The EMA covid-19 data leak, and what it tells us about mRNA instability
BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n627 (Published 10 March 2021) Cite this as: BMJ 2021;372:n627Read our latest coverage of the coronavirus outbreak
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Dear Editor,
I'm not surprised there is confusion about the quantity of mRNA in the vaccine. One of the problems with mRNA is the need to find the 'sweet spot' as to quantity. Too much and it could be lethal, too little and it is destroyed by the body. This was the problem with Moderna's attempt at finding a cure for Crigler-Najjar syndrome.[1]
It is likely that neither Pfizer nor Moderna know what the ideal quantity is or even if there is a single quantity which works for everyone. We do for example know that girls respond differently from boys to various vaccines. We cannot then assume that 'one size fits all'.
Ruth Sharratt
1 Garde D. Lavishly funded Moderna hits safety problems in bold bid to revolutionize medicine. STAT 2017 Jan 10
Competing interests: No competing interests
Dear Editor
We have read the article “The EMA covid-19 data leak, and what it tells us about mRNA instability” [1], published in BMJ on 10/03/2021 with steadily growing concern.
This article questions an EMA decision, and this criticism is based on data unlawfully obtained from EMA. While EMA should do everything to prevent data leaks, computer hacking is a criminal offence. EMA states that the information was partially doctored, and that the perpetrators selected and aggregated data from different users and added additional headings [2]. The data published on the dark web are not verifiable, extremely questionable and thus, the propagators of such information should not be provided with a legitimate platform.
It is unclear to us why a respected journal chose to present unverifiable information, in the process damaging an institution that has worked for 25 years in a transparent and successful manner. Evaluation of new medicinal products is difficult; it requires competence, and it takes time to go through all the information supplied by applicants. Therefore, it is part of the procedure and perfectly acceptable that after the first reading, the authorities pose numerous questions to applicants. However, the responses to these questions, which were adequate to reassure the regulator as reported in the public assessment report [3], have not been taken into account in the BMJ article. Besides, EMA is not the only regulatory authority which has looked at these data. The vaccine has been approved and is now in use in more than 40 countries, including many European countries but also Australia, Canada, the United States, Chile, Singapore and a number of Middle Eastern countries.
We now have data on the use of the Pfizer-BioNTech vaccine in a real-world setting. In the UK, data from the SIREN study, a prospective cohort study among staff working in publicly funded hospitals, were used to determine vaccine effectiveness of the vaccine. The study demonstrates that the vaccine effectively prevents both symptomatic and asymptomatic infection in working age adults [4]. Similarly, all newly vaccinated persons in Israel during the period from December 20, 2020, to February 1, 2021, were matched to unvaccinated controls. Estimated vaccine effectiveness at 7 or more days after the second dose was higher than 90% for all outcomes assessed, including documented infection, symptomatic Covid-19, hospitalization, and severe disease [5]. In the US, where tens of millions of doses of the Pfizer vaccine have been administered, a retrospective cohort analysis of a high-risk population, residents of skilled nursing facilities, found that even with partial vaccination, Pfizer-BioNTech COVID-19 vaccine provided protection to the residents [6].
We believed that the BMJ promotes Evidence-Based Medicine, and would only publish articles based on hard, verifiable data. We can only imagine that this editorial somehow escaped your vigilance and professional scrutiny.
Sincerely yours,
Pieter Neels, International Alliance for Biological Standardization - IABS, Geneva, Switzerland
Elizabeth Miller, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health London School of Hygiene & Tropical Medicine, United Kingdom
Pierre Van Damme, Centre for the Evaluation of Vaccination, Vaccine & Infectious Diseases Institute, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.
Joris Vandeputte, International Alliance for Biological Standardization - IABS, Geneva, Switzerland
Thomas Verstraeten, P95 Epidemiology & Pharmacovigilance, Leuven, Belgium
Albert Osterhaus, University of Veterinary Medicine, Hannover, Germany
Steffen Thirstrup, Affiliate Professor, Department of Drug Design and Pharmacology, Translational Pharmacology Faculty of Health, University of Copenhagen, Denmark
Marc Baay, P95 Epidemiology & Pharmacovigilance, Leuven, Belgium
Stanley Plotkin, University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, United States
1. Tinari S. The EMA covid-19 data leak, and what it tells us about mRNA instability. Bmj 2021;372:n627. doi: 10.1136/bmj.n627 [published Online First: 2021/03/12]
2. European Medicines Agency. Cyberattack on EMA - update 6 2021 [Available from: https://www.ema.europa.eu/en/news/cyberattack-ema-update-6March 15, 2021.
3. European Medicines Agency. Comirnaty - COVID-19 mRNA vaccine (nucleoside-modified) 2020 [Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/comirnatyMarch 15, 2021.
4. Hall VJ, Foulkes S, Saei A, et al. Effectiveness of BNT162b2 mRNA Vaccine Against Infection and COVID-19 Vaccine Coverage in Healthcare Workers in England, Multicentre Prospective Cohort Study (the SIREN Study). Lancet preprint 2021 doi: http://dx.doi.org/10.2139/ssrn.3790399
5. Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med 2021 doi: 10.1056/NEJMoa2101765 [published Online First: 2021/02/25]
6. Britton A, Jacobs Slifka K, Edens C, et al. Effectiveness of the Pfizer-BioNTech COVID-19 Vaccine Among Residents of Two Skilled Nursing Facilities Experiencing COVID-19 Outbreaks — Connecticut, December 2020–February 2021. Morb Mortal Wkly Rep 2021;ePub: 15 March 2021 doi: http://dx.doi.org/10.15585/mmwr.mm7011e3
Competing interests: PN is a regulatory consultant and is working with a number of COVID-19 developers of vaccines and antibodies. PVD declares organisational financial interest, through research grants to the University of Antwerp for the conduct of COVID19 vaccine trials. TV is the managing director of P95, who has received consulting fees from mRNA vaccine manufacturers. ST is a former member of CHMP, now working as a regulatory consultant. MB is an employee of P95, who has received consulting fees from mRNA vaccine manufacturers. SP is a paid consultant to numerous companies developing vaccines against COVID-19, including Moderna but not Pfizer. Other authors declare no competing interests.
Dear Editor
Reading this important article has reminded me of a concern I had when reading what the MHRA's Public Assessment Report [1] on the Pfizer/BioNtech vaccine said about the lipid nanoparticles used as excipients - ALC-0315 and ALC-0159.
They are novel excipients (at least in UK-authorised medicinal products) and the justification for not having conducted pharmacokinetic (PK) studies is that they “are generally not considered necessary to support the development and licensure of vaccine products for infectious diseases (WHO, 2005; WHO, 2014)”.
But on reading WHO, 2005 - which is a reference to WHO Guidelines on nonclinical evaluation of vaccines [2]- I see that PK studies are not normally needed but should be considered on a case-by-case basis (para 4.2.6) ), and toxicity studies should be performed where new excipients (and preservatives) are used for which no toxicological data exist (para 5.2).
I also note that the still extant EMA 2006 guidance [3] states “Pharmacokinetic studies are usually not required for vaccines. However, such studies might be applicable when new delivery systems are employed or when the vaccine contains novel adjuvants or excipients. The need for PK studies and their design should be considered on a case by case basis and it is recommended that applicants should obtain scientific advice from EU Competent Authorities” (para 4.1). The 2006 guidance is being revised, and this text is missing from the current draft revised version [3].
I would have expected therefore at least an explanation as to why PK studies were not considered necessary.
I also see that the EMA's Public Assessment Report [4] states that in January 2021 (and April 2021) “additional information about the synthetic process and control strategy for” ALC-0315 and ALC-0159 “should” be provided by BioNTech, with final reports in July 2021, in order to “confirm the purity profile and ensure comprehensive quality control and batch-to-batch consistency throughout the lifecycle of the finished product”.
I have no pharmacological expertise, but it seems to me that an explanation should be given as to why PK studies were not considered necessary, and the additional information that was due to be provided in January 2021 should be disclosed, along with the April and July updates when provided. The EMA should also explain why paragraph 4.1 of its 2006 guidance has been dropped from its draft revised guidance.
Yours sincerely,
Peter Roderick
1. https://assets.publishing.service.gov.uk/government/uploads/system/uploa...
2. https://www.who.int/biologicals/publications/trs/areas/vaccines/nonclini...
3. https://www.ema.europa.eu/en/clinical-evaluation-new-vaccines#current-ef...
4. https://www.ema.europa.eu/en/medicines/human/EPAR/comirnaty#product-info...
Competing interests: No competing interests
Dear Editor
It is regrettable that the regulatory authorities and pharmaceutical companies have not been forthcoming with more information about the levels of mRNA needed for a good vaccine response.[1]. It may be partly understandable that they are trying not to give publicity and credence to unscrupulous and mischievous hackers whose intentions are not noble and academic. But during a pandemic, public trust is a valuable commodity and like a broken glass, it is hard to fix once it has been shattered. Hence further information from regulatory authorities and pharmaceutical companies is crucial.
The state of Israel has entered into an unprecedented agreement with Pfizer in terms of sharing detailed patient level information.[2]. The Israeli researchers have reported high degree of efficacy for the Pfizer vaccine.[3]. Pfizer would have batch level data on the amount of mRNA levels in the vaccines supplied to the Israeli population.
The precise levels of mRNA may be commercially confident. But that shouldn’t stop Pfizer and Israeli regulatory authorities from analysing the existing efficacy data against batch level mRNA content. Then, if appropriate, a statement can issued saying that varying levels of mRNA in different batches did not affect vaccine efficacy in the Israeli population. This would provide reassurance to the Public and Health Professionals.
References
1 Tinari S. The EMA covid-19 data leak, and what it tells us about mRNA instability. BMJ 2021;372:n627. doi:10.1136/bmj.n627
2 Staff R. Israel sharing COVID-19 data with Pfizer to help fine-tune vaccine rollout. Reuters. 2021.https://www.reuters.com/article/us-health-coronavirus-pfizer-israel-idUS... (accessed 13 Mar 2021).
3 Wise J. Covid-19: Pfizer BioNTech vaccine reduced cases by 94% in Israel, shows peer reviewed study. BMJ 2021;372:n567. doi:10.1136/bmj.n567
Competing interests: No competing interests
Response to Neels et al.
Good investigative journalism requires an ability to competently deal with materials that originate from hacking or leaking. We always take into consideration the provenance of such materials, and ensure that our handling and reporting on the materials is such that it serves the public interest.
We appreciate Neels and colleagues sharing their views, but disagree with their statement that Serena Tinari’s article "questions an EMA decision" if this is meant to suggest that BMJ has somehow implied that EMA’s judgment about mRNA integrity was incorrect. The BMJ article neither states nor implies that regulators have erred in their decisions about appropriate mRNA integrity levels. Rather, the BMJ article highlights the lack of transparency regarding any specifics over how the issue that arose in November 2020 was resolved, and also questions the alleged confidentiality regarding current regulatory standards related to quality acceptability criteria such as percentage mRNA integrity. The leaked documents are used in the BMJ article as a window into the complexities of mRNA vaccine manufacturing and the importance of mRNA integrity, an issue that has received insufficient attention.
Neels and colleagues write that the BMJ article did not take into account the fact that Pfizer’s response satisfied the EMA. We disagree. The BMJ article states: "The issue was satisfactorily addressed, the agency [EMA] underlined, when further information was supplied by the manufacturer.” But again, the key problem is that neither EMA nor FDA, MHRA, or Health Canada offered much detail about just how those concerns were satisfied.
Neels and colleagues write: “We believed that the BMJ promotes Evidence-Based Medicine, and would only publish articles based on hard, verifiable data. We can only imagine that this editorial somehow escaped your vigilance and professional scrutiny.”
We will continue to advocate for transparency and access to data, and believe them to be vital to the practice of evidence-based medicine. Neels and colleagues suggest the article we have published is not “based on hard, verifiable data,” but provide no evidence of error. The BMJ article made clear, that according to EMA, “whilst individual emails are authentic, data from different users were selected and aggregated, screenshots from multiple folders and mailboxes have been created, and additional titles were added by the perpetrators.” This does not mean the material is fully unusable or without value, and we are confident in our use of it. We continue to believe that publishing this article, partially based on material from the leaked documents, was in clinicians’ and the public’s interest.
Peter Doshi and Rebecca Coombes
Competing interests: We commissioned the article by Serena Tinari. Full competing interests for all BMJ editors are available here https://www.bmj.com/about-bmj/editorial-staff and information about the funding for our investigations is available here: https://www.bmj.com/investigations