Persconferentie n.a.v. reactie EMA aan MEP Marcel de Graaff

Op 4 oktober 2023 is door een aantal Europese Parlementsleden (Marcel de Graaff, Gilbert Collard, Francesca Donato, Joachim
Kuhs, Mislav Kolakušić, Virginie Joron, Ivan Vilibor Sinčić and Bernhard Zimniok) een verzoek ingediend bij de EMA (European Medicines Agency) om met onmiddellijke ingang de handelsauthorisatie voor de uitgifte van de mRNA Covid-19 vaccinaties in te trekken.

Op 18 oktober 2023 ontving Europarlementarier Marcel de Graaff onderstaand antwoord van de EMA in zijn emailbox. Naar aanleiding van dit antwoord van de EMA is een persconferentie belegd waarin onthutsende feiten aan de orde kwamen.

Deelnemers aan deze waren: Marcel de Graaff (Europarlementariër FVD),Joachim Kuhs (Europarlementariër AfD), Willem Engel (farmacoloog), Vibeke Manniche (arts) en Max Schmeling (statisticus).

Door op onderstaande afbeelding te klikken of deze link wordt u doorverwezen naar onze video-website waar u de persconferentie kunt bekijken. Onder de afbeelding is de email opgenomen die Marcel de Graaff als antwoord van het EMA heeft ontvangen.

Reactie EMA aan MEP Marcel de Graaff

Marcel de Graaff MEP
European Parliament
ASP 06E240
60, rue Wiertz / Wiertzstraat 60
B-1047 Brussels
Belgium

Email: [email protected]

18 October 2023
EMA/451828/2023
European Medicines Agency

Dear Honourable Members of Parliament Marcel de Graaff, Gilbert Collard, Francesca Donato, Joachim  Kuhs, Mislav Kolakušić, Virginie Joron, Ivan Vilibor Sinčić and Bernhard Zimniok

Thank you for your letter of 4 October 2023 in which you call for the suspension of the marketing  authorisations of the mRNA COVID-19 vaccines Comirnaty and Spikevax.

The European Medicines Agency is committed to protecting public health by conducting thorough scientific assessments of medicinal products for the EU. We are equally dedicated to ensuring that the  public and their representatives in the European Parliament are informed of the reasons why their  medicines are authorised and of the measures we take to monitor them once they are available.

We should also emphasise that EMA focuses mainly on one aspect of EU health policy, namely the  authorisation and monitoring of medicines and vaccines. When our scientific committees issue  recommendations, other bodies, such as the European Commission, the European Centre for Disease  Prevention and Control (ECDC) and national health and vaccination authorities can consider them as  they develop immunisation policies to protect the public.

Please find below direct responses to the questions you raise in your letter.

1. The authorised indications

You state that based on the authorised indications, the vaccines ‘should only be administered to  individuals who seek personal protection, and they are not authorised for the purpose of reducing  transmission or infection rates (transmission control)’. You also state that the authorised indication  does not align with uses promoted by ‘pharmaceutical companies, politicians, and health  professionals’.

You are indeed correct to point out that COVID-19 vaccines have not been authorised for  preventing transmission from one person to another. The indications are for protecting the  vaccinated individuals only.

The product information for COVID-19 vaccines clearly states that the vaccines are for active  immunisation to prevent COVID-19. In addition, EMA’s assessment reports on the authorisation of  the vaccines note the lack of data on transmissibility.

EMA will continue to be transparent about the approved uses of COVID -19 vaccines and identify  areas where we need to tackle misconceptions.

2. Authorisation of vaccines targeting the Omicron XBB.1.5 subvariant

You note that data from clinical trials are not available for adapted vaccines targeting Omicron  XBB.1.5 subvariant. Given this and the fact that the international public health emergency is over,  you question the need for authorising the adapted vaccines at this time.

We would like to stress that the authorisation of adapted COVID-19 vaccines is not contingent on  the continuation of the public health emergency. The authorised indications do not restrict the use  of the vaccines to an emergency.

Furthermore, data from clinical trials were not a scientific requirement for the Omicron XBB.1.5 adapted vaccines because of the information derived from the originally authorised and earlier  adapted vaccines.

In its decisions to recommend authorisation of vaccines targeting the Omicron XBB.1.5 subvariant,  EMA’s human medicines committee (CHMP) considered all the available data on both the originally  authorised vaccines and earlier adapted ones, including data on safety, efficacy and  immunogenicity (how well they trigger immune responses). In addition, the Committee assessed  laboratory data on the responses of the adapted vaccines against XBB.1.5 and related strains of  SARS-CoV-2, the virus that causes COVID-19. Please also note that for Spikevax XBB.1.5, the  Committee assessed some clinical data from an ongoing study.

Where the ending of the public health emergency may be relevant is in the vaccination strategies  of EU Member States and the advice given to the general population. In this regard, the product  information for COVID-19 vaccines state that the use of the vaccines ‘should be in accordance with  official recommendations’.

3. Environmental risk assessments for genetically modified organisms (GMOs)

I understand you have concerns about Regulation (EU) No 2020/1043/EU (“the Regulation”) which,  as stated in its Article 2 of the Regulation, allows for the conduct of some clinical trials with  products containing GMOs without a prior environmental risk assessment.

You also note that, according to Article 4, the Regulation shall ‘apply as long as WHO has declared  COVID-19 to be a pandemic or as long as an implementing act by which the Commission  recognises a situation of public health emergency due to COVID-19’.

It is important to first clarify that mRNA vaccines are not considered genetically modified organisms. It is our understanding that the Regulation was intended for other vaccines, such as vaccines that ‘contain attenuated viruses or live vectors, which may fall within the definition of a  GMO.’[1] 

That said, we can provide you with information on the status of the environmental risk  assessments for Comirnaty and Spikevax.

At the time of the initial authorisations of Comirnaty and Spikevax, the CHMP noted in its published  assessment reports that, due to their nature, ‘vaccines and lipids are unlikely to result in a  significant risk to the environment’. The Committee further noted that it was acceptable for  environmental risk assessment studies not to be provided in the applications for marketing  authorisation. You can find more information in the published assessment reports on EMA’s website as well as the CHMP Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use.[2]

On the basis of the Regulation, you also imply that with the end of the public health emergency,  companies should now provide prior environmental risk assessments for adapted vaccines.

Having clarified that the vaccines are not GMOs and the Regulation does not therefore apply, we  would also like to clarify that adapted vaccines are not new vaccines with marketing authorisations  separate from those of the originally authorised vaccines. Any theoretical environmental risks they  may pose are considered to be the same as those of the originally authorised vaccines.

On a separate note, national authorities approve clinical trials in the EU and would therefore be the  authorities to receive any environmental risk assessments required before the start of a clinical  trial.

4. Safety, efficacy and quality of vaccines

Safety

In response to your comments about the safety of the vaccines, we would like to point out that  EMA and national authorities continuously monitor data on reported side effects. It is also  important to clarify that a report of a suspected side effect is not in itself evidence that a vaccine  caused the adverse event in question.

Such adverse events can occur for other reasons in vaccinated people, as they do in unvaccinated  people. With a large proportion of the general population having had the vaccines, we expect many  reports of conditions occurring at or soon after vaccination.

To determine whether a vaccine caused an event, authorities have to assess all the relevant data,  including data that might indicate that the condition occurs at a higher rate in vaccinated or  recently vaccinated people than in others.

As shown in the product information for both vaccines, most side effects are mild, although more  serious ones can occur. You note the risk of myocarditis and pericarditis, which EMA has assessed  and described in the product information.[3], [4] All safety information should be considered carefully  before administering or recommending vaccination.

Efficacy

You say that ‘a fundamental requirement for a vaccine is to stimulate long-term immunity’, noting  that ‘if a vaccine only offers protection for less than a year, it falls short of this crucial criterion’. We take from your comment that no vaccine should be authorised without evidence of long-term  protection.

While long-term protection is always desirable, imposing such a requirement would have severe  consequences for public health and put vulnerable people in danger. Establishing long-term  protection may also not be feasible and, in the case of COVID-19, will be complicated by the  evolution of SARS-CoV-2, a situation that we also observe with influenza.

When EMA recommends the authorisation of a vaccine, it provides information on the data it  assessed to help vaccination authorities and healthcare professionals make recommendations to  the wider public.

Qualitative and quantitative properties

In your section ‘Lack of declared qualitative and quantitative properties’, you refer to the lack of  data on the prevention of transmission rather than the qualitative and quantitative properties of  the vaccines. We have addressed the issue of transmissibility above.

Quality of submitted documentation

In arguing against the authorisations of the vaccines, you refer to ‘irregularities and illegalities in  altering the categorization of medicines’ and ‘changes in the rolling review and conditional  marketing authorization procedures, as well as modifications to the definitions of vaccines and  immunity’. We comment on these concerns, to the extent that we can, in the sections below.

You also cited a BMJ article by Paul D Thacker about Ventavia, a contract research organisation that worked on some clinical trial sites for Comirnaty.[5]

EMA, in close collaboration with the US Food and Drug Administration (FDA), looked into the issues  reported in the BMJ and concluded that the deficiencies identified do not jeopardise the quality and  integrity of the data from the main Comirnaty trial and have no impact on the benefit-risk  assessment.

The main trial that supported the authorisation of Comirnaty included around 44,000 people and  was conducted in about 150 sites around the world. Ventavia enrolled around 1,000 subjects in 3  sites in the United States, representing less than 3% of the total study population. The issues  affected one of those 3 sites and mainly concerned a lack of trained staff which resulted in  deficiencies such as delays in data entry and query resolution. The marketing authorisation holder  audited the company at the end of 2020, and corrective actions were taken, including oversight  visits and hiring of additional staff. These actions were deemed appropriate.

Ventavia also recruited participants in studies on the use of Comirnaty in children and as a booster  (representing about 1.6% and 3.5% of the total study populations respectively). As with the main  study, EMA looked at the relevant data and concluded that the issues reported at the concerned  site have no impact on the assessments of the benefits and risks of the vaccine for these uses. The  corrective actions taken by the company were put in place before these later trials started enrolling  participants.

Summaries of product characteristics and package leaflets

You note that the summaries of product characteristics (SmPCs) for Comirnaty and Spikevax ‘are  so voluminous that they have become de facto illegible for both doctors and citizens making  informed consent impossible’. You also note a similar problem with the package leaflets.

These documents have indeed grown in size as new strengths and new adapted vaccines have  been approved. EMA is currently considering ways to improve the way information is presented in  SmPCs and package leaflets, not only for COVID-19 vaccines but for all medicines evaluated  centrally in the EU. We are also looking at other ways to present information in our lay language  questions and answers (Q&A) documents (what we call medicines overviews).

Good manufacturing practices

You refer to emails released by hackers, some referring to the quality of Comirnaty. It is important  to note that during the evaluation of medicines, issues arise which need to be resolved before EMA  can recommend an authorisation. A collection of selected emails cannot provide an accurate or full  picture of what the issues were or how they were resolved. In this case, the issue concerned mRNA  integrity (i.e. whether mRNA in the vaccine remained intact as expected).

While some truncated mRNA pieces were found in the vaccine, the CHMP concluded in 2020 that ‘proposed specifications for RNA integrity and 5’-Cap are considered to be scientifically justified and  acceptable. Nevertheless, additional data to complete the characterisation of the active substance  and finished product, and considering clinical experience, are considered important to confirm the  adequacy of these specifications, and these data should be provided post-approval as specific  obligations to the MA [marketing authorisation]’.

The company has since provided all the required information, and the specific obligations have  been fulfilled. The CHMP has accepted the latest specifications proposed by the company.[6]

5. Legal status of EU authorisations of Comirnaty and Spikevax

You have raised a number of concerns about EU Regulations and Directives. You question the initial conditional marketing authorisations of Comirnaty and Spikevax, as you believe that Regulation  (EU) 2019/5 [7], Regulation (EU) No 2020/1043 [8] and Regulation (EU) No 2021/756 [9] do not meet the  framework laid down:

• on environmental risk assessment and reporting in Regulation (EU) No 2001/18 [10] and Directive 2009/41/EC [11];
• on safety for medicinal products laid down in Directive 2001/83/EC [12], Commission Directive 2003/63/EC [13] and Regulation (EC) No 1394/2007 [14];
• concerning the granting of a union licence laid down in Regulation (EC) No 2004/726 [15] and Regulation (EC) No 2008/1234 [16].

You also state that the changes in Regulation (EU) 2019/5 ‘should not be used to go outside the  framework of existing classification and categorisation, only clarification is allowed, no categories  can be added that conflict with the current system, full legislation is needed for that.’

Further, you state that ‘the addition of codes/sequences’ in Regulation (EU) No 2021/756 ‘conflicts  with the classification and categorisation’ of Directive 2001/83/EC, Directive 2003/63/EC and  Regulation (EC) No 1394/2007.

You also assert that parts of Regulation (EU) No 2020/1043 (concerning trials of GMOs for COVID 19) and Regulation (EU) No 2021/756 (concerning variations to marketing authorisations of  coronavirus vaccines) are ‘contrary to Articles 141 and 168’ of the Treaty on the Functioning of the

European Union. Furthermore, you say that Regulation (EU) 2019/5 was used in violation of Article  290(1) of the Treaty.

We read these concerns as being related to the Regulations and Directives themselves. While EMA  is bound by them, we are not in a position to comment on the appropriateness of Regulations or  Directives adopted by Parliament and the Council or on their compatibility with the Treaty.

With regard to extensions of marketing authorisations, you note that Regulation (EU) No 2021/756 (concerning variations to marketing authorisations of influenza and coronavirus vaccines) was  adopted after the authorisations of Comirnaty and Spikevax. The implication is that the Regulation  does not apply to adapted Comirnaty and Spikevax vaccines. Please note that the text of the  regulation clearly recognises that ‘based on the scientific assessment by the European Medicines  Agency, the Commission has thus far authorised several COVID-19 vaccines’, and the Regulation  provides for variations to the authorisations of these and future vaccines.

You also highlight Article 19 of Regulation (EC) No 2008/1234 (concerning variations), which states  that ‘an extension shall either be granted a marketing authorisation in accordance with the same  procedure as for the granting of the initial marketing authorisation to which it relates or be  included in that marketing authorisation’. Please note that this article does not preclude relying on  relevant data from the initial marketing authorisation. Furthermore, and as noted above, the  authorisation of the adapted vaccines for Comirnaty and Spikevax are covered by Regulation (EU)  No 2021/756, which amends Regulation (EC) No 2008/1234.

With regard to Article 1 (4) of Directive 2001/83/EC, vaccines are listed as agents used to produce  active immunity. You say that there is no evidence that these vaccines provide immunity (i.e.  protection against infection or disease).

It is true that the protection wanes over time as the virus itself evolves, and this is one of the  reasons why adapted vaccines have been authorised. It is important to note that with SARS-CoV-2,  people may be exposed to the virus several times and repeated exposure may increase the chance  of infection even in vaccinated people.

COVID-19 vaccines also provide protection against severe disease, including hospitalisation. This is  particularly important for vulnerable people who are at increased risk.

You also state that ‘a vaccine must contain an antigen; this antigen requires its own registration in  the Vaccine Antigen Master File (VAMF)’ as laid down in Directive 2003/63/EC. ‘The reason for this  method’, you say, ‘is that homogeneity and quality and active dose can be determined per  treatment. This is not the case with coding sequences.’

It is important to note that for mRNA vaccines, the antigen (the particle that triggers an immune  response) is not the mRNA active substance itself but the spike protein formed after vaccination.

That said, we would like to clarify what a VAMF is. EU legislation provides for the option of  presenting all required information on a vaccine antigen as a VAMF (i.e. as a stand-alone part of  the marketing authorisation application (MAA) dossier for a vaccine). A VAMF is particularly useful  when a specific vaccine antigen is used in different vaccines. In such cases, with a single  evaluation of a VAMF, authorities can assess the same antigen used in several vaccines at the  same time. The VAMF system is therefore only aimed at simplifying the evaluation of vaccines, and  the use of VAMFs is optional. When the option of a VAMF is not used, companies, like for any other  medicine, have to include the relevant information on the vaccine antigen directly in the MAA  dossier concerned.

You can find more information in the Guideline on Requirements for Vaccine Antigen Master File  (VAMF) Certification on EMA’s website.[17]

6. EMA reflection papers

Citing EMA’s Reflection paper on the classification of advanced therapy medicinal products [18] and  EMA’s Reflection paper on criteria to be considered for the evaluation of new active substance (NAS) status of biological substances, you make the following case: that mRNA is considered an  example of gene therapy and therefore any significant change in the sequence of mRNA require s a  new application.

As you noted in your letter, Commission Directive 2009/120/EC does not consider vaccines against infectious diseases gene therapies, as the aim of vaccination is not to restore, correct or modify  human genes. Furthermore, the extensions to marketing authorisations of COVID-19 vaccines are  covered by Regulation (EU) No 2021/756.

Finally, we take note of your call for immediate action to suspend the marketing authorisations of  Comirnaty and Spikevax, including the authorisations of the adapted vaccines targeting the Omicron  XBB.1.5 subvariant.

EMA’s CHMP can only recommend suspensions of the marketing authorisations if the evidence shows  that the risks outweigh the benefits. The evidence continues to show that the vaccines provide  protection, which is particularly important for vulnerable people. Removing these vaccines as an option  for EU Member States and for healthcare professionals without due regard to available data would  therefore be a great disservice to the EU and to public health.

I would like to thank you for writing to the Agency and I hope this reply addresses your concerns.

Yours sincerely,

Emer Cooke

Executive Director

[1] https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32020R1043
[2]https://www.ema.europa.eu/en/environmental-risk-assessment-medicinal-products-human-use-scientific guideline
[3]https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac 29-november-2-december-2021
[4]https://www.ema.europa.eu/en/documents/prac-recommendation/signal-assessment-report-myocarditis pericarditis-tozinameran-covid-19-mrna-vaccine_en.pdf
[5] Thacker PD. Covid-19: Researcher blows the whistle on data integrity issues in Pfizer’s vaccine trial. BMJ.  2021;375:n2635. Published 2021 Nov 2. doi:10.1136/bmj.n2635
[6]https://www.ema.europa.eu/en/documents/variation-report/comirnaty-h-c-5735-r-0137-epar-assessment-report renewal_en.pdf
[7] Amending Regulation (EC) No 726/2004, Regulation (EC) No 1901/2006 (concerning medicines for children) and  Directive 2001/83/EC
[8] Concerning trials of GMOs for COVID-19
[9] Concerning variations to marketing authorisations of influenza and coronavirus vaccines and amending Regulation  2008/1234
[10]Concerning GMOs in the environment
[11]Concerning use of GMOs
[12]Concerning human medicines in the EU
[13]Amending Directive 2001/83/EC
[14]Concerning advanced therapy medicines
[15]Concerning the establishment of the EMA and the centralised procedure
[16] Concerning variations
[17]https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-vaccine-antigen-master file-vamf-certification_en.pdf
[18]https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-classification-advanced-therapy medicinal-products_en-0.pdf