In May 2018 the Oireachtas Health Committee recommended an inquiry into prescription of valproate medicines in Ireland and prompt roll-out of supports for families affected by foetal anticonvulsant syndrome. But these recommendations have not yet been acted upon. Catherine Reilly reports
The Department of Health is “closely monitoring” a UK independent safety review into the response to concerns about sodium valproate, an anticonvulsant sold in Ireland under the brand name Epilim.
It is also “aware” of the French government’s approach to redress for families affected by foetal anticonvulsant syndrome (FACS), according to a Department spokesperson.
Babies born to women taking valproate-containing medicines during pregnancy have a 30-to-40 per cent risk of developmental disability and a 10 per cent risk of birth defects. Furthermore, children exposed in utero are more likely to have autism or autism spectrum problems and signs of attention deficit hyperactivity disorder. The HSE advises that women should not stop taking the medication before discussing this with their doctor.
The Independent Medicines and Medical Devices Safety (IMMDS) review in the UK, established by government in 2018, is examining how its healthcare system responded to concerns about sodium valproate and two other medical interventions. The report is anticipated in late February or March.
The French government, meanwhile, has opened a compensation scheme for people affected by FACS.
According to a timeline produced by the UK review team, papers were published from the late 1960s drawing attention to concerns about the teratogenicity of anti-epileptic drugs. Sodium valproate was licenced in Ireland in 1975 and the licence was extended to bipolar disorder in 2008.
However, in 2018 the European Medicines Agency (EMA) announced new Europe-wide safety measures on sodium valproate as women were “still not always receiving the right information in a timely manner”, following previous measures announced in 2014. The 2018 stipulations included a visual warning about risks in pregnancy being included on the outer packaging of all valproate medicines.
“The summary of product characteristics (SmPC) and the patient information leaflet have been updated to include the new strengthened warnings and recommendations,” Sanofi, the makers of Epilim, informed the Medical Independent (MI) in March 2019.
“A warning statement has been added to the outer cartons and a pregnancy warning symbol has been added to both the outer carton and the blister packaging.” The company said it had “provided information and warnings in relation to its sodium valproate products, including their use during pregnancy, in accordance with regulatory requirements”.
A change was instigated in the number of tablets per box to reduce the potential for pharmacists dispensing in plastic bags without warning materials, a situation that has greatly concerned patient groups (see panel).
Other EMA measures included that sodium valproate should not be used during pregnancy unless no other effective treatment is available and it must not be used in women able to have children unless the conditions of a pregnancy prevention programme are met. Research published in 2019 by clinicians in Children’s Health Ireland at Crumlin indicated that children as young as two years of age, for example, were being referred for diagnosis of FACS, also termed foetal valproate syndrome (FVS).
In May 2018, the Oireachtas Health Committee recommended an independent investigation into use of valproate medicines in Ireland. The committee said further consideration should be undertaken with regard to compensating FACS patients.
In his forward to the report, Chair of the committee Deputy Michael Harty (Independent) wrote that adequate services should be made available to families promptly.
“It is noted that individuals with FACS are not affected by chance, but by the failure to adequately inform and counsel women who were prescribed valproate medicines.”
A HSE-commissioned study has estimated that up to 1,250 children have experienced some form of neurodevelopmental delay and between 153 and 341 children, a major congenital malformation arising from sodium valproate exposure in utero from 1975 to 2015.
Minister for Health Simon Harris previously stated that he awaited a HSE report on the matter before giving “further consideration” to whether an inquiry was “appropriate”. In October, this report on the HSE Valproate Response Project was issued to the Department. It provided an overview of the HSE’s actions on the EMA requirements and made no reference to a potential independent inquiry.
The issue was raised again at the Health Committee last month by Sinn Féin Senator Rose Conway-Walsh, with the Minister indicating that the HSE report will be published. It is understood the Health Committee will convene another meeting on sodium valproate sometime in early 2020.
Deputy Harty told MI: “Certainly from the evidence we received from the support group and advocates, it was very strong that there should be an inquiry into what happened. “But also the fact there weren’t focused treatments or therapies, or a care pathway, for people who had been affected because the effects of valproate are quite wide across medical disciplines and the evidence we heard was that many children or adults were going to multiple specialties, but there was no coordination between those specialties in relation to a diagnosis.” Senator Conway-Walsh confirmed to MI the unpublished HSE report is “very limited” and it does not address “the point of who knew what and when”. As to what parties should pay compensation, Senator Conway-Walsh cited the company and the State.
Senator Rose Conway-Walsh
“In some cases it wasn’t only prescribed, the dose was increased in pregnancy,” she said. “Also there are questions to be answered around the licensing and the decision making around the licensing…
“I think somebody has to be accountable for this. There was no need for these children to be born with the disabilities that they have been born with and why should a child in France be treated any different to a child in Ireland?”
Senator Conway-Walsh said a public inquiry need not be lengthy or expensive. “We owe it to these families, the stress they have gone through. And the stress for mothers, you can imagine, mothers …almost blaming themselves, ‘if I hadn’t taken this drug my child would have been born without a disability’. But they didn’t know. So the anguish of the mothers that I meet is ‘I allowed this to happen to my child’; that is desperate, terrible.”
Her party colleague, Deputy Louise O’Reilly, has also raised questions. She told MI many affected families are paying for access to therapies due to the long public waiting lists. Mothers have had to give up employment to be full-time carers for their child or children, she added.
“The issue of compensation has to be on the table, because the issue of damage has to be on the table,” Deputy O’Reilly told MI.
“As to who pays the compensation, there is a massive global pharmaceutical company involved in this … I wouldn’t put all the blame for this at the door of the State necessarily because there is a massive, global pharmaceutical corporation involved as well.” “As soon as the Minister publishes the report that he commissioned, we [in the Health Committee] are looking to bring the advocates in and the Chief Medical Officer, because obviously the Chief Medical Officer has an important role to play here as well … and any other personnel that might be relevant.”
Deputy John Brassil (Fianna Fáil), a pharmacist who is also on the Health Committee, said he has been surprised by the scale of continued exposure to sodium valproate in pregnancy even into recent years.
“When I was qualified as a pharmacist back in 1999, at some stage in my course, which was between ‘94 and ‘99, I remember doing pharmacology, I remember doing valproate and being told by the lecturer about the issues and dangers [in pregnancy]…,” according to Deputy Brassil, who trained in Ireland.
He said Sanofi should pay compensation to those affected (Sanofi has previously said the product was “at all times” supplied in Ireland with a warning of the risk of malformations in babies born to women taking it during pregnancy).
“If they saw fit to change the packaging in recent times, then the packaging should have been that way always. I am not sure the whole potential for foetal abnormality was over-stressed enough.”
Asked if the State and the company should pay compensation, he said this needed to be determined by an inquiry.
“I’d like to know why valproate wasn’t always red-flagged to the degree it should have been. What brought about the change in recent times where the packaging is now very clearly telling patients about the concerns and the dangers for women of childbearing age, and the whole prescribing of it.”
MI asked the Health Products Regulatory Authority (HPRA) if it had conducted any analysis of product information distributed with Epilim since its licensing, including consistency with the product literature distributed in other countries and with published medical literature/studies.
“The HPRA has had ongoing engagement with relevant stakeholders regarding valproate in recent years,” responded a spokesperson. “In that context, the HPRA has previously provided examples of the product information available for Epilim since it was first authorised for use in Ireland. These documents provide an indication of the precautions and warnings in place in relation to pregnancy since 1975 and how these warnings evolved over the years, as new information regarding the risks of exposure in pregnancy became available.”
On whether the HPRA has had any engagement with the IMMDS review and/or the Medicines and Healthcare Products Regulatory Agency about this review, the spokesperson said the Authority was not a party to the process.
“However, given its significance, we are monitoring progress closely through publicly available information. We await the IMMDS report, which is expected to be published in late February or March  and it will be thoroughly examined.”
The spokesperson said following the updated EU-wide recommendations in 2018, the HPRA approved amendments to the product information for all sodium valproate-containing medicinal products authorised in Ireland.
Direct healthcare professional communication letters were approved by the HPRA and “widely distributed” by Sanofi as part of the response.
“The HPRA also approved an updated suite of risk minimisation materials for valproate-containing medicinal products, which include guidance and tools for healthcare professionals (including prescribers and pharmacists) and patients.”
The RCSI, in collaboration with the HPRA, is currently undertaking an impact assessment project on the effectiveness of risk minimisation measures to prevent harms from teratogenic medicines, including sodium valproate. This research is being undertaken within the framework of a Health Research Board Applied Partnership Award.
Following the new EMA measures in 2018, the HSE launched a valproate response plan. Communications were issued to GPs and pharmacists and to around 3,000 women/girls in receipt of valproate through State drug schemes. A temporary phone line was also established.
The response plan, which was led by the Office of the Chief Clinical Officer and included patient representation, had a variety of aims. These included estimating the number of children/adults who may have been impacted; developing a diagnostic pathway for children/adults who may have FACS; establishing a programme for women’s health in epilepsy; and developing a care pathway for people affected.
There has been some progress. Two specialist nurses have been appointed to the women’s health in epilepsy programme, but there was a commitment to six posts in total. Last month, a HSE spokesperson said the programme has recruited two advanced nurse practitioners and commenced two obstetrical epilepsy clinics in large maternity hospitals in Dublin.
“Ultimately, the programme is expected to develop important information on not only expanding the understanding of valproate in epilepsy and pregnancy, but also all medicines that are prescribed for epilepsy,” outlined the spokesperson.
“There is a commitment to recruit four additional advanced nurse practitioners, included in the 2019 service plan, and funding for these posts has been secured.”
In regard to recruitment of a permanent geneticist to facilitate diagnosis, the spokesperson said interviews have been completed and the successful candidate has been offered the post. “The dedicated FVS locum clinic was run through November 2019 and currently has no waiting list. The recruitment process for the consultant geneticist post has completed the interview process and we are awaiting a start date in Q2 of 2020.”
A HSE subgroup has developed a report outlining a care pathway. MI understands it recommends the establishment of a national assessment team to assess the care and support needs of all people with a confirmed diagnosis of FACS.
The HSE’s spokesperson told MI that “work to fund and implement the pathway is currently in development”.
This pathway is for patients “who have been diagnosed with FVS. Patients who have suspected FVS can be referred by their GP to local support services while they are awaiting diagnosis.” In December, the Department said it has not yet received this report.
Advocates are concerned that access to this pathway will require a diagnosis, as they say there are still lengthy waits for a diagnosis through the clinical genetics service.
Ms Karen Keely, Chair of the Organisation for Anticonvulsant Syndromes (OACS) Ireland, said the new disability pathway should be revisited in order to facilitate all families impacted by sodium valproate/Epilim.
“OACS Ireland, the body who represent the families affected in Ireland, tried to reinforce this issue with the Valproate Project Group,” she outlined in a statement to MI last month. “We believe that any mother who gives birth to a child while taking valproate and who subsequently presents with symptoms should fall under the new disability pathway for FACS until a diagnosis is determined.”
The Department of Health, she added, should ensure that children impacted by valproate are “treated in a similar manner to their EU counterparts”.
OACS Ireland remain firmly committed to securing an independent inquiry. The Department informed MI that the Minister “looks forward to meeting the patient advocates in early 2020”.
“OACS Ireland are seeking assurances from Minister of Health Simon Harris that an independent inquiry takes place,” stated Ms Keely.
She said the recommendations of the Oireachtas Health Committee in regard to an inquiry and further consideration of compensation need to be addressed immediately. “OACS Ireland and Epilepsy Ireland look forward to our meeting with Minister Harris in the near future,” she said.
According to Ms Keely, it is imperative to find out “who knew what and when”.
Mr Peter Murphy, CEO of Epilepsy Ireland, said the organisation remains concerned that the HSE direct communications exercise to patients included only girls/women in receipt of sodium valproate in the previous six months. He said the HSE indicated it was not possible to locate women who had previously been on the drug.
He expressed concern that all women and their children potentially affected by valproate are made aware of this possible connection, including women who took the drug in the past, but who no longer do so.
The HSE stated that, in collaboration with Epilepsy Ireland and OACS Ireland, it held a conference in Dublin in March 2019 to increase awareness of the issue. Mr Murphy also underlined that an inquiry is imperative.
“OACS and ourselves have said there needs to be an inquiry, to find out why this situation occurred, where is the accountability, what can we learn to avoid a similar situation in future, and most importantly to deliver answers for the families affected. The positive work that has happened to minimise future risks doesn’t absolve the need to look into the past and get answers for these families.”
PANEL: PSI investigating statutory complaint on Epilim supply
A statutory complaint has been made to the Pharmaceutical Society of Ireland (PSI) in relation to the supply of Epilim to a patient.
Since March 2019, two “matters” have been brought to the PSI’s attention in regard to the supply of Epilim to patients.
“One of these was raised as a concern and the PSI is seeking observations from the relevant pharmacy on the matter,” a PSI spokesperson told MI. “The other was raised as a statutory complaint. The latter is still in deliberative process (which is confidential) and I am unable to provide any further details on it.”
In March 2019, the PSI informed MI it had received 13 “concerns” in relation to Epilim since April 2018. The information it had received “indicated that supplies of valproate medicines have been made without the required alerts, educational material, or counselling by pharmacists”.
Commenting at the time, the spokesperson said it followed up on these concerns where specific information was provided in relation to the pharmacy involved. Follow-up included issuing letters to the superintendent pharmacists and conducting visits to three pharmacies to review issues relating to those concerns.
During 2019, a reminder to pharmacists about the appropriate supply and counselling of patients receiving valproate was included in a PSI newsletter.
“The PSI is the appropriate body to which any person may provide information or make a complaint in relation to their concern about how they have been treated in a pharmacy and about a pharmacist’s care, behaviour, or practice. And the PSI will take the appropriate regulatory action,” the PSI’s spokesperson concluded.
In recent years OACS Ireland has highlighted numerous instances of patients receiving ‘Epilim in a bag’, without any warning materials.
The potential for this occurrence appears to have reduced since Sanofi decreased the number of tablets per box.
Women’s health programme needed to prevent ‘another valproate scandal'
Medical Independent 3 April 2019
Catherine Reillyreports from a conference on the impact of sodium valproate (Epilim) in pregnancy and hears why new epilepsy medicines should be kept under surveillance
The development of a women’s health in epilepsy programme will be crucial in helping to prevent another potential scandal surrounding antiepileptic drugs (AEDs) in pregnancy, National Clinical Lead for the Epilepsy Clinical Care Programme Dr Colin Doherty told a one-day conference on the impact of sodium valproate (Epilim). The drug Epilim is licensed in Ireland to treat epilepsy and bipolar disorder. Exposure during pregnancy is associated with major birth defects and development disorders in children.
In women who take valproate while pregnant, around 10 babies in every 100 will have a birth defect (in the general population two-to-three babies in every 100 will have a birth defect, while epilepsy drugs generally carry around a six-in-100 risk).
Additionally, in women who take valproate while pregnant, 30-to-40 children in every 100 may have problems with development. Children of women who take valproate in pregnancy are also more likely to have autism or autism spectrum problems and to have signs of Attention Deficit Hyperactivity Disorder (ADHD). The HSE advises women that they should not stop taking their medication without a discussion with their doctor. The women’s health in epilepsy programme, which is in its early stages, aims to enable annual review of women with epilepsy attending the service; establishment of a formal Epilepsy Pregnancy Register; and access to epilepsy advanced nurse practitioners (ANPs) in each maternity network.
According to a document for the HSE authored by Dr Doherty, the first report of foetal abnormalities concerning sodium valproate was published in 1984. The European Medicines Agency (EMA) agreed to strengthen measures around valproate in 2014. However, “it was generally agreed that penetration of the issue was suboptimal”. This led to further EMA measures, including a pregnancy prevention programme, announced in 2018.
The paper said there were 30 anticonvulsant drugs and “it took 30 years to realise the full negative effects of VPA [valproate]. It is our intention that should never happen again”. On the need for a women’s health programme in epilepsy, Dr Doherty told the conference that the “pitch” he made to the HSE Chief Clinical Officer Dr Colm Henry was “we don’t want to be sitting here in 15 or 20 years’ time realising there was another valproate out there”.
The consultant neurologist said there were “lots of new medicines in epilepsy coming through all the time”. While there was “probably none quite as bad as valproate”, he said this issue needed to be kept under surveillance. Speaking to the Medical Independent, Dr Doherty said the scale of the risks associated with valproate had been under-recognised and that caution was required in respect of other AEDs.
He noted a comment by a woman attending the conference who contended that a certain AED was causing foetal malformations. Dr Doherty said “all of our data says it isn’t” and the drug appeared to be the safest AED for women in pregnancy. However, Dr Doherty said these types of issues needed to be followed-up, “and we need to follow their children’s development”.
Currently, it is “very rare” for a neurologist in Ireland to initiate sodium valproate in a woman “but not unheard of”, according to Dr Doherty. “I have women of child-bearing age on valproate because nothing else works,” he told MI. Last year, the HSE launched a valproate response plan following measures mandated by the EMA. Communications were issued to GPs and pharmacists, and to around 3,000 women/girls in receipt of valproate through State drug schemes. A temporary phone line was also established. Ms Cora Flynn, ANP Lead Nurse, Epilepsy Clinical Care Programme, said there were 57 individual callers and “a lot of these telephone calls were very raw, very upsetting”. She said there was frustration for people trying to access services.
Ms Flynn said there were ongoing efforts to identify women previously on valproate through outpatient reviews. Data presented at the conference indicated that over 1,000 people could have been affected by foetal valproate syndrome from 1975 to 2015.
Consultant Clinical Geneticist Prof Andrew Green said funding had been approved to recruit a consultant to facilitate diagnosis, yet this position was not filled. “But as soon as they are, that clinic will be running,” he told the conference. Currently, routine referrals to clinical genetics have a two-to-three-year wait, he said.
Mr Des O’Flynn, Head of Service, Primary Care, Community Healthcare Organisation 9, who is leading a group examining primary care/community support needs for affected families, said this process was nearing its conclusion.
At the conference, a number of families affected by the valproate scandal expressed their anger towards the Health Products Regulatory Authority (HPRA) that more stringent warnings and measures had not been in place many years ago. Patient representatives reiterated their call for an inquiry into historical use of sodium valproate.
The conference in Dublin was hosted by the HSE, Epilepsy Ireland, OACS Ireland, Foetal Anti-Convulsant Syndrome (FACS) Forum Ireland and Trinity College. https://www.medicalindependent.ie/womens-health-programme-needed-to-prevent-another-valproate-scandal/
More than 1,000 Irish children potentially affected by valproate syndrome, estimates HSE study
Medical Independent 13 March 2020 A conference this month will examine the consequences of sodium valproate exposure in the womb, with a new report indicating that the numbers affected by developmental delay and birth defects may be higher than previously thought. Catherine Reillyreports
Over 1,000 people in Ireland could have been affected by foetal anticonvulsant syndrome (FACS) following exposure in utero to the drug sodium valproate, according to a recent analysis commissioned by the HSE. In Ireland, sodium valproate (Epilim) has been licensed for use in epilepsy since 1975 and in bipolar disorder since 2008.
Babies born to women taking valproate-containing medicines during pregnancy have a 30-to-40 per cent risk of developmental disability and a 10 per cent risk of birth defects. Between 153 and 341 children are estimated to have experienced a major congenital malformation and up to 1,250 children some form of neurodevelopmental delay following exposure to sodium valproate in utero, according to Rapid assessment of the number of women and children exposed to sodium valproate in Ireland 1975-2015.
These figures are based on estimations and emerging international data on rates of major congenital malformation and neurodevelopmental delay, associated with exposure in utero, according to the paper seen by the Medical Independent (MI).
The estimates were subject to a wide range of assumptions and limitations and should be viewed as “a broad guide” for those tasked with planning diagnostic and management services. The FACS Forum, an umbrella of patient stakeholder organisations, previously estimated that “at least” 400 children had been affected by FACS. While the HSE report includes important caveats on data reliability, it places the issue as “potentially a bigger problem than anybody had anticipated”, commented Mr Peter Murphy (pictured below), CEO of Epilepsy Ireland, a member organisation of the FACS Forum.
Diagnostics As well as lack of supports for affected families, another major shortfall in responding to FACS has been poor access to diagnostics. This issue has been examined in a Valproate Response Project Plan, initiated in 2018 through the HSE’s Office of the Chief Clinical Officer.
This project came on foot of new actions mandated by the European Medicines Agency (EMA) following publication of recommendations by its Pharmacovigilance Risk Assessment Committee (PRAC) in February 2018. The PRAC stated that women were “still not always receiving the right information” on sodium valproate risks “in a timely manner”, despite previous measures announced in 2014 (see panel below). Currently, very few people in Ireland have received a diagnosis of FACS, with the lengthy wait to access a clinical genetics service a significant factor in this.
According to minutes of a meeting of the HSE Valproate Response Project Team in November, interviews were held for a consultant geneticist as part of establishing a diagnostics pathway and the post was offered to a candidate. However, MI understands the offer was not taken up.
This is “a critical post” because diagnosis will be the entry point to a care pathway, which is in the advanced stages of planning.
“It is important and positive that the funding was approved [for the post] and obviously the next step is to get it filled,” said Mr Murphy. He also welcomed approval for two new epilepsy nurse posts as part of a women’s health in epilepsy programme. “The plan is that there’s another four posts coming on-stream, hopefully in 2019. The initial two are in Dublin and after that, the follow-on four posts would be regionally-centred.” It is understood these nurses will play a key role in the pregnancy prevention programme mandated by the EMA.
As previously reported by MI, a HSE clinical advisor warned senior management in October 2017 that the HSE knew the names and addresses of 1,700 women of child-bearing age (16-to-44 years) prescribed sodium valproate and had to consider its “duty of care” by potentially writing to them directly.
This action was belatedly completed last year, whereby up to 3,000 women (eight-to-55 years) in receipt of the drug through State schemes were issued with letters. This was preceded by communications to GPs and pharmacists, as well as work to establish a short-term support service for concerned patients. While the communications piece was slow to develop, Mr Murphy said it appeared to “work quite well” when it occurred. “We don’t want it to be forgotten, and for the moment it hasn’t been addressed, is whether there is a way to contact all the people who were previously on valproate but who are no longer on valproate,” added Mr Murphy. It is understood the HSE is preparing a report for the Department of Health on the overall issue and level of ongoing funding required. While “a lot of progress” has been made, “there are still gaps out there” and uncertainty on future funding as the HSE response project prepares to wrap-up, outlined Mr Murphy.
Investigation The need for an investigation into historical prescription of valproate is one of the key issues being pursued by the FACS Forum.
In June 2018, a representative wrote to Minister for Health Simon Harris to “follow up on your commitment to look at an independent inquiry and financial redress for those who have been affected, and your promise to revert to us by the end of May”.
The letter, obtained by MI under Freedom of Information law, noted the recommendation of the Oireachtas Health Committee in May 2018 that “further consideration and examination is undertaken with regard to compensating FACS patients”. The letter also referred to the Committee’s recommendation that an independent investigation be conducted into the historical use of valproate medicines in Ireland and their ongoing effects.
In July, Minister Harris responded that “as regards the possibly of an inquiry or investigation, the HPRA [Health Products Regulatory Authority] is already working to compile a dossier of the information provided to prescribers and patients in Ireland with regard to sodium valproate since the drug was first licensed in Ireland”. He added that a number of proposals in the HSE’s draft project plan “could achieve many of the goals of an investigation”.
With regards to financial redress, Minister Harris wrote: “I will need to give this further consideration, as recommended by the Joint Committee. You will appreciate that this issue is particularly complex given the number of different parties involved, to one degree or another, when a woman is prescribed and dispensed sodium valproate.” Mr Murphy believes an independent investigation is imperative. “If it was found there were failings in the regulatory system, for example, well then, the issue of compensation comes up. First of all, it is about establishing the facts and the history here.”
On the “dossier” referenced by Minister Harris, the HPRA informed MI it provided the Department with “a compilation of sample product information for Epilim (sodium valproate) products as an illustration of the precautions and warnings for these medicines in place over the years”.
According to Mr Murphy, the HPRA has made available to the FACS Forum historical summary of product characteristics (SPC) and patient information leaflet (PIL) materials.
“What is needed is to cross-check [these materials] against what was known and published at the time, to identify if [the materials] were changed in a timely manner,” said Mr Murphy, adding that this would need to be examined as part of any investigation.
A spokesperson for Sanofi, makers of Epilim, said it had provided “information and warnings in relation to sodium valproate products, including their use during pregnancy in accordance with regulatory requirements.” It did not believe there was “any basis for compensation by the company”. Conference The important issue of ‘who knew what and when’ will be the focus of a talk by Prof Carl Heneghan, Director of the Centre for Evidence-Based Medicine, University of Oxford, UK, at the first ‘National Conference on the Consequences of Sodium Valproate (Epilim)’, which will be held in Trinity College on Friday 22 March. It has been organised by the HSE, Epilepsy Ireland, Organisation for Anti-Convulsant Syndrome (OACS) Ireland, FACS Forum and Trinity College.
Prof Heneghan recently co-wrote a paper in BMJ Evidence-Based Medicine, which stated that “evidence was clear as far back as 1990 that there were risks of congenital malformations in women exposed to valproate”.
Sands of time: wheels of valproate response creak into action
Medical Independent 20 August 2018
A Valproate Response Project Plan has been initiated through the HSE’s Office of the Chief Clinical Officer. According to a draft document released to the Medical Independent (MI) following a Freedom of Information request, the intended life cycle of the project is a six-month period that commenced in June and will run to 30 November.
Babies born to women who take valproate-containing medicines during pregnancy have a 30-to-40 per cent risk of developmental disability and a 10 per cent risk of birth defects. In Ireland, sodium valproate (Epilim) is licensed for epilepsy and bipolar disorder. The risks have been well-described in medicine for many years.
In February, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) concluded that women were “still not always receiving the right information [on sodium valproate risks] in a timely manner” following previous measures announced in 2014. New actions, including a pregnancy prevention programme, have been issued. As previously reported by MI, a HSE clinical advisor warned a senior national manager and colleagues in October 2017 that the Executive knew the names and addresses of 1,700 women of childbearing age prescribed the drug and that it must consider its “duty of care” by potentially writing to them directly. However, while a direct communication is being planned by the HSE, it has not happened to date.
In effect, the Valproate Response Project Plan is the HSE’s response to the EMA measures. The project steering team includes a patient representative from the Foetal Anti-Convulsant Syndrome (FACS) Forum.
The specific objectives of the project include ensuring that women of child-bearing age who continue or commence Epilim/sodium valproate and other anticonvulsant medications are monitored and subject to an annual specialist review; supporting the implementation of a pregnancy prevention programme; ensuring people impacted by current or historic risks of Epilim exposure in the womb are provided with “immediate information and support”; quantifying the number of impacted children/adults; exploring the requirements of affected children and adults; and developing a diagnostic pathway and establishing a “Task Force on Women’s Health on all anti-convulsant medications”.
A cost estimate of just over €2 million is cited in the draft document, which refers to access to a diagnostic pathway as a key priority of the project work stream. The document notes that access to diagnostics has a two-to-three year waiting time and that the “current general waiting list is 1,700 patients”. Under a section on dependencies and risk, the document also states: “Contingency plans developed but our capacity and capability to respond remains a risk” and “development of services is based on funding and recruitment of skilled resources”.
A HSE spokesperson told MI that implementation of the project plan has commenced. Around €2 million would be needed to undertake the proposed actions but recurring annual funding will be less than this sum, according to the Executive. “The Patient Support Liaison Service has been initiated and the development of a diagnostic pathway and a women’s health programme is underway,” they added.
A Valproate Response Team prepared communications for prescribers and patients based on new guidance being developed by the Health Products Regulatory Authority (HPRA). A pre-alert letter to all prescribers has already been issued and three post-alert communications were “now in train”, said the HSE’s spokesperson.
These communications are a generic post-alert letter to prescribers, advising that the HPRA has issued new guidance which has now been sent; a patient-specific, post-alert letter to prescribers, asking them to contact named patients which has now been sent; and a “follow-up letter” to each patient, noting they are on valproate and if they have not yet been contacted by their GP, that they should make an appointment. This letter will be sent in the coming weeks, according to the HSE’s spokesperson, who added that issuing of the above communications was punctuated by timelines related to publication of the updated HPRA guidance. “The priority for this communication is to ensure that patients taking this medicine would be reminded of the risk of taking this medicine while pregnant, but at the same time, have the opportunity to discuss the new programme with their doctor or prescriber and receive any support required in terms of information on contraception. “It was agreed that supports needed to be put in place for all patients who receive a letter and have concerns. This could include patients with epilepsy, patients with mental health disorders, as well as people who feel they may have been affected by valproate.
“Patient representatives have advised that people with such concerns will want to talk to knowledgeable individuals and have asked that the HSE work to ensure that people receiving this information are supported as best they can be.
“A patient support team has been established, staffed by Advanced Nurse Practitioners/Clinical Nurse Specialists in epilepsy and by non-clinical call-takers, who are available on a freephone number which is now in operation, from Monday to Sunday, 10am to 6pm.
“This team is currently contacting callers, providing informed advice, and ensuring that patients are directed to appropriate services. These services are likely to include referral for diagnosis, referral to speak to existing specialist team, referral to contact GP/prescriber, referral to HSE funded counselling supports, etc.”
A spokesperson for the HPRA said it approved an updated suite of educational materials and risk minimisation materials for valproate-containing medicines on 18 May and these materials were published electronically and accessible on its website from 19 May. The educational materials are comprised of a revised healthcare professional guide, patient card and patient guide, annual risk acknowledgment form, pharmacy warning sticker, pharmacy dispensary poster, and shelf-barker.
“Hard copies of these materials were distributed by Sanofi to the aforementioned healthcare professionals and distribution was completed on 6 June. Of note, the brand name ‘Epilim’ has been included on these materials, which was a priority issue for patient organisations nationally. The patient card will be attached to the outer packaging of all Epilim preparations and will reach the Irish market by Q4, 2018. In the interim period, copies of the patient card have been provided to all community pharmacists to facilitate provision of the card and patient counselling with each dispensing of a valproate-containing medicine.
“Following a request from the HPRA, Sanofi submitted an application to the HPRA to include a warning on the outer carton of Epilim preparations in the form of a visual symbol and boxed warning and to include a visual warning symbol on the tablet blisters. These applications were approved by the HPRA in May 2018.” The Authority’s spokesperson added that, in order to remind healthcare professionals about the risks of valproate-containing medicines and to reinforce the implementation of the risk minimisation measures, it requested that Sanofi collaborate with GP software providers to investigate the possibility of including pop-up alerts when prescribing valproate-containing medicines. In June, Sanofi confirmed that it had obtained a commitment from the three software providers in Ireland to implement pop-up alerts with go-live dates in early July.
“The updated product information (Summary of Product Characteristics (SmPC) and Package Leaflet (PL)) for valproate-containing medicines, adopted on foot of the referral, were approved by the HPRA in July 2018 and are available on the HPRA website.
“Following extensive feedback from healthcare professionals, patients and patient organisations on the need to reduce the pack size in order to ensure that all patients receive a package leaflet and the outer carton with the visual reminder (text and symbol) at each dispensing, the HPRA requested Sanofi to introduce a reduced pack size of 30 for their Epilim preparations to the Irish market. Sanofi committed to introducing this reduced pack size, with a proposed timeline of Q4 2018. The HPRA approved an application for this reduced pack size in August 2018.”
The HPRA and RCSI have been granted funding by the Health Research Board (HRB) to conduct research into the effectiveness of risk minimisation methods. Preliminary work has been undertaken over the summer, with the research due to start in September. Meanwhile, the FACS Forum has said the delay in issuing the direct communication letter to patients, who number around 3,000 in the eight-to-55 age range, is “putting women on valproate and their children at further and unnecessary risk”. Ms Karen Keely, Chair of OACS Ireland, further informed MI: “Members of OACS Ireland have been working with the HSE to develop and implement a valproate action plan. The HSE has, we understand, identified the necessary funding to make the plan happen. OACS Ireland urges the HSE to move swiftly on implementation of the plan so that no more families have to suffer the potentially devastating effects of taking Epilim during pregnancy.”
Campaigners are calling for an investigation into prescription of valproate and compensation for those affected. https://www.medicalindependent.ie/sands-of-time-wheels-of-the-valproate-response-creak-into-action/
HSE clinical advisor warned of 'duty of care' on valproate risk
Medical Independent 28 May 2018
A HSE clinical advisor warned a senior national manager and colleagues that the Executive knew the names and addresses of 1,700 women of childbearing age prescribed a drug that can harm the foetus in pregnancy and must consider its “duty of care” by potentially writing to them directly. The advice was sent in October by HSE National Clinical Advisor and Group Lead, Primary Care, Dr David Hanlon, to Dr Áine Carroll, HSE National Director for Clinical Strategy and Programmes and colleagues.
The Medical Independent (MI) understands that direct communication from the HSE has not occurred to date. However, letters were issued to GPs and pharmacists in February and March this year, advising them to identify females of childbearing potential who have received valproate recently and contact any identified patients “directly in the next few days”. The risks should be reviewed as well as the need for effective contraception, according to the letter.
The women are being dispensed Epilim (sodium valproate), which is licensed in Ireland for epilepsy and bipolar disorder. Babies born to mothers who take valproate-containing medicines during pregnancy have a 30-40 per cent risk of developmental disability and a 10 per cent risk of birth defects. The risks have been known for many years.
According to 2016 data, around 1,700 women aged 16-44 were being dispensed Epilim through the community drug schemes. In February this year, the European Medicines Agency (EMA) announced additional protective measures around valproate, as previous actions were not deemed sufficient in terms of risk management.
The Health Products Regulatory Authority (HPRA) has been communicating with prescribers and dispensers on the EMA findings.
Dissecting the response on sodium valproate
Medical Independent 28 May 2018
With public health authorities’ approaches to patient safety events under huge scrutiny, the issue of sodium valproate exposure in pregnancy again highlights inherent flaws in health structures. Catherine Reilly reports
"Is this essentially a safety incident? Should it be reported and managed as such? Is the DG [HSE Director General] aware? Is the Dept [Department of Health] aware? Is SCA [State Claims Agency] aware of scale? Is Minister aware of scale? Immediate concern is those currently at risk….”
Last November, an internal email by HSE Clinical Advisor Dr David Hanlon raised pressing questions on the matter of sodium valproate (Epilim) prescribing to women of childbearing age. Babies born to mothers who take valproate-containing medicines during pregnancy have a 30-to-40 per cent risk of developmental disability and a 10 per cent risk of birth defects. Epilim is licensed in Ireland for epilepsy and bipolar disorder.
Dr David Hanlon
But the risks have been well described for some years. Foetal anticonvulsant syndrome (FACS) was first reported in the early 1980s and “well established and accepted” by the mid-1990s, CEO of Epilepsy Ireland Mr Peter Murphy told the Oireachtas Health Committee last month. “There was a key paper on this in 1995, which outlined the many different symptoms that could have been experienced. It was in the early 2000s that the link with developmental delay, autism and ADHD became known.”
The matter came under renewed attention following the commencement in March 2017 of a review by the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) of measures announced in 2014.
The PRAC, which is vice-chaired by Ms Almath Spooner of the Health Products Regulatory Authority (HPRA), issued its latest recommendations in February (see panel, top-right). It found that women were “still not always receiving the right information in a timely manner”.
Records obtained by the Medical Independent (MI) under Freedom of Information (FoI) legislation show how the issue of sodium valproate prescription was the subject of ongoing communications within the HSE in 2017. These emails predominantly involved Dr Áine Carroll, HSE National Director for Clinical Strategy and Programmes, the relevant HSE clinical programmes — neurology, epilepsy and mental health — and the Medicines Management Programme (MMP), while there was also engagement between the HSE and HPRA. However, action at the highest level of the HSE was slow to formulate.
In October 2017, Ms Sarah Clarke, Programme Manager with the MMP, updated colleagues on a meeting held with the HPRA on the issue. She wrote that, from a recent analysis, there were around 1,700 women (aged 16-to-44 years) in receipt of valproate under the community drug schemes. “Despite a number of communications from the HPRA to prescribers (direct mailing and in their drug safety newsletter) and the development of the HSE Valproate toolkit in 2016, recent patient group information outlined that this information was not available to or known by many patients.” A number of potential areas were discussed, including “direct communication to female patients on treatment and availability of timely review”, she reported.
Dr Hanlon, a GP and HSE National Clinical Advisor and Group Lead, Primary Care, informed Ms Clarke and colleagues of his view that “a significant number of women” were potentially at risk “and we have no assurance or certainty that this message has reached them”. In his email, which was copied to Dr Carroll, who is a member of the HSE Leadership Team, Dr Hanlon outlined: “I do feel we have to consider what our duty of care is here, and what the standard should be. Not only do we know that there are about 1,700 women potentially exposed, but we also know their names and addresses, their doctor and their pharmacist. In addition, the State has provided these medicines to these women. I think we must consider whether we have a duty to write directly to these women, to their doctor and to their pharmacist specifically identifying them as being potentially at risk…
“I do feel this would go a long way towards discharging a direct duty of care to these particular individuals. This is probably a matter on which we should have legal advice, but I would suggest that an action such as this is relatively proportionate, and probably will not cost us much more than the cost of getting the legal advice… “Given the apparent failure of our conventional approaches, and the special concerns which have been attached to this matter, I think a direct action such as this would be the most effective and the most efficient way of ensuring that these women and those involved in the care are notified… ” The appropriate review and support structures would be required to respond to anyone at risk, he noted.
Ms Clarke agreed with Dr Hanlon that he was raising issues that needed to be considered. The “main driver” for work on this matter “will need to come from a more leadership position (sic) in the HSE”, she also noted.
In November 2017, Dr Hanlon again informed HSE clinical advisors and Dr Carroll that the HSE should consider writing to known female patients taking sodium valproate. He said open disclosure “would suggest that this is appropriate”. In the same communication, Dr Hanlon said “we need to sort out the authority and governance on this matter, as a key question is, who has the authority to take appropriate action? I am thinking it is at National Director level, either Áine [Carroll] or Philip [Crowley]. Do we have a properly constituted ‘incident management’ group?” Under the heading of ‘Consider’, he wrote: “Is this essentially a safety incident? Should it be reported and managed as such? Is the DG aware? Is the Dept aware? Is SCA aware of scale? Is Minister aware of scale? Immediate concern is those currently at risk. Short-term priority is to have future controls. Medium-term is to establish supports for those potentially exposed. Longer term is issues of liability, if any. Delay means greater liabilities potentially and more culpability.”
Dr Hanlon suggested a number of actions labelled as ‘ASAP’. These included a letter to GPs “highlighting the issue” and “asking them to check their records to identify patients under their care… ” The day after Dr Hanlon’s communication, the HSE’s Director of Quality Assurance and Verification Mr Patrick Lynch thanked Dr Carroll for bringing the matter to his attention. “This is indeed a serious risk that requires an urgent response. I am copying the relevant National Directors and we need to agree a process for establishing the response, given that responsibility spans a number of divisions. I am also copying John Connaghan [now Interim HSE Director General],” wrote Mr Lynch.
A Department of Health spokesperson told MI: “The HSE’s National Clinical Advisor and Group Lead for Primary Care has written to GPs and pharmacists to request that they directly contact patients who have received sodium valproate with regard to the patient safety implications of the drug, and to refer patients to specialists for further review, if required.” MI understands these letters were sent on 21 February (GPs) and 6 March (pharmacists). It is understood a direct communication from the HSE to named patients has not yet occurred. The HSE had not commented by press time.
In Ireland, approximately 400 children may have been affected by FACS but just 43 have had a diagnosis from the genetics service in Our Lady’s Children’s Hospital, Crumlin, Ms Joan O’Donnell, Chair of the FACS Forum Ireland, recently told the Oireachtas Committee.
The testimony of a mother from Dublin was among those read to the Committee by Chair of the Organisation for Anti-Convulsant Syndrome Ireland (OACS) Ms Karen Keely: “Every day the same questions loom… if only I had known? What could I have done differently, if anything? Can I fix my girls now?… ” Such questions are confronting hundreds of families in Ireland and they have had few avenues to pursue.
An email to the HSE in June 2017 from a parent, whose name was redacted, outlined how they had been advised to contact the HSE National Clinical Programme for Epilepsy by communication channel HSE Live. This parent enquired about supports for affected children. In response, the programme manager Ms Edina O’Driscoll said “there are currently no additional services for children potentially affected specifically with Foetal Anticonvulsant Syndrome outside of existing services for children with support needs”. She advised the parent to contact their GP, local epilepsy service or Community Resource Officer if engaged with Epilepsy Ireland.
The parent thanked Ms O’Driscoll for responding but said they had been “given the run-around” by the HSE. The parent included a link to a 2016 study by Irish clinicians published in the journal Seizure and highlighted a section which stated that the risks of anti-epileptic drugs in pregnant women “have been known for many years: In particular, the risks associated with VPA [valproate] have burgeoned”.
The parent wrote: “Due to the fact that the HSE are aware of these studies, and that there are children other than mine affected, I am rather shocked that this drug was given to me without telling me about the secondary effects.” The attitude towards women given the drug was one of “basically, ‘tough’,” stated this parent. At the Department of Health, meanwhile, there was lack of clarity around which section should lead on the issue of valproate exposure in pregnancy. For example, in response to an internal request for briefing material for the Minister in June 2017, an official in the National Patient Safety Office (NPSO) responded: “As indicated previously, this is not an area for which the NPSO would have responsibility. Having talked to colleagues in Acutes and the CMO’s office, it is not clear where responsibility does lie.”
As of June 2017, some 3,118 girls/women aged eight-to-55 years were receiving Epilim through the community drug schemes, as compared with 3,226 the previous year.
Broken bulk dispensing has been a concern in respect of this medication, with some patients being dispensed the drug in plastic bags without a patient information leaflet. In Ireland, Epilim has been distributed in 100-tablet boxes, although Sanofi has recently been mandated by the HPRA to distribute the product in 30-tablet boxes. A spokesperson for Sanofi commented: “Subject to approval by the HPRA, it is Sanofi’s intention to reduce the 100-pack size to a 30-pack size. The proposed timeline for industrial implementation at manufacturing sites is Q4 2018. Alternate presentations of valproate are currently available in 30 sachets.”
The overall issue has attracted more fulsome attention since an EMA public hearing last September and accompanying media coverage, according to Mr Murphy of Epilepsy Ireland. “I think there was probably an under-estimating of the problem [by health authorities],” he tells MI. “I don’t think the issue got the attention it deserves from the HSE or at Departmental level, when you consider there are thousands of women taking this drug… I am not sure anyone really grasped the issues we were talking about for a number of years… ”
He says access to a diagnosis and appropriate supports remain significant problems.
“Most of the women who have come into contact with Epilepsy Ireland and the OACS group don’t have a formal diagnosis; what they can say is, they were on Epilim during pregnancy and they have a child with disabilities that are consistent with foetal valproate syndrome,” he says.
It is a long road to obtaining a diagnosis. “You might start with your GP; in some cases I have heard of people having to convince their GP to make a referral to a paediatrician, then you are looking at a paediatrician potentially, or hopefully, referring onwards to clinical genetics and that is where the real logjam is at the moment — it seems to be about two years,” outlines Mr Murphy.
He says “potential accountability issues” are at play and “there should be an obligation on the State” to provide adequate supports. The HSE has recently established a group to engage with parents on their families’ needs. Mr Murphy says the dispensing of valproate in the drug schemes has been declining in recent years but not necessarily at the rate required. Valproate is widely regarded as one of the most effective drugs in controlling seizures, he points out.
According to Mr Murphy, it is crucial that a comprehensive pregnancy prevention plan is implemented for girls/women prescribed valproate, as required by the EMA. This programme will include an annual treatment review by a specialist. However, the annual review will pose “some very practical problems” in an “under-resourced” neurology service. The HPRA has received 250 suspected adverse reactions to Epilim since it was first authorised in Ireland in 1975. Dr Joan Gilvarry, Director of Human Products Monitoring, HPRA, says that sodium valproate exposure in pregnancy has been actively on the Authority’s radar for many years.
Dr Joan Gilvarry, HPRA
She says the HPRA is not the regulator of the clinical professions and a systems-wide approach is required.
“We, as the regulator of the product, have done and are doing everything we possibly can… we are not in the doctors’ surgery, we are not in the pharmacists’, when it is being dispensed and prescribed, so we need everybody’s help to ensure the message is getting to patients… ”
She says the HPRA oversaw a wide range of communications on the issue over several years, including drug safety newsletters and “Dear healthcare professional” letters.
During the PRAC review last year, she maintains that the Authority did not stand still.
“We did put warnings on the outer labels during last year, we issued two drug safety newsletters during the year, we sent warnings to pharmacists via the Pharmaceutical Society of Ireland (PSI), so we kept communicating on exactly what was happening and giving advice to healthcare professionals on what to do in the meantime… we have been working incredibly hard on this from a HPRA point of view right over the last long time, but specifically in the last five years.” On why the message has not always been translating, she says this may relate to the ‘patient journey’.
“It is a very effective medicine and it is the only medicine that can be used for some patients,” says Dr Gilvarry. “The difficulty I see at times is, it could have been prescribed [for example] by a paediatrician to an eight-year-old girl 15 years ago, and she is stabilised on it, she is doing very well on it, and monitored by the GP going forward… ” This type of patient is not necessarily referred back into neurology care. “And then she becomes a woman of child-bearing age, she gets pregnant and then it is too late. There are so many people involved in the patient journey here… it is a multi-stakeholder issue.”
Dr Gilvarry says the Authority raised with the PSI the issue of dispensing in plastic bags without the patient information leaflet.
“And you must understand, we don’t regulate the pharmacists, we are not there when it is being dispensed; it is the PSI who do that, but I know they have issued warnings to the pharmacists on numerous occasions to ensure the package leaflet goes [in] and to talk to the patient when they are dispensing.”
The HPRA made no official complaint to the pharmacists’ regulator, she confirms. “I have been in contact with the PSI when we do hear of this, that it is being handed out in a plastic bag without the package leaflet, and the PSI have issued warnings on numerous occasions about this,” adds Dr Gilvarry. She says the HPRA and RCSI have recently been funded by the Health Research Board (HRB) to conduct research into the effectiveness of risk minimisation methods.
On whether the Authority would welcome an investigation of historical use of valproate in Ireland, as sought by the FACS Forum, Dr Gilvarry said “it won’t be our decision, but we will support any decision made by the Department of Health and the Minister”. She added that patient groups have been influential in raising the profile of this issue.