Assisting Baroness Cumberlege in ref Review into Primodos, Sodium Valproate, Vaginal Mesh

Submission to the Cumberlege Review Concerning the Safety of Medicines and Medical Devices in the UK on behalf of the Organisation for Anti-Convulsant Syndrome (OACS Charity) and #FACSaware

Introduction

” This document contains the legal and moral arguments for a Public Inquiry into medicine and devices regulation to focus on valproate as a case study.

The history of the licensing and regulation of valproate is particularly enlightening and highlights that we as patients were not informed of the risks associated with valproate and neither were many of our Doctors. “

Emma Friedmann,
FACSaware

The Scope of this Submission

This submission is made on behalf of the Organisation for Anti-Convulsant Syndrome (known as OACs), the Foetal Anti-Convulsant Network (known as #FACSaware) and the individuals and families that both groups represent.

An outline of the essential work undertaken by these groups is provided below.

This submission is made to Baroness Cumberlege in her role as chair of the Government ordered Review announced by the Secretary of State for Health, Jeremy Hunt, on 21 February 2018. The purpose of this Review is to consider – in the context of medicinal products/devices identified as, Primodos, Sodium Valproate and Vaginal Mesh:

  1. ‘Firstly, the robustness and speed of the processes followed by the relevant authorities and clinical bodies to ensure that appropriate processes were followed when safety concerns were raised;
  2. Secondly, whether the regulators and NHS bodies did enough to engage with those affected to ensure their concerns were escalated and acted upon;
  3. Thirdly, whether there has been sufficient co-ordination between relevant bodies and the groups raising concerns; and
  4. Fourthly, whether we need an independent system to decide what further action may be required either in these cases or in the future’.
    Mr Hunt explained; ‘This is because one of the judgments to be made is whether, when there has been widespread harm, there needs to be a fuller, or even statutory, public inquiry. Baroness Cumberlege will make recommendations on the right process to make sure that justice is done and to maintain public confidence that such decisions have been taken fairly’.

This submission relates to Sodium Valproate. It aims to help Baroness Cumberlege to consider these focal issues as they relate to Sodium Valproate.

The Purpose of this Submission

It is now well established by clinical researchers, in medical literature and across the regulatory community that Sodium Valproate is a teratogen; and that children exposed to this drug in utero suffer an increased risk of physical, developmental and neurological injuries. That cluster of injuries is known as ‘Foetal Valproate Syndrome’ (FVS).

With adequate warnings directed at both the users of Sodium Valproate preparations and their treating clinicians, FVS was, and is, an almost entirely avoidable injury. Yet, as at the date of this submission, as many as 20,000 individuals in the UK have been diagnosed with (or may suffer from) FVS.

In our submission the persistence of FVS as a diagnosis in the UK, and the number of individuals affected, is evidence of a long history of regulatory and legal failure in the prescription of Sodium Valproate as an anticonvulsant in the UK.

Those affected by FVS continue to pay the highest price for that failure:

‘I am mourning my child now and will be mourning the death of her when she’s gone, this is the result of Valproate, no parent wants to see their child slowly die in front of them’

They do so without any acknowledgment on the part of the manufacturer or regulator of the role that they have played in creating and perpetuating the incidence of FVS in the UK; and crucially they do so without compensation.

Against that backdrop, this submission sets out; the legal case for a Public Inquiry into the regulatory and legal failings exposed by FVS and describes both the urgent need, and moral imperative, for compensation to be paid to all those affected by FVS in the UK.

To achieve that purpose this submission is divided into 3 chapters:

  1. Chapter 1; provides the background on the clinical history and impact of Sodium Valproate in the UK;
  2. Chapter 2; sets out the legal case for a Public Inquiry and is focussed upon dealing with the first three issues raised by Mr Hunt in his announcement on 21st February 2018: These are the Governmental, regulatory and legal failings that have resulted in FVS and have necessitated the 40-year old campaign for justice led by groups such as OACS Charity and FACSaware.
  3. Chapter 3; sets out the moral imperative for the creation of a Compensation Fund, identifying the clinical and psychological needs of those affected by FVS and possible mechanisms through which such compensation could be awarded.

Executive Summary

  • Sodium Valproate medicines are used to treat various conditions such as epilepsy, the manic phase of bipolar disorders (since 2009) and severe migraines (this application is off label use in some EU countries).
  • In the UK the primary use of Sodium Valproate is, and has always been, in relation to epilepsy as an anticonvulsant (AED).
  • There is little doubt that Sodium Valproate is an effective medication in treating patients at risk of epilepsy associated convulsions.
  • Sodium Valproate is marketed internationally under a range of brand names. In the UK, Epilim is by far the most dominant Sodium Valproate preparation available.
  • Epilim was first licensed for usage in the UK in 1973. The company responsible for manufacturing and marketing the drug in the UK is now known as Sanofi.
  • It is now accepted across the clinical and regulatory community by, for example, the National Institute for Health and Clinical Excellence (NICE), the MHRA and European Medicines Agency (EMA) that Sodium Valproate is a teratogen and that wherever possible prescription should be avoided in female patients of childbearing age.
  • The congenital birth defects associated with in utero exposure to Sodium Valproate include:
    • Neural tube defects (NTDs), such as spina bifida
    • Cleft lip and palate
    • Facial and skull malformations
    • Heart, kidney, urinary tract and sexual organ malformations
    • Limb defects
    • Developmental delay
    • Autism Spectrum Disorders (ASDs)
    • Attention Deficit Hyperactivity Disorder
    • Ear malformations and auditory processing
    • Skeletal malformation
    • Arthritis in older children
    • Effects on the endocrine system
    • Sexual identity problems (which occur due to a mismatch between genital development and neural / sexual identity development).
    • Psychomotor issues.
    • Withdrawal symptoms – associated with prenatal Sodium Valproate exposure.

It is important to understand that this list is not exhaustive.

  • When these congenital abnormalities, either singularly or in combination, are identified in children exposed to Sodium Valproate in utero they are diagnostic signifiers of FVS.
  • The controversy surrounding Sodium Valproate is focused upon the teratogenic potential of the drug and the historic failure of the regulator and manufacturer to communicate that potential to clinicians and patients.
  • It is submitted that by the early 1980s the regulator/manufacturer was in possession of sufficient information to conclude that Sodium Valproate was a teratogen which increased the risk of congenital abnormalities above the risks associated with epilepsy in general or where alternative AEDs were used.
  • However, this information was not communicated directly to patients until as late as 2005; whilst, in our submission, appropriate care pathways for women of child-bearing age using Sodium Valproate were not instituted by the regulator/manufacturer until as late as 2016.
  • That failure of the regulator/manufacturer constituted a dereliction of their statutory duties under the Medicines Act 1968, and successive legislation, to safeguard patients and warn of the adverse risks associated with medications.
  • That failure also created a fundamental ‘Information Gap’ between regulator/manufacturer-clinician/patient out of which the tragedy of FVS has developed.
  • An info-graphic describing this ‘Information Gap’ is provided at Appendix B and in Chapter 2 of this submission. The case for a Public Inquiry into medical product regulation in the UK is made with reference to the creation and maintenance of this ‘Information Gap’ which is exposed through the history of FVS in the UK.
  • Those affected by FVS and their families have complex care needs and are in the unusual position of having to cope with children with often profound disabilities whilst dealing with the fact of their own epileptic and or mental health condition.
  • For many of the mothers with epilepsy who are caring for children affected by FVS, stress is a trigger for their epileptic convulsions; the fact that they have been unheard and uncompensated for so long, despite their persistent campaigning, has often exacerbated their own clinical condition – this has added injury to injury.
  • We describe, in Section 15, the Double Disability which the mothers of FVS children experience; the fact of their own epilepsy in addition to the problems experienced by their children with FVS, a condition brought about by the Epilim which has enabled them to live normal lives. This imposes a significantly greater burden on these women than would be the case if they did not suffer from epilepsy.
  • Setting aside the emotional and psychological costs; the physical care needs of those affected by FVS place significant financial demands on the individual families affected and upon the NHS and/or Local Authority, who have been left to shoulder the significant cost burden associated with FVS.
  • Sanofi, the manufacturer responsible for Sodium Valproate, has made very significant profits as a result of its marketing of Sodium Valproate in the UK without shouldering any of the consequential costs of FVS injuries.
  • Litigation initiated against Sanofi on behalf of those affected by FVS and their families was discontinued when the Legal Aid Agency decided to withdraw legal aid funding in 2010, three weeks before Trial: Consequently, FVS sufferers have been denied access not only to compensation but also the opportunity to bring the fact of the manufacturer’s and regulator’s failures into the public domain.
  • This contrasts with the experience of FVS sufferers in other jurisdictions.
  • In 2016 the French Government instituted payments to FVS sufferers through a centrally constituted Compensation Fund.
  • The recent reparative actions of the French Government in respect of FVS, contrast with the historic inaction of successive UK Governments: This contrast is noteworthy given that both jurisdictions have had to deal with:
    • the same drug (Sodium Valproate)
    • the same injuries (FVS)
    • the same manufacturer (Sanofi); within
    • the same legislative framework- by virtue of the European wide Product Liability Directive.
  • The scale of the task of compensating UK FVS sufferers is hard to estimate; however, the moral imperative to facilitate such compensation is abundantly clear:

‘I can tell you from my experience of 32 years that there has never been enough support/facilities within the community to cover the needs of my daughter or any other person with learning difficulties/special needs or disabilities. There has been a continuous lack of understanding of the complexities of FVS’

  • In summary, this submission seeks the following outcomes:
    • A compensation and care package for all those affected by FVS;
    • A Judge led Public Inquiry into the regulation and licensing of medical products within the UK, focussing upon FVS as a case study; and
    • Scrutiny of how consumers can be better safeguarded and, if necessary, compensated, in a revised regulatory framework post-Brexit.

Download the whole document via FACSaware group on Facebook.

 

Valproate Medicine : Chronology of Research, Regulation and Knowledge

Fetal Valproate Syndrome : The “Information Gap”, Infographic by FACSaware

Infographic showing the chronology of what happened and when.

It exposes the gaps in who received information and the lack of additional regulation.

Sources FACSaware group on Facebook.

Valproate should have a restricted licence for prescribing only by nominated prescribers and on a named patient basis

Weighing the risks of valproate in women who could become pregnant

A baby in utero looking out and seeing his/her mother taking valproate is a scenario not to be contemplated. It could be equated to someone being forced to take poison against their will. The result is almost certainly organ damage including brain damage. Beautiful healthy babies forced to ingest poison against their will and ending up with lifelong disability. In cold stark terms this is what is being discussed. A class action by such affected individuals once born and once endowed with human rights and protection, would certainly sober up the situation and rein in any distracted prescribing practices.

This graphic way of reasoning does not take into account the mother’s illness and need for safe treatment, nor the prescribing doctor’s dilemma with imperfect treatments and unpredictable risks to the mother either from epilepsy or bipolar illness. However it is outrageous that thousands of women in Europe and USA are inadvertently taking valproate without knowing what the risks are. A “named patient only” regime by designated prescribers only, may be a safer way to go.
Large court settlements have been awarded to “valproate babies” and it is a sad day for mother and child to have to come to this end, instead of what should and maybe could have been a much happier day (healthy baby and mother). Inevitably due to human error accidents will happen, but what is truly insupportable is that young women and their babies wake up to a sad situation and say “but no body told us.

Babies in utero are human beings, and at present in most jurisdictions their human rights are put on hold until they reach their majority – birth. How would anyone feel about being disabled for life because they were helplessly poisoned while awaiting their inheritance? The same could be said of foetal alcohol people who were poisoned in utero. A class action by those negligently harmed by valproate or any toxin in utero would focus medical and pharmacological opinion on what safeguards need to be in place. Valproate should have a restricted licence for prescribing only by nominated prescribers and on a named patient basis.

Eugene G Breen‘s response to : “Despite international consensus on the harmful effects of valproate during pregnancy, women should not be denied the human right to make their own decisions after fully informed discussion, say Heather Angus-Leppan and Rebecca Liu
Physician/Psychiatrist
62/63 Eccles St Dublin 7, Ireland

2018 measures to avoid valproate exposure in pregnancy recommended by the European Medicines Agency

PRAC new restrictions on valproate use; pregnancy prevention programme to be put in place

The European Medicines Agency’s experts in medicines safety, the Pharmacovigilance Risk Assessment Committee (PRAC) are recommending new measures to avoid exposure of babies to valproate medicines in the womb. Babies exposed are at risk of malformations and developmental problems.

Main measures recommended by the PRAC

Where licensed for migraine or bipolar disorder

  • In pregnancy – valproate must not be used.
  • In female patients from the time they become able to have children – valproate must not be used unless the conditions of a new pregnancy prevention programme (see below) are met.

For epilepsy

  • In pregnancy – valproate must not be used. However it is recognised that for some women with epilepsy it may not be possible to stop valproate and they may have to continue treatment (with appropriate specialist care) in pregnancy.
  • In female patients from the time they become able to have children – valproate must not be used unless the conditions of the new pregnancy prevention programme are met.

Drugs Packaging

  • The PRAC has also recommended that the outer packaging of all valproate medicines must include a visual warning about the risks in pregnancy. In addition to boxed text, this may include a symbol/pictogram, with the details to be adapted at national level.
  • A patient reminder card will also be attached to the outer package for pharmacists to discuss with the patient each time the medicine is dispensed.
  • Companies that market valproate should also provide updated educational materials in the form of guides for healthcare professionals and patients.

New valproate pregnancy prevention programme

Assessing patients for the potential of becoming pregnant, and involving the patient in evaluating her individual circumstances and supporting informed decision making, pregnancy tests before starting and during treatment as needed, counselling patients about the risks of valproate treatment, explaining the need for effective contraception throughout treatment, carrying out reviews of treatment by a specialist at least annually, introduction of a new risk acknowledgement form that patients and prescribers will go through at each such review to confirm that appropriate advice has been given and understood.

Read the full press release.

Mise en garde, boîtes de Dépakote®

L’ansm agit au nom de l’Etat “pour des produits de santé sûrs, efficaces et innovants”

Récents pictogramme et mise en garde sur les boîtes dépakote®.

Image via l’ansm (agence nationale de sécurité du médicament et des produits de santé) sur Twitter.

Valproate : le formulaire d’accord de soins utilisé seulement une fois sur deux

Médicaments contenant du valproate : le niveau d’application des conditions de prescription et de délivrance est insuffisant

Plusieurs mesures ont été mises en place par l’ANSM depuis 2015 afin de réduire les risques liés à l’utilisation pendant la grossesse des médicaments contenant du valproate ou un dérivé (Depakine, Depakine Chrono 500, Micropakine, et génériques, Depakote, Depamide) et en particulier une démarche sécurisée de prescription et de délivrance. Cette démarche repose sur la présentation en pharmacie pour les patientes d’un formulaire d’accord de soin co-signé avec le médecin spécialiste associé à une ordonnance de ce spécialiste datant de moins d’un an. L’ANSM, en collaboration avec l’Ordre des pharmaciens, a demandé à Sanofi de réaliser une étude pour s’assurer de la bonne application de ces conditions de prescription et de délivrance (CPD).

” … le respect des conditions de prescription et délivrance était de l’ordre de 31% en 2016. Il n’atteint que 47% en 2017. … Le formulaire d’accord de soins n’était présenté que pour 50% des dispensations en 2017 (33% en 2016)… ”

Les résultats de l’étude montrent que les CPD ne sont pas suffisamment respectées.

“Actuellement, tout n’est pas fait pour éviter le valproate chez la femme enceinte. Il faut que l’information soit la plus répandue possible”

Dominique Martin, directeur général de l’ANSM.

L’utilisation des médicaments contenant du valproate ou un dérivé nécessite une attention particulière de l’ensemble des professionnels de santé et une information complète des patientes. En effet, ces médicaments présentent des risques importants de malformation et de troubles neuro-développementaux pour les enfants s’ils sont utilisés pendant la grossesse.

Communiqués ANSM
  • Médicaments contenant du valproate : le niveau d’application des conditions de prescription et de délivrance est insuffisant – Communiqué, ansm, 20/10/2017.
  • Dossier Valproate et dérivés de l’ANSM.
Articles de Presse:

Valproate Drug Harms : EMA Public Hearing in London

Many pregnant women are still unaware of epilepsy drug risks

The public hearing was part of a review of the safety of using valproate-containing medicines in women and girls who are pregnant or of childbearing age by EMA’s Pharmacovigilance Risk Assessment Committee (PRAC). There is a risk of malformations and neurodevelopmental problems in babies who are exposed to valproate in the womb, and the review follows concerns that European Union (EU)-wide risk minimisation measures currently in place do not seem to be sufficiently effective.

Warnings to young women who might become pregnant that the epilepsy drug sodium valproate could cause birth defects and developmental problems in their babies could have been made public more than 40 years ago, according to campaigners.

EMA Public Hearing about Drug Valproate Use in Pregnancy

Pregnant women still unaware of epilepsy drug risks

Was there a deliberate decision not to publish Valproate’s risks ?

The public hearing was part of a review of the safety of using valproate-containing medicines in women and girls who are pregnant or of childbearing age by EMA’s Pharmacovigilance Risk Assessment Committee (PRAC). There is a risk of malformations and neurodevelopmental problems in babies who are exposed to valproate in the womb, and the review follows concerns that European Union (EU)-wide risk minimisation measures currently in place do not seem to be sufficiently effective.

Warnings to young women who might become pregnant that the epilepsy drug sodium valproate could cause birth defects and developmental problems in their babies could have been made public more than 40 years ago, according to campaigners.

Epilepsy drug warnings DO NOT reach enough women, 2017 survey finds

Almost 70% of women surveyed about a powerful epilepsy drug have not received new safety warnings about the dangers of taking it during pregnancy

Two thirds of women who take the antiepileptic drug sodium valproate said they had not received new safety warnings about the dangers of taking it during pregnancy, a survey carried out by epilepsy charities has found. A similar survey last year found that half of women taking the drug were unaware it could harm their fetus.

The new results are to be presented at a public hearing on the safety of valproate drugs organised by the European Medicines Agency on 26 September in London. …

… continue reading Women still not being told about pregnancy risks of valproate on The BMJ doi.org/10.1136/bmj.j4426, published 22 September 2017.
Featured image credit @bmj_latest.

Depakine : un silence coupable

Envoyé Spécial 16 mars 2017 : Enquête sur le Scandale de la Dépakine

Cet anti-épileptique est accusé d’avoir provoqué de graves malformations sur les enfants exposés in utero. Retour sur un scandale sanitaire et sur l’inertie des autorités de santé.

En savoir plus
  • Envoyé Spécial, émission du 16/03/2017 – Dépakine, le silence des médecins – Enquête sur le scandale de la Dépakine, un anti-épileptique pointé du doigt pour ses effets secondaires : chez la femme enceinte, il peut entraîner des malformations et des troubles neurologiques chez le nouveau-né. Vidéo publiée le 17 mars 2017 par la chaine APESAC.
  • Regardez cette liste de vidéos sur les médias et médicaments sur notre chaine YouTube.