Blood clot fears: how misapplication of the precautionary principle may undermine public trust in vaccines.
The arrival of effective vaccines against COVID-19 has been one of the few good news stories of the pandemic. However, communicating the safety of vaccines has long been difficult, as shown by most countries having some level of vaccine hesitancy, including hesitancy towards COVID-19 vaccines specifically.
Just as regulatory authorities – such as the European Medicines Agency (EMA) and the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) – had systems in place to assess if the vaccines worked, so too did they create carefully thought through vaccine safety plans to deal with any safety signals arising after the vaccines’ deployment.
However, this week the EU’s plan for vaccine safety was thrown into confusion. At least 12 EU states have suspended use of the AstraZeneca COVID-19 vaccine because of concerns of a possible link between the vaccine and blood clots. These concerns are registered in spontaneous reports, where a patient or healthcare professional suspects a link between an adverse event they’ve witnessed and the vaccine. Reporters do not have to be sure of a link, and these reports do not prove there’s any association between the vaccine and the event.
The number of blood clots reported among people taking the vaccine, assuming even a fairly high level of under-reporting, does not seem to be higher than would be expected in the general population. Many things happen after vaccination that would have happened without the vaccine.
That said, in some countries, such as Norway and Germany, an extremely rare form of blood clot in the brain called cerebral venous sinus thrombosis (CVST) has been reported. Incidence of CVST in the normal population is hard to measure, although Johns Hopkins Medicine has said it may affect around one in every 200,000 people each year. In Germany, the incidence of CVST post vaccination has exceeded this rate, so the EMA is carefully examining each case to look for possible contributing factors.
But so far, the World Health Organization, EMA, MHRA and AstraZeneca have all said that there is no evidence of a causal link between the vaccine and clots, and the EMA has said it is firmly convinced that the benefits of the vaccine far outweigh the risks. Yet if this is the case, why have the advisory committees of some EU states decided to suspend the vaccine?
A good tool badly used
A major reason appears to be the misapplication of the precautionary principle. This is where you take anticipatory action to avoid potential harm, even when the evidence around that harm is uncertain. It can be a useful tool when needing to make a decision in a situation that includes risk and uncertainty.
The precautionary principle evolved from critiques of risk assessments that were based on scientific methods. These, it was argued, were too conservative, requiring too much evidence to prove risk, and so perhaps biased towards seeing an absence of harms.
The earliest forms of the principle are thought to have arisen in West Germany in the 1970s, where “Vorsorgeprinzip” was used in environmental policy to limit actions that were suspected but not proven to cause ecological damage. Past case studies of harms for which there were early warnings but only later actual evidence – such as asbestos – show the sorts of outcomes that the principle can potentially help avoid.
Regarding pausing the AstraZeneca vaccine, the principle has been cited explicitly by some EU states. Others have invoked it implicitly in interviews, saying they will “err on the side of caution”. However, there are trade-offs – and that’s the primary reason why we can say the principle has been misapplied.
COVID-19 vaccines are being used to prevent deaths. Decisions to suspend their use will slow vaccination campaigns by reducing vaccine availability. Suspensions might also affect vaccine uptake by sparking wider concerns about safety among the public. Confidence in the AstraZeneca vaccine is already relatively low in Europe, with high-profile comments about its effectiveness having dented uptake.
So rather than avoiding risk, the principle has instead moved countries away from one risk (blood clots) towards another (lower vaccine coverage). The impact of the latter could be much larger.
Even if this weren’t the case, the principle has still, arguably, been misapplied. Plans for COVID-19 vaccine safety monitoring until now have been based around rigorous scientific evaluation of safety signals, careful communications to ensure vaccine hesitancy is not increased, and ensuring that signals are investigated to examine if any risk requires regulatory action.
Because potential safety signals arise often in vaccine and drug safety, with many being false signals, the precautionary principle doesn’t fit with such plans. It is too sensitive, and in the case of COVID-19 vaccines, doesn’t initiate any safety assessments that aren’t already happening.
As we have seen this week, misapplication of the precautionary principle leads to erratic decision making that fails to do the very thing it intends to: lower risk. The decisions made could potentially have long-term health effects both in the EU and globally. As a result, one might say we need to be more cautious about the application of the precautionary principle.
Post publication note
This article was first published at The Conversation on March 16th 2021. Since it was published the information about the risks associated with the AstraZeneca vaccine have become clearer, although the central argument of this piece still stands.
A few years ago I set up a small group teaching session for pharmacy students based around a fatal adverse drug reaction, using a video developed by the World Health Organisation. This year it is an inter-professional education event run by pharmacy and nursing academics. Sadly it will be taking place over Zoom, rather in the building you can see above, but that has made timetabling an inter-professional event easier than normal.
In the past I have used the event to discuss both technical and communication issues that led to the patient’s death, and for the impact the video has on first year students to raise the issues of harm in clinical practice. While revising the preparatory material, I decided to make it less technically focused, and more focused on the impact of the event and team communications. I’ve also given some limited pre-reading to enable a better understanding of the video dramatisation they are going to watch. It’s written in a less academic style than I normally use, based more around story telling. Here is the text I wrote for the teaching session, just in case it is of interest to people. For those who want an in-depth look at the case involved, you can read the Toft Report here in PDF format.
Just an Ordinary Day
Every day thousands of healthcare professionals go to work.
To earn a living. To make a difference. To help people.
And every day healthcare professionals are involved in incidents that lead to patient harm, and in some cases deaths.
With very rare exceptions, none of them went to work to do this.
Here is a story.
In the 1960s, a team of scientists at Eli Lilly in the US investigated a naturally occurring chemical from the rosy periwinkle plant. The chemical was called vincristine, and they tried to use it to treat diabetes.
A press photo circa 1961 showing some members of Eli Lilly’s vincristine research team By Crossgates - Own work, CC BY-SA 4.0.
It didn’t work.
But it did cause myelosuppression (suppression of the bone marrow’s ability to produce blood cells).
They tested it in leukaemia.
Vincristine became a key drug in many cancer regimes. Its use in leukaemia and lymphoma has saved many lives.
Fast forward to 2001
A 18 year old boy in Nottingham had successfully been treated for lymphoblastic leukaemia. He was in remission, and in the maintenance phase of his chemotherapy. This consisted of intravenous vincristine and intrathecal (into the spinal fluid) cytosine every three months.
Wayne Jowett had been under treatment for 2 years, but he was out of the other end. His treatment had given him a future.
But a terrible mistake would take all this from him.
On the 5th of January 2001 a doctor would inject vincristine into Wayne Jowett’s spine. The vincristine worked its way up his spine progressively paralysing him. He spent the rest of his life on paediatric intensive care, dying on the 2nd of February 2001.
The doctor was charged and convicted with manslaughter, but there were multiple failings at the hospital that led to this incident. This was not the mistake of one person.
Mistakes are rarely caused by the solely by the actions of one person. Systems of work, the way we communicate with each other, the design of equipment we use can all conspire to put those at the point of care in unsafe positions which can can harm those we seek to care for.
Like Wayne Jowett.
This session will use a World Health Organisation dramatised case similar to that of Wayne Jowett to highlight how such errors can occur. Together you will explore how the event happened, and how things could be improved to avoid such events in future. The specifics of the drugs matter less, than how the mistake arose.
What you need to do
During the session you will watch a video of the dramatised event. You can use this document to help you analyse the events (read it before the session). Use a scrap of paper to jot things down to avoid using your computer.
You will then work as a mixed group of nursing and pharmacy students to look at the event, to find all the contributory factors that led to this event, and to look at the team working between the various professionals in dramatisation. This is a great opportunity to see different perspectives on each others professions as depicted in the video, and to learn from each other.
In order to protect each other, yourselves, and your patients from future errors.
Our research group has a new paper (Open Access) looking at the experiences of multi-professional prescribers using an electronic prescribing system. We suspected some differences between the professional groups (nurses, pharmacists, and doctors), but they all reported similar experiences. The pharmacists had some differing perspectives because of their monitoring role in prescribing, but their own experiences matched those of the other professions. Not entirely unexpected given what we know about human cognitive bias.
We present an analysis of six major interacting themes involved in the production of a prescription. Many of these echo areas found in other studies.
We conclude that:
Medical and non-medical prescribers have similar experience of prescribing errors when using CPOE, with the broad areas of concern aligned with existing published literature about medical prescribing. Causes of electronic prescribing errors are multifactorial in nature and prescribers describe how factors interact to create the conditions errors. Solutions focused on a single factor, such as system design or training, may only result in only limited impact on prescribing errors. While interventions should focus on direct CPOE issues, such as training and design, socio-technical and environmental aspects of practice remain important.
Alshahrani, F., Marriott, J.F. & Cox, A.R. A qualitative study of prescribing errors among multi-professional prescribers within an e-prescribing system. Int J Clin Pharm (2020). https://doi.org/10.1007/s11096-020-01192-0
Photo by National Cancer Institute
Medicines Safety Week: Special Medication Safety Edition of the International Journal of Pharmacy Practice
Over the past year I’ve been working on a Special Edition of the International Journal of Pharmacy Practice on focused on medication safety with some colleagues from Cardiff University. It’s been a long haul, but we have just got it out for medication safety week 2020. It has been an interesting process of filtering and reviewing papers, but I think we have an interesting mix of papers, that fit around the WHO’s global patient safety challenge.
We also have an editorial in the issue, which gives a whistle stop tour of the papers and how they fit with the WHO framework. It concludes as follows.
This Safety edition illustrates the breadth and diversity of pharmacist involvement in research on patient safety from an international perspective. A recent report from the International Pharmaceutical Federation (FIP) entitled Pharmacists’ role in ‘Medication without harm’ summarises the evidence base for pharmacists’ contributions to patient and medication safety and concludes that ‘all pharmacists may consider themselves as medication safety pharmacists — advocates for safety within the healthcare system and for each individual patient’. The contributions in the Medication Safety Special Edition aim to add positively to the evidence base for medication safety, and we hope that the increasingly important role of pharmacists in medication safety and related research is demonstrated by the range of papers included from around the world.
It’s Medicines Safety week. The twitter hashtag #medsafetyweek shows a lot of international activity to encourage awareness of the harms of medicines, with a special emphasis on the importance of everybody playing their part in reporting suspected side effects of medicines. Every report counts.
The MHRA’s Yellow Card Scheme has been established since 1964 and has just reached the milestone of having a million reports submitted. When you make a single report, you might think it won’t have great impact, but it can. The MHRA as part of today’s celebrations have highlighted the case of a single patient reporting, leading to a change in medicine information. I think this sort of story telling about the reporting of side effects is so important to encourage further reporting. It’s great to see the MHRA doing this.
However, it isn’t the only story. You might think once an individual report of a suspected side effect has been analysed, it just disappears into the haystack of reports where we are looking for those valuable needles. However, because of the way in which we find side effects in databases such as the Yellow Card Scheme, through signals of disproportionality, every existing card also helps find side effects from new reports that are submitted.
Disproportionality analysis is primarily a tool to generate hypotheses on possible causal relations between drugs and adverse effects, to be followed up by clinical assessment of the underlying individual case reports. It is based on the contrast between observed and expected numbers of reports, for any given combination of drug and adverse event.
Unlike trying to find a needle in a haystack, where the haystack is in the way, finding an adverse effect in a database requires the haystack of previously submitted reports to find a possible link between a drug and a side effect.
Those million reports continue to serve a purpose.
Every report counts. Twice.
Photograph: Photo by Idella Maeland
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