COVID-19, due process and an SNR problem

At a press conference streamed live on March 18, the head of the European Medicines Agency (EMA) announced that the body – which serves as the European Union’s drug and vaccine regulator – had concluded that the AstraZeneca COVID-19 vaccine was not associated with unusual blood clots that some vaccine recipients had reported in multiple countries. The pronouncement marked yet another twist in the roller-coaster ride the embattled shot has experienced over the past few months. But it has also left bioethicists debating how it is that governments should respond to a perceived crisis over vaccines during a pandemic.

Over the last two weeks or so, a fierce debate raged after a relatively small subset of people who had received doses complained of developing blood clots related to potentially life-threatening conditions. AstraZeneca, a British-Swedish company, didn’t respond to the concerns at first even though the EMA and the WHO continued to hold their ground: that the vaccine’s benefits outweighed its risks, so people should continue to take it. However, a string of national governments, including those of Germany, France and Spain, responded by pausing its rollout while scientists assessed the risks of receiving the vaccine.

Aside from allegations that AstraZeneca tried to dress up a significant mistake during its clinical trials of the vaccine as a ‘discovery’ and cherry-picked data from the trials to have the shot approved in different countries, the company has also been grappling with the fact that the shot was less efficacious than is ideal against infections by new, more contagious variants of the novel coronavirus.

But at the same time, the AstraZeneca vaccine is also one of the more affordable ones that scientists around the world have developed to quell the COVID-19 pandemic – more so than the Pfizer and Moderna mRNA vaccines. AstraZeneca’s candidate is also easier to store and transport, and is therefore in high demand in developing and under-developed nations around the world. Its doses are being manufactured by two companies, in India and South Korea, although geographically asymmetric demand has forced an accelerating vaccination drive in one country to come at the cost of deceleration in another.

Shot in the arm

Now that the EMA has reached its verdict, most of the 20 countries who had hit the pause button have announced that they will resume use of the vaccine. However, the incident has spotlighted a not-unlikely problem with the global vaccination campaign, and which could recur if scientists, ethicists, medical workers and government officials don’t get together to decide where they can draw the line between abundant precaution and harm.

In fact, there are two versions of this problem: one in countries that have a functional surveillance system that responds to adverse events following immunisation (AEFIs) and one in countries that don’t. An example of the former is Germany, which, according to the New York Times, decided to pause the rollout based on seven reports of rare blood clots from a pool of 1.6 million recipients – a naïve incidence rate of 0.0004375%. But as rare disorders go, this isn’t a negligible figure.

One component of the post-AEFI response protocol is causality assessment, and one part of this is for experts to check if certain purported side-effects are clustered in time and then to compare those to the illness’s time distribution for a long time before the pandemic. It’s possible that such clustering could have prompted health officials in Germany and other countries to suspend the rollout.

The Times quoted a German health ministry statement saying, “The state provides the vaccine and therefore has special duties of care”. These care considerations include what the ministry understands to be the purpose of the rollout (to reduce deaths? To keep as many people healthy as possible?) read together with the fact that vaccines are like drugs except in one important way: they’re given to healthy – and not to sick – people. To quote Stephan Lewandowsky, an expert of risk communication at the University of Bristol, from Science:

“You’ve got to keep the public on board. And if the public is risk-averse, as it is in Europe … it may have been the right decision to stop, examine this carefully and then say, ‘The evidence, when considered transnationally, clearly indicates it is safe to go forward.’”

On the other hand is the simpler and opposing calculus of how many people didn’t develop blood clots after taking the vaccine, how many more people the virus is likely to have infected in the time the state withheld the vaccine, how many of them were at greater risk of developing complications due to COVID-19 – topped off by the fact of the vaccines being voluntary. On this side of the argument, the state’s carefulness is smothering, considering it’s using a top-down policy without accounting for local realities or the state’s citizens’ freedom to access or refuse the vaccine during a pandemic.

Ultimately there appears to be no one right answer, at least in a country where there’s a baseline level of trust that the decision-making process included a post-vaccination surveillance system that’s doing its job. Experts have also said governments should consider ‘mixed responses’ – like continuing rollouts while also continuing to examine the vaccines, given the possibility that a short-term review may have missed something a longer term exercise could find. One group of exerts in India has even offered a potential explanation.

The background rate

In countries where such a system doesn’t exist, or does but is broken, like India, there is actually one clear answer: to be transparent and accountable instead of opaque and intractable. For example, N.K. Arora, a member of India’s National COVID-19 Task Force, told The Hindu recently that while the body would consider post-vaccination data of AstraZeneca’s vaccine, it also believed the fraction of worrying cases to be “very, very low”. Herein lies the rub: how does it know?

As of early March, according to Arora, the Union health ministry had recorded “50-60” cases of AEFIs that may or may not be related to receiving either of the two vaccines in India’s drive, Covaxin and Covishield. (The latter is the name of AstraZeneca’s shot in India.) Reading this with Arora’s statements and some other facts of the case, four issues become pertinent.

First is the deceptively simple problem of the background rate. Journalist Priyanka Pulla’s tweets prompt multiple immediate concerns on this front. If India had reported 10 cases of disease X in 20 years, but 10 more cases show up within two weeks after receiving one dose of a vaccine, should we assume the vaccine caused them? No – but it’s a signal that we should check for the existence of a causal link.

Experts will need to answer a variety of questions here: How many people have disease X in India? How many people of a certain age-group and gender have disease X? How many people of different religious and/or ethnic groups have disease X? How many cases of disease X are we likely to have missed (considering disease-underreporting is a hallmark of Indian healthcare)? How many cases of disease X should we expect to find in the population being vaccinated in the absence of a vaccine? Do the 10 new cases, or any subset of them, have a common but invisible cause unrelated to the vaccine? Do we have the data for all these considerations?

Cornelia Betsch, a psychologist at the University of Erfurt, told Science that “most of the cases of rare blood disorders were among young women, the group where vaccine hesitancy already runs highest”. Can India confirm or deny that this trend is reflected in its domestic data as well? This seems doubtful. Sarah Iqbal reported for The Wire Science in September 2020 that “unequal access to health”, unequal exposure to potentially disease-causing situations, unequal representation in healthcare data and unequal understanding of diseases in non-cis-male bodies together already render statements like ‘women have better resistance to COVID-19’ ignorant at best. Being able to reliably determine and tackle sex-wise vaccine hesitancy seems like a tall order.

The second issue is easy to capture in one question, which also makes it harder to ignore: why hasn’t the government released reports or data about AEFIs in India’s COVID-19 vaccination drive after February 26, 2021?

On March 16, a group of 29 experts from around the country – including virologist T. Jacob John, who has worked with the Indian Council of Medical Research on seroprevalence surveys and has said skeptics of the Indian drug regulator’s Covaxin approval were “prejudiced against Indian science/product” – wrote to government officials asking for AEFI data. They said in their letter:

We note with concern that critical updates to the fact sheets recommended by the CDSCO’s Subject Expert Committee have not been issued, even though they are meant to provide additional guidance and clarify use of the vaccines in persons such as those with allergies, who are immunocompromised or using immunosuppressants, or using blood thinners/anticoagulants. There are gaps in AEFI investigations at the local level, affecting the quality of evidence submitted to State and National AEFI Committees who depend on these findings for making causality assessments. The National AEFI Committee also has a critical role in assessing cases that present as a cluster and to explore potential common pathways. In our letter dated January 31, 2021, we asked for details of all investigations into deaths and other serious AEFIs, as well as the minutes of AEFI monitoring committees, and details of all AEFI committee members and other experts overseeing the vaccine rollout. We have not received any response.

City of Omelas

The third issue is India’s compliance with AEFI protocols – which, when read together with Pulla’s investigation of Bharat Biotech’s response to a severe adverse event in its phase 3 trials for Covaxin, doesn’t inspire much confidence. For example, media reports suggest that medical workers around the country aren’t treating all post-vaccination complaints of ill-health, but especially deaths, on equal footing. “Currently, we are observing gaps in how serious adverse events are being investigated at the district level,” New Delhi-based health activist Malini Aisola told IndiaSpend on March 9. “In many instances local authorities have been quick to make public statements that there is no link to the vaccine, even before investigations and post mortem have taken place. In some cases there is a post mortem, in some cases there isn’t.”

Some news reports of people having died of heart-related issues at a point of time after taking Covishield also include quotes from doctors saying the victims were known to have heart ailments – as if to say their deaths were not related to the vaccine.

But in the early days of India’s COVID-19 epidemic, experts told The Wire that even when people with comorbidities, like impaired kidney function, died due to renal failure and tested positive for COVID-19 at the time of death, their passing could be excluded from the official deaths tally only if experts had made sure the two conditions were unrelated – and this is difficult. Having a life-threatening illness doesn’t automatically make it the cause of death, especially since COVID-19 is also known to affect or exacerbate some existing ailments, and vice versa.

Similarly, today, is the National AEFI Committee for the COVID-19 vaccination drive writing off deaths as being unrelated to the vaccine or are they being considered to be potential AEFIs? And is the committee deliberating on these possibilities before making a decision? The body needs to be transparent on this front a.s.a.p. – especially since the government has been gifting AstraZeneca’s shots to other countries and there’s a real possibility of it suppressing information about potential problems with the vaccine to secure its “can do no wrong” position.

Finally, there’s the ‘trolley problem’, as the Times also reported – an ethical dilemma that applies in India as well as other countries: if you do nothing, three people will get hit by a train and die; if you pull a lever, the train will switch tracks and kill one person. What do you do?

But in India specifically, this dilemma is modified by the fact that due process is missing; this changes the problem to one that finds better, more evocative expression in Ursula K. Le Guin’s short story The Ones Who Walk Away from Omelas (1973). Omelas is a fictitious place, like paradise on Earth, where everyone is happy and content. But by some magic, this is only possible if the city can keep a child absolutely miserable, wretched, with no hope of a better life whatsoever. The story ends by contemplating the fate of those who discover the city’s gory secret and decide to leave.

The child in distress is someone – even just one person – who has reported an AEFI that could be related to the vaccine they took. When due process plays truant, when a twisted magic that promises bliss in return for ignorance takes shape, would you walk away from Omelas? And can you freely blame those who hesitate about staying back? Because this is how vaccine hesitancy takes root.

The Wire
March 20, 2021