Joint Committee on Health debate - Wednesday, 25 Apr 2018

Foetal Anti-Convulsant Syndrome: Discussion

Chairman

In our first session today we shall meet with representatives from the foetal anti-convulsant syndrome forum, FACS, the Health Products Regulatory Authority, HPRA, and the HSE. On behalf of the committee I welcome Ms Joan O'Donnell, Ms Karen Keely, and Mr. Peter Murphy from the foetal anti-convulsant syndrome forum; Dr. Joan Gilvarry and Dr. Almath Spooner of the HPRA; and Mr. Kilian McGrane, Dr. John Murphy, Dr. Peter McKenna and Ms Cora Flynn from the HSE.

Before the meeting commences, I draw attention to the fact that by virtue of section 17(2)(l) of the Defamation Act 2009, witnesses are protected by absolute privilege in respect of their evidence to the committee. However, if they are directed by the Chairman to cease giving evidence on a particular matter and they continue to do so, they are entitled thereafter only to a qualified privilege in respect of their evidence. Witnesses are directed that only evidence connected with the subject matter of these proceedings is to be given and are asked to respect the parliamentary practice to the effect that, where possible, they should not criticise or make charges against any person or entity by name or in such a way as to make him, her or it identifiable. The opening statements submitted to the committee will be published on the committee website after the meeting. Members are reminded of the long-standing parliamentary practice to the effect that they should not comment on, criticise or make charges against a person outside the House or an official either by name or in such a way as to make him or her identifiable.

I invite Ms Joan O'Donnell to make her opening statement.

Ms Joan O’Donnell

I thank the Chairman, Deputy Harty, and members of the committee for the invitation to present today. I am here as chair of the foetal anti-convulsant syndrome forum, FACS and I am joined today by my colleague Ms Karen Keely, chair of the Organisation for Anti-Convulsant Syndrome Ireland, OACS, and Mr. Peter Murphy, CEO of Epilepsy Ireland. Karen and I will give the opening statement during which Karen will give some insight into the lived experience of families. Peter and I will be available to answer questions that committee members may have.

Sodium valproate, or Epilim, is a drug licensed in Ireland for the treatment of epilepsy and bi-polar disorder. Foetal anti-convulsant [valproate] syndrome - or FACS - describes a syndrome that affects children born to women who were prescribed Epilim during pregnancy. Children exposed to this drug in the womb have an 11% chance of malformations at birth compared with a 2% to 3% in the general population. Malformations include neural tube defects, malformation of limbs, digits and organs, cleft palate among many, many more physical conditions. An additional 40% of children experience developmental delay and have a three to five times greater risk of developing autism, autistic spectrum disorder and ADHD. We estimate that approximately 400 children may be affected by FACS in Ireland, but just 43 have a diagnosis from the genetics department in Our Lady's Hospital for Sick Children, Crumlin.

In 2014, the European Medicines Agency, EMA, strengthened the warnings and restrictions on the use of valproate in women and girls. In 2017, the agency reviewed how these recommendations were being implemented due to concerns that EU member states, including Ireland, were not implementing the recommendations properly. In February of this year, the EMA issued additional instructions aimed at further tackling issues around reducing risk for women and girls of childbearing age.

The FACS forum asks that the Government deal with this issue on three fronts. The first is in the context of those who are already affected. We call on the Government to undertake a national study to identify how many children in Ireland are affected by this condition. An independent investigation into the historical use of valproate in Ireland is needed. A system of redress must also be established to meet the lifelong care needs of children and to address the impact of diagnosis on families. This will go a long way towards avoiding the need for legal solutions for already stressed families, some of whom are represented in the Public Gallery today and the many more who would have liked to be here and who are watching online.

The second front is the need to put in place services for families who are currently affected. Valproate-related disabilities are complex, wide-ranging and individual. Obtaining a diagnosis is difficult and lengthy and treatment often involves attending many unconnected and un-co-ordinated specialist services. Often, families have more than one child affected and full-time caring is required. It is, therefore, critical that we develop a streamlined diagnostic pathway, develop a national register of those affected and audit their needs. Most important, we must put in place the services and supports they so desperately need now.

The third front is the need to reduce the risk of children being born with FACS in the future. There is an urgent need to fully implement the recent decision of the European Medicines Agency ruling and recommendations that I mentioned earlier. We in the FACS forum have been greatly encouraged by the measures proposed, and the commitment shown by the Health Products Regulatory Authority, the HSE, and the Pharmaceutical Society of Ireland among other stakeholders. We want to see all of this progress impact on the actual numbers of children being born with FACS. Therefore, we need a systems-wide commitment that all new risk reduction initiatives will be fully monitored, fully implemented and independently evaluated and additional action taken if necessary.

Finally, we want a commitment from HSE that all women currently prescribed Epilim, especially those under GP-only care, be given priority referrals in 2018 to a specialist for an urgent treatment review. This is now required by the EMA ruling and we ask that this happens with immediate effect. I thank members for listening and I will now hand over to my colleague Ms Karen Keely.

Ms Karen Keely

I have been asked to read out some statements from mothers whose children have been affected by FACS. A mother from Cork said:

I took Epilim when I was pregnant. My five year old son has a diagnosis of childhood autism. My son was non-verbal and he needed speech therapy he also needed an OT assessment for his sensory needs. None of these services were available to my son and my husband and I had to pay privately. The devastating impact this has had on our family is unthinkable to bear at times.

A mother from Mayo has said:

Since the birth of my two children, never a month goes by without hospital or specialist appointments for my two children, they are 14 and nine, their disabilities range from global development delay, scoliosis, speech and language, dyslexia and physical difficulties. I had to resign in 2016 from employment to become a carer. Last December, my daughter wanted to end her life, this is the effect of sodium valproate.

A mother from Dublin said:

The impact that the lack of correct information on sodium valproate had on my life has been incredible. Personally, the everyday guilt can be all consuming, and has me stuck in a vicious cycle of guilt. 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? What will their future hold? It’s infuriating, it makes me nauseous with a mixture of emotions.

A mother from Carlow has said:

There is no time for me and while I’ve come to accept this I do still realise it’s not good for me, but I have to keep going. What else can I do? The constant battling for services my child has needed over the years has left me as a mother feeling not good enough, exhausted physically, mentally and emotionally. The isolation and routine of my everyday life has fuelled my depression. I cry often for myself, for my child, with my child and in frustration and anger.

I thank the committee members for hearing me.

Chairman

I thank Ms Keely very much for reading those testimonies. I now invite Dr. Joan Gilvarry to make her opening statement.

Dr. Joan Gilvarry

Good morning, Chairman and committee members. My name is Joan Gilvarry and I am the director of human medicines at the HPRA. I am joined by my colleague Dr. Almath Spooner, the pharmacovigilance and risk-management lead at the HPRA. Dr. Spooner is also the Irish delegate on the European Medicines Agency pharmacovigilance risk assessment committee, PRAC, which has been referred to already this morning.

The PRAC is the committee at the EMA responsible for assessing and monitoring safety issues for human medicines. It is composed of experts such as doctors, pharmacists, scientists and patient organisation representatives from all EU member states. We are grateful for the opportunity to talk to the committee this morning about the regulation of this medicine, which is known in Ireland under the brand name Epilim. We will discuss the recent European reviews in which we have been actively involved and our collaboration with national colleagues, namely, the Department of Health, the HSE, the clinical leads in neurology, psychiatry and primary care, the Pharmaceutical Society of Ireland, PSI, and patient representatives from Epilepsy Ireland and the Organisation for Anti-Convulsant Syndrome, OACS. I would particularly like to thank the patients and their representatives for their collaboration with us over the past number of years.

Valproate-containing medicines have been licensed across the EU and in many countries worldwide since the 1960s and in Ireland since 1975. It is an effective treatment for epilepsy and bipolar disorder and for some patients may be the only treatment option. When the medicine was first approved, the prescribing information included a warning about the risk of congenital abnormalities if taken during pregnancy. These warnings were strengthened on many occasions in subsequent years as new information became available. More recently, new studies were published internationally which showed a higher than expected risk of congenital abnormalities, together with a risk of neurodevelopmental disorders in children born to mothers who had taken valproate during their pregnancy. This prompted a European-wide safety review of all the available data by the PRAC. This review was commenced in 2013 and was finalised in 2014 concluding that children exposed in utero to valproate were at a high risk of serious developmental disorders, in up to 30% to 40% of cases, and-or congenital malformations, in approximately 10% of cases. In the interests of patient safety, the PRAC recommended that valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women unless other treatments were not effective or not tolerated. The prescribing information and package leaflet for patients were updated with new recommendations around supervision of treatment by a specialist, the importance of using effective contraception and the need for regular treatment reviews. In addition, warnings around use in female children, adolescents and women of childbearing potential, and the need for discussion of such issues with the patient, were highlighted.

Following that European review, the HPRA communicated extensively with neurologists, psychiatrists, paediatricians, obstetricians, GPs, specialist nurses, pharmacists and the HSE to emphasise the new warnings and recommendations. These communications included letters from the pharmaceutical company that was mandated by us to doctors and pharmacists, following approval by the HPRA. It appeared in several editions of our Drug Safety Newsletter, warnings in national prescribing formularies and on our website. Additionally, materials designed to minimise the risks with the medicine, for example, a guide for patients and a patient alert card, a healthcare professional guide and a prescribing checklist were developed and distributed. We also met patient representatives at that time and discussed it with them.

In 2017, following concerns across Europe that the measures taken in 2014 and relayed over a number of years were not sufficiently effective in increasing awareness and reducing exposure to valproate use during pregnancy, a second European-wide safety review was initiated. This review was again conducted by the PRAC which considered that these concerns were well founded. During the review, the first ever public hearing was held at the European Medicines Agency where the views and experiences of patients, including our Irish colleagues who are present today, were heard and this proved to be invaluable in the development of the latest safety recommendations. The outcome of this review has led to the introduction of new contraindications, essentially a ban on the use of valproate during pregnancy, strengthened warnings and further measures to prevent exposure during pregnancy, including a pregnancy prevention programme. The programme will incorporate measures such as assessment of individual patients regarding their likelihood of becoming pregnant, pregnancy tests before and during treatment as needed, the need for effective contraception while on treatment, and carrying out reviews of treatment by the prescribing specialist at least once a year. Most important is the requirement for the doctor to involve the patient in evaluating her own individual circumstances, to have a discussion with her on treatment and therapeutic options, to inform her of the risks and how to minimise the risks, and counselling around pregnancy prevention.

Additionally, the HPRA has mandated that the outer packaging of all valproate-containing medicines must include a visual symbol warning about the risks in pregnancy in addition to the boxed text that is already approved. The blister packs inside the outer packs will also carry a visual warning symbol. The patient reminder card will be attached to every treatment pack for pharmacists to discuss with the patient each time the medicine is dispensed. As an interim measure, pending the production of the new cartons, stickers with the warning and pictographs are being made available to pharmacies. Updated versions of the healthcare professional and patient guides and of the patient alert cards are being distributed to help support healthcare professionals and patients in their discussions on the minimisation of risk and to further ensure that all affected patients receive full and accurate information. Also, based on specific feedback from patients, the pack sizes are being reduced to packs of 30. All of these recommendations are currently being implemented in Ireland with significant progress already achieved.

Last week we published and distributed a special edition of our Drug Safety Newsletter to all registered doctors and pharmacists in the country and a letter was sent to relevant healthcare professionals by the company following approval by the HPRA. Over the years the HPRA has worked closely with our national colleagues, including the patient groups, the HSE, the clinical leads, the PSI and the Department of Health. Our priority at the HPRA is patient safety, and to ensure that women and girls are aware of the very real risks of taking valproate during pregnancy. We will continue working together to facilitate timely and effective implementation of the new recommendations nationally and, crucially, to support their successful introduction into everyday clinical practice. I thank members for their time. Dr. Spooner and I are very happy to take any questions members may have.

Chairman

I thank Dr. Gilvarry and call on Mr. Kilian McGrane to make his opening statement on behalf of the HSE.

Mr. Kilian McGrane

I thank the committee for the invitation to attend this morning's meeting. I am joined by my colleagues, Dr. John Murphy, consultant neonatologist at the National Maternity Hospital and the HSE's clinical lead for neonatology, Dr. Peter McKenna, clinical director for the women and infants programme and Ms Cora Flynn, who is an advanced nurse practitioner in epilepsy in St. Vincent's University Hospital, and also a member of the HSE's sodium valproate national response team.

We would like to address some of the concerns about the use of sodium valproate medication during pregnancy. The agent, available since 1967, is widely used to treat patients with epilepsy. It is particularly useful in the treatment of juvenile myoclonic epilepsy, JME. In addition to patients with epilepsy, the medication may be used in psychiatric patients with bipolar disorders. The concerns about the use of sodium valproate in pregnancy stem from the adverse effects that it may have on the foetus. It is accepted that this drug may cause malformations and-or neurodevelopmental delay in the unborn infant. The risk of a congenital malformation is 10%. The types of malformation associated with the drug are spina bifida, limb abnormalities, cleft lip or palate, unusual facial appearance with a narrow prominent forehead and receding chin. The risk of neurodevelopmental delay is approximately 30% to 40%.

There may be delays in motor development, speech delay and memory problems.

In a paper entitled Fetal Valproate Syndrome: An Irish Experience, the department of genetics at Crumlin hospital describes 29 cases diagnosed in the period from 1995 to 2016. This publication demonstrates the wide spectrum of abnormalities that can result from the exposure to sodium valproate during pregnancy. Pregnant women with epilepsy are commonly encountered at antenatal clinics. It is estimated that in Ireland approximately 400 women with epilepsy go through pregnancy each year. In the current era, it is uncommon to find that an expectant mother is on sodium valproate medication. Most are on alternative anti-epileptic drugs such as Kepra or Lamictal. The default position is that sodium valproate should not be prescribed to female children, female adolescents, women of childbearing potential or pregnant women. There may be exceptions when no other agent is able to control seizures, for example in some cases of juvenile myoclonus epilepsy. In this scenario, the patient should be under a neurologist who can oversee, modify and monitor the treatment. Important factors are the use of effective contraception and the need for rapid consultation if the patient becomes pregnant All healthcare professionals need to be fully aware of the risks posed by taking sodium valproate during pregnancy. Pharmacists should be in a position to both explain and give the patient the "Key Facts - Valproate and Pregnancy" card. The information contained on this card highlights the risk to the foetus.

The matter of unintended consequences must also be considered. Epilepsy is a serious disorder. In the last tri-annual report for the UK and Ireland, there were 14 deaths from epilepsy in pregnancy, or 0.4 per 100,000. A patient with epilepsy should not stop her medication suddenly if she becomes pregnant. The right course of events is that she should seek urgent medical advice and be changed to an alternative medication, where possible, in a controlled manner.

On a more general note regarding foetal malformations, it should be noted that in the four-year period from 2009 to 2011, there were 136 cases of spina bifida, 121 cases of anencephaly and 31 cases of encephalocoele recorded in Ireland. Thus, one per 1,000 pregnancies is affected. Countries that have introduced folic acid fortification of food have seen a 60% reduction in the incidence of these conditions.

This concludes my opening statement. Together with my colleagues, I will endeavour to answer any questions members may wish to pose.

Chairman

I thank Mr. McGrane. Will now open the meeting to our members. We will take members in groups of three. The witnesses might make a note of the questions that are asked. Our first three members are Deputies O'Reilly, Donnelly and O'Connell.

Deputy Louise O'Reilly

I thank the witnesses for attending and for their evidence. I have a few questions. Most of them are for the HSE. There seems to be some discrepancy in the figures we are hearing. Mr McGrane talked about 29 cases as having been diagnosed. We also heard there were 43 diagnosed and potentially 400. This gets to the heart of my point, which is that there really does not seem to be much by way of verifiable data. The witnesses might explain how the numbers are collated and what they use as a measurement to decide what numbers should or should not be counted.

The witnesses might also outline how Ireland compares with other European countries in dealing with this issue, for example, in terms of the services that might be available for the sufferers and those who have been diagnosed, and also in the paths to diagnosis. There seems to be some resistance or difference there. Are the witnesses satisfied that there are sufficient systems in place now and that women are warned? I was contacted by someone fairly recently to say that she is of childbearing age, that she picked up her medication, which was in a see-through bag, and that there was no patient alert card with it. How is it policed? How does the HSE ensure that when it is issued, the alert card actually gets to the patient? I think the witnesses will accept that it has not done so in all cases. What penalties are there for people who do not comply with a patient alert card? I am sure everybody wants to comply and do their best. Is there any penalty?

Regarding the victims of this, Dr. Gilvarry mentioned the 1960s and 1970s in her statement. She stated that new studies have been published more recently. It strikes me that there is a fair amount of information available that would have set off alarm bells. Dr. Gilvarry might elaborate on exactly what she meant by "more recently". I am interested in when the risks were known about, how serious the level of knowledge would have been, and how it was communicated. I think there are doctors who would have prescribed in good faith without being aware at all that there was an issue. There may have been a time when there was some awareness among the medical community that there may have been a risk, but it might not have been widely known. Then there was a period, which I would be interested in exploring with the witnesses, when the risks were very well known and the prescriptions continued. Those women's children would now be in their 20s and 30s and they are dealing with a range of complex and difficult conditions. As was outlined, the women very often have more than one child in this situation. Perhaps the representatives from the HSE might outline for us what is in place for them. Is there a specific package or are they simply in the mix with everybody else, trying to scrap it out for the services that are there? Or, as was outlined by Ms Keely, do they have to go to the private sector to purchase services that should be available in the public system? What specific packages are in place and how can they be dealt with?

I may come back with other questions at a later stage if that is okay.

Deputy Stephen S. Donnelly

I thank the witnesses for attending. I convey particular thanks to the FACS and to Ms Keely for giving voice to what the parents and children have been experiencing. It has been heard. My first question is for the forum. There is clearly a lot of co-operation between it, those who have been affected and the relevant agencies of the State. Do the forum members believe that the State bears any liability for what has happened? What services are they not getting? Do they have a sense of the kind of costs that are being incurred by families supporting children who have been affected?

For the HPRA, is it possible to establish a causal link in an individual case? There are shocking levels of causality that can be found through clinical testing but, on the basis of an individual case, is it possible to say that a particular boy or girl has physical or neurological issues that can be causally linked to the drug?

I ask the HPRA and the HSE why there have been so few diagnoses. If approximately one tenth of the estimated number has been diagnosed, why is that figure so low? I ask the HSE what the response has been to the requests that have been laid before the committee this morning from the FACS. It has requested that there be a study on the number of children, an investigation into how this happened in the first place, and that the services required be provided. As Deputy O'Reilly said, the parents and children are not looking for a slice of a finite pie. Is there a package that has been put in place?

Is there any estimate of the cost to the State of providing the required services or the cost per family or child? Mr. McGrane mentioned children not reaching full potential as a result of neurological development delay. Does that mean the child will reach his or her full intellectual capacity but take longer to do so, or that the child or adult will have a permanent intellectual issue?

I have a question for the representatives from either the HPRA or the HSE. Mr. McGrane stated that it is now uncommon for the drug to be prescribed to pregnant women. Given the evidence before us that 30% to 40% of children whose mothers used the drug during pregnancy have serious issues, is there a clinical reason it is still prescribed to some pregnant woman? If its use is uncommon among pregnant women, some are being prescribed it. Is there an overriding clinical reason that makes the risk worthwhile in those cases or has its usage by such women not been eradicated because not all prescribers are fully aware of the dangers?

Deputy Kate O'Connell

I thank all present for attending, particularly the witnesses and the parents of affected families. My view is that, regardless of the causes of the conditions the children have, the State has responsibility to assist those children and their families. I am a community pharmacist. I have dispensed valproate for years and have long been aware of the congenital issues with the prescribing of the drug. In many cases women have been stabilised on the drug since their teenage years and then start a family. My understanding is that there was a failure in the counselling of women who were taking valproate as to the appropriate treatment for them in regard to a transition from not wanting a baby to starting a family. Are the HPRA and the HSE happy that that failure has been rectified and there is no chance that any woman who has been long stabilised on valproate will slip through the net and not receive the appropriate counselling? For some patients, it is the only product that will keep their epilepsy under control. That causes a serious problem when such people want to start a family. Decisions must be made in such a situation. Changing the medication of a woman who is stabilised on epileptic medication while pregnant could be very dangerous to the mother and the developing life in her womb.

As regards the EU-wide response, are the Department and the other witnesses happy that the response in Ireland was as fast and robust as that of our European counterparts? Are we at the same level as other countries in that regard? Much information and many bulletins, stickers, leaflets and so on have been sent to community pharmacists and I am very happy to see that happening. However, it is clear that did not work in the initial phases. The HPRA statement indicates that the first interventions to get this information out did not have the desired effect. However, it was done again and seemed to have a better response. Has there been an assessment of what might be a better response were this ever to arise again? Is the dissemination of information to patients on this medication best achieved by sending stickers, leaflets and cards and educating pharmacists and GPs? I suspect that, in this day and age, that is not the best way to make an impact.

As regards the continued review of the product, it is now clearly linked to congenital disorders. It is very important to point out that it has been so linked since it came on the market. However, there has been a marked rise from over 10% to 40% in the number of people who have developed mental issues. What is being done? In the case of drugs such as isotretinoin, also known as roaccutane, the initial recommendation was that they should not be used by women of child-bearing age, followed by a recommendation that prospective fathers should not use them. Are the witnesses considering the effect of valproate on sperm generation? Many girls on the medication were exposed to it in utero. Are such girls now grown up and have any studies been carried out on the effect on their reproductive systems? Is there any information on the effects on the offspring of mothers who were on the medication?

Ms Joan O'Donnell

I will deal with the questions regarding State responsibility, services and costed services and then hand over to Mr. Murphy.

We must consider the issue of the State's responsibility. We recently met the Minister for Health, Deputy Harris, and clearly informed him that, as we understand it, the State bears the responsibility to ensure that women and children who have been affected by this drug get answers in terms of accountability. The Minister has committed to get back to us by the end of May and consider the issue of compensation. My colleague, Mr. Murphy, will be able to tell us more about what is happening in other jurisdictions on this issue. France and the United Kingdom are very much moving in the direction of compensation. There is a mismatch between when the dangers of the drug were known and when patient information leaflets were changed. There is a huge culpability and liability since 2014, when the EMA had made a ruling but that was not being implemented by a state. There is clear accountability since that ruling. This was the first time the PRAC revisited a drug on which it had made recommendations in order to ensure that those recommendations were being properly implemented.

Yesterday, we heard of a woman in Cork who collected her medication in a plastic bag without a label. It is a similar situation to that earlier referred to by Deputy O'Reilly. There must be an investigation into this matter. We must understand who is responsible. The families and parents affected are under enormous stress. As we explained, they are going from Billy to Jack in terms of getting services for their children. There is no co-ordination of services. It is extremely difficult to get a diagnosis and many people are leaving work in order to care for children. The costs are both unbearable and unmanageable. It is not for us to quantify them. We are an unresourced body trying to advocate on behalf of women and do not have the resources to carry out that sort of cost analysis. There is financial cost but also a cost in terms of lives, quality of life and lost and damaged relationships. The costs to people's lives are immense. We must establish accountability and make some retribution or redress on that basis. We hope that there will be a cost analysis on the Cumberlege report, which has just been issued in the UK, because it has been resourced.

As far as I am aware, there has been no resource put into this here. I will hand over at this point to Mr. Murphy.

Mr. Peter Murphy

On Deputy Donnelly's question regarding the State and its responsibility, it is important to reiterate that these disabilities are not bad luck or random incidents, they have been caused for reasons other than chance such as exists in the general population. Our overall position is there is a huge public interest reason as to why this issue should be investigated. Rather than us coming here today and saying X or Y is responsible, what we need is an independent inquiry to look into these questions and come up with answers. There are a lot of parties that would need to be involved in that discussion.

As for what is happening in other countries, the UK recently announced a review of this drug and a number of other products and drugs with a view to determining whether the State has responded adequately over the years to safety issues. As part of this review, the issue of a compensation scheme is being examined. France has gone a step further in that the state there has accepted its responsibility and established a compensation fund of approximately €10 million. The French Minister for Health has acknowledged that this is merely a starting point. Crucially, in France there have been moves to involve pharmaceutical companies in the process. As I understand it, if the pharmaceutical companies do not make an offer of compensation to an individual then the state will cover it. Obviously, the legal system in France is different to ours.

Deputy O'Reilly asked when the risks were known. I am sure the Health Products Regulatory Authority, HPRA, will have more information on this but from our point of view foetal valproate syndrome was first reported in the early 1980s and it was well established and accepted by the mid-1990s. 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. We have reviewed the information that was provided on the summaries of product characteristics, SPCs, which are the documents provided to pharmacists and healthcare professionals about drugs and we have found discrepancies in terms of reporting of risks on those materials compared to the data that would have been known at the time, as well as some variances between what was on the UK data sheets and what was on the Irish data sheets at the same time. These are all issues that could be looked at as part of an inquiry to establish what may have happened over the years.

Deputy Kate O'Connell

Can Mr. Murphy elaborate on the point regarding the differences in the data sheets between the two countries?

Mr. Peter Murphy

For example, there is an increased risk of polytherapy with valproate in pregnancy. From what we can see, this was first included in UK data sheets in 2002 but not in Ireland until 2008. From 2001, in the UK it was recommended that Epilim be used in women of childbearing age only in severe cases or in those resistant to other treatment but a similar recommendation was not in place in Ireland until 2012. There were a number of other discrepancies. Historically, the information has been available in the data sheets but ten or 15 years ago, that information was minimal. It has since expanded over the years. The question is whether it has always reflected everything about a drug that has been known and accepted.

Chairman

Would Dr. Gilvarry like to comment?

Dr. Joan Gilvarry

I will ask my colleague, Dr. Spooner, to answer the question about the studies that led to the European review and to some of the other questions.

Dr. Almath Spooner

I thank members for their thoughtful questions, which I will try to answer as sequentially as possible. Deputy O'Reilly asked how we will monitor impact, which is a critical question because as well as looking back and learning lessons, we need to work together to ensure that future generations are protected. It is important to emphasise that at this point, we have taken the most definitive regulatory step possible. We have contraindicated the use of sodium valproate - Epilim - in women of childbearing potential unless the requirements of the pregnancy prevention plan are followed. Following amendment of the licence, it is now a requirement of the licence that the pregnancy prevention plan is implemented, which is an important change. We have tried communication. We are moving from process to impact. The objectives and the goal of risk minimisation is that women of childbearing potential will have full information on the risks, with the overall goal being that exposures and pregnancy are avoided. We do not want to see future children harmed by this medicine.

Deputy Louise O'Reilly

On amendment of the licence, has that been done?

Dr. Almath Spooner

This is a European story. As members have acknowledged, the European decision-making process finalises with the European Commission decision and those administrative steps are ongoing. The recommendation is firm. It is just the physical changes to the documentation that have yet to be made. It is in the process of being finalised. In this regard, we are speaking about weeks or months rather than any longer.

Deputy Louise O'Reilly

Would Dr. Spooner like to comment on the issue regarding the woman in Cork yesterday? It would appear that the regulations are not having the desired impact. Practically speaking, how will this translate into action? I am sure that like me, other Deputies have been contacted by women of childbearing age who have been prescribed this medication but have not been alerted to this issue.

Dr. Almath Spooner

That would be a concern for the HPRA and all of us working to ensure that these medicines are used safely by those who need them but not in pregnancy. We will be working collaboratively with patient groups and the HSE on this issue. We received notification last week from the Health Research Board in regard to an application in which we sought to do academic collaborative work with the RCSI that would bring some independent perspective to analyse drug utilisation data to make sure that these measures are effective in practice. I appreciate that members will have anecdotes of situations where practice needs to adapt. We need systematic evidence to be generated to ensure the measures are working in practice and that women who are at risk are not being exposed. We will be undertaking this work with patient groups and academics.

The pharmacovigilance risk assessment committee, PRAC, was established in 2012. It was the product of amendments to European legislation, which I am sure many members have followed. PRAC was established as a committee independent of the licensing committee. It was given regulatory teeth and its outcomes are binding. At the time of its establishment, recognising the public health importance of this issue, this was one of the very first reviews we did. I am vice chairman of that committee and I am doing all I can to make sure that this is robustly addressed in terms of analysing the scientific data but also following through on other issues. As rightly said by my colleagues, this is the first example of a referral in which we have undertaken a look-back in terms of whether measures are working or if we need to do more and the answer was yes.

We can only do that using a collective multi-stakeholder approach. We regulate the products and now need to ensure the knowledge of the harm associated with the medicine leads to changes in clinical practice.

I emphasise and acknowledge that we are talking about a chronic condition. Deputy Kate O'Connell referred to Isotretinoin, but members will appreciate indications and population. Acne is very different from epilepsy. We have concerns and do not want to have unintended consequences. Switching a woman's prescription from sodium valproate to an alternative requires time, but it requires specialist expertise, in particular. That is why the PRAC has made it a requirement of the licence that an annual review be conducted by a specialist when sodium valproate is prescribed for women with a credible risk of pregnancy. That is not a provision attached to a licence lightly; it is simply to recognise the importance of the health risk.

Some Deputies addressed the common theme of why identifying the risks had taken so long. As the congenital defects are visible, members can understand why they were identified early on. Warnings about such risks were issued right from the beginning. However, as neurodevelopmental disorders are more subtle, it takes time to make a link with exposure in utero. Deputy Stephen S. Donnelly made an astute observation on delays, but I wish to emphasis that we are not talking about delays but disorders. The PRAC has clearly outlined that they are disorders where children do not catch up in their development. That is something that came through very clearly in patient testimonies. We understand the magnitude of the risk. We understood there was the potential for harm if sodium valproate was used in pregnancy. What we have seen over time is an evolution in the understanding of the risk and its magnitude and the impact on children and their families. That understanding has been facilitated by the fact that, as a committee, the PRAC has focused on hearing directly from patients. It has both a public health focus and a patient engagement focus. The way we conduct pharmacovigilance today differs greatly from how we did so in the 1980s. One aspect is the new data streams, a new willingness to engage with patients to hear about their experiences.

Another aspect is the epidemiology evidence required to make a link. That evidence was unavailable in the 1970s and 1980s. The first of the research papers came through around 2008. It was a Meador et al landmark study which, as some Deputies mentioned, provided the most robust evidence of a causal link between neurodevelopmental problems and the treatment. There is convergence and an acceptance of the risk. As Deputy Stephen S. Donnelly mentioned, it is difficult to make a causal link at an individual patient level. However, we know, based on the epidemiological studies, that 11% of patients have physical defects and approximately 30% to 40% have neurodevelopmental problems, within which there will be a spectrum, by which I mean that some patients will be more severely affected than others. The data stream on which we have relied is the epidemiological evidence, rather than trying to make individual causality assessments which, by definition, is very difficult.

On the questions posed by Deputy Kate O'Connell, I hope I answered her question about referral to a specialist for an annual review. I have explained that when treatment is initiated, concern about harm in pregnancy might seem a remote concern. That is why, as part of the global package of measures, we have advocated for the avoidance of the use of sodium valproate in young females, with a view to reducing the complexity involved for individual patients, given all they could suffer in the healthcare system in having to ultimately transition from one treatment to another. Our goal into the future is to prevent exposure to sodium valproate in pregnancy. At one of the stakeholder meetings Mr. Peter Murphy of Epilepsy Ireland said we must move beyond process to impact. My organisation is in full concordance with him on that point.

Deputy Kate O'Connell

Why was there such a difference between the United Kingdom and Ireland in terms of inclusion in data sheets, as mentioned by Mr. Peter Murphy? That was unusual. Why was there a discrepancy in the information included? As outlined, in 2002 information became available on the summary of product characteristics, SPC, in the United Kingdom but it did not become available here until 2008. Who has responsibility? Does it rest with the HPRA as regards individual member states or the maker - Sanofi?

Dr. Almath Spooner

It is the marketing authorisation holder. Will the Deputy allow my organisation to consider the comparative analysis as it would be remiss of me to respond without having the details in front of me? The general process is the marketing authorisation holder submits a variation to us; we assess it and one anticipates that the company, as a global company, will submit variation to all of the regulatory authorities.

Deputy Kate O'Connell

Yes.

Dr. Almath Spooner

Also, it would have been an agent that would have gone through the EU referral process by the licensing committee, the Committee for Medicinal Products for Human Use, CHMP, for the harmonisation of product information. We would like to understand why historically there might have been some differences. We need to carry out a piece of work to analyse whether there were substantial differences. I am sure we will be happy to discuss the matter with Mr. Peter Murphy and his colleagues and update the joint committee should it be necessary to do so.

Chairman

I thank Dr. Spooner. I will call two members who have not contributed to the debate so far. I call first Deputy Bernard J. Durkan who will be followed by Senator Colm Burke.

Deputy Bernard J. Durkan

I thank the Chairman. I welcome all of the delegates. We are all concerned about the tragic consequences and the effect this matter has had on individuals and their families. Which country first identified the seriousness of the risks involved? There appears to have been strong support for the drug in Scandinavian countries, but I am not sure whether that remains the case. The drug is still recommended and used in Iceland. I know that it was used or used in combination with something else in the 1960s. Some body somewhere first detected its negative aspects and I would like to know more about the matter.

Why, when it was first discovered, was no Government health warning issued? I am not necessarily referring to the Irish Government. The international community should have recognised the potential risk and applied a health warning to protect both patients and the professionals who might have found themselves in the position of prescribing the drug in certain circumstances.

Is the drug permitted for use in all European Union member states? Do containers containing capsules or tablets display warnings? If so, when did that take place? Is the matter in hand?

Negative side effects have been identified. How long did it take for a warning to be issued to all member states and practitioners throughout the European Union? It is important that we know such information.

There are alternatives. What are they and how effective are they? Have they been prescribed and recommended for use throughout the European Union? Have they been prescribed and recommended for use in this country? Have GPs and consultants been advised of their potential use and to what extent have they been so advised?

On the HPRA's response, it appears on the face of it that matters were beefed up to European speeds. However, I do not know and would like it to be confirmed.

With reference to European agencies, on many occasions we have discussed the effectiveness of the Irish system versus the European system and the need to have one overall system to provide for the Rolls-Royce tests.

Has that taken place in this instance? In the European system, tests should be well ahead of everybody else and should be on a par with the best internationally.

It was 2009 when some concern arose at European level. Were warnings issued throughout the system to all European countries? If not, why not? Were there any discoveries by the HPRA in Ireland?

In October 2013, when the concerns were obvious to everyone, how effective a warning was issued throughout the system, to doctors and patients who might have been recipients of this treatment? How quickly was the warning issued and how effective was it and was it sufficient to alert people to the seriousness of the situation? Herd protection is one thing but individuals have rights in all systems. It is not true to say that it was tragic - which it is - but necessary. There are alternatives, and they need to be examined and treated as equally effective treatments.

Senator Colm Burke

I thank the witnesses for their very comprehensive presentations. I know some of them face a difficult task in dealing with this issue.

Some of the issues I wished to raise have been raised already so I will be brief. According to the presentation, since 1993 there are about 400 children with developmental delay and about 100 with physical malformation. Do we have accurate figures, including for the number of families affected? Are there situations where there might be more than one child in a family affected? Every child needs support but it is something that needs to be examined at the earliest opportunity and to ensure that those families have adequate support. I am interested to know how many families need support now? What further work needs to be done to try and establish a very accurate figure on this so that the supports can be put in place?

I have a general question for Dr. Gilvarry on the overall process in regard to medication and medicines in Ireland. Over the last two years, we as a committee have come under a lot of pressure to make sure that medication, if one can call it that, be made available in cases where there is no clear scientific evidence that it does not have detrimental effects in the long term. Here, we have a situation where we have medication that has gone through all the research and development, has been in place and working for 25 or 30 years and problems are arising with it. Is any process to review medications available in Europe or Ireland, where even if a product is around for 20 years, we might need to review it occasionally? I know it would be a difficult task because there are so many pharmaceuticals on the market. Just because a product solves some problems, that does not mean that it might not cause others.

When a problem is identified in Europe or Ireland, have we a process that reacts fast enough when deficiencies in what is being provided are highlighted? Big pharmaceuticals are very well able to defend their positions and they have the power of public relations to ensure that any deficiencies found in a medication are downplayed. They can put their own pressures on bodies, including us as Members of the Oireachtas that we should back off on raising queries on the issue. Have we sufficient red alert systems in place? Is there a need to be far more proactive in that area? There are so many medications available and we have an issue where one medication may not go with another. Medical practitioners are always under pressure, and trying to keep them up to date is difficult. Have we done enough in this area? We might criticise the HPRA sometimes for not processing a product fast enough and we must be careful to make sure that when products are on the market, they deliver what they say they will.

We need to look at these areas. There seems to have been a delay in this case. The information did go out but it is about it going out to the relevant people and being effective in getting the message across to them. I am not clear about whether the way we did that messaging was effective.

Chairman

I apologise for having cut Mr. McGrane off earlier. He now has the opportunity to answer all those questions.

Mr. Kilian McGrane

I will ask my colleague, Dr. John Murphy, to deal with the discrepancy between the cases referenced in the study here and what Ms O'Donnell said about confirmed diagnosis. He might also respond to Deputy Donnelly's reference to why there are so few diagnoses.

Dr. John Murphy

Deputy O'Reilly hit upon a very important issue on the discrepancy in figures. There is always a problem with data collection, in how it is collected and how we centralise the collection of that data, particularly when a drug has a number of side effects. If it clearly had one side effect, and one side effect only, one would imagine that the relationship would be very clear but this one was different. Sometimes it causes a physical disability, other times it causes a problem with a child's learning abilities and so on. Those are very different issues. The other problem about malformation is that it varies. For instance, a child might be born with a cleft lip or palate and will go into the service with plastic surgeons, or a child will be born with spina bifida and will be sent off with neurosurgeons. A child might have a hand or thumb deformity and will be dealt with by an orthopaedic surgeon. It means that early on, the children will go off in very different directions. How it will happen that the relationships will be made, and how it is reported centrally, or will it be reported back to the company which makes the drug is an important issue.

If the child only has neurodevelopmental problems, they will not manifest early on, they may only develop and become apparent in the second half of the first year when the child is a toddler. That is well after the pregnancy has ended and the relationship may not be remembered or enough emphasis might not be placed on it. That leads to discrepancies.

I will let Dr. McKenna come back in, then I will ask Ms Joan O'Donnell for a comment and then I will bring in the Senator.

Senator Colm Burke

Can we set up a process for dealing with this? The problem seems to be that there is no process for dealing with it.

Dr. John Murphy

There are a number of parallel groups. We in the clinical lead programme in paediatrics and neonatology were contacted by the HSE to look into the matter. We are setting up a meeting shortly. We are bringing together a group of consultants and specialists who deal with children with these types of disorders and the relationship with Epilim to see what we should do to best progress things. We will meet in the next few weeks to try to progress things rapidly. I am aware there are a lot of issues and anxieties around it.

Dr. Peter McKenna

There is not always diagnostic certainty about this. Dr. Murphy has also said this. If a mother was on a high dose of Epilim and a child was born with an obvious physical abnormality such as spina bifida, then it is entirely reasonable to conclude that one has led to the other. If, however, a mother was exposed to a low does for a short period of time during the pregnancy and the child subsequently developed a behavioural disorder, it is much more difficult to attribute the subsequent behavioural disorder with absolute certainty and clarity to the small dose of sodium valproate to which the child was exposed for a short period of time. This situation is not like many diagnoses that are absolute, where one can say "Yes" or "No". There are degrees of greyness and subtlety here that will need to be borne in mind.

A possible explanation for the difference between the 400 and the 40 is that the 400 might refer to the number of women who took the medication during the pregnancy and whose babies were exposed to it, while the 40 refers to the number who have received the absolute diagnosis. I speculate when I say this but it would appear to be the most reasonable explanation for the big disparity between the 400 and the 40.

Ms Joan O’Donnell

I will respond to some of the figures very briefly and then Mr. Peter Murphy will come in also. The 29 cases referred to in the report were just the number that the study looked at. Our figures, from Professor Andrew Green, chief geneticist in Our Lady's Hospital for Sick Children, Crumlin, tell us that 43 cases have been diagnosed that have come through the genetics department at Crumlin hospital. Professor Green also tells us that this figure does not include anybody who was not diagnosed via that and who may have had spina bifida, for example. The estimation of 400 children affected is one we ran by Professor Green. We extrapolated from the UK figures, where an estimated 20,000 children have been affected. We looked at the figures over the course of the years since Epilim was introduced in Ireland and we also made allowances for the declining prescription figures currently. We are happy to share this figure for estimation, which is the most robust estimate we can make at the moment. We have had some medical opinion on it and they seem to concur that the figure of 400 looked about right.

I will now turn to the issue of diagnosis. The HSE's perspective in this regard is from a clinical point of view. I totally understand that the HSE representatives here today are looking at the complexity of the issues and grappling with how difficult it can be to diagnose, but I also want to put a parent's perspective on it. Parents know their children best. They very often report to us that their concerns about their children are dismissed, that their expertise in regard to their own children is ignored and that they are batted back out of the system. We also hear that parents are going to France, Northern Ireland and other jurisdictions, including the UK, because there is a two year waiting list here. We are concerned that perhaps there may be a reluctance to diagnose because of the complexity of the issues. These are all aspects that we need to get over. We need to create a comprehensive system of supports and a clinical pathway for children who are affected.

Mr. Peter Murphy

With regard to the numbers and where the numbers come from, Ms O'Donnell has made the point, but I want to highlight the real significance of gathering the numbers as a very early step in this process. I am aware it has been discussed a lot here.

A register is already in existence at Beaumont Hospital, which is an epilepsy and pregnancy register. It is a national register and this is being mooted by a number of parties, including the Department and the Minister, as a potential solution to this. There are a number of challenges to overcome but the infrastructure is, potentially, already in place. It only gathers data relating to epilepsy and does not gather bipolar information. It also only gathers the information for a limited period after a child is born. The key issue with the register is that for many years it has not been funded by the State but by industry support, which has recently run out. With investment by the State, there is a framework and an opportunity to transform and expand an existing register to gather data on pregnancies and information on individuals affected, as well as their treatment needs and the effectiveness of their treatment.

We were asked whether we were up to speed in Ireland. In our response in recent times we have been very much up to speed and the HPRA has been very proactive, as have all parties, in addressing the risk issues. The key point in respect of the risk for the future is that a lot of things were done in 2014 and a lot of boxes were ticked at that time. A lot of letters were sent out and information materials were developed and distributed by the HSE and the drug company. There were drug safety newsletters and changes to patient leaflets and everybody is now aware of this, including specialists and pharmacists. Sending out information has never been the problem. The problem is that the information is not getting through, for whatever reason, to some women on the ground.

Every time we in Epilepsy Ireland raise this issue we get two reactions. One is to ask if we will ever stop talking about it as people feel they already know about it. The other is from upset individuals like those who, following the "Prime Time" programme last year, could not sleep because they had never heard of the issue. The Organisation for Anti-Convulsant Syndrome did a survey of 100 pharmacies last year and found that less than 20% were even aware of the existence of the pharmacy card. It is not a question of doing things but of monitoring what is being done and the impact on the ground. We need to know that we will not be back here in two or three years' time having the same conversation. From the point of view of FACS Forum and Epilepsy Ireland, that is one of the critical questions.

The pharmacy regulator has set specific expectations for pharmacies. There is a mixture of trust and enforcement and all parties, including the HPRA and the HSE, need to be really clear about what they are going to do if we are still reporting medications going out in bags in six months' time, or the fact that 20% of women are still not aware of this.

Deputy Louise O'Reilly

I had asked a question on what penalties there were, if any. It is clear that there are none and that these are just recommendations. There is no possibility of enforcement and we are relying on people who are very busy to implement this. It is clear that it is not being implemented in all cases and that is worrying. The epilepsy in pregnancy register was raised. Can Mr. McGrane, speaking specifically for the HSE, say if it is possible that it can be adapted to take account of historical cases, as well as being used for the future? I appreciate that it may not be always possible to give a 100% diagnosis but if a mother has taken Epilim during pregnancy and has a child with some or all the symptoms as described, would it not make sense to assess the problem in a realistic way and assess its extent? There is a significant difference in the figures, that is, between 400 and 43, and if there was more openness on the part of the HSE to accept there might be an issue, it would be an awful lot easier to deal with it.

Do the witnesses think the register can be adapted to deal with cases retrospectively? If it can, when will it be done? If not, will a register be established separate to that?

Chairman

We are under a bit of pressure for time. I will bring in Deputies O'Connell and Donnelly and return to the witnesses for answers to those questions.

Deputy Kate O'Connell

The evidence of today is that there have been deficiencies in how this was handled, whether in Ireland or in the EU. It seems to have accelerated in recent years, ending up with a contraindication of the product in pregnancy. It is clear that there has been an issue with the dissemination of information, from EMA level down to real-life people, meaning people on the medication were not aware of the issue. I refer to the recent 20% figure to that effect coming from the UK. What are the HPRA and the Department going to do to ensure it does not happen again that such a thing takes so long to be felt on the ground? Many community pharmacists have an area for information and it is their responsibility, along with prescribing doctors, to get the information to people. There seems to be a deficit in the information getting to people who were on the medication and about to get pregnant or who had already had children.

The link with neural tube defects is quite interesting and my understanding is that the rate of neural tube defects is rising here more quickly than in any other European country, partially due to the lack of folic acid supplements in foods. Can the Department say what we are doing about that? We have brought it up many times in this committee, both in connection with the eighth amendment and the national maternity strategy.

I am not making any correlation between thalidomide and this product but after the thalidomide cases there was an overhaul in how we assessed medication. Can the HPRA comment on the risks associated with not continually reassessing the safety of drugs and with licensing a drug for use without sufficient evidence to support its clinical safety? What are the risks of a rush to approval of a particular medication without knowledge of its long-term effects on pregnancy and babies? We might think a central nervous system, CNS, drug would not have an effect on developing life but clearly it does. This committee has recently heard of moves to license drugs without the appropriate safety information.

Where does the responsibility of the drug company lie in respect of this? This drug is off patent and it is very cheap now but it was very expensive 15 years ago. Time passes quickly.

Where does the drug company's responsibility lie? What if Sanofi just decided for market reasons or because it was too much hassle to withdraw the drug from the market? How can the State encourage it to live up to its responsibilities?

Deputy Stephen S. Donnelly

I return to the parents' requests. I address my questions to Mr. McGrane. I heard three main requests. One was for a study on the children affected. We have debated that at some length and it sounds like progress can be made. The second request was for an investigation to be launched. Mr. McGrane may have indicated that that has been requested but it sounded more like a clinical conversation. Is an investigation into what has happened being launched, as has been requested?

My next question is on services. We have heard the parents' voices: "Never a month goes by without hospital or specialist appointments"; "I had to resign in 2016"; "Last December my daughter wanted to end her life"; "I have been stuck in a vicious cycle of guilt"; "The constant battling for services". It is clear that these parents are in a desperate situation and they should not be battling for services. The budgetary implications of helping them are tiny relative to the apparatus of the State. This is for a very small number of people and they are being spread all over the place.

Are the HSE and the Department acting as a matter of urgency to help these parents and their children? If so, critically, when will the parents and their children see a difference in their lives in terms of the battles they are having on behalf of their children?

Chairman

I will ask the witnesses from the HSE to speak first after which we will hear from the representatives of the HPRA.

Mr. Kilian McGrane

I will start with Deputy O'Reilly's question about the register. I cannot answer specifically as to whether the register in Beaumont can be modified. Perhaps Ms Flynn can comment.

Ms Cora Flynn

I was involved in setting that up with Professor Delanty in 2000. The Irish data pools in to the British data with Jim Morrow and John Craig in the Royal group of hospitals. It prospectively gathers information on women when they become pregnant with what medications they are on. It monitors them through their pregnancy and then three months after the baby is born, the outcome of the birth is collected. It stops at that point.

It collects information on all antiepileptic drugs, not just valproate. However, the reporting of it is not mandatory - it is by clinician perspective. It depends on whether that woman is engaging in a specialist service. GPs can also register the pregnancy. It is currently funded by pharma.

Mr. Kilian McGrane

The issue is that we would need to see whether that register can be adjusted and what is technically required to put in the retrospective aspects of it. The broader issue is that the Minister has requested the HSE's clinical specialists to meet with FACS. Within that, one of the first things we have to do is quantify the scale of the challenge faced by families. That means we need some database of people affected.

This flows neatly into Deputy Donnelly's question about the range of services. We need to quantify the scale of the challenges in order to map out the service pathways and identify the associated costs. I appreciate it is small in a total budgetary context. However, if there are 400 families with complex multidisciplinary needs, we need to make a budget provision for that. The budget provision would also need to include a register if we are to establish one. It is a fairly significant piece of work. The first phase is that we get the right clinical experts to meet with FACS to ensure we have a full understanding of the breadth of challenges they face. We can quantify the scale of the problem and then put together the plan for how we resource this prospectively. Obviously the issues retrospectively are separate and I think they have been discussed at this stage.

Deputy Stephen S. Donnelly

On the plan, I imagine parents have a fear that while this important work goes on, nothing might be seen on the ground for months or even years. Can Mr. McGrane give any reassurance to the parents as to when they might expect to see service provision to their children?

Mr. Kilian McGrane

It is very difficult to quantify a timeline in this context because we do not know the scale of the problem. We know it is a very significant issue for a significant number of families. Once we get people together we can start to do that. I hope some things can be done before a separate budget allocation can be provided. I do not want to make a commitment to something we cannot honour until we know the scale of the problem. I appreciate that is very disappointing for the families, but they have engaged already. They are part of the HSE's response team that has been meeting since late last year.

The Deputy raised the issue of the investigation. I am not quite sure as to what an investigation would entail. I do not know what role the HPRA would have. A number of questions were asked on timing, such as when this was contraindicated in a way that it should no longer be used. Obviously we would need to have other neurology experts advising on the occasions when it should be used, at which point we are into a different territory. That is subject to further discussion. I certainly could not make a commitment on it today. I can understand why families would want to know why this has gone on for as long as it has. It is entirely reasonable.

Dr. John Murphy

Based on the contacts we have had from Dr. Colm Henry in the HSE we have arranged an initial meeting on 10 May to meet members of the parents group to discuss where we are with the issues. Obviously we take a lead from them because they have children who are affected and we do not quite know where they fit into the system at the moment. We do not know how robust and clear their diagnosis has been. We do not know what the gap in their services is and what they require. We need to build it up. We will have an initial meeting on 10 May. We will not be slow; we will move fast on this. It is an important issue for the families.

Ms Cora Flynn

The difficulty is being brought from a GP to a paediatrician to then a paediatric neurologist and onwards to an adult neurologist. They find that very fragmented. Once there is a suspicion and if these cases can be identified and triaged urgently onto a pathway that is specifically resourced for them, I believe that will meet their needs. They have a wait to get to the paediatrician, a wait for the paediatric neurologist and perhaps another wait for the adult neurologist. That is where the time lag is. In the meantime the person needs services. That fragmentation needs to be leaner and those identified triaged and resourced.

Dr. Peter McKenna

The three issues Deputy Donnelly raised are legacy and historical ones. We in the women and infants health programme have as an aspiration that women with epilepsy would be seen at specialist clinics where there could be liaison between obstetric services and neurology services. This is difficult to achieve in all but the biggest hospitals at the moment owing to the scarcity of neurologists. There are very few in the country and their services are spread very thinly. That would be one of our aspirations.

Another one would be that women who attend these clinics would have access to specialist scanning with targeted anomaly scanning so that if possible, the problem could be diagnosed at an early stage should there be an anatomical problem. The third is that they could be put in contact with paediatric services upon discharge so that if there was any developmental problem, they could access remedial services as soon as possible. The aspiration of those in the women and infants health programme would be to deal not just with the valproate issue but with women who need specialist epilepsy services.

Chairman

I will call speakers from the HPRA and then come back to the witnesses from FACS. I call Dr. Gilvarry.

Dr. Joan Gilvarry

I will let Dr. Spooner start with some of the questions.

Dr. Almath Spooner

The two main questions addressed to us were from Deputy O'Connell. My understanding is that there were two main pillars to those. One was on the risk minimisation. Communication does not seem to have been optimally delivered and the Deputy asked what we are doing differently now. We are making it a requirement of the licence that these things are done. I refer to any failure to provide patient cards or failure to provide precise information on the magnitude of the risk. Use of the medicine in a woman of childbearing potential who is not on effective contraception will be off licence now.

That is a change.

In terms of the enablers, we are putting a formal pregnancy prevention programme in place. That is recognising that there have been deficiencies associated with a lack of clarity on different roles and responsibilities around the patient journey. What is the role of the regulator, the specialist, the general practitioner and the community pharmacist? What are the clinical enablers that allow steps to be taken at the appropriate time in terms of decisions on therapeutic options but also information provision? The new recommendations and the new clarity on the licence, supported by what will be a pregnancy prevention programme that will be branded "Prevent" and that will have a suite of measures that have been fully informed by engagement with patients and health professionals, will be a very substantial change and a framework around risk communication as opposed to ad hoc bulletins and the like. We have to recognise that we are doing this for this medicine because of the magnitude of the risk, which is not neutral in terms of burden. This is a medicine a woman will be on for a long period of her life and the risk of pregnancy will vary, so it needs to be adapted to the woman's individual circumstances.

In terms of moving forward, we have a more robust approach now to communication, at least from the perspective of what we are accountable for, which is the regulation of the product.

On the question about the other pillar of risk management, which is around evidence generation and how we research medicines at a population level when we have uncertainties, linked to that is the availability of electronic resources, electronic health records, and having the possibility to research population use of medicines. In terms of much of the pharmaco-epidemiological research, we have had a lot of discussion on the complexity around interpreting individual cases but we have had studies which can get around many of those issues with sophisticated data linkage. That is not always possible for every medicine but what is clear now is that for every medicine we have a risk management plan and at the time of initial authorisation we ask about the uncertainties and we plan proactively to reduce those uncertainties. If sodium valproate was being put on the market today, having seen the non-clinical data and having the concerns about physical defects, we would be requiring the company to do pharmaco-epidemiological studies.

I hope I can provide some reassurance that, going forward, lessons have been learned. We have a much more robust approach to the vigilance of medicines in pregnancy. Perhaps the thinking in the past was that we cannot research medicines that are used by women who are likely to become pregnant. There was a reluctance to research. That has evolved. We understand that women will be treated for chronic conditions. They will want to plan pregnancies and they need reliable and complete information on the relative harms for different medicines in pregnancy. As regulators, we are accelerating efforts, a term used by Deputy O'Connell, and that is a fair reflection. As part of that, and I do not want to get into regulatory speak, in the next year at the Pharmacovigilence Risk Assessment Committee, PRAC, as well as having the research we are doing at national level, we will be developing a good vigilance practice guideline that will be binding on the marketing authorisation holders. That will be taken into account in all of the risk management plans and the planning of studies to reduce uncertainty so that we do not see these kinds of issues arise in the future with such a time lapse before we get complete and accurate information on the magnitude of the risk. I hope that answers the question but if I have overlooked anything, please remind me.

Chairman

Thank you very much, Dr. Spooner. I might give the final word to Ms Joan O'Donnell.

Ms Joan O'Donnell

Does Mr. Murphy want to say something first?

Senator Colm Burke

Chairman, I asked a specific question about the systems in place with regard to medications that are available for a long period of time and I am not clear if it was answered.

Dr. Joan Gilvarry

I will come in on that. Somebody said there was a rush to approval of products. There is never a rush to approval of products. They must meet pre-specified quality, safety and efficacy data and that is continually monitored throughout the life cycle of that product. We get periodic safety update reports from the company. We continually monitor adverse reaction reports and detect signals through the European database. If there is a red alert, as the Senator calls it, it can be referred immediately by us or any other member state to the European committee for a full scientific review. That is what happened here.

As Mr. Murphy said, we have extensively and repeatedly communicated on the product to healthcare professionals in recent years and the problem is that the message is not getting through. We regulate the product. We recently asked the HSE, the clinical leads and the lead in primary care to come in to us to see how they can help us get the message through to the GPs via the neurologists, to the prescribers via the psychiatrists, and also to the pharmacists via the Pharmaceutical Society of Ireland, PSI, which was represented at that meeting. We are not in the doctor's surgery when the doctor is prescribing and talking to the patient. We are not in the pharmacists when the medicine is being dispensed, but all of these are trying to assist us now. The PSI recently sent communications to other pharmacists to make sure the package leaflet and the patient alert card is given at the time of dispensing, and the head of primary care has written to all the GPs to tell them they need to identify the patients who are on this treatment at this time. They are following up, which is very good and I appreciate it, with the GPs in terms of identifying the patients who are women of childbearing age whom they have on this medicine.

We need help to implement all our recommendations. We cannot do them alone. We need the pharmacists, the HSE, the neurologists, the GPs, the psychiatrists and everybody in the healthcare system to listen and implement what we have been saying for years.

Ms Joan O'Donnell

I will say a few words and then hand over to Mr. Murphy. We appreciate all the areas covered. The role of the State and how we deal with the legacy issues is still outstanding. We would like the opportunity to return to that issue.

The speakers from the HSE and the Health Products Regulatory Authority, HPRA, spoke about the unintended consequences of taking people off medications early, etc. The unintended consequences of not dealing with this issue now will be devastating. They have been devastating for people so far. The first person with a diagnosis of foetal anti-convulsant syndrome, FACS, in Ireland was born in 1987. Unfortunately, we are fairly sure there are children born in Ireland who are living with this condition today. That is what we are dealing with and it is the reason we are here. What is the role of the State in this and where does accountability lie? Those questions are still outstanding after this.

We very much welcome and look forward to seeing the initiatives outlined by the HSE and, in terms of when we knew about the products, the time lags between when information leaflets were changed in the United Kingdom versus Ireland. That is my final comment.

Mr. Peter Murphy

Deputy Donnelly asked about the calls for an investigation. I would highlight that when we met the Minister, he committed to reply to us on that specific issue by the end of May. We look forward to his response on that. He wanted to address the issue with his team and his officials internally, and he has promised to come back to us very soon.

In essence, we have three questions on that investigation. First, what happened in the past across the entire system? Second, why did it happen? Third, what can we learn from it? That is an investigation worth having, not just for the parents involved and the people who are affected today but learning for the future in terms of other medications, groups or parents who might well be here in ten years.

On the service needs, we have to remember that the first step in putting any plans in place for service provision will start with a diagnosis. The very first question that needs to be addressed in the entire area is how we will address diagnosis of potentially hundreds of cases in a service where, in the national centre for genetics, we have four consultant geneticists, ten counsellors and a waiting list of more than 1,300 people, including about 400 who have been on the list for more than 18 months.

It is clear that the national genetic strategy must be funded, resourced and started. There has been much debate on that issue and I presume it has been discussed by the committee.

Another service issue mandated by the new European guidelines, and the pregnancy prevention plan in particular, is that all women taking this drug must have an annual review by a specialist rather than a general practitioner, GP. The question of how we will fit 500 or 1,000 women newly diagnosed with epilepsy into the specialist neurology service in Ireland in the current situation whereby it is already under-resourced remains outstanding and has not been addressed in detail today. There are 34 neurologists nationwide but there should be double that number according to minimum guidelines from the British Association of Neurology. There is a resourcing issue in that regard. The reviews must be carried out but we must ask how that will be done in practice when we have so few resources, including consultant neurologists, epilepsy specialist nurses, etc., to handle this scenario.

Deputy Louise O'Reilly

As Mr. McGrane indicated that the Minister has advised that matters are to be put in train, I suggest that the committee reconvene in a number of months to get a progress report and an update. It would be helpful if anything of relevance were communicated to us in writing in the intervening time.

Chairman

The committee will meet in private session to consider the evidence that has been given and our response. A transcript of the meeting will be sent to the Minister. On behalf of the foetal anti-convulsant syndrome, FACS, forum, the Health Products Regulatory Authority, HPRA and the Health Service Executive, HSE, I thank the witnesses for giving evidence this morning.

Sitting suspended at 11.32 a.m. and resumed at 11.44 a.m.