As I said back in October, delivering a successful Covid-19 vaccine quickly was a huge challenge, but the diversity of the UK’s vaccine portfolio and the amendments made to the Human Medicines Regulations 2012 (HMRs) meant that the UK was in a strong position to carry out a successful mass vaccination programme as soon as a vaccine could demonstrate its safety, quality and efficacy. Six months later, two vaccines have been widely administered in the UK (AstraZeneca/Oxford and Pfizer/BioNTech) – as of 3 April 2021, 31,523,010 first doses and 5,381,745 second doses have been administered. A third vaccine is also now available (Moderna).
One of the key changes I discussed back in October was to Regulation 214 of the HMRs. Previously, only doctors and other qualified prescribers could administer vaccines. Now, under newly inserted Regulation 247A, a wider range of persons are able to safely administer a licensed or temporarily authorised Covid-19 or flu vaccine. As a St John Ambulance volunteer vaccinator, I’ve spent a lot of time at the ExCeL London NHS Covid-19 vaccination centre over the last few months, and have seen the impact of this change first hand. Under national protocols, after extensive training, I’ve had the opportunity to work with pharmacists, nurses, paramedics, doctors, medical students and other volunteers to deliver the Covid-19 vaccine to citizens in East London. Relying on Regulation 247A, the NHS has been able to make use of a huge number of volunteers and retired healthcare professionals to support, and speed up, the mass vaccination programme.
Another key change to the HMRs relates to temporary licensing conditions. Both the AstraZeneca/Oxford and Pfizer/BioNTech vaccines are temporarily authorised under Regulation 174 of the HMRs and, in a similar way to marketing authorisation conditions, are subject to various conditions. For both vaccines, various safety-related conditions are placed on AstraZeneca, Pfizer and BioNTech, including:
- to provide further data that is generated by them, or which otherwise come into their possession, which is relevant to the risk / benefit profile of the vaccine;
- to respond in a timely manner to any requests for further supplementary data relating to the vaccine; and
- to operate a comprehensive pharmacovigilance system in accordance with UK legislation for licensed products, as if they were marketing authorisation holders.
AstraZeneca is also subject to an obligation to promptly and regularly liaise with the Medicines and Healthcare products Regulatory Agency (the MHRA) to ensure the safety specification of its vaccine is adjusted in light of evolving data.
Vaccine Yellow Cards
The Yellow Card scheme run by the MHRA, which is the UK’s system for collecting safety information relating to medicines and medical devices, is particularly important in the case of temporary licensing and will assist AstraZeneca, Pfizer and BioNTech in meeting these conditions.
Side effects/adverse incidents reported on so-called ‘Yellow Cards’ by healthcare professionals and members of the public are evaluated by the MHRA’s team of doctors, pharmacists and scientists, together with other available data, in order to identify unknown safety concerns and continuously assess the benefits and risk profile of each medicine or medical device.
The most recently published safety report for the UK covers data up to 21 March 2021. On that date, 40,883 Yellow Cards had been reported for the Pfizer/BioNTech vaccine and 99,817 Yellow Cards had been reported for the AstraZeneca/Oxford vaccine – this gives an overall reporting rate of around 3 to 6 Yellow Cards per 1,000 doses administered for both vaccines.
It is important to remember that a Yellow Card report does not necessarily mean there is a causal link between the relevant medicine and the adverse event. Many suspected adverse drug reactions reported on Yellow Cards are coincidental and not related to the relevant medicine – Yellow Cards are monitored to differentiate possible new side effects from events that would have happened regardless of whether or not the relevant medicine was administered. For example, for the Yellow Cards relating to both vaccines, there have been 127 reports of crying, 12 reports of electric shocks, 9 reports of clavicle fractures and 3 reports of dark circles under the eyes.
As with other types of vaccines, the overwhelming majority of reports relate to short-term injection-site reactions and generalised symptoms such as ‘flu-like’ illness, headache, chills, fatigue, nausea and fever. Two specific concerns continue to be monitored extremely closely by the MHRA and the Commission on Human Medicines (the CHM), as well as international regulators:
- severe allergic reactions – on 30 December 2020, the MHRA’s independent scientific advisory body, the CHM recommended that anyone with a previous history of allergic reactions to the ingredients of the relevant vaccine should not receive it. The MHRA continues to monitor reports of serious allergic reactions; and
- rare and specific blood clots – up to 24 March 2021, 22 reports of cerebral venous sinus thrombosis and 8 reports of other thrombosis events with low platelets had been reported out of a total of 18.1 million doses of the AstraZeneca/Oxford vaccine given by that date. On 7 April 2021, the MHRA announced that there were 79 case reports of blood clots associated with the low platelets reported so far, with 19 deaths, whilst over 20 million doses of the AstraZeneca/Oxford vaccine have now been given – this gives an overall risk profile of 4 per 1,000,000. The MHRA concluded that, whilst it is a strong possibility and the evidence is strengthening, more work is needed to prove beyond doubt that these clots are caused by the vaccine. However, both the MHRA and the Joint Committee on Vaccination and Immunisation (the JVCI) reinforced the message that the risk of these clots is extremely low. Similarly, on the same day, the European Medicines Agency announced that these blood clots should be listed as a very rare side effect of the vaccine, but the benefits of the vaccine still outweigh the side effects and no EU-wide restrictions will be put in place.
The importance of the risk/benefit profile
Even where there is a causal link between a medicine and certain adverse events, the risk/benefit profile has to be considered as a whole. The reality is that all medicines can cause severe side effects, and all have a risk of, for example, interaction with other medicines and conditions. Around the world, approximately 1.35 million people a year die from road traffic accidents, yet we still use cars.
Medicines regulators around the globe will generally approve a medicine for use where its benefits outweigh its known risks. For each medicine, this balance will be continuously reviewed as new data becomes available, and may change over time and vary for certain groups of people and in different countries. The Covid-19-vaccines are no different. The modelling of potential benefits against potential risks of the AstraZeneca/Oxford vaccine discussed by the MHRA and JVCI on 7 April 2021 shows that the risk/benefit is positive for all adults except those aged 18 to 29 in a low exposure scenario (Covid-19 incidence of 2 per 10,000; roughly the UK in March), and the risk/benefit ratio is positive for all adults in a medium exposure scenario (Covid-19 incidence of 6 per 10,000; roughly the UK in February) or a high exposure scenario (Covid-19 incidence of 20 per 10,000; roughly the UK at the peak of the second wave). On this basis, the JVCI has recommended that adults aged 18 to 29 with no underlying health conditions are offered an alternative vaccine when available.
Over 2.8 million Covid-19 deaths have now been reported around the world and many countries have spent the best part of a year in lockdown – as the MHRA’s Chief Executive June Raine said, ‘the balance of benefits and known risks is still very favourable for the vast majority of people’. The fact that the MHRA’s review has resulted in updated JVCI advice shows that the pharmacovigilance systems in place are working.