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Drug safety: EudraVigilance and an evolving system

Published on 12/03/18 at 12:15pm

The importance of drug safety is back in the news due to sodium valproate and Ben Hargreaves examines how the EMA is ensuring that the issue is at the forefront of the agency’s work.

The EudraVigilance system came into place in the EU in 2001, designed to act as a central database that could be reported to and house data of suspected adverse drug events. The system is contacted both when suspected adverse events are encountered in the clinical trial setting and following marketing approval of products.

The aim of the system is to build up a profile of drugs all the way through development so that, should warning signs begin to appear across EU nations, the Pharmacovigilance Risk Assessment Committee (PRAC) is able to evaluate the signals and take appropriate action.

EudraVigilance connects all stakeholders in healthcare, with marketing authorisation holders (MAHs), regulatory authorities, academia, healthcare professionals and patients able to access data within the system.

When outlining the benefits of the enhanced EudraVigilance system, the EMA highlighted several key areas:

  • Simplified reporting of individual case safety reports (ICSR) and reduced duplication of efforts, as MAHs no longer have to provide these reports to national competent authorities, but can send them directly to EudraVigilance
  • Better detection of new or changing safety issues, enabling rapid action by regulators to protect public health
  • Enhanced interoperability based on the use of the ISO/ICH agreed standard for individual case safety reports
  • Better searchability and more efficient data analysis
  • Increased system capacity to support large volumes of users and reports
  • More efficient collaboration with the World Health Organization as EMA will make the reports of individual cases of suspected adverse reactions within the EEA available to the WHO Uppsala Monitoring Centre directly from EudraVigilance; Member States will no longer need to carry out this task

ICSRs are how all stakeholders communicate regarding adverse events, including any problems that occur with products and how consumer complaints are registered. As mentioned in the EMA’s breakdown, ICSRs no longer have to be submitted by MAHs to national authorities and then duplicated to be submitted to the EMA. Instead, EudraVigilance will do the legwork for MAHs by sharing the information simultaneously to all necessary stakeholders. The system allows for a far more efficient system for those involved.

Though the process should simplify matters for all stakeholders, there is still an ongoing learning curve for those involved to reconcile the differences of the new system. The EMA will provide MAHs and clinical trial sponsors in the EEA with the tools to learn more about the system and how to most effectively utilise it, by providing e-learning and face-to-face trainings, webinars and information days.

Road bumps in the future

The process of implementing the new system has gone off seemingly seamlessly, with only certain periods of downtime of the system leading up to the change over date of 21 November 2017, and even these periods being covered by alternative reporting arrangements.

So, with all going well, what could cause a hitch in the future? As with anything EMA-related at the moment, the source of most of the agency’s headaches is Brexit; although, in this case, the onus is on the UK to arrange for its future beyond the EU. Three unnamed senior government figures told the Financial Times that the UK is pushing to stay within the EMA post-Brexit. This would mean that the UK would still have access to the EudraVigilance system and would not have to craft its own system for reporting safety issues.

This seems the most reasonable path to take, especially given that the MHRA currently takes on 40% of the workload of the EMA. This would allow the EMA to still tap into the UK’s knowledge-base in the area and call on its support for drug regulation. However, there are numerous signs that the agency is bolstering its staff numbers to avoid being used as a political football as part of the Brexit negotiations. The EMA has already stated that it is planning for a form of hard-Brexit: it announced in a press release back in April 2017 that “work will now start on the basis of the scenario that foresees that the UK will not participate in the work of EMA and European regulatory system as of 30 March 2019”.

As part of this process, the EMA has been encouraging recruitment from its other agencies. The Danish Medicines Agency, for instance, has already posted that it is looking to up its headcount by more than 20%. The same was seen by Spain’s medicines agency, with it looking to recruit a further 40 staff members to pick up the slack left by an EMA unable to utilise the MHRA’s workforce.

The EMA’s finalisation of its headquarters, in a move to Amsterdam, has cleared up one of the major questions that was hanging over the agency. Now, the next issue will be to ensure a smooth transition when the move takes places in 2019. This will be a test of how efficiently the agency will be able transpose its IT interface in a frictionless move to ensure that EudraVigilance is still operational during the transition period. This will be a major test and the biggest one that the EMA has faced in its short history.

Preventing tragedies

The updated Eudravigilance system is designed to ensure safety signals are received and can be acted on with the greatest urgency possible. Incidents of drugs exhibiting new safety signals after having been approved are now, thankfully, few and far between due to the work refining the approval process by the EMA.

There are cases of pharmaceutical drugs reaching the attention and lexicon of the general public. Historically, one such case is the thalidomide scandal that rocked the medical establishment in the 1950s and 1960s, even continuing into the 1970s in certain countries such as Spain. The drug was widely prescribed to pregnant women for the treatment of morning sickness, only for numerous cases of birth abnormalities to occur.

The disastrous impact of the drug on many families led to many changes to drug regulations globally, with the FDA reacting by strengthening its regulatory and scientific basis for approving drugs. This led to the agency making amendments to the Federal Food, Drug and Cosmetic Act that meant companies had to prove that drugs were both safe and effective. In addition, the companies were tasked with monitoring safety reports that emerged after their products had the market – one of the precursors to the EudraVigilance system.

The disaster led to the creation of the Committee on Safety of Drugs (CSD) in the UK, and similar organisations were set up across Europe to prevent such a scandal occurring again. The CSD had an agreement with the pharmaceutical industry that no drug it deemed unsafe could be put into clinical trials or marketed to the public.

The number of safety measures that were introduced has meant that there has been an equivalent drop in the number of drugs reported to be unsafe. However, this has the paradoxical effect of drawing a huge amount of attention to cases where drugs do begin to have worrying side-effects.

Breaking new ground

The latest case bears some worrying similarities to the thalidomide scandal and has been regarded so seriously that it has been debated in the UK’s Houses of Parliament and resulted in the first convening of an EMA public debate on the issue.

The drug is sodium valproate and its use is in sufferers of epilepsy; the treatment is a last resort that can be one of the few drugs that is able to manage symptoms for sufferers. It is then a very important treatment, but it is also known to be dangerous for pregnant women to continue taking the treatment.

A number of children have been born with birth defects as a result of the treatment, despite the risks of the drug having been known for the last four decades. During the EMA public hearing on the drug, Catherine Cox of the Fetal Anti-Convulsant Syndrome Association suggested that the risks of the drug were purposely kept from the public: “These warnings could have and should have been given in 1974 […] However, there was a deliberate decision not to publish them”.

Cox was referencing a letter delivered to health professionals that noted that it had been found to be potentially harmful human foetuses, but was kept quiet to avoid spreading fear over the drug. Healthcare professionals were warned that: “This compound has been shown to be teratogenic in animals, meaning it could harm the human foetus.”

Getting the conversation started

Pharmafocus spoke to Chantal Spittles, PR Manager at Epilepsy Action, about the fight to spread awareness of the potential risks posed by the drug to women planning a family. Spittles explained about the impact of the treatment: “This has been going on for a long, long time and a lot of mothers have been sharing their stories about experiences they’ve had. When women have babies born with developmental delays or birth defects as a result of sodium valproate, it is not often evident that that is the case from birth; it can be a few years before it comes to light – that obviously has a lifelong impact for the mothers and the child as well.

“We know that there is not enough awareness of the risks associated with taking the drug so we carried out a survey last year, in conjunction with two other epilepsy charities, and we found that 18% of women taking the drug aren’t aware or weren’t aware of the risks of birth defects when taking valproate. It was a survey of over 2,000 women, aged 16 to 50, from childbearing age to beyond that, women aren’t aware of how risky taking the drug can be.

“Equally, we know that for a lot of women it’s the only drug that works; our view is that women should be given the right information so that they can make an informed choice when they’re younger or when it comes to planning a family as they become older.”

Spittles raised the issue that conversations about the potential effects of the drug are not being effectively held at a national level, and noted that this issue had been raised at the EMA public hearing: “We talked about the survey and the lack of awareness, the fact that those conversations aren’t happening. The MHRA published a toolkit back in February 2016 to help healthcare professionals talk to women about the issue and to provide information to patients, but 58% of women taking the drug hadn’t receive those materials. There are clearly a number of issues as to why these conversations aren’t happening.”

When asked if the EMA holding its first public hearing on the issue was indicative of the seriousness with which the agency was taking the issue, Spittles replied: “This has been a long time coming and it was a major hearing. There were a range of people giving evidence and I think, clearly, the situation isn’t working as it stands. For those mums who have had children born with developmental delays or learning difficulties, I’m sure that they would say that this has come too late. Equally, the fact that the meeting happened was encouraging. There was also a debate in UK parliament around the same time, which suggests that an awareness is now coming to light. Hopefully we can work to get the conversations happening more often and prevent other mums from going through what we know has happened, sadly, to some families already.”

Conclusions drawn from the public meeting

The EMA released its recommendations from PRAC as a response to the public hearing on the drug. PRAC announced that it is suggesting new measures to be undertaken to ensure the avoidance of any further foetal exposure to valproate medicines.

The recommendations suggest that valproate should not be used at all for the treatment of migraines or bipolar disorder during pregnancy. It suggests the same for those living with epilepsy, except under circumstances where this is not possible, in which case they must receive specialist care.

In addition, a visual warning will be placed on the outer packaging of all medicines to highlight the risks of taking the medication while pregnant. PRAC also recommends those companies that market the drug should provide updated educational materials for both healthcare professionals and patients.

There is also a new valproate pregnancy prevention programme that will assess patients on a case by case basis, providing patients with additional information to ensure that they are able to make an informed decision regarding beginning a family.

Dr Jim Morrow, founder of the UK Epilepsy and Pregnancy Register and member of Epilepsy Action’s Women’s Advisory Panel, released a statement regarding the recommendations: “We are pleased the European Medicines Agency committee has listened to people’s concerns about sodium valproate and that their recommendations reflect the seriousness of the risks involved for women with epilepsy in pregnancy.

“We know sodium valproate is an effective, easy-to-use and generally well-tolerated drug for women with epilepsy. Unfortunately, this means non-neurology specialists are more likely to prescribe it, which can mean women can take the drug without being fully aware of the risks involved or having regular reviews.

“For many women with epilepsy, sodium valproate is the only drug that works. However, we know for most others, there are equally effective and well-tolerated epilepsy medicines which are safe to use in pregnancy. We would have liked to see the guidelines state that valproate should not be prescribed as a first-line treatment without a full discussion with a specialist.

“It remains to be seen how and when these recommendations will be implemented and we would like the opportunity to meet UK decision makers to see how they will work in practice. Until things change, women and children will continue to be affected by something that can be potentially prevented.”

Though Morrow welcomes the decision with caveats, it’s clear that the PRAC recommendations should encourage greater communication between patients and doctors before, and during, taking the treatment.

For anyone concerned about the impacts of taking sodium valproate, Spittles commented that: “We have an Epilepsy Action helpline that people can ring, so if they are taking sodium valproate and thinking, ‘I might want to start a family’, and equally that it’s the only drug that works for them, they can ring us and have that chat. Ultimately, it’s up to the individual and helping them to make a decision that’s best for them. What we don’t want is that women suddenly stop taking their medication, because that’s dangerous and can lead to breakthrough seizures, which can be very dangerous. I would say, if you are concerned, speak to your doctor or healthcare professional about the options you have.

“For instance, with guidance, there’s one example that a woman was given time to wean herself off the drug so that when she came to conceive, she’d had a good year to get it out of her system. She was then monitored throughout the pregnancy and she had a healthy pregnancy, thank goodness. However, we know that some women don’t have that experience.”

As a result of the increased public attention to the case of pregnant women taking sodium valproate, the UK government announced that it would launch a review of its handling of the case. In particular, it would look at three factors: the robustness and speed of response, whether it engaged enough with those affected, and whether there needs to be a public inquiry into the case.

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