Regulatory approval of COVID-19 vaccines in the UK

With several COVID-19 vaccine candidates at the final stage of clinical trials and the recent claims of promising interim results from trials involving four of them, regulatory approval of COVID-19 vaccines has become a widely discussed topic in Parliament.

Until the end of the transition period of the UK’s withdrawal from the EU (31 December 2020), the European Medicines Agency (EMA) is responsible for granting licences to allow companies to market COVID-19 vaccines. The UK Government has recently amended its legislation which would allow vaccines to be authorised for temporary use in the UK (prior to licensing) in response to a pandemic.

On 10 November, the Secretary of State for Health and Social Care announced that he had tasked the NHS to prepare for a vaccination programme from any date after 1 December. On 2 December, temporary authorisation for use in the UK has been granted to one COVID-19 vaccine. Priority groups for immunisation have been recommended by the Joint Committee on Vaccination and Immunisation (JCVI), based on epidemiological data, risk from COVID-19 to people in different groups, available data on the vaccines and modelling on the impact of different vaccination programmes.

This article will focus on COVID-19 vaccine regulatory approval, immunisation priorities and people’s attitudes towards COVID-19 vaccines in the UK.

Vaccine development: where are we?

There are currently over 200 COVID-19 vaccines in development. 11 of these are at the final stages of clinical trials (Phase 3). These involve several thousand people who are naturally exposed to circulating SARS-CoV-2, some of whom have received the vaccine.

Phase 3 trials are critical to identify rare side effects and to evaluate whether the vaccine produces enough immunity to prevent COVID-19 symptoms and/or reduce the transmission of the virus. Phase 3 trials usually have two separate expected completion dates:

• The ‘primary completion date’: when data on primary outcomes, the most important aspects for evaluating the effect of the treatment, are collected. There can be different primary outcomes, for example divided according to age groups of the volunteers (does the vaccine work as well in older adults as it works in younger adults?).
• The ‘study completion date’: when all data on primary outcomes, secondary outcomes (aspects not as important as the primary outcomes, but still of interest) and side effects are collected.

In the case of COVID-19 vaccines, an example of a primary outcome would be the number of symptomatic COVID-19 cases 2 weeks following vaccination and a secondary outcome the number of symptomatic COVID-19 cases a year following vaccination.

In China, Russia and the United Arab Emirates (UAE) some vaccines have already been approved for early use in humans before primary completion of Phase 3 clinical trials. The UK is not considering approving any of these vaccines, since no vaccine can be approved for use in the UK until clinical trials are complete.

These data are evaluated by regulatory agencies in the EU (the European Medicines Agency, EMA), and in the UK (the Medicines and Healthcare products Regulatory Agency, MHRA).

So far, the UK Government has secured access to 355 million doses of seven different vaccine candidates that are in different stages of development. These will be available across the UK, the Crown Dependencies and Overseas Territories.

Phase 3

• 40m doses of the Pfizer / Fosun Pharma / BioNTech The primary completion date was expected by 13 June 2021positive interim results were first announced by the companies on 9 November. O16 November, the companies announced to have met all the primary outcomes necessary to demonstrate efficacy. Many experts welcomed the Pfizer / Fosun Pharma / BioNTech preliminary results but with caution, highlighting that there are still a number of uncertainties related to the nature of the protection, storage requirements and how to meet global demand. Even though there are more to be collected, the data available so far are enough to demonstrate the vaccine meeting efficacy, quality and safety requirements. On 20 November, the companies announced submission for Food and Drug Agency (FDA) approval in the USA. On 2 December, the MHRA authorised this vaccine for use in the UK.
• 5m doses of the Moderna candidate. The primary completion date is expected by 27 October 2022, but positive interim results were announced by the company on 16 November. Scientific experts see this as encouraging, but stressed the need for completed data to better assess this candidate.
• 100m doses of the University of Oxford / AstraZeneca candidate. The primary completion date is expected for 22 December 2020, but the company announced positive interim results for Phase 3 on 23 November. The latest published data from earlier trials show the vaccine induces an immune response in older adults. Data on whether this response is enough to prevent SARS-CoV-2 infection in the elderly are not yet available.
• 60m doses of the Novavax candidate. The primary completion date is expected for January 2021 in the UK.
• 30m doses of the Janssen / Johnson and Johnson candidate. The earliest primary completion date is expected for 10 May 2022.

Phases 1 and 2

• 60m doses of the GSK / Sanofi Pasteur candidate.

Preclinical Development:

• 60m doses of the Valneva candidate with the option to acquire a further 40m doses if the vaccine is proven to be safe, effective and suitable.

Approving vaccines for use in the UK

Like any new medicine, before any vaccine can be widely used in people, regulators need to evaluate all the data from preclinical and clinical trials and decide whether to grant a medicines licence (also referred to as a marketing authorisation).

This allows the marketing, sale and supply of a medical product. Simply put, clinical trials need to show that the medical product is effective, safe and has acceptable side effects before it is made available for use.

There are different procedures to apply for a licence for a medical product in the UK, depending on whether the company is seeking to market it only for the UK market or across the European Union (EU). The EMA has a centralised approval process so that companies can make one application in order to have a licence that allows them to market their vaccine across the EU.

For COVID-19 vaccines, any new vaccine must be granted a licence to market by the European Medicines Agency (EMA) until the end of the transition period of the UK’s withdrawal from the EU (31 December 2020). After that, the MHRA will be responsible to granting marketing authorisation in the UK.

How does EU-wide medicine regulatory approval usually work?

The European Medicines Agency (EMA) is the body responsible for evaluating medicines, including vaccines, for the European market. EU-wide medicine approval involves four key stages:

1. Drug companies prepare a marketing authorisation application and submit it to the EMA. For a new vaccine this would include (among others):
   1. Details about how the vaccine is manufactured and what quality control procedures are in place.
   2. Data obtained from preclinical trials, for example, by administering the vaccine to animal models.
   3. Data from clinical trials, for example, the immune response triggered by the vaccine, any side effects observed in volunteers during trials and how well the vaccine works to protect against infection or the disease.
2. The medicine is evaluated by following a series of steps involving detailed analysis by scientific committees. The assessment can take up to 210 days with additional time taken for the manufacturer to provide extra data on request. Overall, the process can last up to a year. Following its assessment, EMA recommends whether a medicine can be authorised for use in people.
3. Within 67 days, the European Commission (EC) takes a final decision on whether the medicine can be marketed in the EU.
4. Following EU-wide marketing authorisation, national authorities make local decisions about whether and how to use new medicines. For vaccines this would include decision-making about how to include new vaccines in national immunisation programmes or as part of other general medical services that offer vaccines.

Once a medicine is introduced into the market, it is constantly monitored to ensure its safety. This process is known as ‘pharmacovigilance’.

How does UK-only regulatory approval work usually?

To market a medical product only in the UK, applicants need to follow a national procedure to apply for a marketing authorisation in all four UK nations. Data from clinical trials are evaluated by the Medicines and Healthcare products Regulatory Agency (MHRA).

This process can take up to 210 days, excluding time taken to provide further information or data required. The MHRA will be responsible to granting marketing authorisation in the UK to COVID-19 vaccines only after the end of the transition period of the UK’s withdrawal from the EU (31 December 2020).

Changing the regulatory approval process for COVID-19 vaccines

The length of this approval process is a barrier to access vaccines quickly during a public health emergency. For this reason, the EU approval process for COVID-19 vaccines has been compressed to ensure they can be available as soon as possible.

Despite a faster process, COVID-19 vaccines can only be approved and used if they comply with all the requirements of quality, safety and efficacy set by regulatory bodies.

How will EU-wide approval for COVID-19 vaccines work?

In the EU, COVID-19 vaccines will follow the same key steps as other vaccines (application, EMA evaluation, EC authorisation, adoption by national authorities, and pharmacovigilance). To accelerate and coordinate regulatory action on development, authorisation and safety monitoring of COVID-19 treatments and vaccines the EMA established the COVID-19 pandemic Task Force (COVID-ETF). This taskforce supports other EMA scientific committees during the evaluation of COVID-19 vaccines.

To accelerate the approval process, the EMA is applying a procedure called the ‘rolling review’. A rolling review involves many cycles, each one lasting a minimum of 2 weeks, during which EMA’s scientific committees review the data as they become available, while clinical trials are ongoing. This means that, if all the previous data are satisfactory, a vaccine candidate under rolling review can be approved within a minimum of 2 weeks following the end of clinical trials. The EMA has published a detailed plan to monitor COVID-19 vaccines after licensing. The COVID-EFT will also play a role at this stage.

Which COVID-19 vaccines are currently being evaluated for EU-wide licensing?

So far, the EMA has started rolling reviews on three COVID-19 vaccine candidates:

• University of Oxford / AstraZeneca candidate; rolling review announced 1 October
• Pfizer / Fosun Pharma/ BioNTech candidate; rolling review announced 6 October
• Moderna candidate; rolling review announced 16 November

Until the end of the transition period of the UK’s withdrawal from the EU, only the EMA has the authority to grant COVID-19 vaccines a licence to market. However, the UK has recently changed regulations to ensure temporary authorisation of COVID-19 vaccines can take place within the UK before any EMA licensing decision.

New measures taken by the UK Government to ensure rapid access to vaccines

The Government has made some preparations for the roll out of a COVID-19 vaccine. This has included amending the Human Medicines Regulations 2012, the main piece of legislation that regulates medicinal products in the UK. It includes provisions on the supply of a medicinal product in response to “the spread of a pathogenic agent.”

The Human Medicines (Coronavirus) (Amendment) Regulations 2020 make several changes to the existing legislation which the Government has said will “support the effective rollout of a COVID-19 vaccine.”

The Human Medicines Regulations 2012 already allowed for the temporary authorisation of an unlicensed product in response to a public health threat, but no conditions were specified before the amendment. New regulation 174A allows for the granting of a temporary authorisation of an unlicensed product (such as a COVID-19 vaccine) subject to specific conditions of safety, quality and efficacy, set out by the MHRA.

The Government has said that the Commission on Human Medicines (CHM), a UK Government independent advisory body, will advise it on the safety, quality and efficacy of any vaccine and that “no vaccine will be deployed unless stringent standards have been met through a comprehensive clinical trial programme.”

On 23 November, the MHRA confirmed they received data from the Pfizer / Fosun Pharma / BioNTech candidate to complete their assessment on the vaccine’s safety, quality and efficacy. On 27 November, the agency confirmed they received the letter from the Department of Health and Social Care requesting the review of the University of Oxford / AstraZeneca candidate. The CHM has responsibility to assess data for both candidates in parallel to the MHRA. With advice from the CHM, the MHRA granted temporary authorisation for use in the UK to the Pfizer / Fosun Pharma/ BioNTech vaccine on 2 December.

In which countries have COVID-19 vaccines been already approved?

In the UK vaccines are not used until Phase 3 studies have been completed and published. This is because this final stage of evaluation demonstrates quality, safety (including rare side effects) and how well a vaccine works under trial conditions (called efficacy). While the approval process is being fast-tracked, the same process and standards for quality, safety and efficacy still apply.

However, some countries are using vaccines before this stage of evaluation is complete. For example, the Chinese Sinopharm / Beijing Institute of Biological Products candidate has been given early approval in China and the UAE before completion of large Phase 3 clinical trials. Similarly, the Russian Gamaleya Research Centre candidate (Sputnik V) has been approved for use in vulnerable groups in Russia before the start of Phase 3 trials.

Often, even if Phase 1 and 2 clinical trials (involving overall several hundreds of people to test safety and the stimulation of an immune response) show promising results, Phase 3 trials (involving several thousands of people) can reveal rare side effects or indicate that the vaccine offers no protection against the disease.

The consensus from the scientific community is that vaccine approval before completion of Phase 3 trials carries risks and the quality, safety, and efficacy of COVID-19 vaccine candidates must still be established, despite the current time pressure.

Russian authorities approving Sputinik V have been criticised, with the medical press highlighting that safety and efficacy data were not sufficient for the vaccine to be approved. Chinese vaccine manufacturers have been criticised for lack of transparency.

Who will first receive a COVID-19 vaccine in the UK?

On 2 December, the Joint Committee on Vaccination and Immunisation (JCVI) published their advice on priority groups for COVID-19 vaccination. This advice is based on a series of considerations, including UK epidemiological data, evaluation of risk from COVID-19, available data on vaccine candidates (including the Pfizer-BioNTech and the University of Oxford / AstraZeneca vaccine) and modelling on the impact of different vaccination programmes.  

Prevention of COVID-19 mortality and protection of health and social care staff and systems are the first priorities considered by the Committee to identify priority groups in the initial phase of the UK COVID-19 vaccination programme. These are: 

1. Residents in a care home for older adults and their carers. 
2. All those 80 years of age and over, together with frontline health and social care workers.
3. All those 75 years of age and over.
4. All those 70 years of age and over, together with clinically extremely vulnerable individuals. Clinically extremely vulnerable individuals include, among others, transplant recipients, some cancer patients and people on immunosuppression therapies.
5. All those 65 years of age and over.
6. All individuals aged 16 years to 64 years with underlying health conditions which put them at higher risk of serious disease and mortality. These include, among others, chronic respiratory and heart disease, morbid obesity, diabetes and severe mental illness.
7. All those 60 years of age and over.
8. All those 55 years of age and over.
9. All those 50 years of age and over.  

As highlighted by MHRA, CHM and JCVI representatives during a press conference on 2 December, local NHS, local public health teams and local leaders and communities have a key role in implementing COVID-19 vaccination with attention to mitigating health inequalities, which might occur in relation to access to healthcare, deprivation or ethnicity. 

Priorities for the next phases of the UK COVID-19 vaccination programme need to be determined, but they could focus on further reduction in hospitalisation and targeted vaccination of those at high risk of exposure and/or those delivering key public services, such as first responders, the military, teachers and transport workers. 

On 12 November 2020, the Scientific Advisory Group for Emergencies (SAGE) noted the need for very effective pharmacovigilance during the COVID-19 immunisation programme, suggesting use of the NHS App to collect safety and efficacy data directly from individuals. Pharmacovigilance to monitor the safety and effectiveness of COVID-19 vaccines is part of the Government’s Winter Plan announced on 23 November. Vaccine safety will be continually monitored by the MHRA and Public Health England, and JCVI will regularly review data on vaccine safety as the programme rolls out.

What are the public attitudes towards a COVID-19 vaccine in the UK?

In recent weeks, parliamentary debate has focused attention on people’s attitudes to COVID-19 vaccines. Surveys on this in the past few months suggest that most people in the UK would have a COVID-19 vaccine if available.

Researchers at the London School of Hygiene and Tropical Medicine monitor public attitudes to vaccines and immunisation. Recent data from their Vaccine Confidence Project on 1,252 parents and guardians in England showed that nearly 90% of them would likely accept a COVID-19 vaccine for themselves and their children.

Another study under peer review from the same institute analysed the effect of misinformation in 8,000 people in the UK and USA. They found that misinformation leads to a reduction in vaccine acceptance, enough to compromise efforts to reach sufficient levels of COVID-19 immunity in the population.

The minimum level of vaccine coverage is not clear and this depends on how well new vaccines work and on the transmission of the virus in a population. However, a modelling study estimated that if one infected person is able to infect another three people, at least two-thirds of the population need to be immune. Another study showed that this value increases to more than 80% of the population if one infected person is able to transmit the virus to almost 6 people.

A lack of confidence in COVID-19 vaccines in a minority of the population and the increased disinformation circulating about vaccines have led to concerns about future vaccination uptake.

How can public confidence in COVID-19 vaccines be achieved in the UK?

As highlighted by a recent report by the British Medical Association, raising public awareness and understanding of immunisation programmes is key to improving immunisation coverage rates.

On 8 November, the UK Government agreed with social media firms (Facebook, Twitter and Google) that companies should not profit from or promote COVID-19 anti-vaccine disinformation. Companies agreed to collaborate with public health bodies to promote accurate messages.

This is part of our rapid response content on COVID-19, written in collaboration with the House of Commons Library. You can view all POST reporting on this topic under COVID-19 and Commons Library research online.

Photo by Daniel Schludi on Unsplash