Early in March, some four weeks after the first AstraZeneca vaccine was administered in Europe, The Daily Telegraph reports that little signals – like flares – started to go off all over the continent. First in Austria, on 7 March, and days later in Denmark, Norway and Iceland, European healthcare regulators began to report small numbers of blood clots and deaths among people who had received the vaccination. Then on 15 March, Germany announced seven cases and three deaths and, like others, suspended use of the vaccine.
The AstraZeneca jab was associated with a “striking accumulation of a special form of very rare cerebral vein thrombosis in connection with a deficiency of blood platelets and bleeding,” said the Paul-Ehrlich Institut, Germanyʼs renowned medicines regulator.
But the report says, in Britain, where the AstraZeneca rollout had started a full month earlier and 11m doses had already been administered, there was nothing. On 11 March, the UK's newly sovereign Medicines and Healthcare products Regulatory Agency (MHRA) put out a statement saying it could see no evidence of a problem. “We continually monitor the safety of vaccines to ensure that the benefits outweigh any potential risks,” said Dr Phil Bryan, the MHRAʼs Vaccines Safety Lead. “Reports of blood clots received so far are not greater than the number that would have occurred naturally in the vaccinated population. “The safety of the public will always come first.”
But, The Telegraph reports, the MHRA was, it appears, wrong. An investigation by The Telegraph has established that signals had been firing unnoticed in the UKʼs Yellow Card database for at least a month, perhaps longer.
The MHRA is quoted in the report as saying: “We are aware of thromboembolic events that occurred in January, however, our first report was received in the week commencing 8 February…. we cannot disclose information about individual cases to protect patient and reporter confidentiality.”
The report says there remains no doubt the benefit of taking the AstraZeneca jab outweighs the risk now associated with the vaccine. This is the judgement not just of the MHRA but also the European Medicines Agency (EMA) and the World Health Organisation (WHO).
Nonetheless, The Telegraph reports, the MHRA faces serious questions as to why it did not detect the signals sooner. The issue is not that it has been left looking flatfooted or even that earlier detection would necessarily have altered its advice, but that the delay left it unable to shape international policy and confidence in what remains a vital vaccine in the fight against COVID-19 for the world.
So why was the MHRA slower than others to spot the early signals?
The Telegraphʼs investigation suggests the issue relates to the algorithms it had in place to interrogate the UK data and its limited access to early emerging data from Europe. Observers say this should be seen in the context of the “operational and logistical challenges” the regulator faced in the run-up to the UK formally leaving the EMA on 31 December, and the MHRA formally becoming a sovereign regulator for the first time on 1 January.
The key to fast-moving pharmacovigilance is to efficiently sift the wheat from the chaff. When a new drug launches thousands of adverse reactions start pouring into regulatory reporting systems from both patients and clinicians.
From January 4 to March 14, a total of 532 “blood system events”, including 20 deaths, came through the UK’s Yellow Card system relating to the AstraZeneca jab, according to an analysis of published MHRA data by Dr Hamid Merchant, a pharmaceutical scientist at the University of Huddersfield. There were thousands of non-blood-related reports besides.
Of the thrombotic events recorded, four related to CVST (but no deaths were recorded), 55 were non-site specific and there were clusters of 64 and 66 cases in the lungs and deep veins respectively. There were then 267 general bleeding events and six deaths, three of which resulted from cerebral haemorrhage. Finally, there were 60 cases of thrombocytopenia, including 2 deaths.
To sift such data, regulators build algorithms that must balance “sensitivity” against leg-work. The more sensitive the algorithm, the more warning signals it will throw up to investigate – and many of those labour-intensive investigations will prove fruitless.
It is not known exactly what parameters the MHRA set but it is clear they were not as sensitive as those used by some regulators in Europe.
The MHRA says it followed a principle of applying “statistical techniques which can tell us if we are seeing disproportionately more cases than we would expect to see based on what is known about background rates of illness in the absence of vaccination”. This is reflected in the regulator’s initial statement when it said clotting reports were not above normal.
But other countries turned the sensitivity gauge up to 11. “Our policy is if it is associated with a death, or very serious adverse drug reaction, we will look into it right away,” David Benee Olsen, senior advisor at the Norwegian Medicines Agency, told The Telegraph.
“I think you have to be careful with looking at the background rate, because for example in this instance, what we were told by physicians was that this rare combination, this thrombocytopenia and CVST, they had never seen this in these kinds of patients, young patients, so it was very difficult to do a background rate versus incidence rate.”
Another reason for the MHRAʼs slower reaction, suggest observers, could be that it lost access to Eudravigilance, the vast European database into which all adverse drug reactions are reported, when the UK left the orbit EMA regulation on 31 December last year.
An EMA spokesperson told The Telegraph: “The MHRA has access to the EudraVigilance gateway only. This allows them to submit cases (or to receive Northern Irish cases), but they cannot check the data in EudraVigilance. “Should the MHRA need data they will have to ask for it… In addition, they can of course look at the data published on the adverse drug reaction (ADR) website.”