patient care through the safer, more reliable use of medicines.

While all Health Boards in Scotland have either implemented or are in the process of implementing/planning for HEPMA, its availability remains inconsistent across the country. However, more recently Scottish Government officials have strengthened focus on supporting the implementation and the wider benefits of HEPMA and are working to re-energise the roll-out as part of developing the digital strategy. Through the implementation of HEPMA, there are opportunities to support service improvement, monitoring, and audit, which will be critical in any wider approach to medicines with teratogenic potential.

A National HEPMA medicines asset has now been established by PHS capturing routine inpatients prescribing episodes where HEPMA has been deployed – currently capturing over 65% of the Scottish population. This asset is available to NHS Boards.

At the centre of the Scottish Government’s health informatics potential is the ability to link datasets and drill down to individual patient level using the Community Health Index (CHI), a unique patient identifier that is used in all primary health care and hospital-based systems throughout Scotland. At present, the CHI can be linked to medicine use data at the primary and community care level across the country.

While the development of HEPMA will be an important feature, it is notable that the majority of medicines with teratogenic potential are used in primary care and these systems will be of greater significance in building a data capability for monitoring outcomes in pregnancy.

National Therapeutic Indicators (NTIs)

National Therapeutic Indicators (NTIs) use prescription data to provide (1) a measure of prescribing activity in specified therapeutic areas, and (2) a comparison across GP practices in Scotland, Health Boards within Scotland, and GP practices within these Health Boards. Data from NTIs are made available to Health Boards, Health and Social Care Partnerships, GP practice clusters and GP practices for use in quality improvement initiatives. There is currently an NTI for measuring the use of sodium valproate, and while there are limitations in its current form, this work plan presents an opportunity to improve this. Effective Prescribing and Therapeutics (EPT) Division engage with TMAG and others to identify subject experts for input into this review to ensure that the suite of NTIs includes other medicines with teratogenic potential and appropriate indicators are developed.

Scottish Therapeutic Utility (STU)

Effective Prescribing and Therapeutics maintains the Scottish Therapeutics Utility (STU) and makes it available free of charge to boards and GP practices. STU is a computer programme that interrogates data from GP IT systems with a focus on repeat prescribing and, more recently, high risk prescribing. It generates a suite of standardised reports to facilitate targeted medicines management activity. STU has a suite of indicators that mirror the (NTIs) and enables practices to identify patients for review, STU searches are being updated as a result of NTI review.

[1] A medicine with teratogenic potential is any medicine which is known or suspected to have the potential to increase the risk of birth defects or development disorders when taken during pregnancy