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.
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 <strong><em>Medical Independent</em></strong> (<strong><em>MI</em></strong>) 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.
<h3 class=”subheadMIstyles”>Open disclosure</h3>
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 <strong><em>MI</em></strong>: “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.” <strong><em>MI</em></strong> 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 <em>Seizure</em> 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 <strong><em>MI</em></strong>. “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… ”
<img src=”../attachments/0d9a137b-ee49-460f-b5f3-3691acdba88f.JPG” alt=”” />
<strong>Mr Peter Murphy, CEO Epilepsy Ireland</strong>
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.
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… ”
<img src=”../attachments/07bbbbb5-0737-4002-9748-be252a2a72a8.JPG” alt=”” />
<strong>Dr Joan Gilvarry, HPRA</strong>
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.