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JAB INJURY UNDERREPORTING




BY STEVE CHAPLIN


In 2018, the Yellow Card Scheme reported a decline in the number of reported suspected adverse drug reactions, particularly among doctors and pharmacists. This article discusses the possible reasons for this and the action the MHRA is taking to improve reporting rates.


The Medicines and Healthcare products Regulatory Agency (MHRA) recently appealed to health professionals to help reverse the decline in reporting of suspected adverse drug reactions.1 It said that reporting rates had doubled to 27,000–28,000 between 2009 and 2017 but 2018 had seen a marked reversal of fortunes (see Figure 1). Numerically, there were 1364 fewer Yellow Card reports in 2018 than in 2017. Compared with 2017 figures, the percentage fall was greatest among those describing themselves as physicians (down 46%), middling among community and hospital pharmacists (down 14% and 11% respectively) and smaller among nurses, hospital doctors and other hospital health professionals (down 5%, 7% and 7% respectively). Although the percentage decrease in reports was lower for GPs than for other groups (4%), this still represented 280 fewer reports in 2018. One bad year doesn’t necessarily spell catastrophe, so why has the MHRA reacted so strongly?


Yellow Card history

It’s hard to believe, in this era of the far-reaching European Medicines Agency (EMA) and the high cost of clinical trials (consuming 51% of all research and development spending in 2016) and regulatory submission (consuming 7.9%),2 that there was once a time of no regulation at all. Thalidomide changed all that. First marketed in 1956 in Germany and in the UK in 1958, and strongly promoted for morning sickness in early pregnancy, it caused 10,000 cases of limb reduction deformities and internal malformations, of which 500 cases occurred in the UK before it was withdrawn at the end of 1961.3 The UK government set up an inquiry, which recommended the establishment of a Committee on Safety of Drugs (later the Committee on Safety of Medicines, CSM) with a remit of monitoring drug toxicity, clinical trials and therapeutic efficacy and safety. Its first Chair, Sir Derrick Dunlop, asked Bill Inman, a doctor at the Ministry of Health, to develop a system by which drug safety could be monitored.4 He devised the Yellow Card Scheme, which was launched in 1964.


Principles

The MHRA Yellow Card Scheme is a voluntary system of spontaneous reporting of suspected adverse drug reactions, initially by doctors and dentists on a highly visible card form. The two key concepts are ‘spontaneous’ and ‘suspected’. The reports are spontaneous because they are not actively sought as part of a clinical trial but identified as they come to attention in clinical practice. There is therefore no prejudgement about which medicines should be monitored (though attention soon focused on medicines launched less than two years earlier) or which signs and symptoms to look out for, and no formal preselection of patients according to inclusion and exclusion criteria. Reporting suspected reactions avoids the burden on the reporting clinician to establish or even believe causality, allowing attribution to depend on the accumulation of sufficient cases. By casting its net so widely, the scheme aims to tackle the major failing of clinical trials as a mechanism for evaluating safety. By the time a drug is licensed, a few thousand people at most will have been exposed to it, and those individuals would have been carefully selected to minimise risk. Such numbers are sufficient to identify common adverse events, such as the relatively mild and predictable effects due to the drug’s mechanism of action, but far too low to detect potentially devastating and unpredictable rare events within a timeframe of a few years. Rare events are, by their nature, unsuspected and can only be detected by monitoring everyone who is taking the drug. Furthermore, clinical trials are short in relation to the duration of treatment with medicines for long-term conditions whereas a spontaneous scheme can monitor years of use. Most regulatory authorities now use spontaneous event monitoring as part of their obligations for pharmacovigilance, contributing data to the EMA’s EudraVigilance database.4


Tackling under-reporting

The reliability of detecting a new safety signal with a spontaneous system like the Yellow Card Scheme depends largely on the volume of reports it receives. ‘Rare’ adverse events are defined as those occurring in 1/1000 to 1/10,000 patients. The number of reports needed to highlight a potential problem depends on how clearly the event stands out from the background noise of real-world medicine and whether they are consistent with evidence from elsewhere (eg the limited experience in clinical trials, published case reports). The number of reports received must then be evaluated in the context of how many people have been exposed (or prescription numbers, as a surrogate) and whether any risk factors can be discerned. But all spontaneous reporting schemes have a problem with numbers: the MHRA itself says that only 10% of serious reactions and 2–4% of all reactions are reported using the Yellow Card Scheme.1 This means that most iatrogenic morbidity goes unreported. It’s not as if adverse reactions are unusual. In Europe, published studies show that 3–5% of hospital admissions are due to an adverse reaction, that 10% of inpatients experience an adverse reaction during their stay, and adverse reactions may affect up to 8% of outpatients.5 The downturn in reporting in 2018 is therefore a concern. Over time, the CSM/MHRA has tackled under-reporting head-on. It broadened the range of people eligible to use the scheme to include nurses, pharmacists, other health professionals and, from 2005, patients themselves. Electronic reporting (for data from clinical trials), telephone reporting, and now an app, have also been introduced to make reporting easier. All these initiatives contributed to higher reporting rates. From 2012, reports were accepted for events associated with medication error, offlabel use, misuse and abuse, and new legislation required pharmaceutical companies to submit reports from consumers and non-healthcare professionals,6 fuelling further growth in reporting. The MHRA has made use of online media too. As well as its website (https://yellowcard.mhra.gov.uk), it has a Facebook page (@mhragovuk) and a Twitter feed (@MHRAgovuk) where it promotes the Yellow Card Scheme. As Figure 1 shows, these initiatives to encourage public participation have proved a success.


Why is reporting in decline?

The MHRA does not speculate on the reasons behind the fall in reporting in 2018, which was most noticeable among doctors and pharmacists, and there is no obvious reason for it. Research from the 1990s suggests one possibility: lack of time was cited as a reason for not reporting to it by about one-third of GPs and senior hospital doctors, and one-fifth of junior doctors in one UK region;7 and by 21% of a sample of registered UK doctors.8 This is a problem not likely to improve in an NHS facing a shortage of doctors in primary and secondary care.9 A similar problem was reported more recently among community pharmacists.10 Another possibility is that the actions arising from Yellow Card data may be perceived as having a low profile or small impact. The MHRA has published a list of 24 examples of safety issues identified by the scheme between 2013 and 2016.11 Many concerned drugs used by specialists (therefore being of narrow interest) and, of more widely used drugs such as proton pump inhibitors, warfarin or Gaviscon, the result was to strengthen the warnings in the product information. That’s not to argue that these actions were not worthwhile, just unspectacular and unlikely to garner the wider attention the scheme needs to generate enthusiasm.


Summary

The Yellow Card Scheme has been doing well in recent years, particularly among the public, but the increase in reporting rates achieved in 2017 was wiped out in 2018. It is not known whether this is a blip or the start of a trend, but numbers are critical to the success of a scheme that requires a high reporting rate and has always struggled to deliver. The MHRA’s latest message reminds everyone of the value of Yellow Cards and when and how to make a report, at individual and organisational levels


References


1. Medicines and Healthcare products Regulatory Agency.

Yellow Card: please help to reverse the decline in reporting of suspected adverse drug reactions.

May 2019. Available from: https://www.gov.uk/ drug-safety-update/yellow-card-please-helpto-reverse-the-decline-in-reporting-of-suspected-adverse-drug-reactions 2.


Association of the British Pharmaceutical Industry. Global pharmaceutical R&D expenditure along the development cycle. Distribution of R&D expenditure by Phase of R&D. Available from: http://www.abpi. org.uk/facts-and-figures/science-andinnovation/global-pharmaceutical-rdexpenditure-along-the-development-cycle [accessed August 2019]


3. Vargesson N. Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res C Embryo Today 2015;105:140– 56.


4. European Medicines Agency. European database of suspected adverse drug reaction reports. Available from: http://www. adrreports.eu [accessed August 2019]


5. Bouvy JC, et al. Epidemiology of adverse drug reactions in Europe: a review of recent observational studies. Drug Saf 2015;38:437–53.


6. Medicines and Healthcare products Regulatory Agency. Trends in UK spontaneous adverse drug reaction (ADR) reporting between 2008–2012. Available from: https://webarchive.nationalarchives.gov. uk/20141206193208/http://www.mhra. gov.uk/home/groups/pl-p/documents/ websiteresources/con408250.pdf


7. Bateman DN, et al. Attitudes to adverse drug reaction reporting in the Northern Region. Br J Clin Pharmacol 1992;34:421–6.


8. Belton KJ, et al. Attitudinal survey of adverse drug reaction reporting by medical practitioners in the United Kingdom. Br J Clin Pharmacol 1995;39:223–6.


9. British Medical Association. Staffing crisis in NHS laid bare, as new BMA analysis shows that three quarters of medical specialities face shortage of doctors.


Press release. 21 September 2017. Available from: https:// www.bma.org.uk/news/media-centre/ press-releases/2017/september/staffingcrisis-in-nhs-laid-bare


10. Cheema E, et al. Barriers to reporting of adverse drugs reactions: a cross sectional study among community pharmacists in United Kingdom. Pharmacy Pract 2017;15:931.


11. Medicines and Healthcare products Regulatory Agency. Contribution of Yellow Cards to identifying safety issues. Available from: https://assets.publishing.service.gov. uk/government/uploads/system/uploads/ attachment_data/file/731851/Contribution_ of_Yellow_Cards_to_identifying_safety_ issues.pdf [accessed August 2019] Declaration of interests None to declare. Steve Chaplin is a medical writer specialising in therapeutics


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