Sodium Valproate – updated statement

A coalition of 11 UK epilepsy organisations recently met with representatives of the Medicines & Healthcare products Regulatory Agency (MHRA) to discuss proposed MHRA changes to safety measures and policy relating to the use of sodium valproate.

The coalition does not support the MHRA’s current position and believes the proposed regulations are fundamentally flawed without an adequate comprehensive risk/benefit assessment. The coalition considers the overall impact and consequences of the new regulations, as currently proposed, to be unsafe for people with epilepsy and will increase risks to life.

In the interests of reducing risk for people with epilepsy, the coalition wishes to explore conditions for future engagement with the MHRA but need assurances that there will be transparency and meaningful engagement in any discussions. The coalition is still waiting for a response from the Secretary of State to its letter of March 27^th (https://heyzine.com/flip-book/484d94e780.html).

Whilst engaging with the MHRA to seek amendments to the policy, the coalition wish to make clear that such engagements are not – and should not be seen – as an endorsement of the MHRA’s current position on sodium valproate.

Below is the full response that the epilepsy coalition has sent to the MHRA.

Response to MHRA following request for engagement

13 July 2023

Thank you for meeting with us and your circulation of the MHRA minutes of 7^th July 2023.

The coalition does not support the MHRA’s current position on the anti-seizure medication Sodium Valproate. We believe the proposed regulations are fundamentally flawed without an adequate comprehensive risk/benefit assessment. The coalition considers the overall impact and consequences of the new regulations, as currently proposed, are fundamentally unsafe for people with epilepsy and will increase risks to life. Any engagement by the coalition should therefore not be seen as an endorsement by the coalition of the MHRA’s current position on Sodium Valproate.

The coalition will engage with the MHRA to seek amendment to the policy and agree next steps and so reduce the risk of potential harm to people with epilepsy including deaths. We note that the current offer of engagement is limited in scope and that by engaging it is clearly understood that the MHRA cannot communicate with third parties any wording to suggest the Coalition is reassured.

In the interests of reducing risk, the coalition wishes to explore conditions for future engagement. This must mean transparency, meaningful engagement and assurance from the MHRA that they are using all reasonable endeavours to help the coalition to secure a response from the Secretary of State to our letter of March 27^th (https://heyzine.com/flip-book/484d94e780.html).

Conditions required for future engagement.

The coalition considers there are a number of conditions required if future engagement with the MHRA is to be meaningful for all parties and we are therefore requesting a follow-up without prejudice meeting to explore the conditions for future engagement.

1. What does the MHRA want to achieve from engagement with the coalition?

2. What is open to influence and change? Is the policy open to change or is the MHRA simply looking for input on implementation? We requested that the Policy Update for Women be considered separately from policy for men because there are quite different considerations and different evidence.Is this possible ?

3. We request a clear and agreed mechanism for engagement that explains how the coalition will be involved. The engagement process for 11 clinical and epilepsy patient organisations needs to be reset and we would like to establish clarity on what that will look like and how it will work as there are a multitude of different organisations, mentioned.

4. We consider the MHRA approach should reflect openness, transparency, respect, and timeliness in its communication with the coalition. In practical terms that means we need an agreed protocol which includes:
   1. No surprises.
   2. A response to our previous requests for information or explanation as to why a response is not possible.
   3. Timely future disclosure of information.

We would like to explore reasonable notice periods for engagement. Requests for response by return or response in anti-social hours or short notice requests for meetings are not workable for us as a coalition. As a sector of clinical and patient organisations in the health sector we are working under unprecedented pressures. In consideration of this we would like meeting dates agreed with us with a reasonable notice period (minimum three working weeks) and where you are seeking a response in between meetings, the deadline for that is also agreed with us.

5. Any reference to the coalition’s participation with MHRA in public communications should be referred to the coalition before dissemination.

6. The coalition reserves the right to withdraw its engagement if it believes or perceives that the processes and decisions of the MHRA are not respecting meaningful engagement with the Coalition.

7. That the MHRA and the Coalition use an agreed set of wording to describe our current state of engagement whenever communicating with third parties e.g. “That the epilepsy coalition of clinical and patient organisations are engaging with the MHRA with view to amending the policy Update of December 12^th 2022 and to agree next steps to reduce the patient safety risks of the policy, whilst the Coalition continues to seek a response from the government to our letter of 27^th March 2023 and to our freedom of information requests of December 21^st 2022”.

Questions for MHRA

1. We request the appropriate information from the MHRA about the practicalities of implementing the policy – who will be responsible for the actual implementation, monitoring, and risk assessment of the policy? What are the timescales for implementation?

2. Has the MHRA had any input from the Patient Safety Commissioner about the potential impact of the policy?

3. How will the coalition be involved in shaping the communications around the policy – will this be meaningful or simply commenting on materials that have already been drafted? Could we suggest establishing a working group with involvement from charities, clinicians, and patients to work together on this?

4. Will the policy be included in NICE Guidelines and quality standards? How are the NICE epilepsy guidelines group to be involved with the policy ? As the recognised experts in epilepsy, are they going to be able to review the evidence again around Valproate & make independent stakeholder engagements and recommendations regarding its use?

5. Have legal regulatory conflicts been identified? How will these be resolved?

Rationale for the Coalition Position July 6^th

We met with the MHRA for a without prejudice meeting since the Coalition had sent letters to the MHRA in January and February 2023 and sent a letter to the Secretary of State on March 27^th.

As communicated before and during the meeting the Coalition was not taking any position in this meeting with the MHRA but undertook to give a response to the request for engagement.

The Coalition has now met after receiving the minutes of the meeting from the MHRA.

Whilst the information provided at the meeting gave some additional clarity, the Coalition remains seriously concerned and does not have the reassurance needed by the sector for the approach taken nationally and locally.

We do note

1. The MHRA apology for the delay in responding to the Epilepsy Coalition letters and that there was acknowledgment of the frustration caused. The Coalition also notes the MHRA’s desire to work with the Coalition and that the MHRA has confirmed that the Government is working on a response to the Coalition letter of March 27th.
2. The MHRA presented slides on the research on which the Commission on Human Medicines issued advice in 2022 and on which the December 2022 communication was based.
3. Clarity of the intention for there to be a key message that people with epilepsy will have Patient Choice, with fully informed consent based on the known risks and benefits of valproate and other anti-seizure medications; that no patient will be forced to switch from valproate against their wishes. The Coalition welcomes the MHRA acknowledgement that there will be individuals where valproate will remain first line treatment due to several factors including the type of epilepsy and it is important to monitor outcomes of the updated regulatory action.

4. The MHRA confirmed that the Acknowledgement of Risk Form (ARAF) allows for any compelling reasons why the PPP does not apply to be documented and that refusal to engage would be something to be recorded in the clinical notes not in regulatory documents.

5. The Coalition notes that the MHRA has confirmed that ahead of further announcements, press releases will be shared with all key patient organisations and a public assessment report will be published.

We also note, however, for patient safety assurance purposes

1. There is still no transparency in the public domain of the data that is being relied on. We ask again for the MHRA to respond to our request for a separate policy for men and women (because the evidence we are aware of is very different and of very different quality).Information needs to be clear and the rationale for a regime of two prescribers and whole system monitoring needs to meet the needs of exploring all options and the proportionality and impact of each option.
2. We remain unassured that national and local systems have and will have in place what is necessary to ensure patients have informed consent in practice. The lack of any safeguards in the system yet to enable this and to pay due regard to the proportionality of all risks to people with epilepsy and their families including safeguarding of life to people with epilepsy and the unborn is of huge concern.
3. Regarding workability as part of patient safety, although we understand now that the MHRA update will be phased starting with newly diagnosed patients and that patients will not be withdrawn against their wishes, the workforce shortages in epilepsy, which were acute before the pandemic, have worsened.We note the exploration of other clinical flexibilities, but without epilepsy being included in the government’s national strategy for major conditions or being required to be included in local strategy, and without an urgent workforce plan, we do not have any assurance regarding the workforce capacity. Equally important is careful regard to the necessary competencies of any professional involved to deliver this policy safely.
4. We note that important points about how patients would be enabled and empowered to exercise informed consent; but that there is no clarity on who is accountable for the policy decision and its implementation. The request for an equalities impact assessment report was also not answered.
5. That the MHRA regulatory guidance will only include the risks of harms of anti-seizure medicines within its scope. As the objective of the increased clinical oversight for patients is to ensure that only those patients who really need valproate will receive it but person-centred risk of SUDEP and epilepsy death and other harms from seizures are outside the scope, we doubt that assurance can be given.We believe genuine patient consent and real patient safety can only be assured by full information which includes person-centred communication of SUDEP and mortality risk alongside information about potential harms to the unborn. Whilst we appreciate educational materials and NICE guidelines may help bring necessary nuance, these fall outside the statutory framework. Existing NICE guidelines since 2004 remain unimplemented, with the NCEPOD report just the latest of national reports over decades, with funding recognition and management of epilepsy risk largely absent in non-specialist settings.
6. That the only evidence point being used for the monitoring of anti-seizure medication for Valproate for comparisons between Integrated Care Boards is the number of prescriptions.
7. The Coalition noted in the immediate lead up to the meeting that it received a letter of response to the letter of February and also was notified about an information update from Sanofi (update found here) concerning issues with their data relating to the anti-seizure medication Valproate for men.This made it difficult for the Coalition to put forward up to date questions. The purpose of the meeting was to provide answers to the Coalition questions. Whilst some questions were answered, the questions in our correspondence to the Secretary of State and many of the questions circulated in writing to the MHRA in advance of the meeting have still not yet been answered.The notification of the information relating to the issues with data and the receipt of information immediately in the lead up to the meeting inevitably means that more questions arose that were not covered in our previously circulated questions.
8. To our knowledge, no other country has introduced a Prevent Programme for men or is accelerating the programme for women, but other countries are waiting to review once there is more research and Sanofi has finalised its PASS data after a thorough review of the issues with the data with men. The Coalition proposed to the MHRA in February the separation of medicines regulatory policy of men from women because the evidence about the benefits and harms of medicines are quite different. We have not had a response yet to that request for separation.
9. Whilst we fully support the concerns of Valproate families that women with epilepsy have access to evidence-based information and preconception counselling about harm to the unborn child, we have yet to see any action on the recommendations of the MBRRACE report since 2016 even though the doubling of deaths was the most statistically significant finding that MBBRACE has ever had. Also, we have yet to have attention from ministers, or the MHRA, to the concerns and evidence from bereaved families and which we have been asking for since 2016 to be part of the balance of a medicines regulatory policy that takes into consideration the benefits and harms of medicines. Your summary in your response to our letter of 8^th February made no reference at all to the specific harms when people who need a lifesaving medicine are restricted in accessing it.
10. There is still no impact assessment. People with epilepsy and their families are one of the most deprived groups of people experiencing social exclusion. The evidence on health inequalities including premature deaths was shared with the MHRA during a meeting in February.
11. Monitoring: Omission of a fundamental point on national monitoring measures for ICS systems that appear to rely on one point of evidence for performance namely the number of prescriptions of Valproate with no points of evidence on outcomes for patients e.g., seizure control, injuries, mortality. We are especially concerned about the evolution of and acceleration of monitoring of data given the concerns we have outlined in our correspondence with the MHRA and the Secretary of State. https://www.hsj.co.uk/patient-safety/what-role-might-better-data-play-in-overcoming-patient-safety-challenges/7035063.article; We are also concerned that whilst any policy necessitates the identification of anyone on Valproate, teams that have explored this in local systems have discovered that there is wide variation between different ICS interpretations on data protection laws. Restrictive interpretations are thwarting the work of local secondary teams who have found that they are not able to cross check secondary care databases with actual prescribing meaning that services are unable to have confidence that they know everyone in the locality on Valproate.
12. We are aware from ministerial statements that you are now in the process of finalising implementation. Our position is that the coalition will continue to engage with policy makers with the same asks that are contained in our letter of 27^th March; will continue to ask for scrutiny of the policy and for the release of what we have asked for under freedom of information requests. We do not know any of your timescales for implementation.
13. We appreciate you taking the time to read our concerns and look forward to your response. It is also important to note, our position comes from a genuine desire to secure appropriate rights and choice for patients, based on safe administration practice and balanced risk taking.  We believe that with transparent communication between us and the MHRA, and genuine partnership working this would be achievable.