Fast-tracking vaccine development for COVID-19 is almost inevitable. We can’t wait the usual decade or more because COVID-19 has such a high morbidity and mortality among vulnerable groups.
But condensing a process that usually takes 10 to 15 years into just 12 to 18 months has consequences. There will be gaps in our knowledge, such as identifying rare and long latency side effects. The challenge is how to expedite development without compromising the safety and efficacy of these vaccines. One way we can address gaps in our knowledge (which exist even with vaccines that undergo conventional development programmes), is to implement rigorous post-authorisation monitoring programmes, a topic we explored in our recent paper published in the BMJ Evidence Based Medicine.
More than 176 COVID-19 vaccine candidates are at various stages of development and 34 are already in clinical trials. As soon as one is licensed for public use, a Risk Management Plan will be implemented which will almost certainly stipulate that post-authorisation safety and effectiveness studies are carried out. Studying the safety and effectiveness of a COVID-19 vaccine is a continuum between ‘pre’ and ‘post-marketing’ phases. For COVID-19 vaccines, these real-world post-authorisation studies provide a vital safety net ensuring the collection and analysis of much more data than was possible in clinical trials.
While clinical trials will detect frequent adverse events, to detect rare events occurring at a low frequency, a Phase III clinical trial would likely need to enrol very large numbers of individuals. This will not be feasible for a COVID-19 vaccine, as clinical trial cohorts are likely to be smaller. However, post-authorisation studies could include several hundred thousand vaccinees or more.
Fast-tracking through Phase II and III clinical trials is foreseen for COVID-19 vaccines. But limiting the duration of observation in fast-tracked Phase II to Phase III studies to six months could potentially miss clinically significant changes in antibodies. By comparison, a post-authorisation study could report incidence of COVID-19 infection among vaccinees over many years.
There are different methodologies for conducting post-authorisation studies and it is important that researchers select the most appropriate options for studying the safety and effectiveness of COVID-19 vaccines.
For example, systems for spontaneous reporting of adverse drug reactions while important to raise signals, are ‘passive’, relying on patients or healthcare professionals to report suspected adverse events and concerns related to effectiveness. For COVID-19 vaccines, it will be important to conduct ‘active’ surveillance studies that prompt patients to report adverse events or lack of efficacy. This means researchers would actively seek to collect data at specific time points for everyone vaccinated and enrolled in the studies, regardless of whether they experienced an adverse event. This approach would reduce the potential for underreporting and bias.
Gathering information from both vaccinees and healthcare professionals would allow for more comprehensive identification of outcomes. This kind of active surveillance was used to monitor the safety of the vaccination developed in response to the 2009-2010 global H1N1 influenza A (swine flu) pandemic.
Monitoring vaccine use in the real-world will show not just whether there are issues with a vaccine itself, but also how natural conditions, such as the seasons changing and increasing infections, impact on the vaccine programme. Data collected for the research would help public health decision-makers understand the demographic characteristics of those who are vaccinated and, crucially, people who did not receive the vaccine too.
Post-authorisation studies can also play a key role in improving public confidence in vaccine safety and efficacy. A UK poll conducted by the Royal Society of Public Health revealed one in five individuals either would not choose to be vaccinated or were not sure. Early and accurate reporting on the safety and effectiveness of any COVID-19 vaccine could help dispel concerns and mistrust about the vaccine and improve take-up.
To make these studies work we will need good collaboration and partnership between stakeholders such as the National Institute for Health Research (NIHR) Clinical Research Networks (CRN), the NHS and the Medicines and Healthcare products Regulatory Agency (MHRA), to ensure we get large numbers of people vaccinated and enrolled in the studies.
The scope, longevity and flexibility possible with post-authorisation studies, means they can provide a crucial safety net in developing COVID-19 vaccines. After all, new COVID-19 vaccines need to meet as high as practicable the same standards of quality, safety and efficacy as vaccines that have followed the conventional development cycle.
Professor Saad Shakir is director of the Drug Safety Research Unit (DSRU) near Southampton, UK
