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Astra Zeneca Covid Vaccine - Basis of dosing recommendations

Branwen Sloper made this Freedom of Information request to Medicines and Healthcare products Regulatory Agency

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Dear Medicines and Healthcare products Regulatory Agency,
In respect of the Astra Zeneca Covid Vaccination Information for Healthcare Professionals, what is the basis for recommending:
1. A full initial dose be administered, despite the scientific evidence showing that half the standard dose results in enormously increased interim protection and significantly increased overall protection following a full second dose?
2. An interval of up to 12 weeks between first and second dose, when the manufacturer's recommended interval is 28 days?
3. Does this variation from the manufacturer's evidenced dosing recommendations breach the terms of the temporary authorisation for use of this vaccine?

Yours faithfully,

Branwen Sloper

MHRA Customer Services, Medicines and Healthcare products Regulatory Agency

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MHRA Customer Services, Medicines and Healthcare products Regulatory Agency

Our Ref: FOI 21/041

Dear Branwen Sloper,

RE: REQUEST UNDER THE FREEDOM OF INFORMATION ACT 2000

Thank you for your enquiry which we received on 13 January 2021.

I confirm that your request is now being handled under the Freedom of Information Act and you should receive a reply within 20 working days from our date of receipt.

If you need to contact us again about this request, please quote the reference number above.

Kind Regards,


MHRA Customer Service Centre

Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU Telephone 0203 080 6000

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MHRA Customer Services, Medicines and Healthcare products Regulatory Agency

FOI 21/041
 
Dear Branwen Sloper,
 
Thank you for your email.
 
The authorisation of the Oxford/AstraZeneca 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.
 
The approval for use of the Oxford/AstraZeneca 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
Oxford/AstraZeneca COVID-19 vaccines, further information (including
information for healthcare practitioners and recipients of the vaccine,
and Public Assessment Reports for each vaccine) are available on the MHRA
website. Links to these are provided below:
[1]https://www.gov.uk/government/publicatio...
 
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: 
[2]https://www.gov.uk/government/publicatio...
 
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:
[3]https://www.cas.mhra.gov.uk/ViewandAckno...
 
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Yours sincerely
 
 
 
MHRA Customer Service Centre
 
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU
 
 

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Dear MHRA Customer Services,

Thank you for your response which - despite its length and detail - has failed to address my questions.

My first question about why the first dose is not the reduced "low dose" used in part of the manufacturer's trial - giving a 50% improvement on the efficacy of a standard first dose - has not been addressed,
"In participants who received two standard-dose vaccines, vaccine efficacy was 62·1% (95% CI 41·0–75·7), whereas in those who received a low dose as their first dose of vaccine, efficacy was higher at 90·0% " - and Table 2 shows protection against asymptomatic infection of two standard doses is only 7.8% compared to 58.9% where the first vaccination was a low dose one followed by a standard second dose.
Source: Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK Lancet 2021; 397: 99–111)

My second question querying the scientific basis for varying the manufacturer's originally recommended 28-day interval between doses has not been addressed - although you did explain the "save the NHS" and public health considerations - which I had not questioned.

My third question, about whether varying the manufacturer's original recommended dosing intervals (28days) breached the terms of the temporary authorisation, has not been specifically addressed.

I should be grateful if you could specifically address the issues I have asked about.

Yours sincerely,

Branwen Sloper

MHRA Customer Services, Medicines and Healthcare products Regulatory Agency

Thank you for your email.  This auto-response is to inform you that your
email has been received and will be reviewed by our Customer Service Team.
We will respond to you as soon as possible. 

 

Please note that we may not respond if your query: 

 

• contains offensive language
• has already been answered in a previous reply to you
• is illegible
• is selling or promoting a product
• is for information only 

 

Medicines and Healthcare products Regulatory Agency
10 South Colonnade, 
Canary Wharf, 
London 
E14 4PU
gov.uk/mhra
Stay connected 
 
For information on how the Agency uses your personal data and your data
protection rights, please see our three centres’ Privacy Notices: MHRA,
CPRD and NIBSC. 

 

The UK has left the EU, and the transition period ends on 31 December
2020. Our [1]guidance and information can be accessed here. 

References

Visible links
1. https://www.gov.uk/government/collection...

MHRA Customer Services, Medicines and Healthcare products Regulatory Agency

Dear Branwen Sloper,

 

Thank you for your email.

 

Please find below answers to the questions you have raised.

 

Q1: As per the Public Assessment Report (PAR) (link provided earlier),
page 35:

 

Efficacy of using an initial half dose

A proportion of participants received a half dose of vaccine for their
first administration. Participants were not randomised between receiving a
half dose (LD) or the standard dose (SD) for the first dose, and because
of other confounding factors, it is not possible to confidently compare
results from the two different dosing regimens. Such factors include
differences in the dosing interval (generally longer for LD), population
studied (younger population for LD), country (UK only for LD) and stage of
pandemic (participants receiving LD were initially dosed at a time when
the incidence of cases in the UK was low). There is not persuasive
evidence of a real difference in VE between SD and LD, and the apparent
difference is considered more likely to be the result of confounding
factors, especially the dosing interval. Conclusions on vaccine efficacy
were primarily based on the pre-planned primary analysis including both SD
and LD participants, and not on subgroups.

 

Q2: The AZ vaccine’s dose instructions ‘The second dose should be
administered between 4 and 12 weeks after the first dose’ are unchanged
from the initial approval.  Section 5.1 of the information for HCPs even
says ‘Efficacy is currently demonstrated with more certainty for dose
intervals from 8 to 12 weeks.’

 

Q3: Not applicable.  Dosing instructions are unchanged.

 

Kind Regards

 

MHRA Customer Service Centre

 

Medicines and Healthcare products Regulatory Agency

10 South Colonnade, Canary Wharf, London E14 4PU

 

 

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