WHO & COVID-19 Mishandling: Endorsing mRNA-based products without sufficient regulatory procedure
Rufika Shari Abidin
PhD in Biomedical Engineering (Vaccine & Protein Engineering, Biotechnology)
D. Endorsing mRNA-based products without sufficient regulatory procedure.
The new DNA-based and mRNA-based products never rolled out before in humans were deployed as vaccines during the COVID-19 pandemic. While the DNA-based 'vaccines' (AstraZeneca) were quickly withdrawn from the market due to myocarditis reports [1-4], the mRNA-based product is now still in the market and has been developed into therapeutics for other communicable and non-communicable diseases. That is why this section will stress more on mRNA-based products.
Apart from the fact that these nucleic acid-based 'vaccines' are not able to prevent infection and transmission and that there are safety issues pertaining to these products never before used in humans, there were actually no specific regulatory guidelines for mRNA vaccines when it was authorized for emergency use. Until now there is still none at the FDA.
The FDA issued the document "COVID-19: Developing Drugs and Biological Products for Treatment or Prevention: Guidance for Industry" in February 2021 [5], which is used as a basis for the early development of mRNA-based COVID-19 vaccines. This guidance refers to "Guidance for Industry: M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals" published in January 2010 (M3(R2) [6] and the "ICH Harmonised Tripartite Guideline Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceutical S6(R1)" published in June 2011 (S6(R1))[7] for the safety evaluation procedure.
The M3(R2)[6] recommends non-clinical safety studies prior to human clinical trials and marketing authorisation such as studies in pharmacology, toxicokinetics and pharmacokinetics, acute toxicity, repeated-dose toxicity, genotoxicity, carcinogenicity, reproduction toxicity and immunotoxicity. This means, the FDA is already aware of the importance of these tests and their basic principles. However, the COVID-19 vaccine regulatory evaluation procedure (especially on mRNAs) seems not to implement these tests appropriately before, during, and after roll-out to the public. The WHO also did not exert significant effort to implement such evaluations as a prerequisite for their recommendation.
The M3(R2) [6] guideline also refers to ICH S6(R1) [7] for appropriate non-clinical safety studies for biotechnology-derived products. The non-clinical safety studies for biotechnology-derived products recommended by the ICH S6(R1) include evaluation in immunogenicity and autoimmunity, reproductive performance and developmental toxicity studies, genotoxicity and carcinogenicity. This means, the FDA is already aware of the importance of these tests and their basic principles. However, the COVID-19 vaccine regulatory evaluation procedure seems not to implement these properly on COVID-19 vaccines, especially on mRNA-based products, before, during, and after roll-out to the public. The WHO also did not exert significant effort to implement such evaluation as a prerequisite for their recommendation.
Moreover, the ICH S6(R1) [7] explicitly states on page 2 that "This document does not cover antibiotics, allergenic extracts, heparin, vitamins, cellular blood components, conventional bacterial or viral vaccines, DNA vaccines, or cellular and gene therapies." This means that there were no proper regulatory protocols for prophylactic mRNA-based products in place when they were authorized for emergency use in 2021.?
The reference to M3(R2) and ICH S6(R1) was missing in both the "Emergency Use Authorization for Vaccines to Prevent COVID-19: Guidance for Industry" published in October 2020? [8] and the "Development and Licensure of Vaccines to Prevent COVID-19: Guidance for Industry" updated in October 2023 [9]. Safety evaluation recommendations in both documents referred to 21 CFR 601.2 [10] and 21 CFR 312.23 [11], which regulate the licensing of biologicals and investigational new drugs, respectively. Reference was also made to "Guidance for Industry: Considerations for Plasmid DNA Vaccines for Infectious Disease Indications" published in November 2007 [12], which regulates plasmid DNA vaccines, but not mRNA vaccines. At the time the guidance for plasmid DNA vaccines was issued by the FDA in 2007, mRNA-based products as we know it today, were not properly developed yet and thus not considered at that time. The FDA guidance for the emergency authorisation of COVID-19 vaccines in 2020 and other authorisations thereafter for 'mRNA-based vaccines' for COVID-19 and other diseases did not make any referral to regulatory guidance for 'mRNA-based vaccines' because such guidance does not exist.?
The FDA's guidance for plasmid DNA vaccines recommends safety evaluation in immunogenicity; cytokine; prime/boost strategies; autoimmunity; local reactogenicity and systemic toxicity; biodistribution, persistence and integration analysis. This means, the FDA is already aware of the importance of these tests and their basic principles. However, COVID-19 vaccine regulatory evaluation procedures (especially on mRNAs) seem not to implement these appropriately before, during, and after roll-out to the public. The WHO also did not exert significant effort to implement such evaluation as a prerequisite for their recommendation.
Some in the biomedical field find it difficult to call the COVID-19 prophylactic mRNA-based products as "vaccines", as these biological products do not prevent infection, or transmission, nor consistently reduce the severity of disease [13-15] and have instead caused a variety of adverse events, which are not mild in nature [16-21]. The literature oftentimes iterates that adverse events after COVID-19 vaccine administration, especially after purported 'mRNA-based vaccine' administration, as rare. However, such studies have increasingly received criticism for their error in data, statistical method and interpretation. Furthermore, if adverse events are fatal, chronically disabling and debilitating or hinder those who are affected from earning or performing daily activities optimally, then even one case of an adverse event is one case too many. This has also been pointed out by those in the field and those who are affected.?
Furthermore, vaccines should contain an antigen component, but the mRNA-based products do not contain an antigen. They instead contain nucleic acid which codes for the antigen [22]. The features of the COVID-19 prophylactic mRNA-based products, therefore, are more in congruence with the FDA definition of human gene therapy products. The FDA guidance "Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Application (INDs): Guidance for Industry" published in January 2020 [23], defined human gene therapy products as "to include all products that mediate their effects by transcription or translation of transferred genetic material or by specifically altering host (human) genetic sequences. Some examples of gene therapy products include nucleic acids (e.g., plasmids, in vitro transcribed ribonucleic acid (RNA)), genetically modified microorganisms (e.g., viruses, bacteria, fungi), engineered site-specific nucleases used for human genome editing, and ex vivo genetically modified human cells, when such products are applicable to the prevention, treatment, or cure of a disease or condition of human beings."
The COVID-19 prophylactic mRNA-based products consist of nucleic acids that mediate their effects at least by translation of transferred genetic material, which fits into the definition of human gene therapy products in [23] above. In the case of integration, these mRNA-based products would also mediate their effects by transcription and possibly also by altering host (human) genetic sequences. The event of integration should have been completely ruled out before, during, and after clinical trials. Such evaluation was not done by the FDA and other health regulatory bodies. The WHO also did not exert significant effort to implement such evaluation as a prerequisite for their recommendation.
Another COVID-19-related guideline titled "Manufacturing Considerations for Licensed and Investigational Cellular and Gene Therapy Products During COVID-19 Public Health Emergency: Guidance for Industry" was issued by the FDA on January 2021 [24], one year after the issuance of Emergency Use Authorization guidance for COVID-19 vaccines [8], and around the time when the first batch of the purported 'mRNA vaccines' were rolled-out to the public (slight difference in timing on different continents). This might explain why the terms "cell-based therapy" and "gene therapy" suddenly popped up in the latest version of the WHO's Amendments to the International Health Regulation in June this year (2024). Were some of those who drafted the Amendment to the IHR (2024) already aware that the "pandemic-related health product", especially the mRNA-based and other nucleic acid-based products rolled out to the public due to COVID-19 was in definition more in congruence with "human gene therapy product" than "vaccine"?
The FDA "Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products" published in November 2013 [24] listed the overall safety considerations for gene therapy products to include:? a) toxicities due to the components of the final formulation (e.g., liposomes and various excipient/contaminants); b) toxicities due to the ROA [route of administration] used; c) aberrant localisation to non-target cells/tissues; d) level and persistence of vector and expressed transgene; e) level of viral replication in non-target cells/tissues; f) immune activation or suppression; g) immune response directed against the vector; h) phenotype/activation state of target cell(s); i) potential for insertional mutagenesis or oncogenicity; j) potential for germline transmission; and k) potential horizontal transmission of replication competent vectors from the patient to family members and health care providers (i.e. shedding). This demonstrates that the FDA as a regulatory agency was aware of such risks potentially posed by products in congruence with the definition of gene therapy products. However, COVID-19 vaccine and therapeutics regulatory evaluation procedures (especially on mRNAs) seem not to implement these appropriately before, during, and after roll-out to the public. The WHO also did not exert significant effort to implement such evaluation as a prerequisite for their recommendation.?
The guidance on preclinical assessment for cellular and gene therapy (CGT) products [24] further elaborates that "When determining the safety of an expressed transgene and/or translated protein, sponsors should consider the following: a) local versus systemic expression; b) level and duration of expression; and c) acute versus chronic effects. While persistent transgene expression may be a desired endpoint for some gene therapy (GT) products, it can also be an undesired outcome for other products due to overexpression, accumulation of transgene protein, or the risk of an abnormal immune response. Prolonged expression of transgenes such as growth factors, growth factor receptors, or immunomodulating agents, may be associated with long-term risks due to unregulated cell growth, malignant transformation, autoimmune reactions to self-antigens, altered expression of the host’s genes, or other unanticipated adverse effects (Refs. 6 and 20). The conduct of long-term preclinical studies should be considered to evaluate these concerns..." and "In addition, potential immunogenic/neutralization responses directed against the expressed transgene and/or directed against self/endogenous proteins can be a concern. For example, delivery of transgenes that encode various endogenous enzymes, receptors or structural proteins may elicit antibodies against both the transgene and against the endogenous components expressed in normal cells and tissues, resulting in an adverse response. Similarly, transgenes that express fusion or chimera proteins can theoretically be immunogenic due to their foreign (xenogeneic) nature. These concerns should be addressed in the preclinical testing program." This demonstrates that the FDA as a regulatory agency was aware of such risks potentially posed by nucleic acid-based products, including the purported 'mRNA-based vaccines' more in congruence with the definition of gene therapy products than vaccines. However, the COVID-19 vaccine regulatory evaluation procedure (especially on mRNAs) seems not to implement these appropriately before, during, and after roll-out to the public. The WHO also did not exert significant effort to implement such evaluation as a prerequisite for their recommendation.
Although the purported 'mRNA vaccines' are more in congruence in definition with human gene therapy products, regulatory authorities did not officially categorise the purported 'mRNA vaccines' as such. Calls from different segments of society to categorise the purported 'mRNA vaccines' as a human gene therapy product (instead of vaccines) and consequently implement relevant regulatory procedures were ignored [22, 26, 27).
The EMA, for example, stated that "...a vaccine against an infectious disease is not considered a gene therapy, as it does not aim to restore, correct or modify human genes," and further that DNA integration assessment was not carried out "as only traces of DNA are present in the vaccine" [28]. This argument neglects the fact that mRNA products mediate their effect by translation of transferred genetic materials (which is included in the definition of gene therapy as quoted above), in addition to having the risk of modifying human genes due to reverse-transcriptase and integrase activity of the endogenous LINE-1 enzyme [29-35], even if the mRNA product was not aimed for such modification. In this context, whether there are only traces of DNA present in the vaccine solution is a totally different, but also important question.
Contaminant DNA fragments have been detected in the Pfizer and Moderna COVID-19 mRNA vaccine preparations [35, 36] . The risk of integration or tumorigenicity of plasmid DNA and naked DNA has been discussed in regulatory and scientific literature [12, 23-25] and emphasis has been placed on antibiotic resistance genes in plasmid DNA [12, 22]. Plasmid DNA has been used as a template to produce the purported COVID-19 'mRNA vaccines' and concerns about integration, tumorigenicity, and antibiotic resistance genes of plasmic DNA should have been included in safety evaluation procedure, but were neglected just like other safety aspects that were not evaluated [22]. Importantly, a human gene therapy product administered to the public as vaccines, especially with mandates, would imply forceful genomic and/or gene modification attempts without informed consent to those who have received them.?
In this section, the focus of the discussion is on FDA regulation because the FDA's decision is usually referred to by other countries, especially by countries where regulatory infrastructure is not sufficiently in place. Moreover, the WHO recently attempted to insert the term "regulatory reliance and mutual recognition" in the pandemic treaty draft [37-40]. Regulatory recognition (not previously the norm) would imply that one regulatory authority in one jurisdiction obviates its independence in decision-making and adopts the decision of another regulatory authority and as such does not require access to complete assessments regarding medical products or regulatory dossiers on efficacy, safety, etc [37]. The obligation to adopt the FDA's (and other referral health regulatory authorities) decision-making for other countries as a consequence of an agreed and legally binding 'regulatory recognition' (because the phrase 'non-binding' was removed in the Pandemic Treaty and the Amendments to the International Health Regulation drafts), taking away rights from member countries to conduct independent assessment or to access to regulatory dossiers would be an authoritarian undertaking with devastating results.
The use of generic and/or repurposed drugs was discouraged by the WHO and other health authorities by demanding scientific-based evidence via resource and time-consuming RCTs. On the other hand, COVID-19 vaccines in general and the purported 'mRNA vaccines' in particular were hastily authorized for emergency use to the public and subsequently licensed without proper safety evaluation. The WHO's and other health authorities' approach to generic and repurposed drugs with known safety profiles during COVID-19 was 'no recommendation until scientific-based evidence through lengthy evaluation procedure becomes available'. In contrast, their approach to COVID-19 vaccines, especially the purported 'mRNA vaccines', was 'haste recommendation even though scientific-based evidence regarding safety through lengthy evaluation procedure was not available'.
The authorisation and subsequent licensing of COVID-19 mRNA-based vaccines have been used as a basis to approve other mRNA vaccines that came after (cancer, RSV, etc.). This is because the FDA's "Guidance for Industry: General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases" published in December 2011 [41] , among others, stated that "Accelerated approval may be granted for certain biological products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments."
Considering that COVID-19 mRNA-based vaccines have not been properly evaluated for safety and were not effective, in addition to adverse events that have been observed after purported COVID-19 'mRNA-based vaccines' administration, the COVID-19 'mRNA-based vaccines' and all other mRNA-based and other nucleic acid-based products for other diseases, which were subsequently accelerated for approval, have to be withdrawn from the market. I join others in the field [42] to call for the withdrawal of COVID-19 vaccines, but also the withdrawal of other vaccines for other diseases which have undergone accelerated authorization and licensing based on the evaluation of the purported COVID-19 'mRNA-based vaccines'.
Nucleic acid-based products, including mRNA-based products, should be scrutinized for safety, but in my humble opinion, the known and unknown interaction of nucleic acid-based (DNA and RNA) products with the basic components of the codes of life should render such products banned from further medical use.?
FURTHER READINGS
1. AstraZeneca COVID-19 vaccines withdrawn worldwide
2. EMA policy to withdraw Astrazeneca (Vaxzeria) COVID-19 vaccine
3. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination
4. Vascular and coagulation and dysfunction due to Spike protein in COVID-19 vaccine
5. COVID-19: Developing Drugs and Biological Products for Treatment or Prevention (v2021)
6. M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals
7. S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals May 2012
8. Emergency Use Authorization for Vaccines to Prevent COVID-19: Guidance for Industry" October 2020
9 . Development and Licensure of Vaccines to Prevent COVID-19 Guidance for Industry October 2023
10. eCFR :: 21 CFR 601.2 -- Applications for biologics licenses; procedures for filing.
11. eCFR :: 21 CFR Part 312 -- Investigational New Drug Application
12. Considerations for Plasmid DNA Vaccines for Infectious Disease Indications: Guidance for Industry
13. Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study?
14. Short term, relative effectiveness of four doses versus three doses of BNT162b2 vaccine in people aged 60 years and older in Israel: retrospective, test negative, case-control study?
15. Mengapa Wajib Vaksin COVID-19 agar Sebaiknya Dihentikan
领英推è
16. It is time to thoroughly evaluate the risks of mRNA drug and vaccine toxicity
17. Molecular Mimicry of the Viral Spike in the SARS-CoV-2 Vaccine Possibly Triggers Transient Dysregulation of ACE2, Leading to Vascular and Coagulation Dysfunction Similar to SARS-CoV-2 Infection, and the references therein
18. A case of biopsy-proven inflammatory dilated cardiomyopathy following heterologous mRNA-1273 third-dose immunization
19. High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms?
20. Cardiac and Neurological Complications Post COVID-19 Vaccination: A Systematic Review of Case Reports and Case Series
21. COVID-19, post-acute COVID-19 syndrome (PACS, "long COVID") and post-COVID-19 vaccination syndrome (PCVS, "post-COVIDvac-syndrome"): Similarities and differences
22. mRNA: Vaccine or Gene Therapy? The Safety Regulatory Issues, and the references therein, focusing on EMA policies
23.Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)?
24. Manufacturing Considerations for Licensed and Investigational Cellular and Gene Therapy Products During COVID-19 Public Health Emergency Guidance for Industry January 2021
25. Preclinical Assessment of Investigational Cellular and Gene Therapy Products Guidance for Industry
26. RNA-based drugs and regulation: Toward a necessary evolution of the definitions issued from the European union legislation
27. Lobbies calling for mRNA vaccines not to be classified as gene therapy
28. European Comission's answer to question on mRNA classification as gene therapy
29. The mRNA-LNP vaccines – the good, the bad and the ugly?
30. Potential health risks of mRNA-based vaccine therapy: A hypothesis
31. Intracellular Reverse Transcription of Pfizer BioNTech COVID-19 mRNA Vaccine BNT162b2 In Vitro in Human Liver Cell Line
32. Comment on Aldén et al. Intracellular Reverse Transcription of Pfizer BioNTech COVID-19 mRNA Vaccine BNT162b2 In Vitro in Human Liver Cell Line. Curr. Issues Mol. Biol. 2022, 44, 1115–1126
33. Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues
34. New Understanding of the Relevant Role of LINE-1 Retrotransposition in Human Disease and Immune Modulation
35. Methodological Considerations Regarding the Quantification of DNA Impurities in the COVID-19 mRNA Vaccine Comirnaty?
36. Florida State Surgeon General Calls for Halt in the Use of COVID-19 mRNA Vaccines
37. TWN on regulatory reliance, recognition, and harmonisation in pandemic agreement drafts and the references therein
38. Pandemic Agreement Draft 7th March 2024
39. Pandemic Agreement Draft 22 April 2024
40. A good review of the amendments to the IHR
41. Development and Licensure of Vaccines to Prevent COVID-19 Guidance for Industry October 2023
42. Americans for Health Freedom calling for the withdrawal of COVID-19 vaccines
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“Den Gamle Dame med Svovlstikkerne†aka “Den Kronisk Svimle Patient†- M?nstergenkendelse, Systemtester, Syg, Under udredning, p? Ressourceforl?bsydelse pr 12/2-2024, “Poesiens Bl? Blomstâ€, V?rdikriger, Frihedsk?mper
2 个月Wow, that’s reassuring ?? Would it be safe to assume that the massive excess death toll, can only be “proven†to our deliberately obtuse governments and health authorities, if we keep dying prematurely in uncomfortably large numbers? Apparently the virus was man-made, but not necessarily lethal; whereas the vaccine is a timebomb, expediting us to a healthcare system, designed to be as unresponsive and unsupportive as a debt collector’s convention… https://www.wch-denmark.org/en/post/does-the-spike-protein-come-from-a-laboratory https://youtu.be/ZJyjV6eeMW4?si=SW_wHRhHuhj-1289
“Den Gamle Dame med Svovlstikkerne†aka “Den Kronisk Svimle Patient†- M?nstergenkendelse, Systemtester, Syg, Under udredning, p? Ressourceforl?bsydelse pr 12/2-2024, “Poesiens Bl? Blomstâ€, V?rdikriger, Frihedsk?mper
4 个月Terrifying ?? We were witnesses, and our dead bodies will provide proof… We must avoid cremation ?? … It will not end well for them ??
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4 个月Very helpful