RNA integrity of experimental modRNA COVID-19 drugs (Pfizer and Moderna)

Jonathan Weissman made this Freedom of Information request to Medicines and Healthcare Products Regulatory Agency

Automatic anti-spam measures are in place for this older request. Please let us know if a further response is expected or if you are having trouble responding.

Jonathan Weissman

Dear Medicines and Healthcare Products Regulatory Agency,

According to the EMA’s European Public Assessment Report (EPAR) on Pfizer’s experimental COVID-19 drug BNT162b2 (Comirnaty), “In comparability studies, a decrease in RNA integrity was observed for the initial Process 2 batches [commercial supply] compared to Process 1 batches [clinical supply].” [1]

With respect to Pfizer’s product BNT162b2 (Comirnaty), please supply all results available to the MHRA indicating the RNA integrity of Process 1 batches for clinical supply and the RNA integrity of Process 2 batches for commercial supply.

In addition to providing the requested evidence on RNA integrity, you should also either:
a) confirm sufficiently high RNA integrity was observed across the clinical supply and commercial supply batches
OR else (should there be a significant decrease in RNA integrity in the commercial supply overseen by the MHRA)
b) justify on what basis any supposed safety studies conducted during the clinical trials continue to apply to the commercial supply batches.

Now please answer this same request with respect to Moderna’s product mRNA-1273 (Spikevax).

Yours faithfully,

Jonathan Weissman BSc MSc MSc
alltherisks.com

[1] https://www.ema.europa.eu/en/documents/a...

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

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London 
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________________________________________ From: Jonathan Weissman
<[FOI #830595 email]> Sent: Sunday, February 6,
2022 10:18:55 PM To: MHRA Customer Services Subject: Freedom of
Information request - RNA integrity of experimental modRNA COVID-19 drugs
(Pfizer and Moderna) Dear Medicines and Healthcare Products Regulatory
Agency, According to the EMA’s European Public Assessment Report (EPAR) on
Pfizer’s experimental COVID-19 drug BNT162b2 (Comirnaty), “In
comparability studies, a decrease in RNA integrity was observed for the
initial Process 2 batches [commercial supply] compared to Process 1
batches [clinical supply].” [1] With respect to Pfizer’s product BNT162b2
(Comirnaty), please supply all results available to the MHRA indicating
the RNA integrity of Process 1 batches for clinical supply and the RNA
integrity of Process 2 batches for commercial supply. In addition to
providing the requested evidence on RNA integrity, you should also either:
a) confirm sufficiently high RNA integrity was observed across the
clinical supply and commercial supply batches OR else (should there be a
significant decrease in RNA integrity in the commercial supply overseen by
the MHRA) b) justify on what basis any supposed safety studies conducted
during the clinical trials continue to apply to the commercial supply
batches. Now please answer this same request with respect to Moderna’s
product mRNA-1273 (Spikevax). Yours faithfully, Jonathan Weissman BSc MSc
MSc alltherisks.com [1]
https://eur01.safelinks.protection.outlo...
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show quoted sections

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

Our Ref: FOI 22/454

Dear Jonathan Weissman

RE: REQUEST UNDER THE FREEDOM OF INFORMATION ACT 2000

Thank you for your enquiry which we received on 7th February 2022.

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.

Please be aware that we publish FOIs replies and these are redacted and are located on our website at the following link below.
https://www.gov.uk/government/collection...

Kind Regards,

MHRA Customer Experience Centre
Communications and engagement team
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU
Telephone 020 3080 6000

show quoted sections

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

FOI 22/454

Dear Jonathan Weissman,

Thank you for your email.

Regarding the below request, the information requested concerns parts of the quality dossier that are commercially sensitive and so would be exempt from release under Section 41 (Information provided in confidence) and Section 43 (Commercial interests). Section 41 is an absolute exemption and no consideration of the public interest is needed. Section 43 is a conditional exemption and a consideration of the public interest is required. We have considered the balance of the public interest when applying this exemption. In this case, we have not identified any issues which would benefit the public, as a whole, by being brought to their attention. Therefore, there is no public interest that outweighs the commercial harm in releasing information about the manufacturing and control of the Pfizer and Moderna vaccines, which can be used by competitors to overcome regulatory hurdles and inform the development of their own vaccine.

It should be noted that all batches of finished product have to be of suitable quality, as predetermined in the finished product specification for each vaccine. Changes between batches of vaccine that are within the finished product specification are acceptable and should not affect the efficacy of the product.

If you have a query about the information provided, please reply to this email.

If you disagree with how we have interpreted the Freedom of Information Act 2000 in answering your request, you can ask for an internal review. Please reply to this email, within two months of this reply, specifying that you would like an Internal Review to be carried out.

Please remember to quote the reference number above in any future communications.

If you were to remain dissatisfied with the outcome of the internal review, you would have the right to apply directly to the Information Commissioner for a decision. Please bear in mind that the Information Commissioner will not normally review our handling of your request unless you have first contacted us to conduct an internal review. The Information Commissioner can be contacted at:

Information Commissioner's Office
Wycliffe House
Water Lane
Wilmslow
Cheshire
SK9 5AF

Yours sincerely

MHRA Customer Experience Centre
Communications and engagement team
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU Telephone 020 3080 6000

show quoted sections

Dear Medicines and Healthcare Products Regulatory Agency,

Your reply is acknowledged but is unsatisfactory on the grounds outlined below. Please therefore immediately conduct an internal review on this freedom of information request.

Disclosing all results in possession of the MHRA on the RNA integrity of the Pfizer and Moderna experimental drugs cannot in and of itself possibly exert “commercial harm… which can be used by competitors to overcome regulatory hurdles and inform the development of their own vaccine.”

Furthermore, disclosing the integrity of the active pharmaceutical ingredient (API) is not “commercially sensitive”, but rather is needful for fully informed consent. Given the necessarily significant upscaling in modRNA manufacture from the clinical batches to the commercial batches, there is a critical need for the public to understand the extent to which purported safety studies conducted during the clinical trials continue to apply to the commercial batches.

As per the EMA’s EPAR on Pfizer, the expression of “aberrant proteins”, truncated spike proteins, can be assumed [1]. The public interest here primarily concerns safety rather than the “efficacy of the product”, as per your reply to my request. If a sufficiently high RNA integrity can be assumed in the commercial batches, the immunological response would, of course, be dominated by responses to full-length spike. However, given the Bansal et al. study in the Journal of Immunology [2] found that, under transmission electron microscopy, freely-circulating exosomes expressing the spike protein can be detected for 4 months following administration of BNT162b2, there is an urgent need to understand the proportion of truncated spike proteins that may be synthesised and then subsequently circulate in the bloodstream.

Yours sincerely,

Jonathan Weissman

[1] https://www.ema.europa.eu/en/documents/a...
[2] https://www.jimmunol.org/content/jimmuno...

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. Ourguidance and information can be accessed here.

________________________________________ From: Jonathan Weissman
<[FOI #830595 email]> Sent: Tuesday, February 15,
2022 12:08:07 AM To: MHRA Customer Services Subject: Internal review of
Freedom of Information request - RNA integrity of experimental modRNA
COVID-19 drugs (Pfizer and Moderna) Dear Medicines and Healthcare Products
Regulatory Agency, Your reply is acknowledged but is unsatisfactory on the
grounds outlined below. Please therefore immediately conduct an internal
review on this freedom of information request. Disclosing all results in
possession of the MHRA on the RNA integrity of the Pfizer and Moderna
experimental drugs cannot in and of itself possibly exert “commercial
harm… which can be used by competitors to overcome regulatory hurdles and
inform the development of their own vaccine.” Furthermore, disclosing the
integrity of the active pharmaceutical ingredient (API) is not
“commercially sensitive”, but rather is needful for fully informed
consent. Given the necessarily significant upscaling in modRNA manufacture
from the clinical batches to the commercial batches, there is a critical
need for the public to understand the extent to which purported safety
studies conducted during the clinical trials continue to apply to the
commercial batches. As per the EMA’s EPAR on Pfizer, the expression of
“aberrant proteins”, truncated spike proteins, can be assumed [1]. The
public interest here primarily concerns safety rather than the “efficacy
of the product”, as per your reply to my request. If a sufficiently high
RNA integrity can be assumed in the commercial batches, the immunological
response would, of course, be dominated by responses to full-length spike.
However, given the Bansal et al. study in the Journal of Immunology [2]
found that, under transmission electron microscopy, freely-circulating
exosomes expressing the spike protein can be detected for 4 months
following administration of BNT162b2, there is an urgent need to
understand the proportion of truncated spike proteins that may be
synthesised and then subsequently circulate in the bloodstream. Yours
sincerely, Jonathan Weissman [1]
https://eur01.safelinks.protection.outlo...
[2]
https://eur01.safelinks.protection.outlo...
-----Original Message----- FOI 22/454 Dear Jonathan Weissman, Thank you
for your email. Regarding the below request, the information requested
concerns parts of the quality dossier that are commercially sensitive and
so would be exempt from release under Section 41 (Information provided in
confidence) and Section 43 (Commercial interests). Section 41 is an
absolute exemption and no consideration of the public interest is needed.
Section 43 is a conditional exemption and a consideration of the public
interest is required. We have considered the balance of the public
interest when applying this exemption. In this case, we have not
identified any issues which would benefit the public, as a whole, by being
brought to their attention. Therefore, there is no public interest that
outweighs the commercial harm in releasing information about the
manufacturing and control of the Pfizer and Moderna vaccines, which can be
used by competitors to overcome regulatory hurdles and inform the
development of their own vaccine. It should be noted that all batches of
finished product have to be of suitable quality, as predetermined in the
finished product specification for each vaccine. Changes between batches
of vaccine that are within the finished product specification are
acceptable and should not affect the efficacy of the product. If you have
a query about the information provided, please reply to this email. If you
disagree with how we have interpreted the Freedom of Information Act 2000
in answering your request, you can ask for an internal review. Please
reply to this email, within two months of this reply, specifying that you
would like an Internal Review to be carried out. Please remember to quote
the reference number above in any future communications. If you were to
remain dissatisfied with the outcome of the internal review, you would
have the right to apply directly to the Information Commissioner for a
decision. Please bear in mind that the Information Commissioner will not
normally review our handling of your request unless you have first
contacted us to conduct an internal review. The Information Commissioner
can be contacted at: Information Commissioner's Office Wycliffe House
Water Lane Wilmslow Cheshire SK9 5AF Yours sincerely MHRA Customer
Experience Centre Communications and engagement team Medicines and
Healthcare products Regulatory Agency 10 South Colonnade, Canary Wharf,
London E14 4PU Telephone 020 3080 6000
------------------------------------------------------------------- Please
use this email address for all replies to this request:
[FOI #830595 email] Disclaimer: This message and
any reply that you make will be published on the internet. Our privacy and
copyright policies:
https://eur01.safelinks.protection.outlo...
For more detailed guidance on safely disclosing information, read the
latest advice from the ICO:
https://eur01.safelinks.protection.outlo...
Please note that in some cases publication of requests and responses will
be delayed. If you find this service useful as an FOI officer, please ask
your web manager to link to us from your organisation's FOI page.

show quoted sections

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

Internal Review of FOI 22/454

Dear Jonathan Weissman,

Thank you for your email.

We confirm that an internal review will be carried out on FOI 22/454. We normally aim to respond to requests for internal review within 20 working days of receipt. However, due to high volumes of queries we are currently receiving related to COVID-19 please be aware that responses may take longer than usual.  

Kind Regards  

MHRA Customer Experience Centre
Communications and engagement team
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf,
London E14 4PU
Telephone 020 3080 6000

show quoted sections

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

Dear Mr Weissman,

Thank you for your email.

We wanted to update you and we apologise that you have not yet received a response. We confirm that we have been experiencing high volumes of FOI requests and internal reviews, and we are working on your 4 requests for internal review in parallel.

Kind Regards

MHRA Customer Experience Centre
Communications and engagement team
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU
Telephone 020 3080 6000

show quoted sections

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

Dear Mr Weissman,

We are writing in response to your request for a review of the Medicines and Healthcare products Regulatory Agency's ('the Agency') reply to your FOI request (22/454). We apologise for the delay in response.

The purpose of this review is to determine whether the Agency dealt properly and fairly with your request under the Freedom of Information Act (FOIA). In particular, it will examine the reasons why information was withheld from you.

You stated in your request for this review that, "Disclosing all results in possession of the MHRA on the RNA integrity of the Pfizer and Moderna experimental drugs cannot in and of itself possibly exert "commercial harm... which can be used by competitors to overcome regulatory hurdles and inform the development of their own vaccine."

Furthermore, disclosing the integrity of the active pharmaceutical ingredient (API) is not "commercially sensitive", but rather is needful for fully informed consent. Given the necessarily significant upscaling in modRNA manufacture from the clinical batches to the commercial batches, there is a critical need for the public to understand the extent to which purported safety studies conducted during the clinical trials continue to apply to the commercial batches.

As per the EMA's EPAR on Pfizer, the expression of "aberrant proteins", truncated spike proteins, can be assumed [1]. The public interest here primarily concerns safety rather than the "efficacy of the product", as per your reply to my request. If a sufficiently high RNA integrity can be assumed in the commercial batches, the immunological response would, of course, be dominated by responses to full-length spike. However, given the Bansal et al. study in the Journal of Immunology [2] found that, under transmission electron microscopy, freely-circulating exosomes expressing the spike protein can be detected for 4 months following administration of BNT162b2, there is an urgent need to understand the proportion of truncated spike proteins that may be synthesised and then subsequently circulate in the bloodstream."

2. Consideration of the issues

Has the Agency answered the request and have any exemptions been properly applied?

This request was for batch data for comparability purposes of clinical trial versus commercial supply and in particular data on the integrity of the active substance.

The FOI response was constructed in the usual manner for a request that relates to information about the quality of a vaccine. The information was exempted under Sections 41 and 43 of the FOIA, accompanied by a discussion of the public interest versus scope for commercial harm & detriment to the confider. The use of these exemptions for the type of information concerned did not deviate from the regular MHRA approach, however, during our review we considered that the scope for commercial harm should be substantiated by the views of a third party. This was completed in order to ensure that the arguments put forward in the original response were tangible, and moreover were not speculative. We also identified an opportunity for the third party to potentially provide reassurance to the requester through provision of certain assurances.

The third party response explained that the detailed test method, acceptance criteria and the test results obtained are considered to be commercially confidential information (CCI). The publication of the test method and acceptance criteria enables competitors to use the test methods for their own vaccines. The third party explained that this would cause material damage to the third party, as competitors will be able to significantly speed up their drug development. Also, the test results/batch data are considered to be CCI. Even when the acceptance criteria of a test are not publicly available, test results can be used to calculate the acceptance criteria of a test method by using a statistical approaches like reference intervals or tolerance intervals (example: For an approximately normal data set, the values within one standard deviation of the mean account for about 68% of the set; while within two standard deviations account for about 95%; and within three standard deviations account for about 99.7%. This means, the test result lies with almost certainty within the range of three standard deviations which can be then assumed to be the acceptance criteria). This approach combined with the information from e.g. ICH guidelines or EMA guidelines on specifications and release can help competitors enormously to establish acceptance criteria for the active substance or the authorised product. This will save the competitor a high amount of test method development work and lead to major business advantages for the competitor and will adversely impact the third party's business.

We agree with this rationale, and maintain the exemptions applied in the original FOI response.

We also asked the third party your statement, included in your request for internal review, and added below for ease of reference,

"As per the EMA's EPAR on Pfizer, the expression of "aberrant proteins", truncated spike proteins, can be assumed [1]. The public interest here primarily concerns safety rather than the "efficacy of the product", as per your reply to my request. If a sufficiently high RNA integrity can be assumed in the commercial batches, the immunological response would, of course, be dominated by responses to full-length spike. However, given the Bansal et al. study in the Journal of Immunology [2] found that, under transmission electron microscopy, freely-circulating exosomes expressing the spike protein can be detected for 4 months following administration of BNT162b2, there is an urgent need to understand the proportion of truncated spike proteins that may be synthesised and then subsequently circulate in the bloodstream".

The third party confirmed that they have intensively assessed the potential for translation of mRNA fragments into truncated proteins/peptides. The assessment results demonstrated that fragment species observed in the vaccine are not expressed as truncated or other proteins/peptides. We hope that this will provide you with some reassurance .

Has the Agency fulfilled its general obligation to be helpful?

The original response was issued within the standard timeline in which to respond under FOIA. The internal review was delayed due to the number of requests received, and to seek views from the third party.

In the response, the author was correct to consider the public interest, however, this aspect could have been improved by also mentioning that the public interest is heightened during a pandemic, albeit that this elevated interest still does not outweigh the basis for commercial harm & detriment to the confider.

3. Conclusion and recommendations

The response sought to provide some reassurances in relation to the quality of the vaccine by inclusion of the following statement, "It should be noted that all batches of finished product have to be of suitable quality, as predetermined in the finished product specification for each vaccine. Changes between batches of vaccine that are within the finished product specification are acceptable and should not affect the efficacy of the product". And, we have expanded on this subject in section 2, above.

The exemptions were correctly applied in the response, and the views of the third party gained during the internal review process substantiated the necessity of use of these exemptions. The views of the third party could have been gathered during the handling of the original response, but there was no overt need to do so given that exemption of this type of information / data is a well-established in MHRA FOI handling.

Please note we are currently working on your three other requests for internal review and we aim to conclude these reviews shortly.

If you remain dissatisfied, you may ask the Information Commissioner (ICO) to make a decision on whether or not we have interpreted the FOIA correctly in dealing with the request and subsequent internal review. The ICO's address is:

The Information Commissioner's Office
Wycliffe House
Water Lane
Wilmslow
Cheshire
SK9 5AF

Kind regards

Customer Experience Centre
Medicines and Healthcare products Regulatory Agency

show quoted sections

Matt Cooper left an annotation ()

Documents showing the RNA integrity of both processes were leaked in December 2020, which show the RNA integrity for BNT162b2.
Process 2 is inferior to Process 1.
This was known to Pfizer, the EMA and other medicines regulators worldwide. EMA had concerns about the fragments pre-approval.
These documents have been in the public domain for over a year.

Typical RNA integrity is typically in the region 55-75%. This is in concordance with electrophoresis data released by the TGA under FOI.