Here we go again. I’m having flashbacks to Trump’s ‘bringing the light inside the body’ and injecting disinfectants as treatments for COVID-19 in April 2020. Not that Trump is always bad, Operation Warp Speed was a great success that Trump was happy to claim credit for in his first term (and he was unfairly criticised at the time). Now, he’s certain that pregnant women should not take acetaminophen/paracetamol1 (US trade name: Tylenol) unless they can’t ‘tough it out’ ,because it is comes with a ‘very increased risk of autism’.2 This is nonsense.

The appointment of Robert F. Kennedy Jr. as the US Secretary of Health and Human Services, and huge cuts to NIH funding mean Trump 2.0 is far worse for science and health than the first iteration. Despite that, there are some good things they are doing; the removal of Direct-to-Consumer Advertising (DTCA) of prescription drugs3, and changes in the management of childhood gender dysphoria more in line with the European shift to evidence-based treatments (resisted by the Biden administration — proving that anti-science positions are strongly tied to an ideological standpoints and not confined to the ‘other side’).4

However, the effect of Trump’s second administration on health, including the effects on research funding, is clearly net negative.

A longer term flashback I’m having is back to the early to mid-2000s, when post-Andrew Wakefield’s claims, the issue of autism and vaccinations was extremely prevalent on the internet pre-social media. Robert F Kennedy Jr. was equally active then, though thankfully not in the administration, and in 2005 published an article in Rolling Stone magazine called Deadly Immunity. This pushed the idea that thiomersal, a mercury containing preservative, was linked to autism. Despite retractions by Rolling Stone because of errors made by Kennedy (such as over-estimating the amount of mercury in childhood vaccines ninety-fold), the pressure grew. Kennedy wasn't the only politician asking questions, Joe Lieberman (Democratic senator) saying in 2005:

‘If you look at the statistics about the incredible increase in autism in the 1990s, it increased 4,000 percent. And at the same time we changed the requirements for the normal vaccine dosage, including a lot of the vaccines that had thiomersal in them. You’ve got to ask yourself, isn’t there a connection between these two things?’

In 2006, John Kerry (Democratic candidate for President in 2004) gave an anecdote from a delivery driver whose child was vaccinated, whose child developed autism within days. These days there may be a view that anti-vaccine views are Republican/MAGA-coded, but historically this isn’t always the case.

Multiple studies showed no effect of thiomersal on autism, and six years after it had been removed from vaccines there was no decline in autism rates. They continued to climb. It wasn't the vaccines.

I was quite active in UK-US mailing lists and blogs at the time, trying to counter anti-vaccine material on the internet. By the late 2000s, it felt like a lot of this had retreated. Who would have guessed that RFK Jr. would end up as Secretary of Health in 2025? It’s a nightmare come true.

Added snake oil

All of that previous period is covered in great depth in Paul Offit’s excellent Autism’s False Prophets (2008), which also covers another component of the vaccine-autism wars: treatments for autism. The concern about vaccine damaged children with autism led to a new industry, cures for autism. In 2004, a father and son team (the infamous Geiers) started promoting the use of Lupron (used in prostate cancer, and precocious puberty — and these days controversially for gender dysphoria). They had no training in paediatrics. They combined this with chelation therapy to try to remove the cause of autism (the mercury), as they argued mercury was bound to testosterone making it hard to chelate the mercury.

Interestingly some of the contemporary debates about the use of puberty blockers in gender dysphoria today (such as the dangers of permanent fertility issues) were happening then in these autistic children being treated for ‘vaccine damage’. So the harms of the movement weren't just a risk of reduced vaccine uptake, but additional harms from the adverse effects of quack therapies. It is therefore no surprise to find another ‘cure’, with limited evidence, for autism promoted at Trump’s press conference.

A small tactical concern concerning public trust

The FDA notice selectively points to the studies which suggest an association with paracetamol, citing a ‘considerable body of evidence about potential risks associated with acetaminophen’ although even then they say that causality has not been proven. They also make the important point that untreated fever can harm the unborn child and warn alternative drugs like aspirin and ibuprofen have ‘well documented harms’ on the unborn child. It is at least somewhat better than Trump’s press conference.

The European Medicines Agency (EMA)’s Chief Medical Officer, Steffen Thirstrup said:

“Paracetamol remains an important option to treat pain or fever in pregnant women. Our advice is based on a rigorous assessment of the available scientific data and we have found no evidence that taking paracetamol during pregnancy causes autism in children.”

And EMA recommend that ‘When needed, paracetamol can be used during pregnancy. As with any medicine for acute treatment, it should be used at the lowest effective dose, for the shortest possible time and as infrequently as possible.’

The UK’s MHRA stated that:

There is no evidence that taking paracetamol during pregnancy causes autism in children.

Paracetamol remains the recommended pain relief option for pregnant women when used as directed.

Wes Streeting, Secretary of State for Health & Social Care in the UK, used similar language on television and X.

The problem with this ‘there is no evidence’ line is that it is not true. There is evidence, the FDA are using it. People on X are using it in a community note attached to Wes Streeting’s tweet.

I rated the community note not helpful, because it isn’t.

The point is, if you say there is no evidence then that gives people an ‘in’ to counter with studies that do show an association, even if the studies are weak, and do not change the overall balance of evidence.

Carl Heneghan and Tom Jefferson have dealt with the study in the community note above in their substack, after people started sending them links to it following a previous post (also worth reading). The study is very weak, even before they start looking at the study details they note problems such as it’s non-systematic nature, and the fact a lead author has a $150,000 conflict of interest.

Social media is currently full of people, and presumably bots, posting studies that show some sort of association between paracetamol and autism, every time someone says there is ‘no evidence’ of such a link. To some that will make those saying ‘no evidence’ look dishonest.

While many will roll their eyes and go ‘Trump', eh?’ and trust their home authorities and experts, there is no need to provide this level of certainty of ‘no evidence’.

The public can deal with uncertainty.

Things are not divided into safe/non safe, there is a balanced judgement to be made based on best possible evidence.

There is nothing to be lost in saying that after examining all current evidence, including those studies that have suggested a possible link, that the balance of evidence, and stronger studies, show that that there is no proven link. Then if someone pulls up a study, however weak, that shows a possible association, you already have it covered.

Post pandemic we have a crisis in trust in experts and authorities5, and building that trust back requires trusting that the public can deal with uncertainty and the need to make judgements.

MHRA COVID vaccine reporting

In March the MHRA moved to a programme of ‘routine data publication and communication of safety concerns for COVID-19 vaccines’, with the last publication here. This makes sense now, with the vaccination programme itself in a more settled phase, compared to the rapidly changing situation in 2021 were openness and transparency needed to be upfront. Public confidence remained high with good vaccine uptake during the pandemic, despite some difficult communication issues. These included rare mild cases of myocarditis and the Thrombosis with Thrombocytopenia Syndrome (TTS) that involved unusual blood clotting events associated with low platelet counts - associated with a number of deaths.

Latest reported COVID-19 vaccine uptake as of April 6th 2023.

The above figures are remarkable, given their expected level of uptake was 75% based on prior vaccination plans. Despite social media focusing on the anti-vaccine lobby, the first dose uptake shows they had a limited effect during the critical phase of the campaign. This is despite a number of adverse effects being openly discussed,

The MHRA is continuing to monitor the safety of the vaccines and report on them, but using their routine systems. The data is online. There is a likely a trade-off between specific publications and public confidence, and a point at which the provision is feeding anti-vaccine types rather than the wider public.

Overall then, I’d say that the MHRA dealt with a complex and hopefully once in a generation (lifetime?) pharmacovigilance event relatively well. If I had to pick out one learning point, I think it is around pregnant women and the messaging around the vaccines at the start of the pandemic. There’s a long academic article on this subject, but given the higher risk for pregnant women from COVID-19 some of the earlier messaging about vaccines might have worked against later messaging.

Coroner’s reports of deaths from medicines

Since 2017 I have been involved in examine the reports of deaths related to medicines reported by Coroners on Prevention of Future Deaths reports, and most recently have published a paper with a group of us who are like-minded showing that 1 in 5 coroner-reported preventable deaths involved medicines. Currently, we are concerned that not enough is being learnt from these events, or perhaps more importantly propagated to the people who are in a position to prevent future similar events.

One of my colleagues, Dr Georgia Richards from the University of Oxford, runs a substack on this project and the Preventable Deaths Tracker website which summarises the PFD data.

Preventable Deaths Tracker

Using open data to prevent future deaths

By Dr Georgia Richards

She also recently gave a talk on this work at the 2023 Chief Coroner’s Conference, which you can listen to here:

Preventable Deaths Tracker

Live from the 2023 Chief Coroner's Conference

Listen now (29 min) | Dr Richards was an invited keynote speaker at the Chief Coroner’s Conference on Friday, 17 March 2023. In this presentation, she discusses three key publications, including: Preventable deaths involving medicines published in Drug Safety by France et al. 2023…

Listen now

3 years ago · 5 likes · Dr Georgia Richards

It’s also notable that PFDs are being used by journalists more these days. Most recently The Pharmaceutical Journal reporting on 20 deaths from obtaining drugs off the internet over the past ten years.

Of the 20 coroner’s reports warning about the supply of drugs online, 8 reports highlighted the risk of accessing medicine through online prescribers, 6 of which expressed concern that there is no requirement for them to contact the patient’s GP before prescribing.

This is particularly a problem “when somebody that’s looking to access medicines is going to a number of different providers in a short space of time”, says Duncan Rudkin, chief executive of the GPhC.

“Each of them can be doing more or less a good job at mitigating the risks associated with each transaction, but nobody’s in a position to put the whole picture together, particularly if the patient is not willing to allow their GP to be contacted … then there’s a kind of a concatenation of risks that come together.

Polypharmacy

Here’s a link to the All Wales Medicine Strategy Group’s Polypharmacy In Older People guide [PDF], which should be of interest to some readers.

Another substack readers might be interested in is Logging the World by Oliver Johnson.

Logging the World

I try to make sense of the world using numbers, and explain mathematics and statistics ideas to a general audience. My book "Numbercrunch" was published in March 2023.

By Oliver Johnson

If you find these posts interesting and think others might do so, spread the word

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That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

Share Is It Safe?

This is Medicines Safety Week, when there is a concerted push to bring attention to the importance of reporting the adverse effects of medicines and drugs. There’s a hashtag on twitter #medsafetyweek you follow, where a lot of grass roots activity is happening (as well as regulators pitching in).

If the only effect is to stimulate a few people to start reporting more often, that’s a big win. Most people never report. If you a healthcare professional and report once this year, you are outperforming most of your colleagues.

If you are in the UK, you can find some posters here for printing.

Deprescribing in Palliative Care

There’s an interesting paper on deprescribing tools in palliative care in the journal Supportive Care in Cancer, that shows that many of the generic deprescribing tools are unsuitable for use in this group of patients, with only one palliative care specific tool externally validated. As with any area of drug-related problems, they note that ‘far more literature on the incidence of PIMs is available, than on methods for reducing them.’

I used to work in a hospice, long before the term deprescribing was coined, and one of the most effective additional quality of life interventions we could do was to remove the burden of drugs that were no longer required. It was, however, an area that required good communication and an understanding of both patient and carers expectations.

Tools can blunt. Experience, knowledge, and the confidence to act on issues is just as important.

Evidence Based Medicine 2.0

David Nunan at the Centre for Evidence-Based Medicine has blog post calling for the reboot of evidence based medicine. It’s an interesting read and I won’t attempt to reformulate it here. I will pick out two elements in the list he gives:

The pandemic gave rise to the worlds greatest Infodemic. Misinformation is rife. But policing and censorship is not the answer. The boundary between debatable unknowns and uncertainty versus misinformation can become very blurred. What would be considered misinformation today becomes tomorrow’s “evidence-based”. The answer is EIHC - confronting, discussing, debating, and refuting ideas based on its core principles - transparent judgements of evidence in context (though social media organisations should be prohibited/regulated from measuring and capturing attention).

Hand in hand with tackling the infodemic is the communication of evidence. This again showed the best and worst. The worst for me was the lack of communication of uncertainty. Here I am not talking about acknowledging uncertainty. The need to “express uncertainty” was stressed by many, but far too few gave examples of exactly how. The best came in the form of efforts to empirically demonstrate that communicating uncertainty doesn’t impact trustworthiness. The EIHC community must build on this and do better with demonstrating how to informatively and accessibly express uncertainty.

These two are linked to some extent, but I think David is right to argue that polling and censorship is not the right approach. At the start of the pandemic there were missteps by authorities. If anything not in line with authorities had been censored at that point, then some useful correctives that have probably saved lives would not have happened. Free and open debate, in journals and the internet is a cornerstone of the how we get to the closest approximation of the truth. If we start to tamper with the ‘Constitution of Knowledge’ we endanger the production of knowledge itself.

“reality based community [is] the social network which adheres to liberal science’s rules and norms … objectivity, factuality, rationality: they live not just within individuals’ minds and practices but on the network”. This community includes not only the hard sciences but also such fields as scholarship, journalism, government and law, in a “marketplace of persuasion” driven by pursuit of truth under clear standards of objectivity.

Talking about vaccine safety

Openness and transparency, and expressing uncertainty, are themes I return to in this podcast on vaccine safety I was interviewed on. I hope it of interest. https://www.buzzsprout.com/618871/9482726

I also touch the issues surrounding academics and twitter, and whether it is a worthwhile pursuit. I have my doubts.

My apologies for the long gap in posts, it’s been a little frantic.

That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

Share Is It Safe?

Apologies for the lack of posts, but May-June is exam season in the UK University systems, and I’ve been focusing on a couple of other writing projects for the past month, along with a break, in which I mostly avoided the internet.

AZ vindicated?

There’s been some coverage of the AZ vaccine and the risk of blood clots again. A very short report in the Lancet1 seems to underline the very low risk of the thrombosis with thrombocytopenia syndrome (TTS) with the second dose, which backs up the spontaneous reporting data from the MHRA.

The Telegraph (in this thread and an article) make mention of another study suggesting that the risks are no higher with the AstraZeneca Vaccine than the Pfizer vaccine.

Just last week, new research scotched damning claims AstraZeneca posed a blood clot risk. A team of researchers from Spain, the UK and the Netherlands compared data from more than 1.3million people and concluded that those who had the UK jab developed blood clots at the same rate as those who had the far more expensive Pfizer/BioNTech.

More importantly, they found people who had Covid-19 developed blood clots at a far higher rate than those who received neither vaccine. 

This appears to be from a Lancet preprint, and appears to be accurate reporting.2 The study compared rates of thromboembolism and thrombocytopaenia with the Pfizer vaccine and the AstraZeneca vaccine, and used a COVID-19 diagnosis as a comparator - highlighting risks of vaccines without the contextual risks for the disease are inherently misleading. They found similar rates for clots with both vaccines, but COVID-19 was far more risky for clots than either. Obviously, this contradicts the spontaneously reported data in the UK and Europe, where the signal of thrombosis with thrombocytopenia syndrome (TTS) is only of concern with the AstraZeneca vaccine. Why is this?

This is an observational study using a primary care database in one area of Spain. As the authors point out:

thromboembolic events were identified using primary care records, and therefore they might be underestimated in all cohorts. For instance, we were unable to identify particularly rare events of special interest, such as CVST or SVT. Although underestimation of events was likely non-differential across cohorts for events before March 2021, we cannot exclude that detection bias following the EMA’s signal alert report might have led to differential measurement error between the vaccinated and comparator cohorts from March onwards.

If the primary care records did not record cases well, then that might explain why the risk thrombotic events might not be different between the vaccines. So, while this is an interesting study using a decent database (from good researchers), and adds some useful data to the mix, I doubt it will have any impact on the decisions already made by the MHRA and EMA with regard to the risks of TTS (and the communications of risk to the public). Although case reports (which is what the spontaneous reports to the Yellow Card scheme are) have their deficiencies, for serious adverse reactions like TTS I’m reasonably confident that the majority of cases are being reported (at least since March when it became widely reported). Any case of TTS occurring in the UK is going to be screened to look for any potential vaccine involvement.

I am not convinced there is a good argument to be made that cases of TTS occurring after the use of the Pfizer vaccine would be preferentially un-reported to the MHRA or EMA, which would explain the difference between the spontaneous reports versus this new study. So, I’m still of the opinion that there is a small risk of TTS with the AZ vaccine that appears far less likely with the Pfizer vaccine. Strong signals in spontaneous data, for all the limitations of such data, need fairly strong counter-evidence to be ignored. I don’t think this study does that.

It does highlight, again, that both the AstraZeneca and Pfizer vaccine are far safer in terms of blood clots than COVID-19. So if you haven’t had the vaccine yet, do get it at the earliest available opportunity.

No prescription, no harms?

There’s an interesting scoping review at Drug Safety on the non-medical and extra-medical uses of Non-steroidal anti-inflammatory drugs (NSAIDs). 3 Sports use comes up a lot as you might expect, including a study I was involved in, but this point stands out…

A common feature across many of the studies was the widely held belief that because a product can be obtained without a prescription and purchased OTC, it does not pose any significant threat to health.

To be fair, the whole class of over-the-counter (OTC) medicines exists for drugs that are considered fairly safe to be used outside of a prescribing setting, so this is perhaps understandable. Perhaps the actual problem is that NSAIDs are inherently risky for OTC drugs.

Change of focus when it comes to risk

I met with a friend at weekend in a full Mexican restaurant, with a live singer, and then went on to a packed bar for a couple of hours. I was trying to work out whether the 20 mile round trip drive was more risky than the 4 hours in an enclosed space. I’ve come to realise on reflection, a few weeks after vaccination, that at a personal level I have defaulted to factoring in COVID-19 as a background risk like any other respiratory infection.

This isn’t to say I’m not concerned about wider societal issues like the immunocompromised, or pressures on the NHS if cases really surged, but the risk of COVID-19 to me personally, based on the effectiveness of the vaccines, is something I am willing to accept without consciously over-thinking every situation.

This comes as somewhat of a surprise to me, since I was pretty much a zealot at the start of the pandemic, including using a mask since the 16th of March 2020 (I remember getting annoyed at a blood donation centre when they would not admit me with a mask). I didn’t stop hand wiping my food shopping down until late summer 2020 and hand gelled constantly. I stopped the latter two behaviours after reading this paper that seemed to indicate surfaces weren't the issue (plus washing your shopping is a nightmare, and my hands were sore).

I suppose it will take time for people to re-adjust their risk ‘thermostat’, but I am not convinced that some of the information environments we create for ourselves with social media help with this process. Nor does some of the reporting about breakthrough infections in the vaccinated.

The reason why this is misleading is excellently illustrated here by John Burn-Murdoch:

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That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

Share Is It Safe?

To start, a brief mention about the AstraZeneca vaccine…. The MHRA Yellow Card figures have been updated… (13th of May release). It doesn't change any of the MHRA/JCVI assessments/advice…

Up to 5 May 2021, the MHRA had received Yellow Card reports of 262 cases of major thromboembolic events (blood clots) with concurrent thrombocytopenia (low platelet counts) in the UK following vaccination with COVID-19 Vaccine AstraZeneca. These events occurred in 149 women and 112 men aged from 18 to 93 years and the overall case fatality rate was 20% with 51 deaths. Eight cases have been reported after a second dose.

The highlight about second doses is mine. Given that the estimated number of first doses of AstraZeneca Vaccine doses up until the 5th May was 23.3 million, second doses at 7.5 million, the reporting rates are roughly:

• First Dose: 1 in 89,000

• Second Dose: 1 in 937,500

There has been prior suggestions (when second dose cases were at 4 cases) that the second dose case reports were in individuals with multiple confounders, which I think this tweet hints at:

Even without that knowledge, the cases after second dose are extremely rare (effectively 1 in a million) and should not be a major concern in any normal understanding of dealing with risks. At around 1 in 100,000 most humans start to consider risks as negligible. I’ve had young at risk people in my own family receive AstraZeneca Vaccine, including second doses, and it hasn’t put them off.

I was sent this graphic, which has also appeared on the appropriate Wikipedia page for James Reason’s cheese model.

Personally, I think the holes are too big in the final slice of cheese representing the vaccine, and that slice ought to be a reasonably thick slice of Parmigiano-reggiano if we are thinking of risk at an individual level.

If we are thinking of population level, with hesitancy, partial vaccine roll out, and the Indian variant, then keep the slice of Gouda.

Reason’s model has been on my mind for another reason this week. I’ve been getting involved with some work around double-checking.

In my own professional area of pharmacy, having two independent individuals checking dispensed medicines in a pharmacy environment is fairly standard practice. It is all too easy to convince yourself you are right when checking yourself due to confirmation bias. Essentially, the second independent check puts in another slice of cheese in the model above, meaning that it is less likely an error will end up in the final dispensed medicine. Your colleague may find the amiloride you dispensed was actually amlodipine. This is pretty much standard practice in pharmacy (unless you are on call).

In the administration of medicines on hospital wards, there has been debate about the utility of double-checking to reduce administration errors of medicines within hospitals. A systematic review 1 in 2020 found that there was insufficient evidence to show any differences in error rates between single and double checking. In the conclusion the authors stated:

Double checking presents at face value as a logical safety precaution which has been embedded in nursing practice for decades. However, as this review reveals, there is no solid evidence-base to support its use. Our review of the evidence shows both an absence of good-quality studies, and generally an absence of effectiveness in reducing medication error rates and patient harm. In most studies, the double-checking process tested was ill-defined and the fidelity of the double-checking process left un-investigated. Given the extent to which it is embedded as part of routine nursing practice, and the considerable costs involved, there would appear to be a compelling reason to establish a sound evidence-base for its ongoing use and to inform decisions about when and how it might be most effective to improve medication safety.

Personally, I think you’d need good evidence to decide to remove the second check. Mistakes in drug administration can be fatal. That said, double checking is not without problems. George Bartram was a 15 day old baby who was given the wrong dose of digoxin, which led to his death. Two nurses were involved in the administration of the drug:

Blaming pressure and time on the ward, Ms Fitzsimmons said: "Because we had calculated it both separately and together and checked it to make sure it was accurate to the book, we believed that we were giving the right dose.

"If we had any doubt whatsoever we would not have given the dose."

An editorial by Pfeiffer et al2 that accompanies the systematic review above discusses the concept of double checking (and proposes a framework for creating stronger research evidence). At one point they state about double checking:

If it is carried out by two people (compared with a technology-based check, like barcode scanning), the detection rate is limited because both people may be affected by the same disturbances in the environment, for example, noise, confusing drug labels or cognitive biases in information processing (eg, confirmation bias). Double checks also may become a mindless routine over time, meaning that the checking persons rely on the other check and are not as attentive as they could be. In addition, checking persons may not dare to raise an identified error to a person of higher authority status.

All of that makes sense, but I do think you have to be careful before discarding the double check.

It would also be interesting to compare nursing and pharmacy double checks. Perhaps double checks in pharmacy are easier to carry out since the environment is more controlled, with less distractions than a hospital ward. The process of dispensing is more physically and temporally separated, and slightly more like a pseudo-manufacturing process. For this reason the second check is likely more independent, with the checker coming to it new without priming by a colleague. On a nurse administration round, two individuals will be working together as they go round the ward, seeing information at the same time. That separation of process is much harder in such circumstances. All very interesting.

Sometime ago, our team did some work on medication errors in Coroner’s reports.3 4 It’s been great to see others build on this. Anis et al have a preprint out concerning deaths related to the use (or lack of use) of anti-coagulants found in coroner’s reports.5 A median of 16 such cases were reported per year, most involving warfarin, with issues around poor systems, poor communication, poor medical records and failures or delays in appropriate assessments being the most reported coroner concerns. Most of the lessons learned about these cases didn't go beyond the local NHS, which is a finding we also saw.

That should change.

That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

Share Is It Safe?

It’s now a month since the last major ‘course correction’ on vaccination in the UK, where the JCVI carried made it preferable for the under 30s to have a vaccine other than the AstraZeneca Vaccine. This week Prof Vam Tam, Dr June Raine (MHRA), and Prof Wei Shen Lim (JCVI) carried out a new press conference.

The major outcome of this is that the AstraZeneca vaccine is not the preferred vaccine for those under 40 years of age. This is largely due to the fall in risk of COVID-19 as the prevalence of COVID-19 falls as a result of both vaccine roll-out and the UK lockdown. This means that the benefit-harm becomes more ‘finely balanced” for the AstraZeneca vaccine for younger age groups, where risk seems to be 1 in 60,000 for the thrombotic . For those under 40 who are due a second dose of AstraZeneca vaccine, the risk is extremely low. None of the few cases reported after a second dose of AstraZeneca vaccine appear to be linked to the anti-PF4 anti-bodies, which is thought to be the immune reaction to the vaccine causing the thrombocytopaenia and thrombosis.

For the past few weeks I have been complaining that the use of the precautionary principle in pausing the J&J vaccine and the AstraZeneca vaccine was wrong-headed, particularly in countries with high prevalence of COVID-19. Does the emerging data on the thrombosis linked to thrombocytopaenia, and the JCVI preference for alternative vaccines in the under 30s (April 7th) and under 40s (May 7th) mean I was wrong to hold this opinion? It’s always worth re-visiting things.

Making adjustments on the basis of emergent evidence seems like a sensible position. When I was suggesting pauses in France and Germany were not sensible, they had significant COVID-19 cases which dwarfed any know risks from the AstraZeneca vaccine. They weren’t Norway (were the risk of COVID-19 was much smaller, a total of 767 deaths since the start of the pandemic). Taking extreme examples, in New Zealand with minimal COVID-19 cases and great healthcare, then the risk of a vaccine would obviously be higher than the benefits (assuming New Zealand could maintain indefinitely this situation), and in India with rising cases and deaths, and a health service that has been overwhelmed the benefits of the vaccine clearly are higher than the harms.

The tricky bit is the transition from high COVID-19 prevalence to low COVID-19 prevalence, and maintaining public confidence in the vaccine as the risk of the disease become attenuated. That’s what is wrong with this graphic. It doesn't include prevalence of disease. If you know you are going to be infected with COVID-19, then it is clear the vaccine is the right calculation.

The Winton Centre for Risk and Evidence Communication have a far better set of graphics, including a very low prevalence version which makes the under 40s decision of the JCVI clear.

Having a vaccine roll-out during a peak of the disease hits a sweet spot, and lets you build up momentum. The UK is now at 67.2% first dose, and 33.5% second dose. Only now are we starting to hit the problem of convincing people to have a vaccine in the face of low disease prevalence. Even then, for many people it isn’t just about personal risk, but also the wider benefits of the vaccine roll-out in terms of opening up society, and a return to a form of life that is perhaps more like before. Issues like travel also factor. So, it isn’t just about balancing fairly abstract risks.

For some countries, they are starting their campaigns with low prevalence of COVID-19, this is turning into a problem.

Less than half of people aged over 50 are willing to get the AstraZeneca vaccine despite it being recommended by Australia’s health officials, according to the latest Guardian Essential poll which found confidence in the rollout strategy is waning.

The survey of 1,090 respondents, taken amid a fresh political furore over hotel quarantine and after weeks of confusion about the government’s vaccine rollout, has also tracked a significant increase in those who said they would never get vaccinated against Covid-19, up from 12% to 16% over the past six weeks.

This makes sense if you look at the 3C model of vaccine hesitancy1:

Vaccination complacency exists where perceived risks of vaccine-preventable diseases are low and vaccination is not deemed a necessary preventive action. Complacency about a particular vaccine or about vaccination in general is influenced by many factors, including other life/health responsibilities that may be seen to be more important at that point in time. Immunization programme success may, paradoxically, result in complacency and ultimately, hesitancy, as individuals weigh risks of vaccination with a particular vaccine against risks of the disease the vaccine prevents that disease is no longer common. 

One of those paradoxes of life!

It will be interesting to see how the different ways of handling COVID-19 pan out in the long term.

One of the other thing happening recently has been the push, and US support for, the loss of IP protection on vaccines. This has been a constant refrain on social media, and is one of seemingly simple cheap fixes. The Apple computer I’m writing this on has IP protection, but if you told me the IP protection was gone it would still take time for to tool up factories and get production rolling. And would they be made to the same quality? For vaccines this is worse, it is an amazingly complex process with incredibly hard logistics. I have a lot of sympathy with this.

The issue is production capacity, not IP. A major push on investment in production facilities is needed, and that costs money. The IP decision costs nothing, but creates no capacity. This is not like the 1990s IP fight over HIV medication.

Pfizer’s CEO has recently posted about this. They risked over $2 billion developing their vaccine, and have concerns about a possible scramble for raw materials that could endanger production.

Currently, infrastructure is not the bottleneck for us manufacturing faster. The restriction is the scarcity of highly specialized raw materials needed to produce our vaccine. These 280 different materials or components are produced by many suppliers in 19 different countries. Many of them needed our substantial support (technical and financial) to ramp up their production. Right now, virtually every single gram of raw material produced is shipped immediately into our manufacturing facilities and is converted immediately and reliably to vaccines that are shipped immediately around the world (91 countries to date.) The proposed waiver for COVID-19 vaccines, threatens to disrupt the flow of raw materials. It will unleash a scramble for the critical inputs we require in order to make a safe and effective vaccine. Entities with little or no experience in manufacturing vaccines are likely to chase the very raw materials we require to scale our production, putting the safety and security of all at risk. 

Of course he would say this, but the case that this is about production capacity, not IP stands. The EU are also skeptical about this.

Other articles on this:

• Waiving IP by Derek Lowe.

• Patents are Not the Problem! Marginal Revolution

• Waiving the vaccine IP is a huge blunder by Tom Chivers

Tom says it well

Saying you’ll waive IP rights is cheap in the worst sense of the word. It gets headlines and approving tweets but it won’t do much good and might do lots of harm. Instead: spend the money. Build factories. Give hundreds of billions of dollars of rich western taxpayers’ money to Covax. Stop trying to push the risk, cost and blame onto the pharma industry.

Share

That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

Share Is It Safe?

This has been a busy week, so not much in this post apart from a Webinar I am running tomorrow at the Yellow Card Centre West Midlands

In this webinar Anthony will outline the key issues in monitoring vaccine safety, including the plans for vaccine safety in the UK around monitoring, detection, and communication of safety issues. Recent news around COVID-19 vaccines will be used as an example, and the role that all healthcare practitioners and the public can play will be emphasised.

You can register here

That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

Share Is It Safe?

Back in the 2009 H1N1 influenza pandemic there was a vaccine safety issue that arose too. In 2010, Finland and Sweden noticed increased cases of narcolepsy, and suspicion fell on Pandemrix, a H1N1 vaccine. A recent systematic review has found that:

During the first year after vaccination, the relative risk of narcolepsy was increased 5 to 14-fold in children and adolescents and 2 to 7-fold in adults. The vaccine attributable risk in children and adolescents was around 1 per 18,400 vaccine doses. 

And in the UK, where Pandemrix was also used, found that it occurred in 1 in 34,500 doses according to a 2020 study. It’s still a bit of a mystery about the mechanism for this adverse effect, which has arguably compelling evidence that it is linked with this particular H1N1 vaccine. The adjuvant AS03 is one culprit, although H1N1 itself appears linked to narcolepsy as well. So we can’t discount adjuvants and other excipient issues from the causal mechanism of vaccine adverse effects…

Science has an interesting piece on the potential for preservatives and proteins to have potentially caused the unusual clotting in some individuals.

Both J&J and AstraZeneca use modified adenoviruses to deliver and express the spike protein gene of SARS-CoV-2. But new data posted Tuesday in a preprint on Research Square show that doses of the AstraZeneca vaccine also contain significant amounts of protein from human cells—presumably from the human cell line used to grow the virus during the manufacturing process. The preprint’s authors, some whom were among the first to identify the VITT side effect, propose that these proteins, together with another component of the vaccine called ethylenediaminetetraacetic acid (EDTA), may set off a dangerous response by the immune system in some vaccine recipients.

Again, a lot of this is unproven as of yet, and it is still worth remembering that these unusual clotting events remain extremely rare events. The MHRA’s latest data for the AZ vaccine is 168 cases with 32 deaths, 1 from 2nd dose (no change, and this case had other reasons for the clotting event). 7.9 reported cases per million. This does not change previous MHRA advice, and it remains and extremely rare event (roughly 1 in 125,000). Their overall view remains the same: 'On the basis of this ongoing review, the advice remains that the benefits of the vaccine outweigh the risks in the majority of people'.

The US has also unpaused the J&J vaccine, with 15 reported cases out of 8 million doses given. So they have unpaused the vaccine despite more cases being found. Which really makes you wonder if they should had paused in the first place after the initial few cases. Such a pause will have damaged vaccine confidence, and protestations that the pause will have increased confidence in the vaccine’s safety seem misplaced to me. There is no evidence that that is the right approach, and contrary examples in Europe over the AZ vaccine. In the UK, where a pause was not used, confidence in the AZ vaccine is holding up.

The messaging about AZ vaccine from European state regulators is already having a direct effect on the most vunerable. Haiti has declined to accept over 750,000 doses of AZ vaccine. Not because they have concerns about safety, but because the population’s view of the vaccine now is such that they would prefer to use a different vaccine.

Ten fold errors in Children by Christine Parry.

Fatal adverse drug reactions: A worldwide perspective in the World Health Organization pharmacovigilance database by Montastruc et al.

The Antiscience Movement Is Escalating, Going Global and Killing Thousands by Peter J Hotez

NOTE: This last piece mainly look at the rise of 'anti-science' in some of the US right. However, the issue isn't anti-science itself, but the identity driven tribalism that puts politics into some areas of science. Similar rejections, about different science, also occurs on some of left too.

And this Trolley Problem meme is excellent on risk….

While we are on this matter again, I think the public acceptance of risk hasn't changed that much. In the UK, AZ vaccine is still being widely accepted in a highly successful vaccination programme. So, if communicated well, the public can still manage extremely rare risks, in a vaccine that carries huge benefits. However, that may have varied in different countries. In some countries with a legacy that may have created already lowered trust in vaccines, and that have had pauses and political statements about a vaccine, things may be different. The AZ vaccine is starting to look like a vaccine that the “West” is not using, but sending off elsewhere. This is regrettable. There’s a lot of talk about vaccine equity in relation to supply, but I think vaccine equity in terms of risk is something we might consider.

I have seem individual EU citizens saying they would happily have the AZ vaccine, despite not being eligible due to the age-related restrictions brought in. So perhaps the risk aversion isn’t from the public, but EU state regulators who have put restrictions in place - some for valid epidemiological reasons (even if EMA has not). After a year of missteps, perhaps an ultra-cautious approach to risk is appropriate - although the UK had its own share of missteps in the opening of this pandemic, so that acts as a counter-example. The MHRA appears to have stuck to its scientific processes, as has the EMA.

At some point this newsletter will stop focusing on vaccines… The next month is going to be pretty busy for for me at work, so the letter may be brief.

That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

Share Is It Safe?

It’s a month after EMA and the MHRA simultaneously announced, after expert advisory group review in both cases, that despite a number of extremely rare reports of cerebro sinus vein thromboses (CSVT) that the benefits of the AZ vaccine still outweighed the harm.

Despite this, The Daily Telegraph has an exclusive : ‘Revealed: Why Britain’s regulator missed the link between the AstraZeneca jab and rare blood clots‘

In the article they argue that because the AZ vaccine started a rollout a full month earlier, meaning 11 million doses had been administered, the UK regulator should have found the CSVT issue.

They argue this was not found because:

1. The MHRA’s signal detection methods were not sensitive enough, and that other countries had turned threat sensitivity gauge ‘up to 11’.

2. The MHRA did not have an open and transparent approach to the CSVT cases and did not tell the public about the issue until the 18th of March when it announced 5 cases.

3. That the MHRA had lost access to Eudravigilance, the European database of spontaneous reports.

The Telegraph does not say that the MHRA covered up the reporting of CVST, but merely says that the MHRA was not as quick to spot the issue as others.

They also note:

‘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.’

They also importantly note:

There remains no doubt the benefit of taking the AstraZeneca jab outweighs the risk now associated with the vaccine. This is the judgment not just of the MHRA but also the European Medicines Agency (EMA) and the World Health Organization (WHO).

So there is no complaint about the regulatory decisions of the MHRA, but a very narrow point about a failure to find the CSVT issue sooner, which they argue has undermined worldwide confidence in the vaccine.

I’m going to walk through the claims in the Telegraph, but first a brief timeline.

7th March: Denmark, Norway, and Iceland report cases of blood clots and deaths. It’s important to note these were not CSVT cases.

11th March: EMA and the MHRA both release similar press releases underlining the benefits of AZ vaccine outweigh the risks (since the blood clots weren’t out of line with expected thrombosis cases in a similar population).. No CSVT is noted.

15th March: Germany’s Paul Erlich Institute reports on seven cases of CSVT, including 3 deaths. Germany suspends the AZ vaccine.

18th of March: Both EMA and the MHRA release press releases and hold conferences on the CSVT issue, having both already convened and consulted with experts on the issue. Both organisations issue warnings to prescribers and patients, but back the benefits over the risks of the AZ vaccine.

7th of April: Both EMA and the MHRA again hold press releases at the same time, noting that the benefits continue to outright the risks of the AZ vaccine.

The Telegraph also has an analysis of a document published by the MHRA, which is just a simple count of cases carried by an academic:

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.

This appears to be based on this document published by the MHRA.

The important thing to note here are the reports related to CVST. The first column is cases, the second is the number of those that were fatal. The term come from an adverse effect standardised set of terminology to enable sharing of regulatory information called MedDRA. Once a spontaneous report is received, in the UK a Yellow Card, it will be coded with this terminology.

So, on the 15th of March when the Paul Erlich Institute was reporting 7 cases with 3 fatal, the UK had 4 cases, none fatal. Germany had administered 1.6 million vaccines, the UK 11 million. Norway also had 5 cases, three of whom died, and had administered 130,000 vaccines.

Another part of this story are some astute and vigilance physicians in Germany:

The VIPIT story began on 27 February, when Sabine Eichinger, a hematologist at the Medical University of Vienna, was confronted with an unusual patient. A 49-year-old nurse had sought help at a local hospital the day before, suffering from nausea and stomach discomfort, and was transferred to Eichinger’s hospital. She had a low platelet count and computed tomography scans found thromboses—blood clots—in the veins in her abdomen and later in arteries as well. “There was little we could do at this stage,” Eichinger says. The patient died the next day.

The combination of low platelet count, or thrombocytopenia, and clots kept Eichinger thinking, however. “It’s very striking,” she says. Platelets, also known as thrombocytes, help form blood clots, so low levels usually lead to bleeding, not clotting. “You would think that low platelets and thromboses are opposites really.” One condition where they occur together is called disseminated intravascular coagulation, when severe infection, injury, or cancer trigger clotting so widespread it uses up all the platelets, “but she had none of these things,” Eichinger says.

Vigilance is key.

The science of detecting adverse effects of medicines and vaccines is called pharmacovigilance. Vigilance is key. Without suspicious healthcare professionals and patients making a suspected link between a vaccine and drug or vaccine, we don’t get reports. And for that reason, along with other reasons, there is a level of under-reporting in pharmacovigilance systems. It can vary, with more severe reactions perhaps more likely to be reported, but if no link is made by individuals, then no report can be made. Under-reporting in one systematic review is estimated to be about 94%. That is, for every one report made, 19 may not be made.

So, whatever reports you have in your database, be it the Yellow Card scheme, or the Eudravigilance system in the EU, you have to be aware that not all the reports may be there. Indeed, if a type of reaction is very novel, then the a-ha moment may not arise in mind of the healthcare professional caring for the patient. It is also worth noting that the reports that are made as suspicions of harm, they are not proven to be be linked to the vaccine.

It is also worth noting that once a suspected adverse effect of a vaccine is highlighted by regulatory authorities and the media, more reports are stimulated. This can be termed a notoriety bias or stimulated reporting.

And now onto a few specifics in the Telegraph:

On March 11, 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 MHRA’s 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 MHRA was, it appears, wrong. An investigation by The Telegraph has established that signals had been firing unnoticed in the UK’s Yellow Card database for at least a month, perhaps longer.

Remember in the timeline at this point, the issue of CSVT had not arisen, and the MHRA statement is dealing with reports of generalised blood clots in Denmark, Norway, and Iceland. There statement as far as it pertains to that issue is accurate. A similar statement was put out by EMA on the same day.

The Telegraph immediately follows the above quote with this:

In January, a patient suffered a brain clot following their first dose of the AstraZeneca jab, The Telegraph has confirmed. Then in early February, two similar cases followed, including a death and a life-changing CVST clot in a young adult. All had low platelets and all were reported into the Yellow Card system.

It is worth noting, that from the start of the use of the AZ vaccine to the 14th of March the MHRA had 4 cases with no fatalities. So, at least one of these cases, the fatal one, was definitely reported later than the 14th of March. The MHRA would not have known of it. So this segment does not prove the 11th of March press release ‘wrong’.

A psychologist argues that the MHRA was slow to respond to the emergence of the AZ vaccine CSVT issue.

Prof Stephan Lewandowsky, a psychologist at the University of Bristol studying the rollout of Covid-19 vaccines, told the Financial Times on Friday: “The MHRA was slow in responding to the emergence of a specific constellation of symptoms associated with the AstraZeneca vaccine and slow to communicate what they were finding — and I am not the only one who thinks so.”

Both EMA and the MHRA communicated about the CSVT issue on the 18th of March and the 7th of April, so the UK was no slower than EMA. The Paul Erlich Institute did not report their cases until the 15th of March. At that point, the UK had only 4 cases reported and no fatalities in 11 million administered vaccines. One could make the argument that the UK should have found the issue sooner because they started vaccinating sooner, but the UK had only 4 reports submitted (none of which were fatal) and all of which fell within the realms of the natural occurrence of this rare event at that point.

The Telegraph also mentions the algorithms used to examine the Yellow Card Data. In simplistic terms, the system looks for a disproportionate number of reports of a particular adverse reaction compared to all the other drugs in the same database. There is a threshold above which it might be that a safety Signal arises.

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. 

There is no evidence that the MHRA signal detection systems were less sensitive than European regulators'. Certainly, I imagine they were more than likely set exactly the same as those at EMA. Such systems are not Marshall amps that one turns up to 11. The comment by Olsen at the Norwegian Medicines Agency about following up serious reports and patient deaths is as true of the MHRA as it is of the Norwegian Medicines Agency. But remember the UK had no fatal cases of CSVT up the 14th of March, and we have no evidence one way or the other than the MHRA was not looking at individual cases of CSVT in more depth.

The Telegraph also notes cultural differences on vaccine pauses and openness about vaccine harms, noting the J&J pause in the US, and the pauses in Europe on the 7th of March. However, the early pauses were not about CSVT, and arguably wrong because EMA did not later endorse them. They also note the warnings of anaphylaxis issues for the Pfizer vaccine by the MHRA, which were eventually withdrawn, and say:

Unfortunately, perhaps, the MHRA did not adopt the same approach with the problems surrounding the AstraZeneca jab - or at least it does not appear to have.

That sentence is heavily caveated for good reason. As already noted, by the 14th of March 2021 the MHRA did not have a good signal. The Telegraph says:

The MHRA says it got its first report of CVST with thrombocytopenia in the week of February 8, but the regulator did not tell the public about the issue until March 18 when it announced five cases. It did so just moments before the EMA opened a high profile press briefing on the issue, which by then was dominating world headlines. 

Remember the German cases were reported on the 15th of March. Before then the UK did not have a clear signal (4 cases), and no deaths. Three days after the German cases were reported the MHRA had issued warnings at the same time as EMA, had held expert committees, and had clearly worked with EMA. The Telegraph tries to make out that working with EMA is a bad thing, rather than good co-operation. Should the MHRA have released a competing press release the day before, without co-operating?

Since then, the MHRA has made three further announcements regarding new cases identified in the UK. Late on Good Friday, after most people had tuned out for the bank holiday weekend, it said it had recorded a total of 30 cases, including seven deaths. Then on 7 April, again during a high profile EMA press conference, it revealed the count had grown to 79 and 19 deaths. The latest figures, quietly released on Thursday evening, show the number of UK clotting cases with thrombocytopenia to stand at 100 with 22 deaths. 

The above suggests the MHRA were trying to sneak new cases our under cover of a bank holiday, undercover of an EMA press conferences, and ‘quietly’ on a Thursday night. That’s quite a way of looking at things.

Would we prefer the MHRA waited until after the Bank Holiday? I doubt it. The release on the 7th of April was during an EMA press conference, but again the MHRA was holding a press conference itself at the same time. Yet another example of the MHRA and EMA working together. The MHRA/JCVI panel was widely broadcast on TV, and highly praised, and was hardly hidden. The data released last Thursday evening was released when expected and changed nothing.

It is not known how many of those 22 deaths are covered in the Yellow Card data Dr Merchant analysed between January 4 and 14 March but it seems likely that a large number of them - perhaps the great bulk - will date back to that period. 

I find this quite confusing. The data Mr Merchant analysed between January 4th and 14th of March contained 4 cases of CSVT and no deaths. So none of those 22 deaths are covered in the Yellow Card data Dr Merchant looked at, because they did not exist at that point.

As noted before, once a rare adverse effect is drawn attention to by regulatory authorities and the media, stimulated reports are created as doctors, particularly haematologists dealing with rare events like this would go looking for them retrospectively. Some of those cases might have happened before the 14th of March, but none of them were reported to the MHRA until after wider reporting of the issue.

Another issue raised in the article is the UK’s access to Eudravigilance:

Another reason for the MHRA’s 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.

I’m extremely skeptical that this is major issue. EMA would want their hands on any data the UK obtained about vaccines given our early roll-out. Since it is clear that EMA and the MHRA have been working closely, look at the co-ordination in three press releases and statements from each body which shows they have been working closely together. It’s also worth noting that on the 11th of March 2021 EMA said ‘As of 10 March 2021, 30 cases of thromboembolic events had been reported among close to 5 million people vaccinated with COVID-19 Vaccine AstraZeneca in the European Economic Area.’

This data would not have strengthened any signal of CSVT the MHRA would have had, so I think it is worth discounting that as an issue.

The key moment was the release of the Paul Erlich Institute data on the 15th of March which changed everything. Within 3 days the UK’s MHRA had acted as quickly as the EU’s EMA.

So, it appears that the MHRA did not have a clear signal in the UK before the astute and vigilant physicians in Germany spotted unusual cases which were reported to EMA by the Paul Erlich Institute. That lead to an increased vigilance worldwide with further cases reported. The Telegraph piece itself notes that a UK group of leading haematologists started discussing a case in the UK on the 16th of March, the data after the Paul Erlich Institute cases had been reported, and reported them on the 17th of March.

If there is anything to be learnt here, it is that one should be vigilant to the potential adverse effects of any new treatment, and if more cases had been reported perhaps a signal may have been detected sooner. But is far from clear that the MHRA had a legitimate signal with 4 cases in 11 million vaccines, or that they have responded slowly to the safety signal raised by the Paul Erlich Institute, or failed to work closely with European colleagues.

Of course, you can construct a retrospective narrative, as the Telegraph has, but hindsight is a wonderful tool for doing so.

I should also make my conflict of interest clear, that I have worked at a MHRA Yellow Card centre, and hold an ongoing honorary position (although I have no committee positions at the MHRA, income from the MHRA, or insider information from the MHRA). I neither speak for the MHRA, not do the MHRA have any hold over me. So what I write is based on publicly available material, and no doubt subject to the biases that I have, some of which I am aware of, and others of which I am no doubt not.

I freely admit to a bias based on knowledge which is in the public domain, that people at the MHRA have been planning for months to address safety monitoring in the COVID-19 vaccines to a high degree of professionalism. I believe people at the MHRA believe passionately in the job they are doing, and find some of the suggestions that things were ‘quietly’ released pretty disgraceful without evidence of such intent. I dislike the tone of the Telegraph article.

I also think that the Telegraph is playing with fire here, during the ongoing vaccination campaign, and I don’t think their story warrants the title ‘Why Britain’s regulator missed the link between the AstraZeneca jab and rare blood clots’.

Because they didn't based on the data they had, from what I can see.

That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

Share Is It Safe?

A short post this week, after both EMA and the MHRA made decisions that the benefits of the AZ vaccine continue to outweigh the risks. In the UK, the JCVI decided out of ‘an abundance of caution’ to advise it was preferable to offer the 20-29 year olds a vaccine other than the AZ vaccine. I wrote a piece at the The Conversation that covers most of this (with links):

In the UK, the Joint Committee on Vaccines and Immunisation (JCVI) weighed up the risks and benefits of the AstraZeneca vaccine for various age groups. It made an independent recommendation that it would be preferable to offer an alternative vaccine to under-30s, since their risk of severe COVID-19 outcomes, such as intensive care admission, is low when the prevalence of the coronavirus is itself relatively low. 

However, as the amount of circulating virus rises, the risk-benefit balance tips in favour of taking the vaccine, regardless of how old you are. If this decision had been made in January, while the second wave was still in full swing, it’s likely that this recommended age restriction wouldn’t have been suggested. 

Indeed, presumably in light of this sliding scale of risk, the EMA noted that EU states should now make their own independent decisions about using the vaccine, based on their local COVID-19 status. Many, though, had already introduced quite significant precautionary restrictions on the vaccine while waiting for the EMA’s assessment, limiting its use strictly to older groups.

As I noted in the piece, EU states have further restricted the use of the AZ vaccine., despite having higher levels of COVID-19 in the UK, which would make the risk benefit of the AZ vaccine even more beneficial if the logic of the JVI was used. The Winton Centre for Risk and Evidence Communication created some excellent depictions of risk, which were used in the meeting of the MHRA and JCVI.

I posted some French translations of these to two well known pharmacovigilance experts in France, and I thought this was an interesting response.

Which I think speaks to the cultural difference, and perhaps level of trust in government, that exists in how any further cases might be perceived in France, compared to the UK. In the UK we have explained the risk, and will be warning recipients of the AZ vaccine about the risks. I don’t think an additional case in the UK would become a political issue.

Note, by political I don’t think Prof Moore is suggesting this is politicians seeking to ‘bash the British vaccine’ as some have suggested, but that further deaths in France would be politically difficult to deal with given the state of trust on vaccines in France.

I’ve been impressed by both the MHRA and EMA over the past week, and this short coverage of the briefing in The Guardian seems a fair summary.

When the news is difficult and the science complicated but the desired message is crucial, who better to deliver it than “JVT”, headlining a panel of four top experts in their field?

The government’s choice of Jonathan Van-Tam, England’s deputy chief medical officer, whose metaphors and analogies are legendary, can only have reaffirmed his cult status as the most trusted face of the Covid-19 pandemic in Britain.

The New England Journal of Medicine has a review of 11 cases of Thrombotic Thrombocytopaenia after AZ vaccine, which includes a plausible mechanism. This is discussed in a Science article by Kai Kupferschmidt and Gretchen Vogel, Hard choices emerge as link between AstraZeneca vaccine and rare clotting disorder becomes clearer, in which I comment briefly on causality and on a the potential of reducing risk by reducing the dose (I’m not convinced). They also run through the plausible mechanisms:

Vaxzevria [AZ vaccine] consists of an adenovirus engineered to infect cells and prompt them to produce the virus's spike protein. Among the 50 billion or so virus particles in each dose, some may break apart and release their DNA, Greinacher says. Like heparin, DNA is negatively charged, which would help bind it to PF4, which has a positive charge. The complex might then trigger the production of antibodies, especially when the immune system is already on high alert because of the vaccine. An immune reaction to extracellular DNA is part of an ancient immune defense triggered by severe infection or injury, Greinacher notes, and free DNA itself can signal the body to increase blood coagulation.

Alternatively, the antibodies may already be present in the patients and the vaccine may just boost them. Many healthy people harbor such antibodies against PF4, but they are kept in check by an immune mechanism called peripheral tolerance, says Gowthami Arepally, a hematologist at Duke University School of Medicine who is working as an external consultant with AstraZeneca on the issue. “When you get vaccinated, sometimes the mechanisms of peripheral tolerance get disrupted,” she says. “When that happens, does that unleash any autoimmune syndromes that you are predisposed to, like HIT?”

No doubt this story will rumble on as more information and cases are accumulated, and their may be knock on effects on other adenovirus vector vaccines as EMA has announced they are looking at reports of blood clots in four people who were given the Johnson and Johnson vaccine. The Russian Sputnik V vaccine and CanSino vaccine use similar technology.

Sputnik

There are also concerns about adverse drug reactions associated with the Sputnik V vaccine arising from a whistleblower, and the Sputnik vaccine is being used more as political tool, than it is a vaccine in Russian where only 6% of the population have received it. Plans for countries like Germany to use it without EU approval seem foolhardy. There are also peculiar practices being reported from Slovakia:

Noting that about 40 countries are using or scheduled to use the Russian vaccine, the Slovak regulatory agency asserted that “these vaccines are only associated by the name.” That raised questions about deviations from the formula reviewed in The Lancet.

“The comparability and consistency of different batches produced at different locations has not been demonstrated,” the Slovak regulator said. “In several cases, they appear to be vaccines with different properties (lyophilisate versus solution, single-dose ampoules versus multi-dose vials, different storage conditions, composition and method of manufacture).”

The Slovak statement could damage Russia’s efforts to establish Sputnik V as a reliable brand. It could also exacerbate lingering doubts left by the vaccine’s highly politicized rollout in Russia, where President Vladimir V. Putin announced that the drug was ready for use in August, before clinical trials had finished.

Russia has repeatedly denounced foreign questioning of its vaccine as the fruit of anti-Russian conspiracies and prejudice, ignoring complaints that Mr. Putin, rushing last summer to declare a Russian victory in the race for a vaccine, violated standard procedure by declaring Sputnik V safe before trials had finished.

Never forget

At the bottom of the EMA Press Release this week it was noted that:

'As of 4 April 2021, a total of 169 cases of CVST & 53 cases of splanchnic vein thrombosis were reported to EudraVigilance. Around 34 million people [.] vaccinated in the EEA & UK by this date. The more recent data do not change the PRAC’s recommendations'

Even though tens of thousands of people have died from COVID-19 over the past few months, and in purely utilitarian terms the vaccines are saving more lives than they cost, it should be remembered that every one of these lives is someone’s relative. Every death is a great loss, and all the families concerned will be suffering. The risk balance of a vaccine is at a population level, and as individuals we choose to accept risk at an individual level. Most get the benefits and but some extremely unlucky people get the harms. I was deeply moved by the composure of a fellow pharmacist Alison Astles’ who spoke in favour of vaccination, despite the death of her brother Neil from suspected clot from the AZ vaccine.

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That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

Share Is It Safe?

AZ vaccine restrictions

Channel 4 news reported tonight on the AZ vaccine, reporting that the JCVI and the MHRA are urgently scrutinising the AZ vaccine and its status ‘hangs in the balance’. Two senior sources are meant to have said to Channel 4 that, while the data is still unclear, there is a growing argument for offering younger people an alternative vaccine. You can watch the story here.

While this is presented as breaking news, this sort of discussion has been occurring in full public view for days.

Here’s Chris Whitty on the side effects of vaccines on the 1st of April (about 23 minutes in). He notes that the MHRA, CHM, and JCVI are all looking at this issue and that for anyone at significant risk of getting COVID-19, such as an 80 year old, the risk/benefit is ‘wildly in favour’ of vaccination. However…

‘The closer you get to someone who is right down at 20 [years of age] the more you have you think through this really very rare side effects that are severe because the risk/benefit might get to parity.’

‘the idea that there might be a point where actually there’s a group you wouldn’t look at from the beginning of this I’ve been really cautious about making a policy on children getting vaccines until we were really confident about adults and that’s not because I’m trying to protect children specifically, it’s just that children get so little problems with severe COVID that you have therefore got to have a very strong justification for vaccination. [.] So it’s always going to be a matter of risk against benefit for particular patient groups.’

And here’s Adam Finn from the JCVI discussing the use of COVID-19 vaccines in children that they are at lower risk, so the balance of benefits and harms is different.

These are exactly the discussions that will be occuring. The specific MHRA data on the cerebral venous sinus thrombosis (CSVT) risk was recently updated:

The risk of having this specific type of blood clot is very small. Up to and including 24 March, we had received 22 reports of cerebral venous sinus thrombosis (CVST) and 8 reports of other thrombosis events with low platelets, out of a total of 18.1 million doses of COVID-19 Vaccine AstraZeneca given by that date. There were no reports for the Pfizer/BioNTech vaccine. We have thoroughly analysed each and every report as soon as it has come in. To note the current analysis prints include data up to and including the 21 March.

That’s about 1 in 600,000, so still very rare. There is no data about age or gender, but a BBC article seems to suggest that it is a wide range of individuals (but not clear where they got that from).

Dr June Raine from the MHRA stated "‘The benefits… in preventing Covid-19 infection and its complications continue to outweigh any risks and the public should continue to get their vaccine when invited to do so.’ and EMA agreed despite more cases being found, with an age adjusted exposure of 1 in 100,000 in the under 60s. EMA also noted, ‘At present the review has not identified any specific risk factors, such as age, gender or a previous medical history of clotting disorders, for these very rare events. ‘

However, the French ANSM reported on 12 cases of rare atypical thromboses to AZ vaccine (1.93 million doses given, so that’s 1 in 160,000). Three-quarters were under 55 years of age, and mainly in women. These should be subset of the wider European data which EMA says shows no gender or age risk. Germany reported on 31 cases of CSVT, with all but two of the cases in women aged 20 to 63 (most of these cases would have been in the EMA review).

Despite all this, EMA still don’t agree with restricting the vaccine to any particular groups on the basis of the existing safety data, along with the MHRA. However, that could change in time.

There is clearly a safety signal, and the data has increased since it first came to attention. There are mechanisms being looked at. There is a causal story being developed as time progresses, but we aren’t there yet. Both EMA and the MHRA seem to be suggesting that there are no identifiable groups who can be singled out for caution with the vaccine, although that may change in the next week or so. The MHRA are in a rolling review, and EMA’s specialist committee (PRAC) will be addressing AZ vaccine issues between the 6-9th of April.

However, even if there are no special precautions for specific groups can be ascertained, there are two non-AZ vaccine factors that are important:

1. Some groups, as Chris Whitty noted, are at an extremely low risk of COVID-19 mortality.

2. The risk of infection is also falling.

3. We have an alternative vaccine, and possibly more coming for the period when the younger age groups will get access to vaccine.

So even if the mechanism of this rare side effect is unknown, even if we don’t have a proven causal link, and even if we don’t know the groups at risk, we could use the low risk of COVID-19 in some groups, and the availability of alternative vaccines, to make different decisions about AZ vaccine’s deployment.

It’s not impossible that both EMA and the MHRA/JCVI might make different decisions on the AZ vaccine based on careful consideration of new information and of the risk of disease to particular patient groups. Or they might not. But it would be better if those decisions were being taken in a calm scientific manner and communicated as a clear story, rather than appearing as something being urged by anonymous sources. The confusing messaging in the EU, which can’t be blamed on EMA who have been following their plans, seems to have undermined the use of AZ vaccine.

Whatever the outcome, both the EMA and the MHRA will need to have a clear set of reasoning for the decisions, and a message that can told to the public. For those who present any such decisions as ‘Oh look, the MHRA and EMA have changed their minds.’, that’s the point. They are meant to review data on an ongoing basis, and make changes (or not) on the basis of the data. As new data comes in, it either weakens or strengthens the safety signal, but it does not tell you that prior decisions were wrong.

There is a clear benefit to rolling out the vaccine in terms of lives saved at the moment, and decisions need to be finely balanced and cautiously taken.

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That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

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A light post this week. It was a busy week at work, and I’ve spent 16 hours down at the vaccine hub this weekend. The atmosphere at the UK’s vaccines hubs is really something to experience. Looking back on my career in the NHS, before I left patients to work with students, there were many times I really enjoyed working in a great team of people. The best were in multidisciplinary teams. Working in the vaccine hubs is like this all the time. Even when it is super busy, it is a joy to work in them.

It feels like making a difference.

After a year of working remotely, getting back into the a situation where you meet new people, both the work colleagues and the public coming through the hub, is energising. If you want to see how great this country is, go and work in a vaccine hub and meet all the nice people coming in. It’s a great reminder how when people meet people they can see the common humanity in each other. Working in Birmingham you get to meet a diverse mix of people, and it feels like both the staff and the people visiting for a vaccine are all involved in this huge project. Which they are.

AstraZeneca and thrombosis

The British Society of Haematology’s President has drawn attention to the rare cases of thrombosis, associated with low platelets, that this newsletter has covered for the past few weeks, noting the importance of reporting any new suspected cases to the Yellow Card Scheme.

An expert team of our peers have recently been involved in diagnosing and managing a rare syndrome of thrombosis associated with low platelets which have been reported in a few cases. At the moment, any causal association with coronavirus vaccination has not been established. However, if you identify patients with this syndrome in proximity to coronavirus vaccination, it is very important that you complete the online yellow card - this will trigger a request from MHRA for further details.

And this issue has been covered in Science in an interesting article about the issue, although I think it is fair to point out that the case is not closed that the vaccine is causally linked to these events, even though a mechanism is being widely lauded as being found. A biologically plausible mechanism is part of the process of establishing causality, but it isn’t a slam dunk. The decision of the temporary halt of the vaccine by a number of countries was still a mistake in my view until further data was available, especially given the continued high level fo COVID-19 cases in many of these countries.

An ad hoc group is meeting at EMA on Monday to add to the existing EMA assessment, looking at the observed cases, possible risk factors, and potential mechanisms, with a possible update on the EMA position in early April. So the story is ongoing…

Leadership

A nice piece on Chris Whitty…

“He is just a decent bloke. Got a few calls wrong at the start, but otherwise was bang on with advice, is very smart, works hard and is just thoroughly decent to people in a high pressure environment.”

That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

Share Is It Safe?

In the last newsletter I gave a predicted outcome of the EMA review.

• The decisions are likely to due to focus on CVST concerns, although the more general concern about thrombosis will need to be addressed.

• The decisions are not a binary choice between stopping the use of AZ vaccine and continue use of AZ vaccine. Other options exist, such as noting the possible link of a rare adverse effect with the vaccine will exist, even without saying that the link is proven, while at the same time noting that the overall balance of benefit and harms still continues to be favourable.

• There are options around further pharmacopidemiology studies that can be carried out to look at the risk of CVST, and continued analysis of clinical cases reported to look for aggravating risk factors and/or alternate explanations.

• There will be decisions made about how to communicate potential risks to the public. This is always the tricky bit.

This turned out to be pretty accurate.

On Thursday both the MHRA and EMA came out with their review outcomes. The main focus was the issue that was highlighted by Norway and Germany around cerebral sinus venous thrombosis (CVST)1.

This can occur naturally, with an incidence of around 3-4 cases per million (A John Hopkins University source noted 5 cases per million). The Paul Erlich Institute reported 7 cases in 1.6 million vaccinations, which is just over 4 cases per million. Peter Arlett, Head of Pharmacovigilance and Epidemiology Department at the European Medicines Agency, at the press conference earlier in the week noted that epidemiology on such a rare condition isn’t that reliable, and that careful examination of all the clinical cases would be necessary.

The MHRA

The MHRA said that the available evidence didn't suggest a link with venous thromboembolism. They also carried out a detailed review of the 5 cases of CSVT reported in the UK (in 11 million vaccinated individuals, so less than 1 case per million). They noted that these clots could occur naturally, and concluded the link to the vaccine was unproven.

The balance of benefits of the AZ vaccine in preventing COVID-19 were confirmed, although they did suggest that:

• Anyone with a headache that lasts more than 4 days or who have bruising beyond the site of vaccination after a few days seek medical attention.

The EMA

The EMA said (and you can watch the entire press conference if you wish) much the same. They noted the vaccine was not associated with any overall risk of blood clots, but did note that the vaccine might be linked to rare blood clots associated with thrombocytopenia (including CSVT). They noted that in 20 million people vaccinated in the UK and EEA (which also includes those states not in the EU, but covered by EMA) there had only been 18 cases of CVST. They also noted that there had been 7 cases of disseminated intravascular coagulation (DIC).

The Committee’s experts looked in extreme detail at records of DIC and CVST reported from Member States, 9 of which resulted in death. Most of these occurred in people under 55 and the majority were women. Because these events are rare, and COVID-19 itself often causes blood clotting disorders in patients, it is difficult to estimate a background rate for these events in people who have not had the vaccine. However, based on pre-COVID figures it was calculated that less than 1 reported case of DIC might have been expected by 16 March among people under 50 within 14 days of receiving the vaccine, whereas 5 cases had been reported. Similarly, on average 1.35 cases of CVST might have been expected among this age group whereas by the same cut-off date there had been 12. A similar imbalance was not visible in the older population given the vaccine.

They noted that ‘A causal link with the vaccine is not proven, but is possible and deserves further analysis.’

They also advised that

Recipients should be warned to seek immediate medical attention for symptoms of thromboembolism, and especially signs of thrombocytopenia and cerebral blood clots such as easy bruising or bleeding, and persistent or severe headache, particularly beyond 3 days after vaccination.

The Summary of Product Characteristics has now been updated.

As a side note, Peter Arlett suggested the disproportionate cases of CSVT in the EU compared to the UK might be because younger frontline workers (disproportionately women) were more likely to have been given the Pfizer vaccine in the UK since it was largely restricted to hospital sites due to the more complex storage issues.

What now?

The immediate drama over the AZ vaccine’s safety is over, with both EMA and the MHRA in close alignment on their decision making and science. The pause in European countries appears over, with a slight wrinkle in France which I’ll cover later.

Broadly the EMA and the MHRA have managed to stick with their scientific plans for managing the COVID-19 vaccine safety, and an important safety signal has been investigated. In addition, the EMA and the MHRA clearly worked closely together as is necessary. Even though a link is not proven, precautionary advice has been issued to warning both patients, and information healthcare staff (which I have already been using in my role as a vaccinator). Additional pharmacoepidemiological studies will be carried out to look at this safety signal. So the system of pharmacovigilance has broadly worked as it has meant to have worked.

EU state level decision making

The earlier pauses before the EMA review was completed still look to me like a poor set of decisions, and those EU countries that continued vaccinating in the face of rising COVID-19 cases look like they made the right decision. Given the rapidity of the EMA review, carrying on vaccinating would have been the safer option given the rarity of the event of concern.

There’s no point in having a carefully thought through safety plan for COVID-19 vaccines at an EU level that is meant to serve the dual purpose of protecting vaccine confidence and investigating real harm, if individual countries do their own ad hoc plans.

And amazingly, despite the EMA review, France is restricting the AZ vaccine to the over 55s, since most of the cases of CSVT and DIC were in those under 55 years of age.

To my mind the vaccine pauses and the French decision on under 55 year olds undermine EMA, and I am starting to wonder about the nature of the committees making these decisions. Are they always the group with the highest competency in pharmacovigilance? I’m not alone.

Montastruc isn’t the only clinical pharmacologist and world leading expert on pharmacovigilance in France, who has expressed such views.

The French decision was taken by HAS, which isn’t the body that normally oversees medicines in France (and whose stated functions don’t seem to fit pharmacovigilance). The French National Agency of Medicines and Health Product Safety, ANSM, was set up after some high profile safety scandals. It’s priorities were means to be safety and vigilance, so I am not sure why they weren't the ones advising the French government.

The German health Ministry halted the use of the AZ vaccine after advice from the Paul Erlich Institut, whose regulatory responsibility is around biological medicinal products (such as vaccines) in Germany, but not the Federal Institute for Drugs and Medical Devices (BfArM). I can’t help wondering if they might have come to a different decision around the pause, if they had consulted each other.

In contrast, Belgium seemed to have relied on its pharmacovigilance body FAMHP, which resisted the pressure to pause the AZ vaccine. They stuck with the calmer approach of EMA throughout the week, even to the extent of cheekily asking for an extra AZ vaccine from countries pausing the AZ vaccine to be sent to them.

Certainly, it appears that some individual states were struggling with making proportionate decisions in the face of concerns over the past week, and perhaps ought to consider reviewing their regulatory alignment on pharmacovigilance with EMA’s scientific processes and expertise in pharmacovigilance.

While the EU may have messed up vaccine procurement, they continue to have a world class medicines safety regulator that EU states should listen to.

Further reading

David Spiegalhalter and Anthony Masters Don’t Fear the AstraZenaca jab, the risks are minimal.

That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

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A midweek posting because things have moved fast on the AZ Covid-19 vaccine, and tomorrow is a big day at EMA, so I thought I would gather some thoughts and links together before that.

Summary of where we are

Around 13 countries have suspended, or paused, the use of the AZ vaccine at this moment in time. A broad concern about reports of thrombosis were the initial concern, but some countries (Norway and Germany) have reported on a very rare cerebral venous sinus thrombosis (CVST) associated with platelet deficiency.

The concern about a more general safety issue around thrombosis something that needs looking at, but would appear to be no higher a risk than would occur if the same patients had not been vaccinated. The cases of CVST are more interesting, and need more work on. The Paul-Ehrlich-Institut (PEI) have now published an English language document on their analysis. [PDF] That document includes 6 younger to middle aged women (20-50 years of age), and another case of cerebral haemorrhage with platelet deficiency and thrombosis. It occurred 4-16 days after vaccination, and the PEI carried out a rapid observed-versus-expected analysis:

The number of these cases after vaccination with COVID-19 AstraZeneca is statistically significantly higher than the number of cerebral venous thromboses that normally occur in the unvaccinated population. For this purpose, an observed-versus-expected analysis was performed, comparing the number of cases expected without vaccination in a 14-day time window with the number of cases reported after approximately 1.6 million AstraZeneca vaccinations in Germany. About one case would have been expected, and seven cases had been reported.

Three of the 7 cases died.

The PEI notes that there isn’t a causal relationship proven yet, and this is still very rare, and in the document they produced they make comments about the comparison with the oral contraceptive (which carries risks of thrombosis) which has been made. They note that women are meant to be made aware of this risk and it is listed in the Summary of Product Characteristics of oral contraceptives. They then rightly refer this on to the European Medicines Agency to make a judgement.

They also recommend to pause the use of the AZ vaccine in Germany. I’ll park that now and come back to it.

So what are EMEA going to do?

Yesterday EMA held a press conference about AZ vaccine. You can watch the recording here.

From this it seems clear to me that EMA intend to stick to their well thought out plans on how to deal with the safety of the COVID-19 vaccines. Some of the things (not exhaustive) that came out of this conference:

• More reports of thrombosis have been submitted since this became a media topic (This is known as notoriety bias).

• EMA are looking at all vaccines with regard to this issue.

• EMA still think the balance of benefits versus harms means the AZ vaccine should still be licensed.

• Peter Arlett’s mastery on pharmacovigilance and how this issue should be approached in broad terms was illuminating.

• The number of cases of thrombosis is lower than might be expected.

• The rare and usual cases of CVST is something they will look at very carefully, and due to the limited epidemiological data for the condition, clinical case analysis is the main focus.

EMA will be reporting on this on Thursday at some point (presumably later in the day given the complexity of the analysis and debate will have to be had.

What will happen?

Well, let’s see, but I think some points can be made about what is likely to weight on decisions being made. It was pretty clear from the conference yesterday that EMA have a competent plan and will be driven by the standard paradigm about balancing harms and benefits, and use of evidence.

So:

• The decisions are likely to due to focus on CVST concerns, although the more general concern about thrombosis will need to be addressed.

• The decisions are not a binary choice between stopping the use of AZ vaccine and continue use of AZ vaccine. Other options exist, such as noting the possible link of a rare adverse effect with the vaccine will exist, even without saying that the link is proven, while at the same time noting that the overall balance of benefit and harms still continues to be favourable.

• There are options around further pharmacopidemiology studies that can be carried out to look at the risk of CVST, and continued analysis of clinical cases reported to look for aggravating risk factors and/or alternate explanations.

• There will be decisions made about how to communicate potential risks to the public. This is always the tricky bit.

Back to the pause

My criticism of the vaccination paused isn’t based around some simplistic notion that we should not discuss potential vaccine harms. Having open transparent discussion of such signals is extremely important for public trust. My concern was that the vaccine safety plans around detection, confirmation, decision making, and communication that were in place at EMA seemed to be being supplanted by knee-jerk decisions at a local level.

So, I’m really glad that EMA seem to be back in the driving seat on this issue.

Now they may be technically within their rights to do this, but it does not mean it was the right decision. The pandemic is still ongoing, and cases (including deaths) are going up in many European states. We also have the AZ vaccine being shipped throughout the world via the COVAX scheme, so anything we do should be done in a cautious controlled manner, that is also open and transparent.

My own personal view is that all of these countries should have carried on without pausing the vaccine, referring the matter to EMA as they have done. Given the rarity of the events in 17 million vaccinations, a pause of a few days is likely to cause far more harm from missed vaccinations and damage to public confidence in vaccines than being open about the issues referred to EMA and not pausing. This is the approach, for example, that Belgium had.

Reversing the pause if EMA makes a decision that vaccine’s balance of benefits and harms is still favourable will be difficult. ‘You said there was a problem 4 days ago!’ some people will say, ‘How can you say it is safe now!’

This goes back to my criticism of the use of the precautionary principle by some of the countries involved. I’ve written a quick piece on this at The Conversation.

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.

I’ve also been a few radio stations and TV stations recently, and this is my piece for the BBC where I talk about this.

Other things worth reading:

Stuart Richie Europe’s AstraZeneca vaccine suspension is bad science that will cost lives.

Derek Lowe What is Going on With the AstraZeneca /Oxford vaccine

Tom Chivers How safe is the AstraZeneca jab

Matthew Herper The curious case of AstraZeneca’s Covid-19 vaccine

David Spiegelhalter There's no proof the Oxford vaccine causes blood clots. So why are people worried?

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That’s all and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

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I thought it was interesting to get some quick thoughts down about the recent suspension in use of the Astra-Zeneca (AZ) vaccine in some EU states, despite the European Medicines Agency’s confidence in the vaccine. So this post is about some of the decision making being made in the light of the concerns about reports of thrombosis after vaccination, how regulatory convergence seems further away than ever, and how misapplication of the precautionary principle is not the cost-free 'erring on the side of caution' option that some seem to think it is.

Let's start by saying that vaccines are a nightmare for regulatory agencies. They provide a future benefit, and immediate risks (even if small). If you have heart failure or cancer, you might be concerned about the risk of side effects from a treatment, but you know that you want the benefit. For a vaccine, the benefit follows an infection the person may or may not get - we'll leave aside the wider benefits of reduced transmission and herd immunity for simplicity.

In the case of COVID-19 vaccines, the high prevalence of cases and a relatively high mortality rate make the decision clear enough for most people, especially with the high effectiveness of all the vaccines we are seeing. Again, we'll leave to one side other motivations that the vaccination campaign also promises. The 'return to normal'. Meeting your family. Not teaching students via Zoom (a big personal driver of mine there).

In the face of a global pandemic, the largely mild transient side effects of the vaccines are a price that most people think are worth paying (to varying degrees, but even the low uptake groups in the UK are over 50%).

However, a long history of vaccines scares and concerns have existed since the invention of vaccination. All drugs have an effect on your body, but there is something about vaccines that seems more invasive. This means that decision making and communication about the safety of vaccines is fraught. Every step needs to be taken carefully, and disaster can strike when poor decisions are made. Think Indiana Jones working his way across a floor that triggers poison arrows, only to blow it when switching his bag of sand for a gold statue.

Regulatory agencies have been thinking about how to create public confidence in vaccines for months. Both the UK's MHRA and the EU's EMA have extensive plans for pharmacovigilance for these vaccines. This is to ensure that we can monitor the ongoing safety of the vaccines in the population, but also to ensure that public confidence in the systems for monitoring the vaccines is high. Both have tried to involve the public and to be transparent about reported harms of vaccines. Both have set up new systems and studies to look for safety signals.

For years there has also been interest in global convergence in pharmacovigilance and drug safety, to try and align regulators like EMA and the FDA. You can also see this in the arguments from some that the FDA ought to licence the AZ vaccine in the states. As recently at the end of February 2021 the International Coalition of Medicines Regulatory Authorities (ICMRA) met to discuss the global response to COVID-19 and International collaboration on vaccine safety.

A workshop was held:

'The participants of this workshop stressed that joint work among regulators was needed in order to learn from each other, take appropriate mitigating measures (where needed) and communicate in a consistent way across regions to build and maintain public trust in vaccines.'

There was support for a Tabletop Simulation exercise to look for real areas for co-operation:

'This could look on a known suspected adverse event of special interest as a test case, for example Bell’s palsy, or the alert raised when Norway reported deaths in frail elderly vaccinees. Other comments related to the importance of collaboration to understand better background incident rates, as well as differential benefit-risk for different populations and the importance of consistent responses at global level.'

The Norwegian frail patient story noted above was an early COVID-19 vaccine story, which while important, did not seem to expose major differences in approach.

So the good news first, in response to the Danish decision to withdrawn the AZ vaccine the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) are currently investigating the cases of thromboembolic events, and in a recent press release (11/3/2021) emphasised the benefits of the AZ vaccine outweighed the risks.

'There is currently no indication that vaccination has caused these conditions, which are not listed as side effects with this vaccine. The position of EMA’s safety committee PRAC is that the vaccine’s benefits continue to outweigh its risks and the vaccine can continue to be administered while investigation of cases of thromboembolic events is ongoing.'

This aligns with the UK's MHRA view published on the same day.

'This is a precautionary measure by the Danish, Norwegian and Icelandic authorities. It has not been confirmed that the report of a blood clot was caused by the AstraZeneca COVID-19 Vaccine. People should still go and get their COVID-19 vaccine when asked to do so.'

The key point is that 'Reports of blood clots received so far are not greater than the number that would have occurred naturally in the vaccinated population.' In the UK over 11 million doses of Az have been used, but there is no signal in the UK data.

The WHO have said that the Astra-Zeneca COVID-19 vaccine should continue to be used since there is no indication that this risk is true.

So, we have convergence and a good message on this issue.

But something has gone wrong in the EU.

The Netherlands, Bulgaria, Denmark, and Ireland have all paused the use of the AZ vaccine. So have Iceland and Norway. While the latter aren't EU states, they are somewhat tied into EU, since marketing authorisations from the EU are valid in all EU states and European Economic Area (EEA) and European Free Trade Association (EFTA) states, and also their decisions are reported in the media as "European". Austria stopped the use of a single batch after one recipient had a clot, and Estonia, Latvia, Lithuania and Luxembourg stopped using that same batch. Others, such as Germany, are sticking with the AZ vaccine. The German Health minister Jen Spahn saying 'From what we know so far, the benefit... is far greater than the risk'. [UPDATE 15/3/2021 Germany has now suspended the AZ vaccine, and Macron has annouced the suspension in France]

The issue seems to be a misapplication of the precautionary principle. Here's Ireland's Deputy Chief Medical Officer:

'Dr Glynn added that he hoped there will be more "reassuring data" this week and that the programme can restart.

"It may be nothing, we may be overreacting and I sincerely hope that in a week's time we are accused of being overcautious," he said.'

The Dutch also cite the precautionary principle.

The precautionary principle, which originally came from environmental concerns, is not an easy fit to pharmacovigilance. An excellent article by Callréus covers this, noting that its use would lead to false positive signals.

Given the large number of false positive signals generated by various data-mining strategies, a parsimonious application of the precautionary principle would be warranted in this area or else the number of market withdrawals would be unreasonable.

So we need to apply the precautionary principle to the precautionary principle when it comes to drug safety. Callréus argued the precautionary principle needs to be adapted for drug safety use:

'Originating from a criticism of traditional risk assessment, the key element of the precautionary principle is the justification for acting in the face of uncertain knowledge about risks. More recent is its appearance in public health and in relation to drug safety issues. Rather than either embracing or rejecting the precautionary principle, studying the experience gained from its previous applications should be the way forward. If believed to be of relevance, in order to avoid arbitrary and unpredictable decision making, its interpretation and possible application need to be adapted to the conditions of pharmaceutical risk management.'

The EMA COVID-19 vaccine plan included their safety monitoring and risk management plan and they helpfully include a pictorial pharmacovigilance cycle.

Here it is.

Sadly, it now seems to be working like this.

It feels like trust in the institutions of EU, have been damaged following the failure of the vaccination programme.

What is the point of having a European Medicines Agency with well thought through plans on vaccine safety if individual EU states are going to do knee-jerk decisions, misapplying the precautionary principle?

In two weeks time, how much confidence will the public have in the AZ vaccine it starts to be used again by states that suspended it on poor evidence? Confidence in the AZ vaccine is already low in the EU with 1 in 4 refusing it, in preference for the Pfizer-BioNTech vaccine. ‘Erring on the side of caution’ is reducing public confidence in vaccines in a pandemic?

What will the effect of this be in the UK, Germany and other states that do back the AZ vaccine? A hyper-connected world, where information is spread on social networks cross borders means that these decisions are not contained within the countries where they are taken. More worryingly, what effect will this have on vaccine hesitancy in countries receiving the AZ vaccine via COVAX? What effect will it have on the public view of vaccination safety in general?

How can you have global regulatory and pharmacovigilance convergence when the decisions of the EMA are second guessed by individual governments? Does local political accountability means that such convergence can only ever be limited in nature?

All the plans in the Pharmacovigilance Plan of the EU Regulatory Network for COVID-19 Vaccines seem to have been ignored as individual members of the EU, arguably with less expertise than EMA go their own way.

Everyone's got a plan until they are punched in the face as they say, and this pandemic has dealt a right hook to rational decision making about vaccine safety.

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That’s all for this week and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

Share Is It Safe?

I was on a panel addressing student concerns about COVID-19 vaccination in our College at the University of Birmingham this past week. We has a great panel of scientists, clinical practitioners, and a local Imam to address concerns. You might think that students on healthcare courses and biomedical don’t have concerns, but they are no different from those already qualified and the general public. The same rumours fly around on WhatsApp and other social media. Merely being on a science degree is not protection against social pressures. But generally, there was a high quality of sensible questions, and it was a useful session.

This tweet comes from Independent SAGE, who should know better.

This is terrible ambiguous framing. Not sure if the ‘Do you feel safe?’ refers to the vaccine safety or if the recipient feels safe from COVID-19.

Independent SAGE is in danger of making an increasing number of missteps as the end game of the COVID-19 pandemic pans out. If they perceive they are becoming insignificant, they may be tempted to make increasingly ‘hot takes’ to gain attention. This will carry reputational risk for those involved, so I am surprised that more aren’t quietly leaving the room now they have had the media attention. I suspect will create an independent SAGE inquiry into the pandemic, and an independent SAGE future pandemic preparedness plan. Oh well.

This article by Hilda Bastian on the ‘100% effective and deaths and hospitalisations’ meme that is common on twitter in The Atlantic is well worth your time.

The data were indeed suggestive of an encouraging idea. Based on the numbers so far, we can expect the vaccines to provide extremely high levels of protection against the most dire outcomes. Still, we don’t know how high—and it’s clear they won’t uniformly cause hospitalizations and deaths from COVID-19 to disappear in vaccinated people.

I think this is important. Too simplistic a message can backfire once you start to get cases of the vaccinated being hospitalised or dying (as is likely given the numbers of people involved). ‘You told us they were 100% effective for death!’ will be the cry, and trust will be the victim.

And you can be vaccine optimist and still think this.

Timing is everything

The German Standing Committee on Vaccination (STIKO) has changed its recommendations on the Astra-Zeneca Vaccine. Initially they did not approve its use in the over 65 year old population, but they have now reversed that decision and brought in a 12 week gap for the AZ vaccine (as in the UK). The BBC report on this change, and draws attention to the low uptake and confidence in the AZ vaccine in EU state. A recent YouGov poll highlights this.

It is notable that the European Medicines Agency did licence the AZ vaccine in older patients. This isn’t a story about an EU institution making a mistake. EMA said (my emphasis):

Most of the participants in these studies were between 18 and 55 years old. There are not yet enough results in older participants (over 55 years old) to provide a figure for how well the vaccine will work in this group. However, protection is expected, given that an immune response is seen in this age group and based on experience with other vaccines; as there is reliable information on safety in this population, EMA’s scientific experts considered that the vaccine can be used in older adults.

The German STIKO committee made a different decision than both EMA and the UK’s Joint Committee on Vaccination and Immunisation (JCVI). STIKO appears to have the same make-up as the JCVI, with experts from ‘pediatrics, family medicine, occupational medicine, virology, immunology, epidemiology, public health, and evidence-based medicine.’ It’s not even that they made a ‘wrong’ decision, since there was a lack of data in the older age group.

STIKO seemed to have failed to make an imaginative leap and take the risk of a relatively sure bet based on known science. This has to be placed in the context of a pandemic that is preferentially killing older individuals. Not making the decision the JCVI made has had consequences, both in terms of reducing vaccine supply to the over 65s and in reducing confidence. It would be fascinating to look at the cultures of the JCVI and STIKO in terms of decision making. The JCVI acknowledged the risk of the decision they made, and made it. Possibly brave, but it was a calculated risk that was more than likely to pay off. The STIKO decision was taking a risk with inaction, that on the balance of evidence would be proved wrong. Changing the decision now, after getting confirmatory evidence for the effectiveness in the over 65s, does not give you the same benefit as making the decision the JCVI made weeks ago.

Sometimes a difficult decision made early, is better than an easy decision made later.

It also worth noting that STIKO has brought in the 12 week gap for the AZ vaccine, as in the UK. In the UK there is a certain type of politically partisan activist on social media which has delighted in calling the UK’s delayed dose strategy ‘partial vaccination’, suggesting it was a policy to spin how the UK’s vaccination policy was doing well, rather than a scientific decision that will save lives. Not sure what they think now.

I don’t for one minute think the STIKO decision is the root of all problems with perception of the AZ vaccine in the EU. As soon as it was licenced early in the UK there were German MEPs saying that the regulatory processes in the EU were better than those in the UK, which would have rubbed off on the vaccine, extremely poor media reporting about efficacy in the German Press, and Macron calling it quasi-effective can’t have helped. Clearly the differential trust between the AZ and the other COVID-19 vaccines is about more than the normal cultural differences around vaccination across Europe.

It’s not all about mRNA

The mRNA vaccines are a step change in vaccine technology, but let’s hear a round of applause for the lipid nanoparticles (LNPs) that the fragile mRNA needs to get into your cells and do its magic. They are the unsung heroes of the COVID-19 pandemic and there is years of science behind their development. Chemical and Engineering News has great article on the development of LNPs, and the potential pitfalls, including toxicity.

The vaccines, appropriately celebrated as a first for mRNA technology, are also a milestone for the nanoparticle field. Although the first drug based on an LNP was approved by the US Food and Drug Administration for a rare genetic disease in 2018, the two authorized mRNA vaccines for COVID-19 present a far bigger opportunity for the nanoparticles than even the field’s founders can imagine. “It is a tremendous vindication for everyone working in controlled drug delivery,” says Robert Langer, a chemical engineer at the Massachusetts Institute of Technology.

“LNPs will be going into millions of arms over the course of this year,” says University of British Columbia nanoparticle scientist Pieter Cullis. “What was a fringe field back in the 1980s has turned into something that is mainstream now.”

The BMJ’s Rapid Response system

I tweeted the above this week. As you can see in my tweet, it looks as though the BMJ website has a story titled “Deep concern over vaccination safety”. They don’t. The link is actually to a rapid response to a BMJ article. The BMJ has no concerns about vaccine safety, but the rapid response suggests deaths from the Pfizer and Moderna vaccine “are off the scale” based on reports to the US Vaccine Adverse Events Reporting System (VAERS). This is nonsense. I’m not going to counter it now because of Brandolini's law, but I can assure you that this is utter nonsense.

The rapid response is written by John Stone, the UK editor of Age of Autism. He has a track record of posting material about vaccines on the internet since the turn of the century. He was a frequent commentator at one of the leading UK anti-MMR websites in the 2000s (JABS), and every blogger in the 200s writing about the UK anti-vaccine movement would have come across him.

He uses rapid responses (or those of similarly minded people) as references in posts on other websites. This gives the appearance of BMJ articles supporting his argument, when all they are links to his own arguments or other non peer-reviewed comments. To an uninformed reader, this link looks more impressive that it actually is: https://www.bmj.com/content/372/bmj.n393/rr-4

Rapid responses are relatively easily posted at the BMJ website, and I’m not sure the BMJ should be letting posts about COVID-19 vaccines of this nature be published on their platform, but they definitely should not look like BMJ articles in shortened form on social media.

The Drug Safety Ghost

Did you know there is a ghost, called Lizzie Church, who haunts University College Hospital. She was a trainee nurse in the late 1800s who accidentally overdosed her fiancé on opium, and then killed herself. She apparently hovers over patients receiving morphine today, protecting them from overdose.

That’s all folks. Stay safe.

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Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme

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I’ve been working at a local vaccine hub over the weekend. It’s been an interesting return to ‘frontline’ practice as a pharmacist, not least because I keep meeting old colleagues and former students. Everyone is tired, so it is a good thing the lockdown appears to be having a great effect on case numbers and hospitalisations, and the vaccine effect is starting to kick in the older age groups.

Talking to patients who have concerns about the vaccines, mainly around ingredients other than the mRNA, has also been fun, but I’m still meeting and hearing of healthcare professionals who haven’t had the vaccine yet, and The Times is reporting over 200,000 frontline NHS staff have not been vaccinated.

But an analysis of official figures reveals that large numbers have still not been vaccinated. Overall, 91 per cent of frontline NHS staff and 72 per cent of care home workers have had a first dose. These figures mask considerable regional variations: about 97 per cent of frontline NHS staff have been vaccinated in the northeast, compared with 76 per cent in London.

The concerns I have heard aren’t much different from the ones that the public have had, including the rumours from social media.

The relative speed of development of the vaccines seems to be the sticking point for some, who are waiting to ‘see what happens’. I’m convinced that part of this comes what we each about the process of drug development at undergraduate level, often highlighting the difficulties and time it takes. There was also some understandable downplaying of expectations about vaccines early in the pandemic that may have stuck in the public consciousness. A private chat with a friend also brought up the fact we are continually told something to cure [insert your disease of choice] will be along in 3-5 years to to cure the disease. It never comes, so the fact this one came within a few months makes people skeptical about it, especially if they are ignorant of the prior work that was leveraged to get the vaccines so quickly.

For healthcare professionals though, I still find it shocking. I think we perhaps need to do more to during undergraduate education to avoid this in future. I haven’t got a fixed view on this, and it goes against my general view on public vaccination, but mandatory COVID-19 vaccination for healthcare professionals looks like a morally defendable position.

Vaccine Hesitancy

There’s a couple of publications about vaccine hesitancy that are worth a read. Chevallier et al offer three recommendations, including testing communications campaigns (pre-registered study designs), using behavioural insights [your mileage may vary on the utility of psychology to deliver] to make vaccination accessible (most of which I think the UK vaccination system has covered), and leveraging the power of social norms.

Have you seen a vaccine card on social media? Got vaccine envy? Good! One of the side benefits of the delayed dose strategy in the UK is that is doubled the expansion of the people spreading vaccination as a social norm. Chevalier et al also note that many initial refuseniks change their mind. This appears to be true…

Since, public support for vaccination in the UK is rising.

Ben Ansell, Professor of Comparative Democratic Institutions at the Department of Politics and International Relations, says, ‘This multi-wave study gives us a rare glimpse of whose opinions have shifted and why. People have become massively more supportive of taking the vaccine overall but important gaps remain especially among groups whose trust in politicians is typically lower: non-voters, younger citizens, and poorer households.’ 

Even though there are gaps that need addressing, In most cases the norm is to be pro-vaccination. I really think that is the message that needs to be got across. It is too easy to accidentally suggest that the norm is the opposite.

I found this graph from the more detailed report of the study very reassuring.

The ONS note over 90% of people would be likely to have the vaccine if offered, but they do report differences in ethnicity. Black or Black British are a particular concern, although hopefully this position may be better in the end (see above).

20 million people have been vaccinated now. There are no significant safety signals arising. The benefits of the vaccines will start to be seen in combining weeks. Let’s be optimistic and hope that positive views become even more common.

Prioritisation

The JCVI have set out their plan to carry on working down through the age groups, and the clinically vulnerable. If you have worked in a vaccine hub screening area, you’d be aware of just how difficult it is to use any criteria other than age. Even determining frontline status in some people can sometimes be awkward, and people have been turned away who got hold of a link they should not have been forwarded. Your GP doesn’t know your job either. Any supposed benefit would be lost in the bureaucratic nightmare of running anything more complicated. There’s also an interesting paper demonstrating focusing on age saves the most lives, when applied to US, German, and South Korean data.

Faxes cost lives

This piece on the comparative failure of Germany’s vaccination campaign is interesting for multiple reasons, but faxes might surprise you. In the UK, Matt Hancock made faxes ‘illegal’ in 2018 in the NHS, but in Germany they are surprisingly not well digitalised and still use thousands of faxes.

Take the fax machines. A technological dinosaur elsewhere in the West, fax machines remain a mainstay in many medical practices and government health offices. That has made coordination across Germany’s nearly 400 health offices particularly difficult. Health Minister Jens Spahn has spent millions trying to put German health care online, so far with only mixed results. 

The fax is merely a symptom of a deeper problem, however. Angela Merkel has talked for years of the necessity to “digitalize” German society, a goal that many other advanced economies have long made a reality. Indeed, the first thing many new arrivals in Germany notice is its lack of connectivity, from the dearth of free Wifi in cafes and restaurants to slow internet speeds. The fact that the German federal government itself still employs nearly 1,000 fax machines in its various ministries tells you everything you need to know about how successful Merkel’s digital revolution is. 

That said, the 1970s technology is comparatively modern to the pen and paper still in use across Germany’s medical profession. That a government can’t rely on antiquated communications tools to immunize Germany’s 83 million inhabitants quickly should be obvious. 

There are also issues around data privacy concerns…

Denmark is going great guns, and unlike the UK is in the EU scheme so can be compared directly with Germany. They are well above the EU average and should be done by June. Part of this is they are banging out single doses, and not holding vaccine back for second doses as some countries are, but also because Denmark isn’t using faxes…

A highly organised and digitised healthcare system in Denmark is key. Aarhus University professor and virologist Soren Riis Paludan points out that on a typical day, Denmark tests 150,000 people for Covid-19. (For comparison, with a similar population size the Republic tested 105,400 people in the past week.)

A digital ID database that public authorities use to communicate with citizens about everything from pensions to daycare places will help the vaccination plan. It means authorities can sort citizens by age, and send out vaccination invitations directly to their mandatory digital inbox.

BMJ Webinar on vaccines

If you have time, this BMJ webinar is worth watching, if only for Ben Goldacre’s comments about lockdown hair at 55 seconds.

The real highlights for me were Susanne Hodgson’s overview of the vaccines at 6:30, Ben Goldacre’s talk on OpenSAFELY at 25:37 (which I think is an amazing piece of work in terms of size and the methods), and Rick Malley on the vaccine dose schedules at 38:31. Well worth a listen.

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That’s all folks. Stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme

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Safety in vaccines is tricky. Unlike most drugs, we give vaccines to healthy people, including a lot of childhood vaccinations, so any harms of a vaccine are extremely important. They influence the threshold of whether a regulator would licence a vaccine at a population level or choose to take a vaccine at an individual level.

The background rate of disease you might otherwise suffer is also important. Yellow Fever vaccine is mandated in many countries, and currently the only disease for which proof of vaccination may be required for travel, but it is associated with serious side effects with a prevalence of 1 in 100,000 - more common in those over 60 years of age. So, even if you are in good health, if the disease in question is serious enough, and prevalent enough, at an individual level some risk can be acceptable.

In the case of the COVID-19 vaccines, the rare reports of anaphylaxis and more common vaccine side effects like feeling groggy, headaches and sore arms seem a worthwhile risk compared to the risk of COVID-19 and its various outcomes. That’s even before you factor in the more widespread societal benefits of herd immunity and opening up society. I mean, we all want to see that Bond film eventually…

Clinical trials of vaccines can find the frequency of more common adverse effects, and can follow-up on unexpected events that might occur in the cohort months down the line. That said, there have been times when clinical trials have found issues with vaccines (a good example is rotavirus vaccine) that required increased vigilance when a vaccine was released more widely. The fact that the COVID-19 trials had no such safety signals to start with is good news.

It is only after wider use of vaccines in the real world that we can find rare and novel events which might exist. So far in the UK, the data from the MHRA’s Yellow Card scheme surveillance of the COVID-19 vaccines shows that the vaccines are safe. The Yellow Card scheme depends on reporters (either patients, carers, or healthcare professionals) reporting suspected adverse drug reactions via the Yellow Card Website. It’s a quick system, so this is great news that nothing has arisen.

However, this is just one part of the safety monitoring. The MHRA had been planning since May 2020 for the roll-out of these vaccines:

1. To rapidly detect, confirm, characterise and quantify any risks not detected in clinical trials, and weigh these against expected benefits.

2. To maintain public confidence by rapidly establishing if any serious events occurring after vaccination are truly casual in nature, and not just co-incidence.

The first point I have already covered, and the second point is extremely important. In any population there is a background rate of events happening all the time. So far there have been over 17 million people vaccinated, mostly in priority groups. Just looking at care home residents alone, it is fair to say there there will have been no end of events which have happened in this cohort of vaccinated people after they received the vaccine. Deaths, new diagnoses, all sorts of rare events will have happened. The key is knowing which of these events is linked to the vaccines, and which are merely co-incidents. Clearly, co-incidental events can be exploited by anti-vaccine groups and state disinformation campaigns (such as those run by China and Russia).

The MHRA are using 4 main approaches to safety monitoring.

1. Enhanced Passive Surveillance

This is essentially the Yellow Card scheme. I don’t like to call it passive myself since, spontaneous reporting depends on active efforts of reporters, and happens in real-time (unlike pharmacoepidemiology studies which retrospectively mine databases which have lain passive until they are looked at), but that’s just me. I wish we didn't undersell spontaneous reporting with the word passive. I think we use the word passive entirely the wrong way round in this respect.

They have enhanced the Yellow Card Scheme by tying in background rates of events from the Clinical Practice Research Database (a database created from GP electronic healthcare data) and having good information on how many people and which type of people have been vaccinated.

Let’s imagine a number of cases of people developing a totally imaginary ‘blue nose” adverse effect which is reported on Yellow Card reports. The MHRA can go away and see how many cases of ‘blue noses” turn up naturally in the CPRD. If the Yellow Card “blue nose” cases are larger than might be expected given the naturally occurring frequency of ‘blue noses’ in the CPRD, then it would be more likely it would be a real effect of the vaccine. Otherwise, it might be just a co-incidence. Those people were going to get blue noses anyway. So this observed versus expected is really useful on sifting out real signals of safety from the chaff of false signals. The MHRA also have to take into account the under-reporting in the Yellow Card scheme, which is common.

2. Electronic healthcare record surveillance

So, this is slower than Yellow Card data, but doesn’t require people to report a suspected adverse effect to a vaccine (so avoids the risk of something not being reported). As your vaccination status is updated in your GP record, the MHRA will start to run Rapid Cycle Analysis, which will be looking for theoretically possible adverse events each week. They can choose new types of possible adverse events to look as they go forward (so if they had reports of ‘blue noses” from Yellow Cards, they could start to look for those). This system should also be even better at filtering out false signals. The MHRA will also be able to look at events in large population cohorts based on the prioritisation groups, they can then compare events that happen pre-vaccination and post-vaccination (this is called an ecological analysis).

3. Targeted active monitoring

The MHRA are also going to active go looking for certain groups of vaccinees, especially those groups of patients who were not recruited into the clinical trials. A random number of people will be selected (about equivalent to a clinical trial sized group) and they will be contacted to see if they have experienced an adverse drug reaction at set intervals of time. This won’t find rare events (for the same reason clinical trials don’t, so no “blue noses” here), but it should lead to a comparator group of patients who didn't fit in the clinical trials (like those who are immunocompromised - who would have been excluded from clinical trials to test vaccine efficacy for obvious reasons). This will add additional safety information for those groups.

4. Formal epidemiological studies

These are the standard safety studies run with drugs and vaccines after marketing. They tend to be used when you think you have a safety signal. “Hey, we have some sort of signal about blue noses, let’s set up a pharmacoepidemiogical study to see if this is real or not.”

The MHRA have a lot of resources to run these, but they can also be set-up with academic units and other organisations who are specialist at running these sorts of studies.

If you want to know more about the MHRA’s plans, all of the above is in greater detail at the MHRA website here. The MHRA have put a lot of thought, planning, and effort in trying to ensure they can find any adverse effects to the COVID-19 vaccines. Firstly, we need to be able to find any such effects, if they exist, in order to minimise their effects (by finding which groups are more at risk). Equally importantly, this helps ensure that there is public confidence in the vaccines and the monitoring, and that if there are new adverse effects we are actively looking for them, and able to counter any incorrect information about adverse effects that may arise (for example from some patient anecdote in a newspaper or social media).

If you have had any of the COVID-19 vaccines, and are in the UK, you can report any adverse effects you experience here on a Yellow Card.

You can find the weekly COVID-19 vaccine adverse reactions page here.

How else can you help find adverse effects to the COVID-19 vaccines?

The ZOE app

Those using the ZOE app, as part of the COVID symptom study can log their vaccines in the App. They have reported fairly mild short-lived reactions found in the clinical trials, and more symptoms after the second dose (as you would expect).

After getting the Pfizer jab, around four in ten people experienced some local after effects, including pain and swelling on the arm where they received the injection. 

Around one in seven also recorded systemic after effects including headache and fatigue, which are in line with the after effects reported in the clinical trial. The reported after effects were short-lived, lasting just a day or two, and we haven’t seen any evidence of longer term health effects.

Interestingly, people recorded more symptoms after the second dose of the vaccine compared with the first. And people who had previously had COVID-19 were also more likely to have after effects following a single jab, compared with those who had never had the disease.

The DSRU study

The Drug Safety Research Unit (DSRU) are running the Active Monitoring of the Safety of COVID-19 Vaccines Study.

The study will recruit at least 10,000 people in the Phase I vaccination group, which includes all those aged over 50, health and social care workers and people who are clinically extremely vulnerable.

The study will use short questionnaires which include questions about the vaccination and your health and any symptoms/conditions following vaccination.

Register your interest here. They are specifically looking for those who have had the Oxford/AZ vaccine at the moment.

So there’s a lot of work being done on safety with COVID-19 vaccines, which should be massively re-assuring. So far, they appear to be hugely effective, even with one dose, and reduce transmission. There is a light at the end of the tunnel.

Quick bits…

Bad-mouthing of the Oxford vaccine by EU politicians comes back to haunt them.

Single dose Pfizer-BioNTech vaccine has 92.6% efficacy, which backs up the JCVI decision. NEJM.

A 3 month gap between AZ/Oxford vaccine doses is better then 3 weeks, which backs up the JCVI decision. The Lancet.

Also big contributions from the EU, the US, and Germany to COVAX. Most of the UK surplus will go to the poorest countries.

The best way to reduce the chance of variants arising is to vaccinate everywhere as quickly as possible and drive down transmission. It’s entirely reasonable that national governments consider their citizens first—that’s realpolitik.

Once the UK has vaccinated our most vulnerable communities and healthcare workers, however, we should make vaccines available to other countries. It’s enlightened self-interest, as well as the right ethical thing to do.

Jeremy Farrar in the BMJ.

The British public agrees.

That’s all for this week and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

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I think I reached my limit on Zoom teaching on Friday. Six hours of it led to my brain imploding. Here’s a few things that may be of interest…

Misinformation and low quality academia

Stuart Ritchie on some of the poor practice that has been endemic in academia and highlighting the flaws in research. Well worth reading.

As so often in academia, a well-meaning idea—the fast-tracking of reviews to improve the pace of scientific progress in a pandemic—worked poorly in practice. That’s because it collided with the toxic academic publish-or-perish culture, where longer CVs mean greater prizes – in the form of tenure, promotion, and other career rewards. Academics had a lot to gain by taking advantage of the rapid reviews, even if their actual scientific contribution was questionable. Combine that with a genuine desire to help out—as well as the fact that many scientists whose labs were closed by lockdowns were otherwise twiddling their thumbs, so tried their hand ineptly at some COVID research—and you have a recipe for an epidemic of tossed-off, low-quality papers.

Another piece to read alongside this is Renée DiResta is in The Atlantic: ‘Virus Experts Aren’t Getting the Message Out’

In the case of the coronavirus, the worst-case predictions of some of those early prescient voices on social media were borne out, even as some city leaders were telling the public—in March—to keep going out to theaters and the CDC was still insisting that only a very narrow group of Americans needed to be tested. Frontline doctors and scientists emerged in droves as the pandemic spread, posting on Twitter, Medium, and Reddit to tell the public about the number and severity of cases they were seeing in their hospitals; their stories further contradicted earlier reassurance from institutions that the flu posed a more serious risk to the United States. And so a meta-debate began: Why were social-media companies elevating the WHO and the CDC when some of their information turned out to be incorrect? And if agencies like these were wrong about COVID-19, what else were the so-called experts wrong about?

Vaccine hesitancy

There’s a couple of interest UK sources on vaccine hesitancy. First a pre-print (I know!) looking at uptake in healthcare professionals of the COVID-19 vaccine, which has some perhaps surprising results, and some that tally with prior concerns. Younger healthcare professionals had worse uptake, but surprisingly doctors had lower uptake than other healthcare professionals, even after multivariate analysis taking into account ethnicity (itself linked to uptake as other studies have found). So, a lot of things to potentially think about, and it is only from one hospital site.

On the other hand…. Some good news on overall refusal rates.

The ONS social survey found that, overall, only one person in 100 offered vaccination had declined, but with variation between age groups. The figure for those aged 30-49 was 5 per cent; for the 50-69s it was 2 per cent, and for the over-70s it was less than 1 per cent.

Good news. Good vaccines. Good uptake. Fingers crossed, a good year.

There is clearly work to do on vaccine hesitancy in some groups, and a need to address individual recipient’s concerns, but I can’t help thinking the length of the pandemic’s effects on our society. and high case rates. give vaccine hesitancy a slightly different flavour. The test will be as we see cases fall, and younger age groups less likely to see a personal benefit from the vaccine.

For that reason, despite my support for not prematurely lifting lockdowns, I find some of the signalling that vaccines won’t lead to changes in how we can operate socially a little concerning. Some might think, why bother getting vaccinated if it isn’t going to improve matters?

The Oxford Vaccine

A good profile of the Oxford vaccine’s Sarah Gilbert and Andrew Pollard in The Guardian. This bit stuck out for me.

“just as researchers have made rapid changes in their work practices to produce vaccines, so has the public understanding of that work altered, said Pollard. “It is only when you go outside the office, you realise the whole world knows about clinical trials and safety reporting and regulators in a way that they never did before. It seems everyone is watching what we’re doing – which is not an experience I have ever had before. Indeed it’s always been quite difficult to persuade people to take an interest in my work!”

I do think a better public understanding of regulation and clinical trials would allay the fears of those who think COVID-19 vaccines were rushed…

Patient groups and drug safety

An interesting paper by Chincilla et al in Drug Safety around patient groups in pharmacovigilance.

Patient organizations also present some ideological limitations regarding their involvement in drug safety activities; they are more likely to participate actively when they have been affected by ADRs in the group, and some organizations consider they would only engage if there is a problem among their members. This situation exposes the lack of systematic integration of patient organizations into the PV community.

There are clearly issues with patient organisations, especially industry funding, but getting them involved in pharmacovigilance is essential.

That’s all for this week and stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

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Reassuring data on COVID-19 vaccines

Vaccines are still given to healthy people and by June 2021 the expectation is that all adults will have been vaccinated. Ensuring we can rapidly find any unknown adverse effects is essential. That is where the Yellow Card Scheme comes in. It is a spontaneous reporting scheme for adverse effects. Spontaneous because it depends on the ‘spontaneous’ decisions of healthcare professionals, patients, and carers making a link between some adverse event someone taking a drug or vaccine experiences and having a suspicion that it might be linked to the use of the drug or vaccine they have taken.

You might think that collecting what are essentially case reports is a fairly useless way of finding adverse events compared to clinical trials or data-mining routine healthcare data. It isn’t. One analysis found such reports contributed to 95% of drug withdrawals. That vigilance and suspicion from reporters is valuable. You need a haystack and a needle to find a needle in a haystack, and spontaneous reporting systems provides both (assuming there is a needle to find, which there might not be).

Clinical trials have deficiencies in finding rare adverse events (greater than 1 in 10,000 people) because of the cohort size, but in the UK now over 12 million people have had a single dose of the AZ vaccine or the Pfizer vaccine. If there are rare but serious adverse effects of the vaccines, this provides a big enough pool of individuals to see potential adverse effects - assuming they are reported. Even with under-reporting rates of 94%, you can still find signals of potential harms. The other benefit is speed. This is real-time data that can be collected quickly as the vaccine programme rolls out.

So far, the MHRA are reporting ‘that the safety of these vaccines remains as high as expected from the clinical trial data that supported the approvals. The safety profile of the vaccines remains positive and the benefits continue to far outweigh any known side-effects.’ Between the 9 of December 2020 and 24 of January 2021, this equates to 3 reports per 1000 vaccinations. Most of this is mild, like sores arms and flu-like symptoms. Of course, as already mentioned there will be quite a high level of under-reporting so sore-arms and flu-like symptoms will probably be far more common. That said, what the MHRA will be concerned about is more serious rare events.

The MHRA don’t just depend on clinical trials and the Yellow Card Scheme, and have a well thought out pharmacovigilance plan you can read here. There will be targeted studies and pharmacoepidemiological studies. I’ve been working in a vaccine hub, and have been impressed by the record keeping, which is going to pay off in the future when these safety studies are conducted.

The MHRA have published a summary of the safety data, as well as individual reports on each vaccine (list here). Up to the 24th of January 2021 the MHRA had received 6,014 reports of suspected adverse effects to the AZ vaccine, and 16,756 reports to the Pfizer vaccine (remember that vaccine had a month’s head-start, so you can’t compare using reports). Amazing only 50 reports were to an unspecified COVID-19 vaccine. In total 101 reports of anaphylaxis were received to the Pfizer vaccine (all recovered), and 13 to the AZ vaccine. Initial advice for people with a history of anaphylaxis to any medicine, vaccines and food to avoid the Pfizer vaccine after some earlier reports was dropped, and now only ‘a previous history of allergic reactions to the ingredients of the vaccine’ are the reason to avoid the Pfizer vaccine.

There have also been some reports of Bell’s Palsy, a form of facial paralysis (which eases with time), but this appears to be not linked to the vaccines. Bell’s Palsy occurs at a natural rate in the population in the absence of the vaccine, so if you vaccinate millions of people, some will coincidently develop Bell’s Palsy after the vaccine is administered without any causative mechanism. The same goes for deaths following the vaccine, particularly when given to frail older patients who were in the initial wave of vaccinations. The trick is to monitor the rates to ensure that they are not higher than one would normally expect in the population.

Overall, this is great news, and the MHRA’s plans for safety monitoring and transparency should give the public trust in the processes in place to ensure safety. As a last point, it has to be re-iterated that this is nothing different than the roll out of any other vaccine or drug. All drugs and vaccines have provisional safety details until used in the wider population, so the COVID-19 vaccines are no more theoretically dangerous in that respect than anything else. However, given the importance of ensuring public trust and ensuring that vaccine hesitancy is minimised, everything the MHRA are doing is important.

If you have been vaccinated, you can report any side effects at this special site: Yellow Card Scheme

Covid Symptom Study

The COVID symptom study are also collecting adverse effect data on the vaccines via their app. Their data appears to have a higher rate of reporting, allowing them to make these statements about the minor groggy symptoms and sore arms:

We found that around one in seven people who received one dose of the vaccine experienced at least one systemic effect within seven days of their jab. 

We also found that around four in ten people who received their first dose had at least one after effect in their arm, most commonly pain and swelling in the day or two after the jab. 

Most symptoms happen in the first two days after vaccination, with headache, fatigue and chills or shivers being the most common

They also find the second dose seems to have more of these minor side effects. These sorts of frequencies certainly tally with the admittedly totally anecdotal data I’ve been receiving from friends and family.

Mixing vaccines

At the start of January there was talk about the UK having a mixed-vaccine dosing strategy, but this was false. However, there were plans for studies to examine if this was a way forward, since there are obvious benefits if this could be done in case of vaccine shortages. The COVID-19 Heterologous Prime Boost study, or ‘Com-Cov’, is now recruiting across eight sites in the UK.

Delayed Doses

The decision by the JCVI to delay UK second doses of COVID-19 vaccines appears to have paid off. Anthony Harnden, deputy chairman of the JCVI, is reported in the Sunday Times as suggesting that the PHE has data, soon to be published, that show that high levels of protection are coming from the first dose of vaccine, reducing infections and mortality. Who knew that the JCVI carefully applying domain expertise to limited clinical trial data to make a decision in a time sensitive context would be a good idea? Delaying that decision until a trial had been done would have meant more deaths. It seems a good call now, especially when data is starting to emerge of a stronger immune response with a longer interval between dosing for the AZ vaccine. In Israel, where 90% of people aged over 60 have had a single dose of the Pfizer vaccine, there seems to be an age specific drop off in COVID-19 cases as well.

Variants

I’ve stopped doom-scrolling about variants. You could spend all day everyday worrying about nightmare scenarios, but until there is really bad news I don’t see the point worrying too much. Slow news is better for you. Tom Chivers has a good piece about variants and what they mean in UnHerd. There is concern about the South African variant, with Oxford University saying their their vaccine offers minimal protection against mild-moderate COVID-19 infection. However work is already being done on the 2nd generation of the AZ vaccine, and Prof Sarah Gilbert is pretty confident that the vaccine still provides some protection against deaths and hospitalisations.

Given we are going to be dealing with COVID-19 for years, getting into a cycle of despair about this on an hour by hour basis seems pointless. We might be in a game of cat and mouse with it for years, but the next 12 months should still be better than the last 12 months. Other companies are developing mRNA vaccines to deal with multiple variants, and there is a rising global capacity in vaccine production. While the variants are a concern that experts need to be on top of, I’m not losing any sleep over them.

COVID conspiracies and information

Researchers at KCL have been looking at social media use and COVID-19. They found social media users were more likely to believe in conspiracy stories. For example:

‘56% of people who believe there’s no hard evidence Covid-19 exists use Facebook as a key information source, almost three times higher than the proportion of non-believers who do (20%).’

Quelle surprise!

Aside from carrying out Buzz Aldrin’s method of persuasion, he punched someone who said he never went to the moon, how do we reach these people? Adam Grant, who has an excellent new book out, has an article out in the New York Times: The Science of Reasoning With Unreasonable People with a suitably immunological metaphor for changing people’s minds:

When we try to change a person’s mind, our first impulse is to preach about why we’re right and prosecute them for being wrong. Yet experiments show that preaching and prosecuting typicallybackfire — and what doesn’t sway people may strengthen their beliefs. Much as a vaccine inoculates the physical immune system against a virus, the act of resistance fortifies the psychological immune system. Refuting a point of view produces antibodies against future attempts at influence, making people more certain of their own opinions and more ready to rebut alternatives.

It’s worth remembering that even the guy Aldrin punched in the face didn’t change his mind….

I already noted earlier how the MHRA was being transparent, and the Full Fact have an interesting report [PDF] called ‘Fighting a pandemic needs good information’, which supports this approach.

It’s better to get on someone’s emotional level and be honest and transparent, rather than beating them over the head with facts.

Other things I came across this week I think are worth reading:

Dhruv Kullar in The New Yorker on how vaccination will change his behaviour. ‘While waiting for new data to come in, or for those around me to get vaccinated, I’ll continue wearing full protective gear when caring for patients. And I’ll keep avoiding close contact with friends and loved ones who aren’t vaccinated.’

Rowland Manthrope at Sky on how the UK Vaccine Deal came about, Bruno Macaes in UnHerd on Why the EU lost the vaccine war, and an interesting interview in La Republica with Kate Bingham who was behind the UK’s vaccine procurement plan (You can see her slide set and an end of year report on the plan online).

The UK had a very strategic approach, which was to secure vaccines quickly. And the European approach seems to be more sort of a more typical procurement approach, which was more about making sure you got the best value for money for your vaccines. 

Stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines and vaccines. In the UK, this means using the Yellow Card Scheme.

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