Brazilian health authority Anvisa announced on Wednesday that a volunteer on the AstraZeneca & Oxford University joint trial of a potential COVID-19 vaccine had died. Although AstraZeneca’s share price fell 1.8% as a result, the pharmaceutical company said there were no concerns about the safety of either the clinical trial or the vaccine, and that the trial would continue.

A death of a volunteer during the course of a clinical trial is known in the pharmaceutical industry as a “serious adverse event.” Serious adverse events include an occurrence among trial volunteers that:

  1. Results in death;
  2. Is life-threatening;
  3. Requires patient hospitalisation or prolongs existing hospitalisation;
  4. Results in significant disability;
  5. May have caused a birth defect or congenital anomaly; or
  6. Requires intervention to prevent permanent damage.

While reporting of serious adverse events in the press (particularly during the current pandemic) may cause alarm, events such as these are common during late-stage clinical trials. This is partly because late-stage clinical trials involve large numbers of participants: in the case of the COVID-19 vaccine for example, 8,000 people had been given the vaccine in Brazil. By pure chance alone, some clinical trial participants will fall ill or even die during the course of any clinical trial, even if they have not been given the drug or vaccine being tested. Because many clinical trials, especially those for vaccines, last many months or years, deaths or other serious adverse events are more routine than not.

It is to be expected that some clinical trials will involve the deaths of participants, such as in trials for proposed new treatments of terminal conditions such as cancer, or for diseases of the elderly. In these cases, the treatment being tested may aim to increase the average longevity of a patient, or to alleviate suffering during end-of-life care. In such an instance, statistical analysis can be used to ascertain whether people receiving the trialled treatment had a significant increase in longevity or improvement in quality of life, particularly when compared to treatments currently available.

In the case of a vaccine trial death, the first question that will be addressed is whether the person had received the test vaccine. That is because, during a clinical trial, test subjects are initially divided randomly into two groups: one group goes on to receive the trialled vaccine, while the other receives a placebo (which can sometimes be a dummy pill, or a treatment or a vaccine for another disease: in the case of the COVID-19 clinical trial, the placebo is a vaccine for meningitis). Working out whether a specific test participant has received the trialled vaccine causes a problem for the regulatory authorities presiding over the clinical trial, because essential to the clinical trial process is something called double blind randomisation of test subjects.

This means that test subjects are divided randomly and anonymously between the placebo and treatment group. But more importantly, the term “double blind” means that no-one involved in the clinical trial, from the medical professionals administering the vaccine to the test participants themselves, knows which cohort individual participants are in. If they did, it may compromise the test results: the behaviour of clinicians may be affected if they have knowledge of whether a participant is taking the test drug or the placebo. Also, participants may suffer from the placebo effect, in which the presence of side-effects or perceived improvement in their condition is entirely caused by their mental expectations.

For this reason, needing to ascertain whether an individual trial participant is in the trial group or the placebo group poses a challenge: no one directly working on the vaccine would be able to access this information. In this instance, a monitoring committee, which has no involvement in the clinical trial and may even reside in a country other than that of the trial participants, must meet and deanonymise the patient in question in order to reveal whether they had received the trialled vaccine. This process can take around a week, so usually a clinical trial will halt until this has happened.

In the case of the AstraZeneca COVID-19 vaccine, the deceased trial participant was revealed to have received the placebo, so their death was unrelated to the COVID-19 vaccine. But if they had been found to have received the vaccine, the monitoring committee would have urgently sought further information about the deceased participant, to ascertain whether there were any safety concerns with the vaccine. Similar would take place in the case of other serious adverse events. In fact, the same AstraZeneca vaccine has halted trials in the US temporarily, while the FDA reviews the safety of the vaccine after one participant developed symptoms of transverse myelitis. Health authorities in other countries, including the UK, have permitted the vaccine trial to continue. Given that this process can take a considerable length of time, during which a clinical trial will be halted, serious adverse events such as this can be financially costly to pharmaceutical companies.

Serious adverse events in large clinical trials are routine. So when you read in the press about a death or illness in individuals on vaccine trials, don’t panic or fear that hope for a COVID-19 vaccine has gone: chances are, the incident has nothing to do with the vaccine.

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