This paper outlines steps that could be taken in Scotland, both by the Scottish Government and others within the healthcare system, in order 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 as a result of all medicines with teratogenic potential. Medicines with teratogenic potential means 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.
In Scotland, progress has been made in relation to reducing exposure to sodium valproate, however it has consistently been noted that 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 will initially be on sodium valproate, and then the learnings and experience used to explore actions to reduce harm associated with other medicines with teratogenic potential.
This paper has been considered by the Scottish Government Sodium Valproate Advisory Group (SVAG) and: (1) summarises the policy background around medicines with teratogenic potential; (2) summarises the current issues relating to medicines with teratogenic potential; (3) describes a work plan to address the issues; (4) outlines key discussion points to highlight areas where work can be focussed and; (5) outlines next steps to be taken to progress this policy area.
This paper also takes into consideration the Public Health Scotland (PHS) analysis on sodium valproate prescribing, the findings for that were published on the BMJ website in June 2022.
Harm caused by medicines with teratogenic potential
Some medicines are known or suspected to cause birth defects and development disorders when taken during pregnancy. Children exposed to sodium valproate in utero have a 10% risk of congenital malformations and a 30-40% risk of neurodevelopmental disorders. (Source: Valproate medicines and serious harms in pregnancy: new Annual Risk Acknowledgement Form and clinical guidance from professional bodies to support compliance with the Pregnancy Prevention Programme).
It is therefore a priority that the Scottish Government works with NHS Scotland and other stakeholders to reduce and eliminate harm from teratogenic medicines where possible. While it is for the Medicines and Healthcare products Regulatory Agency (MHRA) as the independent medicines regulator to investigate any current safety concerns regarding licensing of medicines, this paper outlines areas where action can be taken in a Scottish context to reduce harm from current and future medicines with teratogenic potential. Any approach will need to be multi-layered and multi-faceted due to the differing levels of harm caused by teratogenic medicines, and that 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 Medicines and Healthcare products Regulatory Agency (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 and one surgical intervention. The review considered the teratogenic effects of two medicines, sodium valproate and Primodos. 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. Further to this, on 24 March 2021, the Scottish Government published a delivery plan outlining the steps which are and will 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 work plan seeks to build further on those outlined in the Delivery Plan as well as scope where further action might be taken.
Scottish Government Sodium Valproate Advisory Group (SVAG)
The SVAG was set up by the former Chief Medical Officer in 2019 with a remit to examine steps that could be taken in a Scottish context in addition to the regulatory actions being taken by MHRA and European Medicines Agency (EMA) to reduce harm from sodium valproate.
The expert group is chaired by the Chief Pharmaceutical Officer (CPO), and includes representation from neurologists, psychiatrists, general practitioners, PHS and HIS, with secretariat support provided by the Scottish Government Medicines Policy Unit. In line with the evolving role of the SVAG to encompass all known and suspected teratogenic medicines, the SVAG was rebranded as the Teratogenic Medicines Advisory Group (TMAG) in March 2022. The full membership of the TMAG can be found in Annex B.
Medicine registries consolidate prescribing data for specific medicines and link in data from clinical care and other social administrative databases, allowing the exploration of trends in prescribing patterns and associated patient experiences. They also can help to identify issues that may affect patient safety.
Medicines registries have an important role in improving patient care by monitoring the use, benefits, and risks of medicines. The development and maintenance of publicly held medicine registries help ensure that all 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 support patients and their prescribers to make more informed decisions about available treatment options.
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, initially 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) is due to deliver data this year, identifies people taking sodium valproate, as well as any other anti-epileptic medicines. Discussions have been held and outputs shared with the MHRA about its antiepileptic registry which currently covers England only. As a UK wide antiepileptic medicines registry (originally it was for sodium valproate alone) will take some time to develop, the SER will be of particular benefit to support the Scottish Government’s delivery plan objectives in the interim period. It is, however, important to recognise that sodium valproate and other antiepileptic medicines are used for conditions other than epilepsy, thus an epilepsy register will not identify all patients. However, the SER has the potential to provide Scottish data for the UK antiepileptic medicine’s registry.
National Medicines in Pregnancy Surveillance asset
PHS has been commissioned to prepare a business case on a National Medicines in Pregnancy Surveillance asset. This asset would support surveillance and reporting which would further progress improvements in the safe use of sodium valproate and other teratogenic medicines in Scotland in line with the Scottish Government’s Delivery Plan in response to the IMMDSR. It will also have the capability of monitoring the impact of pregnancy prevention policies and further research into other medications which may have teratogenic properties. Congenital anomaly data will come from the national linked anomaly database and CARDRISS, which includes data on all anomalies diagnosed before a baby’s first birthday.
The Scottish Government has committed to participate in MHRA led UK-wide mandatory medicines registries as part of the UK Health and Care Act 2022. The asset has the potential to be extended to cover the data gaps between the SER and the MHRA antiepileptic medicines registry. The asset also has the potential to be extended to align with data requirements of future MHRA UK-wide registries. The PHS business case is currently being considered.
PHS is also analysing information on COVID-19 cases in pregnant women by linking national data on positive COVID-19 cases to the COVID-19 in Pregnancy in Scotland (COPS) study database of pregnant women in Scotland. The COVID-19 data comes from the NHS Scotland National Clinical Data Store which draws data from the NHS Scotland Vaccine Management Tool (VMT) and any GP practices that are recording delivery of vaccinations directly into GP systems.
UK Covid-19 antivirals pregnancy registry
In February 2022, the MHRA announced a UK-wide registry for antivirals. It was set up as the safety of COVID-19 antivirals in pregnancy has not been established. The registry is being operated by the MHRA in collaboration with the UK Teratology Information Service (UKTIS), to collect information about exposure to COVID-19 antivirals in pregnancy and enable follow-up. The registry is also collecting information on outcomes for pregnancies where conception occurred during or shortly after paternal exposure to antiviral treatment.
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 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.
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.
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 important gaps which must be addressed. Scottish Government Health Digital colleagues are consulting on the first data strategy. The need to record the indication in all prescription settings, and an enhanced ability to make linkages between various datasets are important gaps that remain. Recognising the challenges across the data infrastructure/landscape is crucial and addressing these gaps remains an important priority for the Scottish Government. In developing this work plan to reduce harm from teratogenic medicines, there is a need to be transparent about current data capabilities, focus on building on existing infrastructure and setting out what steps can be taken to build on and improve the current data landscape.
Furthermore, a key aspect of this work will be the ability to monitor outcomes in children who have been born exposed to medicines with teratogenic potential. While registries are an important tool and will certainly have their part to play in this, they tend to be standalone systems and there is an opportunity to develop a more agile and integrated system which can be used to help tailor our approach at various stages across the life journey. This is work to be undertaken, as part of the development of a national medicines surveillance capability in pregnancy, for which a business case is under consideration.
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 whilst there are limitations in its current form, this work plan presents an opportunity to improve this. Effective Prescribing and Therapeutics (EPT) Division would be keen to 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.
Annex A provides action that will be taken forward by the Scottish Government and others within the Scottish Healthcare system. This work plan is not exhaustive and includes initial activities that would support practice to develop related policies and activities that will reduce harm from teratogenic medicines.
Annex A - work plan
Action: Establish a baseline of current practices across Health Boards in Scotland to reduce harm from sodium valproate
Timeframe: Short Term –completed summer 2021
Progress: The ADTC Collaborative wrote to all boards to collect this information which we will be used as a baseline to inform next steps. ADTC Collaborative will update Scottish Government officials on next steps
Comments: To support the development of the sodium valproate learning system and better understand what tools and interventions may be required to be developed there is a need to understand current practices and tools used across health boards i.e. Shared care agreements. Difficult conversation guidance and incapacity also to be considered
Action: Develop a shared learning system including tools and interventions as required
Timeframe: Short term – to be completed winter 2022
Progress: Following initial discussions, it is anticipated that this action will be delivered through the Area Drug and Therapeutics Committee (ADTC) Collaborative in the context of sodium valproate.
This was discussed at ADTC forum and was supported by Boards. Follow up paper brought to SVAG meeting in March 2022. A business case to support this work is under consideration
Comments: The ADTC Collaborative operates as an overarching shared learning system on medicines governance. They already have a track record in successfully delivering the HEPMA shared learning work. Delivery against this action could be commissioned to the ADTC Collaborative and would also be able to share learning, best practice, collaborate on the testing and spread of improvements and provide a platform for sharing advice from the TMAG and others directly to the NHS Boards. The TMAG will also be able to advise on other tools required as appropriate. Once these tools are in place for sodium valproate, it is anticipated that we can extend them further to other medicines with teratogenic potential as required
Action: Compile a list of medicines with teratogenic potential, and review MHRA list of medicines with teratogenic potential and consider this in the context of the IMMDSR recommendations
Timeframe: Short Term – to be expected by autumn 2022
Progress: This is an activity that is already being undertaken by the MHRA. The anticipated timelines for this output are to be confirmed. Scottish Government policy officials have followed up with MHRA
Comments: By ensuring that we have a full list of medicines with teratogenic potential, and that this list is kept under review, we will be able to accurately target actions related to reducing harm to those medicines that require them most in a Scottish context. Learning from the work undertaken to improve safety outcomes for sodium valproate use will be used to complement the list and feed into wider discussions that will agree actions for next steps
Action: Further examine the National Therapeutic Indicators (NTIs) for other medicines with teratogenic potential, and identify any potential links where they can support the IMMDSR Delivery Plan
Responsible: Scottish Government – Effective Prescribing and Therapeutics (EPT)Division
Timeframe: Short to medium term – likely take up to a year to complete (spring 2023)
Progress: This is in the Scottish Government Effective Prescribing and Therapeutics Policy Team work plan. A working group has been set up to undertake a review of the indicators that underpin the National Therapeutic Indicators (NTI) – and Scottish Therapeutics Utility (STU). This working group will pull in subject experts as and when required
The work plan and timescale for the group is still being developed and it is anticipated that the review of the whole suite of indicators will likely take up to a year to complete. EPT would be keen to engage with TMAG and others to identify subject experts who could input into this work
Comments: As with all other NTIs it will be supported with learning and key actions to take as per current narratives to drive improvement. Discuss with PHS to agree most accurate way to identify people of childbearing potential for data gathering and visualisations
Action: Establishment of a national medicines surveillance capability in pregnancy
Responsible: Public Health Scotland
Timeframe: Medium to long term – to be confirmed
Progress: Scottish Government has commissioned a business case from Public Health Scotland (PHS) to establish a national medicines and pregnancy information and intelligence asset which will support surveillance and reporting of sodium valproate and other teratogenic medicines. The PHS business case is currently under consideration
Comments: The basis of this is in pre-existing systems and through the learning of previously commissioned work on sodium valproate, which when combined with national datasets, will allow PHS to monitor exposure to harm on an ongoing basis. This would then allow Scottish Government and others to consider this data to decide what actions need to be taken
Annex B - membership of the Scottish Government Teratogenic Medicines Advisory Group
- Alison Strath, (Chair) Chief Pharmaceutical Officer, Scottish Government
- John Paul Leach, Consultant Neurologist, University of Glasgow
- Laura McIver, Chief Pharmacist, Healthcare Improvement Scotland
- Roch Cantwell, Consultant Perinatal Psychiatrist, Perinatal Mental Health Network Scotland
- Daniel Smith, Professor of Psychiatry, University of Glasgow
- Alastair Cook, Principal Medical Officer, Scottish Government
- Marion Bennie, Chief Pharmacist, Public Health Scotland
- Corinne Love, Senior Medical Officer – Maternity and Women’s Health, Scottish Government
- Andrew Walker, Lead Clinical Pharmacist Adult Mental Health, NHS GGC
- Euan Reid, Lead Pharmacist, NHS Fife
- Scott Hill, National Clinical Lead, ADTCC, NHS Healthcare Improvement Scotland
- Richard Davenport, Consultant Neurologist, NHS Lothian
- Iain Wilson, Clinical Lead (GP), Effective Prescribing and Therapeutics, Scottish Government
- Alpana Mair, Head of Effective Prescribing and Therapeutics, Scottish Government
- Dan Morales, Academic GP and pharmacoepidemiologist, University of Dundee
- Craig Heath, Consultant Neurologist and Honorary Senior Clinical Lecturer, NHS Greater Glasgow and Clyde
- Laura Byrne, Director of Pharmacy, NHS Forth Valley
- Juliet Brock, Medical Officer, Mental Welfare Commission
- Irene Oldfather, Director Strategic Partnerships and Engagement, the Alliance
- Justine Craig, Chief Midwifery Officer, Scottish Government
- Irene Oldfather, Director Strategic Partnerships and Engagement, the Alliance
- Justine Craig, Chief Midwifery Officer, Scottish Government
- First published
- 19 October 2022
- Last updated
- 31 October 2022
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