FOI release

Freedom of Information request on the temporary authorisations of COVID-19 vaccines (FOI 21-599)

Published 13 August 2021

Dear

Thank you for your FOI request.

The temporary authorisations of the Pfizer/BioNTech, Oxford/AstraZeneca and Moderna vaccines was done through an expedited rolling review. A ‘rolling review’ can be used to complete the assessment of a promising medicine or vaccine during a public health emergency in the shortest time possible. This is done as the packages of data become available from ongoing studies on a staggered basis. The temporary authorisation under Regulation 174 permits the supply of identified vaccine batches, based on the safety, quality and efficacy data submitted to MHRA. These authorisations do not constitute a marketing authorisation.

All vaccines are tested through three phases of clinical trials to ensure they meet the gold standard. Phase 1 trials are with a small group of people to make sure there are no safety concerns and determines the appropriate dosage for the best immune response. Phase 2 trials are conducted on a larger group of people to check the vaccine works consistently and that the immune response is sufficient. Phase 3 trials test the vaccines on thousands of people for scientists to assess if the vaccine is producing immunity that will prevent disease. Usually, these phases are run in sequence, but in an effort to find a safe and effective Covid-19 vaccine as quickly as possible, once safety has been ascertained through Phase 1, Phases 2 and 3 are being run in parallel. Extensive checks and balances are required at every stage of the development of a vaccine, and this is no different for a Covid-19 vaccine. No stages in the vaccine development processes were bypassed.

Information on the study conducted using the Pfizer/BioNTech vaccine and its results are available in a peer-reviewed journal, the New England Journal of Medicine (NEJM). A link to this is provided below:

https://www.nejm.org/doi/full/10.1056/NEJMoa2034577?query=featured_home

The temporary authorisations for use of the COVID-19 vaccines in the UK followed a rigorous scientific assessment of all the available evidence of quality, safety and effectiveness by the UK regulator, the Medicines and Healthcare products Regulatory Agency (MHRA). The MHRA expert scientists and clinicians reviewed data from the laboratory pre-clinical studies, clinical trials, manufacturing and quality controls, product sampling and testing of the final vaccine, and also considered the conditions for its safe supply and distribution. The decision was made with advice from the Commission on Human Medicines (CHM), the government’s independent expert scientific advisory body. Regarding the MHRA approval of the Pfizer/BioNTech and the Oxford/AstraZeneca COVID-19 vaccines, further information (including information for physicians and recipients of the vaccine, and Public Assessment Reports [PARs] for each vaccine) are available on the MHRA website. Links to these are provided below:

https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19 https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-astrazeneca
https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-moderna

Please note that a marketing authorisation was granted for the Pfizer/BioNTech vaccine (Comirnaty) following a European Commission (EC) decision on 21 December 2020 (PLGB 53632/0002). Further information is available on the European Medicines Agency (EMA) website, a link to this is provided below:

https://www.ema.europa.eu/en/medicines/human/EPAR/comirnaty

Please also note that a marketing authorisation was granted for the Moderna vaccine on 31 March 2021 following an EC Reliance Procedure (PLGB 53720/0002). Further information is available on the MHRA website and the EMA website, links to these are provided below:

https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-moderna https://www.ema.europa.eu/en/medicines/human/EPAR/covid-19-vaccine-moderna

In addition, the European Commission, following recommendations from the European Medicines Agency (EMA), have granted a marketing authorisation for the Oxford/AstraZeneca vaccine. Further information is provided below:

https://www.ema.europa.eu/en/medicines/human/EPAR/vaxzevria-previously-covid-19-vaccine-astrazeneca

As with any vaccine or medicine, COVID-19 vaccines require continuous safety monitoring and that the benefits in protecting people against COVID-19 outweigh any side effects or potential risks. This is a process known as safety monitoring (pharmacovigilance). This ensures that any potential medium and long term safety issues are promptly and adequately evaluated. As part of our signal detection processes, all adverse reaction reports received are individually assessed and cumulative information reviewed at regular intervals. Be reassured that the MHRA is working in collaboration with partners in the health system to rapidly assess all available safety data in real time and communicate any emerging issues, as necessary.

Throughout this global pandemic, we have always been guided by the latest scientific advice. Having studied evidence on both the Pfizer/BioNTech and Oxford/AstraZeneca vaccines, the Joint Committee on Vaccination and Immunisation (JCVI) has advised that we should prioritise giving as many people in at-risk groups their first dose, rather than providing two doses in as short a time as possible.

The four UK Chief Medical Officers agree with JCVI that at this stage of the pandemic prioritising the first doses of vaccine for as many people as possible on the priority list will protect the greatest number of at risk people overall in the shortest possible time and will have the greatest impact on reducing mortality, severe disease and hospitalisations and in protecting the NHS and equivalent health services.

This is because the evidence shows that one dose of either vaccine provides a high level of protection from Covid-19.

For both vaccines, data provided to MHRA demonstrate that whilst efficacy is optimised when a second dose is administered both offer considerable protection after a single dose, at least in the short term. For both vaccines the second dose completes the course and is likely to be important for longer term protection. The NHS across the UK will prioritise giving the first dose of the vaccine to those in the most high-risk groups. Everyone will still receive their second dose and this will be within 12 weeks of their first. The second dose completes the course and is important for longer-term protection.

The JCVI’s independent advice is that this approach will maximise the benefits of both vaccines allowing the NHS to help the greatest number of people in the shortest possible time. It will ensure that more at-risk people are able to get meaningful protection from a vaccine in the coming weeks and months, reducing deaths and starting to ease pressure on our NHS.

The following Department of Health and Social Care (DHSC) webpage for the independent report ‘Optimising the COVID-19 vaccination programme for maximum short-term impact’ from the Joint Committee on Vaccination and Immunisation (JCVI) provides the rationale for the government’s implemented dosing strategy:

https://www.gov.uk/government/publications/prioritising-the-first-covid-19-vaccine-dose-jcvi-statement/optimising-the-covid-19-vaccination-programme-for-maximum-short-term-impact

Further, the scientific basis from the JCVI concerning the current evidence on efficacy after single doses of the Pfizer/BioNTech, Oxford/AstraZeneca and Moderna vaccines is available in the public domain and is provided below: https://www.gov.uk/government/publications/prioritising-the-first-covid-19-vaccine-dose-jcvi- statement

Regarding your specific questions, please see MHRA’s responses below:

1) Questions regarding the oral evidence Dr June Raine gave to the Science and Technology Select Committee on 09/12/2020 in response to Q783 [ https://committees.parliament.uk/oralevidence/1376/pdf/ ]

Dr Raine summarised that the MHRA require evidence “that the benefits outweigh any risks” in order to “enable access” [to medical products and devices]. MHRA received FOI 20/582 on 30/12/2020 and responded on 04/01/2021. This FOI request is described as “How many people in the UK have died of Covid 19 without any underlying Illnesses? Only Covid 19 deaths please”.

a. How did the MHRA evaluate the benefits of any SARS-CoV-2 vaccines or medicines, including but not limited to reducing mortality, without reviewing Covid-19 mortality data?

b. How has the MHRA evaluate the benefits of preventing Covid-19 for different age groups, ethnicities, or underlying health conditions?

c. What benefits does the MHRA believe an effective vaccine against SARS-CoV-2 would bring to children 16 and younger (to them as individuals rather than benefits to the wider community), who have no known underlying health conditions?

We have provided the links to the PARs in our response above, which detail MHRA’s assessment of the each vaccine, including the evaluation of their efficacy. Regarding question c, please refer to our public statement regarding the positive safety profile for the Pfizer/BioNTech vaccine in 12 to 15 year olds https://www.gov.uk/government/news/the-mhra-concludes-positive-safety-profile-for-pfizerbiontech-vaccine-in-12-to-15-year-olds .

2) Please supply any evidence and/or data supporting the use of more than one SARS-CoV-2 vaccine product in one individual. Specify and separate this for each combination of vaccines for which you hold and information e.g. for 1 dose of the Pfizer-BioNTec BNT162b2 vaccine followed by the Moderna mRNA-1273 vaccine, or the Oxford-AstraZeneca AZD1222 vaccine followed by the aforementioned Pfizer vaccine. If available, please include;

a. Short-term safety, SAEs, and interactions between the vaccines

b. Potential long-term side effects or injuries

c. Which combinations of vaccines the MHRA approves, has not approved, and advises against

d. Efficacy against SARS-CoV-2 infection

e. Efficacy against hospitalisation

f. Efficacy against death

g. Efficacy against transmission

h. Duration of efficacy

MHRA cannot answer this question, the current advice is that these vaccines should not be mixed.

3) Temporary authorisation questions.

a. What vaccine or drug has had the longest period of temporary authorisation by the MHRA?

b. How long was that authorisation given for?

c. What was the authorisation status after the temporary authorisation ended e.g., was it given permanent authorisation, or the authorisation withdrawn?

The information concerning the dates of each vaccine’s temporary authorisation are available on the MHRA website. We have also provided above the dates that the Pfizer and Moderna vaccines were granted marketing authorisations by MHRA.

4) Long term vaccine safety

a. Which vaccines have caused or contributed to long-term injuries that for some individuals have occurred at least 12 months after the vaccine was administered?

b. What were those long-term injuries and what was the MHRA’s response?

Please note that the first COVID-19 vaccine was authorised for use in December 2020 in the UK with others following in 2021, therefore these vaccines have only been in use outside of clinical trials for six months.

The MHRA continuously monitors the safety of vaccines through a variety of pharmacovigilance processes including the Yellow Card scheme. The MHRA, together with independent expert advice from the Commission on Human Medicines (CHM), is responsible for ensuring that the overall balance of benefits in terms of effectiveness, and risks of medicines and vaccines is positive at the time of licensing and remains so thereafter. Further information about the MHRA’s pharmacovigilance strategy can be found here:

https://www.gov.uk/government/publications/report-of-the-commission-on-human-medicines-expert-working-group-on-covid-19-vaccine-safety-surveillance/report-of-the-commission-on-human-medicines-expert-working-group-on-covid-19-vaccine-safety-surveillance

Whilst an acceptable level of information has been received to provide assurance that appropriate standards of quality, safety and efficacy have been met for authorisation of the COVID-19 vaccines, patients included in the clinical trials for COVID-19 vaccines continue to be followed up for at least a year to gather further safety and efficacy data and MHRA will continue to receive data from the companies as it becomes available.

All vaccines and medicines have some side effects. The benefits of the vaccines in preventing COVID-19 infection and associated serious disease and death continues to outweigh any potential risks.

5) Pfizer report 6 deaths during the BNT162b2 trial reporting period of 29/04/20 to 14/11/20 (2 in the vaccine group, 4 placebo), none of which were caused by the vaccine or by SARS-CoV-2. Please supply all evidence and data reviewed by the MHRA up to 02/12/20 that indicated BNT162b2 had any effect on (including reduction of) Covid-19 mortality. We have provided the links to the PARs in our response above, which detail MHRA’s assessment of each vaccine, including the evaluation of their efficacy.

6) The EMA have published guidance that defines the SARS-CoV-2 they’ve already authorised as “parent vaccines” and have implemented easements for the approval of new SARS-CoV-2 vaccines that will target other “strains”. [ https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-regulatory-requirements-vaccines-intended-provide-protection-against-variant_en.pdf ]

a. Will the MHRA be implementing any equivalent easements or will you require exactly the same weight of evidence on safety and efficacy for any new vaccines as was required for the SARS-CoV-2 vaccines already authorised?

b. If your requirement for evidence has changed, specifically what easements will be in place?

c. If vaccine approval easements have or will be introduced, please supply all evidence, data and risk assessments associated with those decisions.

MHRA cannot answer this question. Any assessment of future changes to the authorised vaccines to target new strains will be based on the nature of those changes.

7) Please supply any evidence or data that has been used to determine the risk / benefit assessment of;

a. A third dose of the BNT162b2 / mRNA-1273 / AZD1222 existing SARS-CoV-2 vaccines

b. Any new vaccine including variations of these 3 vaccines. MHRA cannot answer these questions. The currently authorised vaccines are two-dose vaccines and should not be mixed.

8) Please supply the safety / efficacy evidence and data that the MHRA considered when approving the influenza vaccine used in the 2018/19 winter flu season and the same for the influenza vaccine used in the 2019/20 winter flu season.

The Public Assessment Reports (PARs) for all vaccines granted since 31 October 2005 is available either on the MHRA’s website or the European Medicines Agency website. Links to these are provided below:

https://products.mhra.gov.uk/
https://www.ema.europa.eu/en/medicines

9) The Yellow Card scheme might be described as a ‘passive’ monitoring scheme as it requires someone to make a report of their own volition.

a. What active monitoring is in place for the SARS-CoV-2 vaccines that are currently authorised?

b. What percentage of side-effects / SAEs etc for vaccines (or vaccines / medicine data combined) does the MHRA believe have been reported via the Yellow Card Scheme year to date in 2021, on average in 2020, and on average in 2019?

c. What was the mean lead-time for the MHRA to fully review Yellow Card reports for any vaccine (or vaccine and medicine combined) in 2019, in 2020, and year to date in 2021?

9a.

Please see response to question 4 which provides a link to our COVID-19 vaccine surveillance strategy.

The leaflets provided to UK recipients of the COVID-19 vaccines contain information on how suspected side effects can be reported to the MHRA and encourages reporting of any side effects through the Yellow Card scheme. Information on Yellow Card reporting has been included in NHS training materials, as well as the materials available to individuals both before and after vaccination.

The MHRA have also optimised website search functionality and worked with media outlets to encourage them to carry messages about reporting of side effects. We are running a targeted social media campaign currently and would encourage anyone seeing this who has not already done so to report through the Coronavirus Yellow Card site. The Coronavirus Yellow Card site has been designed to enable both self-reporting, and for people to report on behalf of others. Where people do not have access to the internet, they can request a family member or carer to report on their behalf, or alternatively discuss their experience with a healthcare professional, who can report for them.

Furthermore, to raise awareness of the site and Yellow Card reporting, the MHRA have also released a Drug Safety Update and a press release informing healthcare professionals and members of the public that reporting to the new site will enable the MHRA to rapidly identify new and emerging side effects. The general public have also been encouraged to report any suspected side effects to the vaccine to the MHRA via a Yellow Card on the recent televised press briefings.

9b.

The reporting rate for spontaneous adverse drug reactions (ADR) is variable and can depend on a multitude of factors. Although some historical studies have estimated only 10% of ADRs are reported, the actual rate is unknown and will be influenced by public awareness and seriousness of the event. This figure should not be used as the reporting rate of ADRs for COVID-19 vaccines, for which there is high public awareness of the Yellow Card scheme and encouragement of reporting of all events. For more information about how we are monitoring the safety of all COVID-19 vaccines, see the weekly summary of Yellow Card reporting for COVID-19 vaccines. Additionally, we take into account of the variable levels of reporting across all medicines and vaccine as part of our monitoring procedures using statistical techniques.

9c.

All Yellow Card reports we receive are promptly entered onto the MHRA’s Adverse Drug Reaction (ADR) database so that they are available for a process called signal detection. During signal detection, reports are evaluated, together with additional sources of evidence, by a team of safety experts to identify any new safety issues or side effects. We apply statistical techniques that can tell us if we are seeing more events than we would expect to see, based on what is known about background rates of illness in the absence of medication or vaccination. This aims to account for factors such as coincidental illness. We also look at the clinical characteristics to see if new patterns of illness are emerging that could indicate a new safety concern. For the COVID-19 vaccines we supplement this form of safety monitoring with other epidemiology studies including analysis of data on national vaccine usage, anonymised GP-based electronic healthcare records and other healthcare data to proactively monitor safety. These combined safety data enable the MHRA to detect side effects or safety issues associated with COVID-19 vaccines. As well as confirming new risks, an equally important objective of monitoring will be to quickly rule out risks – in other words to confirm that the vaccine is not responsible for a suspected side effect and to provide reassurance on its safety. We also take into account the international experience based on data from other countries using the same vaccines. For further information on how we use the data we collect please view our COVID-19: vaccine surveillance strategy.

10) How many instances is the MHRA aware of, if any, where the SARS-CoV-2 vaccine brand, product or batch number has been incorrectly recorded on a recipient’s NHS records?

This information is not part of the MHRA’s remit, and therefore the MHRA do not hold this data. This will be the remit of Public Health England, who are facilitating the delivery of the national COVID-19 vaccination programme.

11) What oral or inhaled medicines for the treatment of Covid-19 have been authorised by the MHRA or are currently being evaluated?

A list of medicines authorised each month is available on the MHRA website. Further details, including the SmPC, PIL and PAR for each medicine is available through the MHRA portal. Links to these are provided below: https://www.gov.uk/government/collections/marketing-authorisations-lists-of-granted-licences https://products.mhra.gov.uk

12) The SPC for the Moderna mRNA-127 vaccine [ https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-moderna/information-for-healthcare-professionals-on-covid-19-vaccine-moderna ] states in section 4.6 that the vaccine should only be considered for pregnant women “when the potential benefits outweigh any potential risks for the mother and foetus”. What potential risks does this refer to?

Please be informed that this statement regarding the use of COVID-19 vaccines in pregnant women is present in the SmPC for all COVID-19 vaccinations that are currently licensed in the UK. There was limited experience in pregnancy at the time of first authorisation so section 4.6 of the SmPC is precautionary. The reason for the inclusion of this statement is that pregnant women were not included in the clinical trials for these vaccinations, therefore there is limited data on the experience in this cohort. The MHRA assesses all reports of exposure during pregnancy, including those concerning the COVID-19 vaccinations, and follows up with these patients throughout their pregnancies to identify any potential harm to the mother or foetus, and the outcome of the pregnancies.

As with most medicines and vaccines, potential risks include poor outcomes of the pregnancy or effects on the unborn child (miscarriage, stillbirth or additional pregnancy complications). Extensive post-marketing experience of the use of the Pfizer BioNTech and Moderna vaccines in the USA have raised no safety concerns regarding the use of COVID-19 in pregnancy. In addition, clinical trials on the use of COVID-19 vaccines during pregnancy are now starting and there are a number of studies across the UK and elsewhere monitoring the safety in clinical use.

I hope the information provided is helpful, but if you are dissatisfied with the handling of your request, you have the right to ask for an internal review. Internal review requests should be submitted within two months of the date of this response; and can be addressed to this email address.

Yours sincerely,

FOI Team, Vigilance and Risk Management of Medicines Division