Sodium valproate and Safety Communication
Sodium valproate has been in the news recently due to its links to birth defects and the pregnancy prevention programme (PPP), introduced in April 2018, to limit its use in women and girls of child bearing potential. These risks were known when I first started working in PV, over 10 years ago, so I was surprised to see it making such big headlines. How has a well-established side-effect only recently come to the public attention, casting the industry in further bad light? This is not a piece about sodium valproate specifically, but rather the general process of risk management and communication between the industry, regulators and the public.
Valproate medicines have been in use in EU countries since 1967 and are used to treat epilepsy, bipolar disorder, and in some countries to prevent severe migraine headaches. Sodium valproate was licensed in the United Kingdom in 1972 and the datasheet noted that it was known to be teratogenic in animals, but there was no specific information on the effects in humans.
However, it wasn’t until 2014 that the European Medicines Agency (EMA) was asked to strengthen risk minimisation measures. The Medicines and Healthcare products Regulatory Agency (MHRA) added warnings to the packaging in 2016, as well as introducing a toolkit to encourage health professionals to discuss the issue with patients. In 2017 the French regulator (ANSM) requested the EMA to review the effectiveness of its 2014 recommendations, including a public hearing by the Pharmacovigilance Risk Assessment Committee (PRAC) which led to the recent 2018 new measures endorsed by the Heads of Medicines Agencies (CMDh)[1]. The MHRA announcement, for UK implementation, can be found here[2] and the risk minimisation toolkit can be found here[3].
In the interim, what was happened with monitoring of the teratogenic effects of sodium valproate? Essentially, it looks like it was business as usual for marketing authorisation holders (MAHs) and regulators working away in what, to the public, appears something of a black box. A UK registry of epilepsy pregnancies was set up in 1996[4], the National Institute for Health and Clinical Excellence (Nice) issued guidance in 2004[5] on treating epilepsy specifically citing that caution "should be advised on the use of sodium valproate by women and girls of childbearing age because of the risk of harm to the unborn child.” Everyone was ticking along doing everything they thought they should to manage the benefit-risk profile of the drug without really considering the real-world impact (or lack thereof). As recently as 2010, the MHRA were quoted in The Guardian newspaper saying[6]:
“For sodium valproate the product information advises about the potential for birth defects and recommends that any woman taking sodium valproate who is likely to become pregnant should receive specialist advice on these risks. There is also a recommendation that if taken during pregnancy sodium valproate should be used as monotherapy at the lowest effect dose.”
As far as regulators were concerned at the time, this was a well characterised side-effect and the information patients needed was out there. Clearly that has proven not to be the case. This is not to point fingers at the MHRA, I think this episode highlights the gaps throughout the treatment pathway:
· Regulators and MAHs assuming what is common knowledge within the industry has been clearly communicated outside of it. Patient Information Leaflets (PILs) etc. alone clearly do not do the job for important messages.
· Prescribing doctors have been unable or unaware they should be discussing particular issues with patients. With patients allocated just 10-minute slots to see their general practitioners (GPs) in England, is it any wonder that things get missed, especially for patients with complex needs?
· Patients either not engaged in their treatment to read the associated PILs/ leaflets etc. or not empowered enough to feel they can question when they are unsure of the meanings and implications.
Partially as a result of the coverage of sodium valproate, the UK government has announced a review of how safety and side-effect concerns for medicines and medical devices are handled by the NHS and medicine regulators[7], which has received support from the Association of the British Pharmaceutical Industry (ABPI)[8]:
"Patient safety and welfare is a primary concern for everyone in the pharmaceutical industry.
"For each and every patient, it is absolutely critical that the risks and benefits of medicines are identified, considered and continually monitored by healthcare professionals, regulators and companies alike.
"A Review which helps everyone involved in healthcare to understand how to better support patients is welcome and we look forward to seeing the announcement of the Terms of Reference in due course."
The findings of this will make for interesting reading and I suspect will not be far from the three points above. However, should the industry really just sit on its laurels until government or regulator reviews jolt it into changing how things are done?
Not just within healthcare, we are at a crossroads in the relationships between people and the companies they use. There is seemingly a growing dismissal of experts and people also have, and expect, ever greater access to information and decision-making processes. On the other hand, the standards that companies are held to are ever increasing. Social media has made companies very publicly accountable for their actions, whether to individuals, governments or regulators.
I think that often the problems of communication breakdown are exacerbated by overall company attitudes to PV whereas it’s a function that should take a position in the vanguard of bridging these gaps.
Ours is a highly regulated field, which becomes more so with every unfolding ‘scandal’. However, the ensuing media scrutiny often places parties at odds with each other limiting the opportunity to promote a coordinated message on patient safety. As a result, regulators introduce more requirements as a show of strength and companies often do little more than view them as a tick-box exercise to demonstrate that things have been done ‘properly’. Expedited reports submitted? Tick. Signal detection meeting held? Tick. It is done very much to the letter of the law, rather than the spirit. Again, this is not to denigrate individual PV departments. It’s just not a function that has been encouraged or given the freedom to innovate and go above and beyond in many company structures, because it is not perceived as providing a tangible benefit.
The 2012 EU Good Pharmacovigilance Practices (GvPs)[9] have been a huge step in the right direction, particularly modules XV (Safety Communication) and XVI and addendum (Risk minimisation measures: selection of tools and effectiveness indicators; and Educational materials). They provide a framework within which innovative ideas to protect patient safety can be developed and communicated to all stakeholders. Giving MAHs the freedom to develop risk minimisation materials and measures of effectiveness that work to increase patient safety, as well as for the company, opens a new area for innovation. The next step is for PV departments to be encouraged internally to proactively explore the opportunities that this affords, rather than remaining reactive, or doing the same thing over and over because that’s what worked last time and the regulators have previously approved a particular approach.
For instance, the sodium valproate risk minimisation materials (RMM), are a great resource for patients and healthcare professionals. Simple and clear, there is no reason why they should not have the desired effect and requiring the patient to sign a checklist confirming their understanding is a rare step that should guarantee the patient’s attention and engagement. However, the approach will become less effective as more products require similar ‘read and understood’ documentation. Patients generally (and I include myself in this), don’t read PILs to understand the risks of the products they are taking as they are bland and difficult for lay people to fully understand. Similarly, there will be a limit to the kind of materials used for sodium valproate before patients suffer ‘RMM-fatigue’, reading and signing without really engaging. Patient consent in clinical trials is going through a similar revolution, with traditional, quite technical, patient consent documents being replaced with electronic forms, interactive software and videos. If subjects enrolling in clinical trials (who by definition must be more engaged in what they are taking than a patient in the real world) require more than bland leaflets, then real-world patients certainly will.
There is also the practical implication of increased time and resource needed from the healthcare system where it shoulders the burden of delivering the materials. Jeremy Hunt (UK Secretary of state for Health and Social Care) may point the finger at everyone else[7], but will the funds be released to enable the NHS to work with them? If RMMs add an extra 1 minute to GP consultations, that’s an extra 10% budget required. If a company can produce innovative and effective (non-promotional!) materials requiring shorter delivery time (and hence reduced budget), it will be an important differentiator to competitor versions beyond the headline cost of the product.
The reputation of the pharmaceutical industry and the publics’ relationship with it is something I find myself coming back to time and time again. It needs to shed itself of the image of being a secretive club where the patient is considered as nothing more than a cash cow. The stereotype isn’t true with patient safety deeply ingrained, but it’s not successfully communicated to the public. Sodium valproate isn’t a scandal because it is teratogenic, but because those at risk of the effects weren’t appropriately informed. RMMs, the availability of summary risk management plans (RMPs) on the EMA website (although increasing awareness of these is required) etc. all begin to demonstrate that the industry is listening and increasing transparency, but we can’t stand still and wait for the next scandal to change how we do things.
Our job in PV is not just to make sure our products are safe, but also that we have the confidence of the public. The rise of automation, global company integration and harmonisation is driving efficiency and allows PV to do more with less and add real value. Communication and increasing transparency with the public should be at the forefront of this. The reputational and practical implications can have significant economic benefits, from influencing benefit-cost balances to reducing the chances of, and mitigating costs associated with, future scandals. A scenario where everyone’s a winner.
Drive Phase PV is a pharmacovigilance consultancy and provider of pharmacovigilance services, supporting patient safety throughout the life-cycle of our clients' products. Contact us to discuss optimising your PV communication processes. Whether via SOP development or provision of training, we deliver a tailored packaged to seamlessly fit to your company structure and strategy.
3. https://www.gov.uk/guidance/valproate-use-by-women-and-girls
4. http://www.epilepsyandpregnancy.co.uk/
5. https://www.nice.org.uk/guidance/cg137/chapter/1-guidance#sodium-valproate (replacing https://www.nice.org.uk/guidance/cg20)
6. https://www.theguardian.com/society/2010/nov/08/epilim-anti-epilepsy-drug