Presentation to the OPECST — Christine Cotton (5 April 2022)

English translation of her slide deck presented to France’s Parliamentary Office for the Evaluation of Scientific and Technological Choices (OPECST). Source: https://christinecotton.com/Presentation-CC-OPECTS-2022-04-05.pdf

Evaluation of the methodological practices implemented in the Pfizer trials in the development of its messenger-RNA vaccine against COVID-19 in light of Good Clinical Practice OPECST Presentation Christine COTTON 1

To Maxime Beltra Christine COTTON – 05/04/2022 - © Truth is a science with a future

Outline • My experience • Reminder on clinical trials • Expert review of the Pfizer trial • Efficacy • Follow-up time / Tolerability • Immunogenicity • Conclusion on the trials • Follow-up data • Adverse effects and Pharmacovigilance • Real-world data • State of knowledge to date • General conclusion 2

Christine COTTON – 05/04/2022 - ©

My experience 3

Christine COTTON – 05/04/2022 - ©

Biostatistician, former CEO of a CRO. Who am I? • Master’s degree in economics and statistics • 23 years in the pharmaceutical industry • Founder and CEO of my company for 22 years: a CRO - Clinical Research Organization: subcontractor in charge of monitoring, data management, statistics • Biostatistician, SAS® programmer • Clinical trial methodology • Drafting of the statistical sections of clinical trial protocols, • Development of the Patient Booklet including the data to be collected during the trial • Calculation of the number of subjects to include in a trial • Development of randomization lists • Writing of the statistical analysis plan • Programming of statistical analyses (SAS®: descriptive analyses, common tests (Student, Chi-square, Wilcoxon …), analysis of variance, covariance, survival analyses (Kaplan-Meier, Cox models ..), multivariate models, • Development of the tables to include in the clinical report according to the ICH E3 recommendation • Statistical Expert in IDMCs (Independent Data Monitoring Committee) 4

Experience • All types of trials in varied therapeutic areas: oncology, dermatology, central nervous system, gastrointestinal system, autoimmune diseases, osteoarticular system, dentistry, pulmonology, ophthalmology, nutrition • Phases 1, 2, 3, 4 • Parallel groups, Latin squares, cross-over • Observational studies • ATU, RTU [temporary/recommended use authorizations] Clients: AbScience, AstraZeneca, Aventis, Bausch & Lomb, Bayer, Debiopharm, Galderma, Horus, Intergroupe Francophone du Myélome, Institut de recherche Servier, Ipsen, Janssen-Cilag, Medtronic, Menarini, Orfagen, Pfizer, Pherecydes Pharma, Pierre Fabre, Roche, Sanofi, Thea, Takeda, Synthelabo, United Pharmaceutical, Virbac, Yamanouchi, Various hospitals https://cordis.europa.eu/project/id/601857/reporting • Data management • Setting up the websites enabling collection of clinical trial data (data management) • Coding of adverse effects using the MedDRA dictionary Christine COTTON – 05/04/2022 - © Quality Assurer of the CRO: • Drafting of Standard Operating Procedures according to pharmaceutical industry recommendations, • Monitoring of the quality policy and indicators • Multiple audits

Reminder on clinical trials 5

Christine COTTON – 05/04/2022 - ©

Levels of evidence Source: Level of evidence and grading of good-practice recommendations - April 2013 https://www.has-sante.fr/upload/docs/application/pdf/2013-06/etat_des_lieux_niveau_preuve_gradation.pdf 6

Christine COTTON – 05/04/2022 - © Real-world studies therefore have a level of evidence far lower than that of trials. For more than a year, health decisions have been based on real-world studies and not on the results of clinical trials.

General framework of trials • For any New drug or vaccine, clinical Trials must be carried out: • Based on clinical endpoints representative of the disease If you want to test a treatment for Benign Prostatic Hyperplasia, a score summing urination-related symptoms: how many times, difficulty holding back … you do not measure fever • It is therefore a matter of methodology: • choice of the primary efficacy endpoint, • choice of analyses, • choice of measurement times (visits), • choice of the mode of data collection … • Calculations performed by biostatisticians and not by physicians: number of patients to include in the trials, analyses to carry out to provide the results 7 • 3 phases of development in humans after testing in animals, Phase 1 in volunteers to assess tolerability, Phase 2, dose-finding, Phase 3 pivotal trial, confirmatory trial, the one that gives rise to Marketing Authorization (MA) if the results are conclusive Christine COTTON – 05/04/2022 - ©

Stakeholders in a trial 8

Christine COTTON – 05/04/2022 - ©

Regulation Hundreds of directives and recommendations to follow, grouped under the name Good Clinical Practice to follow https://www.ich.org (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2-guideline-good-clinical-practice-step-5_en.pdf • To harmonize practices worldwide • To minimize the risk of error in benefit/risk assessment in order to guard against any risk of using in real life a product that is potentially ineffective or even dangerous.

Benefit / Risk balance in the case of a vaccine Benefit Risk: Efficacy / immunogenicity Adverse events A methodology is needed that is capable of identifying the elements likely to make the results deviate from their true value; these elements are called bias. Some biases arise, among others, From the calculation of the endpoints themselves From poor quality of participant follow-up within the centers, reducing the quality of the reported data From non-randomization, for example an allocation of treatments such that low-risk subjects are systematically assigned to one treatment. 9

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“It is commonly accepted that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. …. With regard to pharmaceutical products, although there is a variety of stakeholders, including patients and physicians, as well as government and industry, the protection of the patient through quality risk management should be considered as paramount.” https://database.ich.org/sites/default/files/Q9%20Guideline.pdf 10 Definition of Risk

“The sponsor must implement a quality management system at all stages of the trial process. It must focus on the activities essential to the protection of human subjects and to the reliability of the trial results. During the development of the protocol, the sponsor must identify the processes and data that are essential to ensure the protection of human subjects and the reliability of the trial results. Risks must be considered both at the system level (e.g., standard operating procedures, computerized systems, personnel) and at the clinical trial level (trial design, data collection, informed consent process). Predefined quality tolerance limits must be established, taking into account the medical and statistical characteristics of the variables as well as the statistical plan of the trial, in order to identify the systematic problems likely to have an impact on subject safety or the reliability of the trial results.” See page 21 of Guideline 5.0 Quality Management Christine COTTON – 05/04/2022 - ©

Experimental vaccines? Pfizer https://clinicaltrials.gov/ct2/show/NCT04368728?term=pfizer&cond=Covid19&draw=2 Moderna https://clinicaltrials.gov/ct2/show/NCT04470427?term=mRNA1273&draw=2 11

Christine COTTON – 05/04/2022 - © The trials are still ongoing for any participant who has not reached the end of follow-up, whatever their age, adult, adolescent, child. The anti-covid vaccines are experimental products authorized on a derogatory basis.

Usual Clinical Development versus COVID-19 vaccines BARDA/ASPR/HHS https://www.fda.gov/media/143560/download Classic development / Accelerated development 12

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Expert review of the Pfizer trial 13

Christine COTTON – 05/04/2022 - ©

I did not examine ONLY the protocol; it is by comparing the protocol against the results that one can identify the problems. The protocol alone was written according to vaccine protocol templates. The problems here arise from the fact that the other vaccines placed on the market on the basis of similar templates • did not concern a little-known disease such as covid, particularly in early 2020 • did not concern an innovative product never used before • were not intended to be administered to billions of human beings across the entire planet • that the Covid trials had an accelerated development as never seen before • that these trials, in addition, benefited from “fast track” procedures allowing • a priority review • an accelerated approval, • a Rolling Review, the laboratory being able to submit complete sections of its biologics license application (BLA) or its new drug application (NDA) for FDA review, rather than waiting for each section of the NDA to be completed before the entire application could be reviewed. In general, review of the BLA or NDA does not begin until the pharmaceutical company has submitted the entire application to the FDA. • https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track I have never worked directly on vaccine trials; my expertise does not concern the product but essentially the statistical methodologies which, whatever the field, remain governed by the same standards of quality and rigor, the notion of bias not depending on the clinical field in which one works. It was also necessary to have some perspective on the disease in real life (post-vaccination infections), on the adverse effects, and to examine the successive reports to validate the existence of bias or not. 14

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Q2. You examined the protocol of the clinical trial carried out by Pfizer/BioNTech to obtain an MA for the Comirnaty vaccine. Based on your own experience of clinical trials, possibly for other vaccines, what elements caught your attention? Documents examined • The clinical study protocols: https://www.nejm.org/doi/suppl/10.1056/NEJMoa2107456/suppl_file/nejmoa2107456_protocol.pdf • The clinical reports • Of 10/12/2020: 92-page report https://www.fda.gov/media/144246/download 53-page report https://www.fda.gov/media/144245/download • Of 09/04/2021: https://www.fda.gov/media/148542/download • Of 26/10/2021: https://www.fda.gov/media/153409/download • Cumulative analysis of post-authorization adverse-event reports of 28/02/2021 https://phmpt.org/wp-content/uploads/2021/11/5.3.6-postmarketing-experience.pdf • Successive Risk Management Plans - Last updated 26/11/2021: https://www.ema.europa.eu/en/documents/rmp-summary/comirnaty-epar-risk-management-plan_en.pdf • Pfizer presentation to the CDC of 22/09/2021 https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-09-22/02-COVID-Gruber-508.pdf • FDA audit: https://www.fda.gov/vaccines-blood-biologics/comirnaty • Ventavia affair: https://www.bmj.com/content/375/bmj.n2635 15

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• Randomized: experimental product allocated according to a predefined design or stratification factors • Controlled: versus placebo, 0.9% saline solution • Blinded: for the participant, the investigator, the coordinator, the site staff; the physical appearance of the candidate vaccines and the placebo may differ. The staff in charge of storage, distribution, preparation and administration are not blinded • Phase 1,2: several doses of candidate vaccines, candidate vaccine BNT162b2 at a dose of 30 μg selected after Phase 2 • Multicenter: several clinical sites • Objective of Phase 2-3: to assess the efficacy of BNT162b2 in preventing the development of symptomatic COVID-19 starting 7 days after the 2nd dose of vaccine in participants without prior COVID-19 infection. • Population: • Initial protocol: over 18 years old • Amendment 6 of 8 September 2020 allows the inclusion of 16-17 year-olds • Amendment 7 of 9 October 2020 extends the population to 12-15 year-olds • …. Characteristics of the Pfizer COVID-19 phase 3 trial 16 Christine COTTON – 05/04/2022 - ©

• Visit schedule • Visit 1: 1st dose placebo or candidate vaccine, Day 1 • Visit 2: 2nd dose to be injected between 19 and 23 days after the 1st visit • Visit 3: 1 week after dose 2 in phase 1-2, removed from phase 3 • Visit 4: 2 weeks after dose 2 in phase 1-2, removed from phase 3 • Visit 5: 1 month after dose 2 • Visit 6: 6 months after dose 2 • Visit 7: 12 months after dose 2 • Visit 8: 24 months after dose 2 Characteristics of the Pfizer COVID-19 phase 3 trial 17 Christine COTTON – 05/04/2022 - ©

[Timeline: M1 to M25; V1 Dose1, V2 Dose2, V3, V4 V5, V6 V7 V8; Interim analysis]

Efficacy 18

Christine COTTON – 05/04/2022 - ©

Measurement of Efficacy • Primary endpoint: first appearance of symptomatic COVID-19 starting 7 days after dose 2, defined by the presence of at least one of the following symptoms reported by the participant among: • Fever, • Onset or worsening of cough, • Onset or worsening of shortness of breath, • Chills, Onset or worsening of muscle pain, • Loss of taste or smell, • Sore throat, • Diarrhea, • Vomiting. • And a positive PCR test. Counting the number of participants with this event for each group, then statistical comparison https://www.fda.gov/media/144246/download 44,000 participants recruited in total, about 38,000 taken into account in the first interim analysis in December 2020 0.044% 0.88% Results December 2020 19 Christine COTTON – 05/04/2022 - © This does not mean that 95% of people are “immunized.” In reality, 0.88% - 0.044%, there is 0.84% fewer confirmed symptomatic covid cases for the vaccine

Method of symptom reporting in the trial 20 Christine COTTON – 05/04/2022 - ©

Methodological evaluation of efficacy https://phmpt.org/wp-content/uploads/2021/11/5.3.6-postmarketing-experience.pdf Analysis of the cumulative post-authorization safety data, important identified risks, important potential risks and missing information from 01 December 2020 to 28 February 2021 by the Pfizer laboratory. As early as February 2021: real-world post-vaccination infection rate in the reported AEs of 4.6% = Vaccine failure = 100 times the infection rate of the clinical trial, which was 0.044%

Analysis of AEs by Pfizer • No PCR test except at inclusion and at the injection of dose 2 • The participant has the responsibility to report his/her symptoms to the site No PCR test performed → No COVID-19 = Success for the vaccine 21 Bias highlighted Christine COTTON – 05/04/2022 - ©

• Possible incomplete reporting in the electronic diary or poor assessment by the participant who does not have the competence to judge his/her state of health • Poor assessment by the site staff via a teleconsultation or simple phone call for symptoms suggestive of COVID-19 or a possible reaction to the vaccine (diarrhea, vomiting, muscle pain, fever) • Use of antipyretics that suppress the symptoms, fever and pain (% use of antipyretics ≈ x 3.5 in the vaccine group compared to the placebo group) • Suspected but unconfirmed symptomatic cases almost 2 x more numerous in the vaccine group; why are these cases unconfirmed? • Non-response by the site

Efficacy on severe cases and people over 75 Severe cases 22 Over 75 years No efficacy on severe cases for lack of cases 95% CI (-124.8 to 96.3) No efficacy on the over-75s for lack of cases 95% CI (-13.1 to 100) Christine COTTON – 05/04/2022 - ©

OPECST report December 2020 https://twitter.com/JFEliaou/status/1339313680111038467?s=20&t=N5hOuOdMgelNGzp-BxhWDw Source: https://www.assemblee-nationale.fr/dyn/15/rapports/ots/l15b3695_rapportinformation.pdf OPECST report of 15/12/2020 – page 17 “Efficacy could not be established for the over-75s due to too-small numbers” Why was the information conveyed that the vaccines protected the over-75s without proof? No proven efficacy for severe cases Why was the information conveyed that the vaccines prevented severe forms without proof?

Efficacy in adolescents and children Source: OPECST Report – 06/07/2021. The scientific and technical aspects of the fight against the Covid-19 pandemic http://www.senat.fr/rap/r20-741/r20-7411.pdf 24 0.0% 1.6% Christine COTTON – 05/04/2022 - © Clinical Report - 9 April 2021 on 12-15 year-olds. Clinical Report – 26 October 2021 on 5-11 year-olds https://www.fda.gov/media/153409/download https://www.fda.gov/media/153409/download Erroneous understanding of the results: • This is not about immunity but about the number of symptomatic cases • The trials were far from complete in June 2021. This does not mean that 100% of adolescents are “immunized.” In reality, 1.6% fewer symptomatic covid cases (at least 1 symptom) confirmed for the vaccine

Efficacy in adolescents and children Clinical Report – 26 October 2021 on 5-11 year-olds No efficacy demonstrated on severe cases 0 cases out of 1968 participants https://www.fda.gov/media/153409/download HAS Vaccination strategy against Covid-19 - Role of the mRNA vaccine COMIRNATY® in 5-11 year-olds https://www.has-sante.fr/upload/docs/application/pdf/2021-12/strategie_de_vaccination_contre_la_covid19placee_du_vaccin_a_arnm_comirnaty_chez_les_5-11_ans.pdf Clinical Report - 9 April 2021 on 12-15 year-olds No efficacy demonstrated on severe cases 0 cases out of 1983 participants HAS Vaccination strategy against Covid-19 - Role of the mRNA vaccine COMIRNATY® in 12-15 year-olds https://www.has-sante.fr/upload/docs/application/pdf/2021-06/strategie_de_vaccination_contre_la_covid19-place_du_vaccin_a_arnm_comirnaty_chez_les_12-15_ans-_recommandation.pdf https://www.fda.gov/media/153409/download 25 Covid risks established by the HAS. Covid risks established by the HAS

No efficacy demonstrated on transmission https://www.ema.europa.eu/en/medicines/human/EPAR/comirnaty 26 Christine COTTON – 05/04/2022 - © Any efficacy demonstrated on the chosen primary endpoint cannot claim to demonstrate that the vaccine prevents COVID-19 transmission, Transmission not studied, therefore efficacy not demonstrated on transmission This is confirmed by the opinions of the HAS and the ANSM as early as December 2020 “with no demonstrated impact on transmission” “vaccine effective for individual protection”

OPECST report December 2020 Source: https://www.assemblee-nationale.fr/dyn/15/rapports/ots/l15b3695_rapport-information.pdf OPECST report of 15/12/2020 27 Christine COTTON – 05/04/2022 - © “The vaccines having only been tested for their ability to prevent the occurrence of symptomatic forms, their action on viral carriage is unknown” “there can be collective immunity only when vaccination prevents transmission” OPECST report December 2020 28 Page 102 https://www.assemblee-nationale.fr/dyn/15/rapports/ots/l15b3695_rapport-information.pdf OPECST report of 15/12/2020 Christine COTTON – 05/04/2022 - © “I recall that to eradicate an infectious disease, a vaccine must both prevent severe forms and prevent the spread of the virus”

Efficacy conclusion Dubious estimate of the real number of symptomatic COVID-19 cases • Conclusions on the demonstrated efficacy of the vaccine are unreliable. • Multiple biases in the counting of symptomatic COVID-19 cases confirmed by PCR test • Very surprising way of managing participants in the clinical trial, since any person with COVID-19, even asymptomatic, could infect those around them, thus transmitting a potentially fatal disease, which apparently did not worry the laboratory much, whereas health policies all advocate mass screening and isolation aimed at limiting the spread of the disease • Poorly chosen primary endpoint, not representative of the disease. It would have been much more appropriate to choose a primary endpoint counting all COVID-19 cases and not only symptomatic cases, since all the health measures aimed at containing the epidemic include screening of all cases • Why did the laboratory not choose to perform regular PCR tests on all participants? • Why did the laboratory not choose to perform regular serologies to check whether the participant had had COVID-19? • Why count from 7 days after dose 2, knowing that there are a great many cases in the days following an injection? 29 Christine COTTON – 05/04/2022 - © Conclusions that are not only erroneous but also not representative of the epidemic

Follow-up time / Tolerability 30 Christine COTTON – 05/04/2022 - ©

Follow-up time Median follow-up time of 2 months after dose 2, a shortened time compared to the old directives, 6 months minimum https://www.fda.gov/media/144246/download Clinical Report – 10 December 2020 on the ≥ 16 year-olds Clinical Report - 9 April 2021 on 12-15 year-olds https://www.fda.gov/media/144246/download Clinical Report – 26 October 2021 on 5-11 year-olds https://www.fda.gov/media/153409/download 31 Christine COTTON – 05/04/2022 - ©

Tolerability bias - 1 Clinical study report – 09/04/2021 - Unknown benefits and missing data cited on page 38 • Duration of protection • Efficacy in certain populations at high risk of severe COVID-19 • Efficacy in people already infected with SARS-CoV-2 • Future efficacy of the vaccine, influenced by the characteristics of the pandemic • The evolution of the virus and/or the potential effects of co-infections. • Efficacy of the vaccine against asymptomatic infection • Efficacy of the vaccine against the long-term effects of COVID-19 disease • Efficacy of the vaccine against mortality • Efficacy of the vaccine against transmission of SARS-CoV-2.” 32 https://www.fda.gov/media/144246/download Christine COTTON – 05/04/2022 - © The short observation period of participants does not allow assessment of medium- and long-term safety, which is mentioned in the “Comirnaty Risk Management Plan” for the months in chapter SVII.3.2 “Presentation of missing information.”

Duration of protection unknown “the number of participants in the current clinical development program is too small to detect the potential risks of myocarditis associated with vaccination. The long-term safety of the COVID-19 vaccine in participants aged 5 to <12 years will be studied in 5 post-authorization safety studies, including a 5-year follow-up study to assess the long-term sequelae of post-vaccination myocarditis/pericarditis.” Tolerability bias - 3 Source: Clinical report on 5-11 year-olds of 26/10/2021 https://www.fda.gov/media/153409/download 33 Christine COTTON – 05/04/2022 - © Insufficient numbers at the time of the interim analyses for the 12-15 year-olds and 5-11 year-olds to identify serious adverse effects

Risks and missing information Missing information in the risk management plan of November 2021; already present in December 2020 • Use during pregnancy and breastfeeding • Use in immunocompromised patients • Use in frail patients with comorbidities (e.g., chronic obstructive pulmonary disease [COPD], diabetes, chronic neurological disease, cardiovascular disorders). • Use in patients with autoimmune or inflammatory diseases. • Interaction with other vaccines • Long-term safety data https://www.ema.europa.eu/en/documents/rmp-summary/comirnaty-epar-risk-management-plan_en.pdf 34 Christine COTTON – 05/04/2022 - © No data in the clinical trials for efficacy, tolerability, or immunogenicity in these populations

Risks and missing information - Booster Vaccination strategy against Covid-19. Role of a booster with the mRNA vaccine COMIRNATY® 13/10/2021 Page 81 https://www.hassante.fr/jcms/p_3290614/fr/strategie-de-vaccination-contre-la-covid-19-place-d-un-rappel-par-le-vaccina-arnm-comirnaty Authorizing a booster is therefore a MAXIMAL risk-taking • No efficacy data on the booster, nor on symptomatic/asymptomatic Covid, severe forms, hospitalizations, deaths • No data on tolerability in patients with comorbidity • No data in subjects with a history of Covid • No data on pregnant women • Duration of protection still unknown 35

Risks and limitations already known to the OPECST in December 2020 Source: https://www.assemblee-nationale.fr/dyn/15/rapports/ots/l15b3695_rapport-information.pdf - OPECST report of 15/12/2020 36 Christine COTTON – 05/04/2022 - © “there is no hindsight on long-term tolerability (more than 3 months)” “The British health authorities recommended not vaccinating people likely to have severe allergic reactions (typically those who permanently carry injectable adrenaline” Why did the HAS remove the recommendation not to vaccinate people likely to have severe allergic reactions?

Tolerability conclusion 37 Significant risks recognized for patient health as early as December 2020: • Anaphylaxis, • Vaccine-Associated Enhanced Disease (VAED). • Median follow-up time of 2 months after dose 2, no conclusion possible on tolerability beyond 3 months • Insufficient numbers at the time of the interim analyses to identify serious effects • Concealment of a serious effect during the interim analysis in 12-15 year-olds (testimony of Maddie de Garay, 13 years old, before Senator Ron Johnson) Why is this effect not in the report? (only abdominal pain reported across the entire complete clinical picture) Bias highlighted Christine COTTON – 05/04/2022 - © Incomplete tolerability evaluation Erroneous risk assessment 1 very serious effect out of 1131 participants on BNT162b2 Would the vaccine have been authorized for 12-15 year-olds if this effect had been reported in the clinical report?

Immunogenicity 38 Christine COTTON – 05/04/2022 - ©

Immunogenicity bias The neutralizing-antibody titration presented already indicated a decrease in immunity less than 2 months after the second dose (titrations removed in phase 3). Pfizer admission: “data from Israel and the United States suggest that vaccine protection against COVID-19 declines about 6 to 8 months after the second dose.” Decrease in antibody levels before dose 3 (before booster); the booster dose was set up to compensate for the vaccine’s protection 39 https://www.fda.gov/media/144246/download Report of 10/12/2020 - phase 1-2 results. Pfizer presentation to the CDC 22/09/2021 Christine COTTON – 05/04/2022 - ©

Confirmation of the antibody drop Source: preprint https://www.biorxiv.org/content/10.1101/2020.09.08.280818v1.full.pdf Source: final https://www.nature.com/articles/s41586-021-03275-y This graph is found Only in the preprint article but not in the final https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontechannounce-data-preclinical-studies-mrna 40 Christine COTTON – 05/04/2022 - © In the preclinical study on macaques, a decline in neutralizing antibodies was already observed at 2 months after dose 2

If antibody titration had been chosen as the primary endpoint, no MA would have been obtained. Immunogenicity conclusion 41 Christine COTTON – 05/04/2022 - © • The trial design (absence of titration at 3 months after dose 2) therefore contributed to masking the antibody drop, which was nonetheless foreseeable as early as the first report in December 2020 and in the results on macaques • This is all the more questionable as the laboratory had planned a booster dose as early as December 2020 • Why was the laboratory already studying a BOOST as early as December 2020? HAS opinion of December 2020.

Non-compliance with Good Clinical Practice • An employee of Ventavia, a contract research organization, CRO, reported serious violations of good clinical practice and other improper practices • storage of products at an inadequate temperature • failure to respect anonymity, • errors in sample handling, • chaotic follow-up of serious adverse events ….. • failure to perform PCR tests for all participants presenting symptoms of COVID-19 in order to validate or not the presence of the case. • Concerns only 3 centers having enrolled 1000 participants, but this highlights uncertainties about training, supervision and follow-up of the centers by the laboratory, as well as uncertainties about the quality of participant follow-up by the centers, leading to an underestimate of the number of symptomatic COVID-19 cases, the primary endpoint of the study. This also casts suspicion on the management of all the other centers. https://www.bmj.com/content/375/bmj.n2635 42 Serious violations of good clinical practice affecting the assessment of efficacy and tolerability Christine COTTON – 05/04/2022 - ©

Q12. Do you know whether the health authorities investigated the whistleblowing about malpractice by a former employee of Ventavia, the CRO to which Pfizer/BioNTech delegated part of its clinical trial? • The list of audited facilities does not appear on the FDA’s website, so I do not know. The FDA audit, conducted on 9 centers, does not allow these doubts to be removed, since, by the FDA’s own admission, during the audits conducted on the centers, “the part on data integrity and the verification of the BIMO (Bioresearch Monitoring) inspections was limited because the study was ongoing and the data required for verification and comparison were not yet available to the auditor” https://www.fda.gov/vaccines-blood-biologics/comirnaty https://datadashboard.fda.gov/ora/cd/inspections.htm

Date / Event 31/07/2020 Visit 1: randomization, 1st dose Numerous medical history and comorbidities: type 2 diabetes, obesity, myocardial infarction in 2017 19/08/2020 Visit 2: 2nd dose 16/09/2020 Visit 3. XX.XX/2020 Visit for Covid because of cough and shortness-of-breath symptoms, date masked? The site does not know whether the patient had COVID. DDC done to change the date of the symptoms into adverse effects. DDC for PCR test not performed. Death COVID pneumonia Case of participant 11281009, man born in 1954 - Site: 1128 - Ventavia Research Group Audit trail of the Patient Booklet in Recent Documents made public following legal action in the USA Page 300 Page 316 Page 329 Page 332 Page 344 Page 333 Page 361

Conclusions on the trials 46 Christine COTTON – 05/04/2022 - ©

[Summary table] Benefit Risk Efficacy Immunogenicity Measured endpoints Failing or Bias The Quality Indicators are all IN THE RED Erroneous reporting of symptoms. No test done → No COVID. Confirmation, because of imbalance between the groups for the unconfirmed symptoms PCR test Use of antipyretics suppressing the symptoms that could lead to a COVID diagnosis. No test done → No COVID. Confirmation, because of imbalance between the groups for the taking of these treatments. No titration between 2 months after dose 2 and 6 months after dose 2: large gap between the visits COULD HAVE MASKED the antibody drop Tolerability Primary endpoint: first appearance of symptomatic COVID-19 confirmed by PCR test starting 7 days after dose 2 The participant has the responsibility to report his/her symptoms to the site Antibody titration / Duration of protection Bias: elements likely to make the results deviate from their true value Median observation time of 2 months. Too short for medium and long term Sample size too small to detect serious cases, notably in the 12-15 year-olds and 5-11 year-olds (≈ 2300). Maddie de Garay, SERIOUS event (disability) not reported in the report No data beyond 2 months after dose 2 at the time of the interim analyses. No possibility of concluding a duration of protection > 3 months Non-response by the site. No test done → No COVID. Confirmation Ventavia Numerous unknowns cited in the RMP, because populations not studied in the trial. Pregnant women … X Real duration of protection = 4 months Unreliable results. Erroneous assessment of the B/R B/R Balance X 95% No tolerability problem. Recognized risks: anaphylaxis, VAED, Myocarditis/Pericarditis 47 Christine COTTON – 05/04/2022 - ©

Source: Level of evidence and grading of good-practice recommendations - April 2013 https://www.has-sante.fr/upload/docs/application/pdf/2013-06/etat_des_lieux_niveau_preuve_gradation.pdf Reminder of GCP recommendations according to the HAS The trial has a level of evidence if: • No major bias • the sample size is adequate 48 Christine COTTON – 05/04/2022 - © The HAS recommendations confirm the absence of validity at the level of evidence of this clinical trial.

Follow-up data 49 Christine COTTON – 05/04/2022 - ©

6-month trial data - efficacy Source: Article of 15/09/2021 in the New England Journal of Medicine https://www.nejm.org/doi/pdf/10.1056/NEJMoa2110345?articleTools=true Comment Surya https://www.bmj.com/content/375/bmj.n2635/rr The results of the analyses of the Pfizer trial at 6 months confirm the efficacy of the vaccines on symptomatic COVID-19 cases confirmed by PCR test, with a vaccine efficacy of 91.3% 50 Christine COTTON – 05/04/2022 - © Placebo participants are permitted, even encouraged, to receive the vaccine. This biases the comparison between the groups for all the evaluation endpoints, rendering the final analysis totally uninformative 51

Mortality due to COVID-19? • 1 Covid-19 death in the vaccine group • 2 deaths in the placebo group. Total mortality • 15 deaths in the vaccine group • 14 deaths in the placebo group • How is the “Unevaluable event” death explained? 6-month trial data - Deaths Source: Article of 15/09/2021 in the New England Journal of Medicine https://www.nejm.org/doi/pdf/10.1056/NEJMoa2110345?articleTools=true Christine COTTON – 05/04/2022 - © Is there a statistically demonstrated effect of the vaccine on deaths due to COVID-19? Is there a statistically demonstrated effect on mortality?

Collection of adverse effects 52 Christine COTTON – 05/04/2022 - ©

Reminder of the clinical trial protocol • Effects reported by the participant • Serious effects collected only for 6 MONTHS after the last dose ??? • Why not until the end of the trial, which ends in May 2024? Booster trial • Booster trial: To Evaluate the Safety, Tolerability, Efficacy and Immunogenicity of BNT162b2 Boosting Strategies Against COVID-19 in Participants ≥12 Years of Age. • https://clinicaltrials.gov/ct2/show/NCT04955626 53 Christine COTTON – 05/04/2022 - ©

General conclusion – Clinical trials • Apart from a “demonstrated” effect on the number of symptomatic covid cases (at least 1 symptom) confirmed by PCR test 7 days after dose 2, the trials demonstrate • No efficacy on severe cases • No efficacy on transmission, • No efficacy on mortality due to COVID-19 Given the number of major biases arising from • the very design of the trial (schedule of planned visits, mode of reporting of symptoms suggestive of a respiratory infection, mode of reporting of adverse effects, choice of an inappropriate primary endpoint, absence of antibody titration between 2 months and 6 months after dose 2…), • the analysis methods (interim analyses over a reduced follow-up duration, 2 months median, max 3 months), • the major deviations from Good Clinical Practice in the investigator centers, given the multitude of international recommendations to follow to ensure a quality worthy of the name Christine COTTON – 05/04/2022 - © The results provided in the various Pfizer clinical reports, having been examined under urgency by the various health authorities, both in terms of efficacy, immunogenicity, and safety, cannot be considered as having integrity and being reliable from the standpoint of Good Clinical Practice, thus biasing the assessment of the supposedly favorable benefit/risk ratio of the Comirnaty vaccine. No authorization should ever have been granted on the basis of their results. Risk-taking to use these products as early as December 2020 54

Q4. Do you have the same objections for the clinical trials conducted by Moderna or AstraZeneca? I cannot commit 100% on the other vaccines [as to] whether the methods of collecting symptoms and adverse effects are identical. If you would like a study on these vaccines, you can commission me to do so. What aspects of the marketing-authorization granting procedure should be reviewed, in your opinion? I am not competent to answer this question. Regarding the vaccines, the problems certainly come from the time taken to examine the documents. Q5. How do you explain that agencies such as the ANSM and its counterparts did not detect these problems or did not reach the same conclusions as you? It is not for me to answer this question; this commission is certainly better placed than I. My only question is: did biostatisticians review the reports? Christine COTTON – 05/04/2022 - © Usually yes; in no case regarding these trials, in which participants were recruited in record time

Based on 8 hours of daily work Participants must report their own adverse effects by calling the investigator centers; because of the large number of participants recruited at the same time, in the event of non-response the effects are not reported, all the more so as the gaps between the visits after dose 2 are large. In my report I recommended asking the Pfizer laboratory to provide the files tracing the phone calls of the participants and the call-backs by the center. All phase 3 vaccine trials involve large populations since the sample-size calculations imply low percentages of sick patients. The smaller the difference between products, the larger the number of patients to recruit to demonstrate a statistically significant difference. The numbers for adolescents and children are very small, making the detection of rare events impossible.

Date / Number of participants / Number of centers / Number of days / Recruitment rate per day / Recruitment rate per hour * 27/07/2020 360; 20/08/2020 11000 25 426 53; 06/10/2020 37000 120 48 541.7 67.7; 14/11/2020 44000 150 40 175.0 21.9 Q6. The Phase III of the clinical trial conducted by Pfizer/BioNTech, whose preliminary results allowed the obtaining of a conditional MA, involved an unusually large number of patients (several tens of thousands), in order to obtain the first results very quickly. Is this not a guarantee of quality in terms of detection of adverse effects? Christine COTTON – 05/04/2022 - ©

Old vaccine-trial recommendations https://www.who.int/immunization_standards/vaccine_quality/clinical_considerations_oct10.pdf?ua=1 The WHO recommendations of 2010 required a sample size sufficient to detect adverse effects down to 1 in 1000. Is the population size in children and adolescents sufficient? The follow-up duration recommended after the last dose must be • at least 6 months for the assessment of tolerability • at least 1 year for efficacy and immunogenicity The follow-up is therefore clearly insufficient in the Pfizer trial from the standpoint of quality. The recommendations were modified under urgency in order to be able to authorize these products, Christine COTTON – 05/04/2022 - ©

Adverse effects and Pharmacovigilance 58 Christine COTTON – 05/04/2022 - ©

Q1 - Regarding the surveillance of adverse effects, what are the obligations of the pharmaceutical laboratory that wants to place a product on the market (or of the companies to which it subcontracts its clinical activity), during the clinical trials it conducts and, then, once the product is on the market? Pharmacovigilance (the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other problem related to medicines) is governed by numerous guidelines. Before the start of the trial, the drafting of a Pharmacovigilance Plan. During the trial, the investigator must notify any adverse event occurring during the trial, including abnormal blood-sample results. SAEs must be reported to the sponsor within 24h in order to allow it to quickly re-assess the benefit/risk ratio and to take appropriate measures in the event of new potential risks. The sponsor must also assess their causality and severity. Not done with the SAE of Maddie de Garay. As a subcontractor, the e-CRFs (websites set up to collect the trial data) that are put in place provide for automatic emails to the sponsor for each SAE entered by the investigator. An unexpected serious effect can end the trial for endangering patients. Christine COTTON – 05/04/2022 - ©

Q1 - Regarding the surveillance of adverse effects, what are the obligations of the pharmaceutical laboratory that wants to place a product on the market (or of the companies to which it subcontracts its clinical activity), during the clinical trials it conducts and, then, once the product is on the market? https://database.ich.org/sites/default/files/E2A_Guideline.pdf then, once the product is on the market? Conditional MA It is health professionals and patients who report the effects. The sponsor must inform the authorities and update the Risk Management Plan and inform the investigators by updating the Investigator’s Brochure and the Summary of Product Characteristics (SmPC). It must enter the effects into the databases relevant to its country (Eudravigilance, VAERS …). Within the framework of the conditional MA, the laboratory must submit every month a “Monthly Safety Update”, a monthly safety report that must be transmitted to the authorities Christine COTTON – 05/04/2022 - ©

More than 141,637,300 injections administered in total as of 10/03/2022 • More than 109,210,500 injections with COMIRNATY (BioNTech-Pfizer) • More than 23,482,000 injections with SPIKEVAX (Moderna) • More than 7,857,200 injections with VAXZEVRIA (AstraZeneca) • More than 1,085,400 injections with COVID-19 VACCINE Janssen 148,877 adverse events reported • 37,219 serious effects reported • 11,067 hospitalizations reported • 1,796 deaths reported 61 ANSM PV report Data from 25/02/2022 to 10/03/2022 https://ansm.sante.fr/actualites/point-de-situation-sur-la-surveillance-des-vaccins-contre-la-covid-19-periode-du-25-02-2022-au-10-03-2022 Christine COTTON – 05/04/2022 - ©

• 1 potential adverse effect reported every 951 doses; • 1 potential serious effect reported every 3,805 doses; • 1 potential hospitalization reported every 12,542 doses; • 1 potential death reported every 77,283 doses. 62 Christine COTTON – 05/04/2022 - ©

ANSM focus on pregnant/breastfeeding women Report No. 6, 27/12/2020 to 07/10/2021 https://ansm.sante.fr/uploads/2021/12/21/20211221-covid19-vaccins-grossesse-8.pdf 69% serious cases compared to 25% for the total population No signal detected since vaccination occurs from the 1st trimester of pregnancy, the period in which there are the most miscarriages https://ansm.sante.fr/uploads/2021/11/19/20211119-covid-19-vaccins-grossesse-rapport-7-2.pdf Report No. 7. Report No. 8 05/11/2021 to 03/12/2021 Christine COTTON – 05/04/2022 - ©

Risk-evaluation signals 64 25 October 2021: CDC safety update “the Pfizer/BioNTech and Moderna vaccines increase the risk of Myocarditis and pericarditis in 12-39 year-olds.” CDC: 573 cases, of which 50% in the under-24s Christine COTTON – 05/04/2022 - ©

12/2020 01/2021 02/2021 03/2021 04/2021 05/2021 06/2021 07/2021 08/2021 09/2021 10/2021 11/2021 12/2021 Appearance of the myocarditis risk in Israel. Between December 2020 and 13 September 2021, 165 cases of myocarditis with Comirnaty reported As of 18 August 2021, 2,574 cases reported to the Vaccine Adverse Event Reporting System (VAERS). 18th report on the pharmacovigilance investigation of the Pfizer vaccine, 537 cases of myocarditis/pericarditis in France, resolving and non-severe for the great majority No myocarditis/pericarditis signal → Confirmed signal https://www.fda.gov/media/150054/download https://cdn.who.int/media/docs/default-source/blue-print/shimabukuro_whoblueprint_myocarditis_who-vr-call_25oct2021.pdf?sfvrsn=40e99d51_7 https://www.hassante.fr/jcms/p_3290614/fr/strategie-devaccination-contre-la-covid-19-place-d-unrappel-par-le-vaccin-a-arnm-comirnaty 7 months to establish a Signal Christine COTTON – 05/04/2022 - ©

Risks in the Consent Form On the consent form of the Cincinnati Children’s Hospital, a center involved in the recruitment of participants of the Pfizer trial, of 04/01/2022, we learn that myocarditis affects between 1/1000 and 1/10,000 children or adolescents. On a population of 6 million, that makes between 600 and 6000 people potentially affected by myocarditis! https://www.icandecide.org/wp-content/uploads/2022/02/Substudy-C.pdf The effects on sperm, pregnancy, and the fetus are not known. On what scientific basis are pregnant women vaccinated? Christine COTTON – 05/04/2022 - ©

Questions • 7. The interlocutors we heard, external to the ANSM or to the French pharmacovigilance process, agree in saying that a health product has never been so monitored, so much was the pharmacovigilance system put on alert, and that it has also never shown so much transparency. Do you agree with these observations? • I am not a PV specialist, particularly in real-world settings; I have only common-sense questions. • Knowing that it was a very innovative product never used, and even less so on such a large population, were staffing levels reinforced? Apparently not at the Tours University Hospital “We are short-staffed” • Does the delay in establishing signals not stem from the lack of staff? https://www.lanouvellerepublique.fr/tours/tours-l-equipe-qui-traque-les-effetsindesirables-du-vaccin-a-fait-six-annees-en-une Christine COTTON – 05/04/2022 - ©

What are, in your opinion, the limitations of the French pharmacovigilance system? Do you see possible improvements? I cannot answer these questions in detail; this does not fall within the scope of my competence; I am a biostatistician, not a PV specialist. Given that the system is based on spontaneous reporting, the quality of the information provided via the forms is low, with a significant underestimate of the number of cases. As a member of the Verity France association, I observe • that people suffering from serious post-vaccination effects cannot obtain an established link between the vaccine and their effects, although they were in perfect health before being vaccinated, • that their medical care is catastrophic because of the denial of side effects by the medical profession, which further delays diagnosis • that PV asks them to do all kinds of tests, which gives the impression that everything is being done to rule out the link between the vaccines and the effects • That the supposedly transient effects such as myocarditis, menstrual problems, ultimately last from their first appearance To improve the system, one could move from a passive pharmacovigilance to an active PV as in the USA on the Vaccine Safety Datalink model. The PBPVs [PV best-practice rules] state that “the ANSM defines the communication plan, as far as possible, in consultation with the marketing-authorization holders and operators concerned, which it informs in all cases, and develops and/or validates the content of the information delivered,” can you enlighten us on the role of the laboratories in the information given to the public? Christine COTTON – 05/04/2022 - ©

69 https://www.idbc.fr/odds-ratio-hazard-ratio-et-risque-relatif-quelles-differences/ Relative risk RR. Odds ratio OR. Hazard Ratio HR Pr(Death Exp.) / Pr(Death non-Exp.) = 0.3 / 0.1 = 3 Odds Exp. / Odds Non-Exp. = 0.43 / 0.111 = 3.85 Takes into account the time of occurrence of the event: instantaneous-risk function (hazard) of the Exp. / instantaneous-risk function of the Non-Exp. at time t The Exp. have 3 x more risk of dying compared to the Non-Exp. Logistic regression < 1: death less frequent in the Exp. group than in the Non-Exp. group; = 1: death equally frequent in the two groups; > 1: death more frequent among the Exp. than in the Non-Exp. group Stratified survival models (Cox) Death / No death / Total / Probability of death / Odds Exposed 30 70 100 30/100 = 0.3% 30/70=0.43. Non-exposed 10 90 100 10/100 = 0.1% 10/90=0.111. Total 40 160 200 OR close to RR if the number of deaths is small Methodological reminder Christine COTTON – 05/04/2022 - ©

71 Objective: To compare, in people aged 75 and over, the risks of severe forms of COVID-19 (hospitalization for COVID-19 and death during a hospitalization for COVID-19) between people vaccinated between 27 December 2020 and 30 April 2021 and those who were not. Data: reimbursement data of the mandatory health insurance, in particular data from the processing of health-care reimbursements and data from health establishments (PMSI). Method: Matching of vaccinated people to unvaccinated controls. Period: from 27/12/2020 to 20/07/2021. At least 1 delta variant between 20/06/2021 and 20/07/2021, i.e., a short epidemic period. 60% of people were vaccinated between March and April 2021. Report published 11/10/2021 EPI-PHARE study Christine COTTON – 05/04/2022 - ©

Source: https://www.assembleenationale.fr/dyn/15/rapports/ots/l15b3695_rapportinformation.pdf OPECST report of 15/12/2020 The study population is 7.2 M people over 75, yet this population is 6.4 M as cited in the OPECST report of 15/12/2020 19% of the Individuals counted in the 2 groups 72 EPI-PHARE study Christine COTTON – 05/04/2022 - ©

If we look during the epidemic period, there are 6 fewer hospitalizations for Moderna out of nearly 182,000 people, 113 for Pfizer out of 1.6 M and 0 for AZ Reduction of the risks of hospitalization / death following hospitalization after dose 1 *Adjustment on the matching variables: age, sex, region, institutionalization in an establishment with or without an internal pharmacy (PUI). **Adjustment on the matching variables listed above, on all the characteristics described in tables 1 and 2, as well as on the vaccination period (January-February vs March-April 2021). EPI-PHARE study Christine COTTON – 05/04/2022 - ©

BIAS in the choice of the unvaccinated population, which is more hospitalized and therefore more at risk Higher protection from the 1st to the 6th day after dose 1, when the vaccine is not supposed to have the slightest effect > Subsequent protection 74 EPI-PHARE conclusion Christine COTTON – 05/04/2022 - ©

Study “Assessment of the risk of myocardial infarction, stroke and pulmonary embolism following the various anti-COVID-19 vaccines in adults under 75 in France” of 18 January 2022. Events counted only within the 21 days after the 1st and 2nd dose; why not count over a wider window (42, 90 days?) or even all events? Unreliable conclusions https://ansm.sante.fr/actualites/les-vaccins-a-arnm-contre-la-covid-19-naugmentent-pas-le-risque-dinfarctus-du-myocarde-daccident-vasculairecerebral-ou-dembolie-pulmonaire-chez-les-adultes-de-moins-de-75-ans https://ansm.sante.fr/uploads/2021/11/08/20211108-covid-19-vaccins-rapport-epiphare-myocardite-pericardite.pdf Study “Association between mRNA COVID-19 vaccines and the occurrence of myocarditis and pericarditis in people aged 12 to 50 in France” of 8 November 2021. Events counted only within the 21 days after the 1st and 2nd dose, which is logical since these AEs appear rapidly after the injections. All the “cases of hospitalization for myocarditis or pericarditis” occurring between 15 May and 31 August 2021 among all people aged 12 to 50 in France were included. Not all patients suffering from post-vaccination myocarditis were hospitalized. The unvaccinated present in the databases are individuals who were ill before being included in the study, since these are SNDS (PMSI) data. Why include patients with a history of myocarditis within the last 5 years? Completely useless. Matched study “each case was matched to 10 controls of the same age, sex and department of residence.” Why no analysis on events from 1 to 21 days, but rather splitting into 1-7 and 8-21?

S. V. Subramanian - Akhil Kumar • Objective: To study the link between the vaccination rate and the number of Covid cases • calculated the number of COVID-19 cases per 1 million people for each country, as well as the percentage of the fully vaccinated population • Data: raw data from Our World in Data • 68 countries that met the following criteria: data available on the second dose of vaccine, data available on COVID-19 cases, data available on the population, and last data update within the 3 days preceding or on 3 September 2021. • Method: no matching • Period: up to 03/09/2021 • Article published 30/09/2021 Increases in COVID-19 are unrelated to levels of vaccination across 68 countries and 2947 counties in the United States European Journal of Epidemiology (2021) 36:1237–1240 S. V. Subramanian · Akhil Kumar https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481107/pdf/10654_2021_Article_808.pdf Christine COTTON – 05/04/2022 - ©

S. V. Subramanian - Akhil Kumar Marginally positive association: countries with a higher percentage of the fully vaccinated population have more COVID-19 cases per 1 million inhabitants. Percentage of counties having experienced an increase in cases between two consecutive 7-day periods, by percentage of the fully vaccinated population in 2947 counties as of 2 September 2021 65% to 70% 65% to 70% Israel Christine COTTON – 05/04/2022 - ©

Are the trial results representative of reality? https://ourworldindata.org/covid-vaccinations 78 Christine COTTON – 05/04/2022 - ©

Start in nursing homes (EHPAD) 17/12/2020 79 Are the trial results representative of reality? https://ourworldindata.org/covid-vaccinations Christine COTTON – 05/04/2022 - ©

Q8. Do you think that the data obtained in real life are more conclusive than the clinical trials conducted by Pfizer/BioNTech in terms of efficacy and safety of the vaccine? Christine COTTON – 05/04/2022 - ©

Real-world studies, mostly retrospective on medico-administrative databases, take into account only part of the information. • Their demonstration of the efficacy of the vaccines on certain populations or on severe cases has a level of evidence far inferior to the trials. • The matching methods truncate the follow-up of the unvaccinated populations by moving them into the vaccinated group, hence the number of patients counted several times. • Cases positive from dose 1 are rarely studied there. • All-cause mortality is never studied. • The studies demonstrating an effect on transmission are all the less reliable because of the appearance of variants; what may appear true at time t becomes obsolete a few weeks later. Why do we not do • Prospective observational studies or safety studies (PASS) in order to study the adverse effects? • A serious pharmacovigilance investigation by contacting the people, as requested by my petition, since the rate of reporting to PV is low? This, in particular, for the appearances of Creutzfeldt-Jakob, whose number is very small; the link with vaccination or not can be established easily. According to Bernard Bégaud, in 1994: “For most of the empirical situations arising within the framework of post-marketing surveillance, the expected number remains small and only one to three cases at most could be accepted as possibly being coincidences.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364871/pdf/brjclinpharm00015-0024.pdf 80

mRNA, a totally innovative technology Source: https://www.msn.com/en-us/news/us/transcript-wp-subscriber-exclusive-albert-bourla-author-e2-80-9cmoonshot-inside-pfizer-e2-80-99snine-month-race-to-make-the-impossible-possible-e2-80-9d/ar-AAUTEjZ Interview A. Bourla “Moonshot: Inside Pfizer’s Nine-Month Race to Make the Impossible Possible” Washington Post Live – 10/03/2022. DR. BOURLA: It was counterintuitive because Pfizer was putting itself on the table, had very good experience and expertise with multiple technologies that could yield a vaccine …. mRNA was a technology, but we had less experience, only two years of work on this subject, and in fact, mRNA was a technology that had never yielded a single product to date, neither a vaccine, nor any other medicine. So it was very counterintuitive, and I was surprised when they suggested to me that this was the way forward, and I questioned it. I asked them to explain how they could say such a thing …. they were very, very convinced that it was the right way forward. They felt that the two years of work on mRNA since 2018 with BioNTech to develop the flu vaccine had led them to believe that the technology is mature and that we are on the verge of delivering a product. So they convinced me. I followed my instinct, which told me that they knew what they were saying. They are very good, and we made this very difficult decision at that moment.” https://www.assemblee-nationale.fr/dyn/15/rapports/ots/l15b3695_rapport-information.pdf OPECST report of 15/12/2020. Mr JF Eliaou Page 108 82 Christine COTTON – 05/04/2022 - ©

JF Delfraissy, president of the Scientific Council, considers that the Covid-19 vaccines are “vaccine-medicines” (25/01/2022) Source https://www.francetvinfo.fr/sante/maladie/coronavirus/vaccin/covid-19-le-vaccin-est-un-peu-un-medicament-avec-une-action-formidable-pourjean-francois-delfraissy_4929057.html State of knowledge to date https://www.cnbc.com/video/2022/03/11/pfizer-ceo-albert-bourla-on-need-for-fourth-covid-vaccine-dose-panvaccine-and-more.html Need for a 4th dose. Interview A. Bourla of 11/03/2022 “Immunity does not last after the 3rd dose, weakening of the immune response after 3, 4 months” 83 Christine COTTON – 05/04/2022 - ©

Jean-François Delfraissy, President of the Scientific Council: “Why vaccinate a young population that has clearly less risk of developing a severe form?” Evolution of the benefit/risk ratio The benefit/risk ratio is to be re-assessed according to new knowledge or the appearance of adverse effects, hence the need to question the relevance of vaccinating, in particular, children and adolescents who are particularly likely to present asymptomatic forms of Covid-19. Source: Conference at Sciences Po Lille - COVID-19: Science, politics and society of 15/03/2022 https://www.sciencespo-lille.eu/actualites/conference-pr-delfraissy-immunologue https://www.facebook.com/164020646985466/videos/1580674918985194/?so=watchlist&rv=video_home_www_playlist_video_list Rochelle Walensky, director of the American CDC (US national agencies in charge of public-health protection): “So many of us wanted to be helpful. So many of us wanted to say: ‘OK, this is our ticket out, right?’ ‘Now it’s over.’ So I think we may have shown too little caution and too much optimism in the face of some good things that came our way.” CDC director Rochelle Walensky, MD, MPH, a Washington University alum. Walensky discussed the pandemic with William G. Powderly, MD, the J. William Campbell Professor of Medicine and co-director of the Division of Infectious Diseases. Their conversation centered on domestic and global challenges facing public health officials as we emerge from the COVID-19 pandemic. Channel of the Washington University School of Medicine https://www.youtube.com/watch?v=I_hYgIpxM4A Christine COTTON – 05/04/2022 - © 84

General conclusion Christine COTTON – 05/04/2022 - © All the recommendations and practices in force for years were flouted, with new recommendations being established under urgency in order to facilitate the authorization of the Covid vaccines. This represents an unprecedented risk-taking. Given the risks already identified, the slowness of the establishment of serious effects by pharmacovigilance, the continued use of the Comirnaty vaccine in real life presents a significant risk to people’s lives. If the 1st interim analysis had been carried out after 6 months of follow-up, no authorization would have been given since the almost-immediate drop in immunity would have been observed It is therefore necessary to suspend as a matter of urgency all vaccination with Comirnaty, for the entire population To support such practices is to “open the door” to the end of a Clinical Research worthy of the name; patients will obviously be the first to suffer. (see McKinsey article “developing a product in 100 days”). 86

If health policies are no longer based on the trial results but on real-world studies that have an unreliable level of evidence, for what reason continue to do clinical trials? What is the future of Clinical Research if a trial not complying with the Good Clinical Practice established for decades is “let through” without saying anything? • For the actors of private research? • For the actors of public research? • For the control bodies in charge of controlling them? General conclusion - 2 Christine COTTON – 05/04/2022 - ©

https://www.mckinsey.com/industries/healthcare-systems-and-services/ourinsights/ten-lessons-from-the-first-two-years-of-covid-19?cid=other-eml-dremipmck&hlkid=ee011309d17944b68fae004742b199ec&hctky=2025206&hdpid=2f587294-e250-4f7d-bedc-4a26119c2b77 87

“The vaccine-development paradigm was transformed because of the urgency and, potentially, for others. Two years later, it is easy to forget how remarkable the development of the COVID-19 vaccines was. Going in only 326 days from a genomic sequence to the authorization of a COVID-19 vaccine by a strict regulatory authority shattered all previous records. In addition, biomedical science delivered several vaccines presenting a high efficacy against severe COVID-19 and a solid overall safety profile. The bar has been raised, and there is now serious discussion of what it will take to reduce to only 100 days the time between the sequence and the authorization for the next threat.” McKinsey article “developing a product in 100 days”). Are we going to ruin, in a few years, an effective and safe Clinical Research?

Q11. What improvements would you suggest regarding the process of issuing vaccine recommendations, particularly with regard to the assessment of the benefit-risk balance? I am not competent to advise those responsible for the vaccine strategy, but it seems to me that: • Communicating on the real results of the clinical trials and not on hopes of efficacy based on modelings and real-world studies that turn out to be false as the variants appear, would have been a choice of transparency beneficial to all. • The laws protecting trial participants all go in the direction of minimizing risks; this should a fortiori apply in real life. • Did we minimize the risk by extending vaccination to people presenting allergic risks, particularly those with an adrenaline pen, when serious effects had appeared in England from the 1st day of vaccination? • Did we minimize the risk by rushing to vaccinate populations not studied in the trials, such as pregnant or breastfeeding women, without any information? • Did we minimize the risk by opening vaccination to populations with very low risks of having a severe covid, on the basis of interim results involving very small populations with a follow-up of 3 months maximum, such as adolescents and children? And this, through a coercion that prevented them from doing everyday-life activities? • Did we minimize the risk by obliging health-care staff to be vaccinated with a product that does not prevent being ill or transmitting, thus depriving us of thousands of people we need, undermining the Public Hospital even further? • Did we minimize the risk by authorizing the booster without any efficacy result? • Why are health data never presented by vaccination status, unvaccinated, 1 dose, 2 doses …? • Why are mortality data inaccessible? 88 Christine COTTON – 05/04/2022 - ©

Q10. Did you communicate your observations to the ANSM, or to the COSV or the HAS, the latter two being responsible for the vaccine recommendations and therefore for the assessment of the benefit-risk balance associated with the vaccines? If so, did you obtain a response from them? I finished my expert review in mid-January 2022; my report was transmitted by email on 11/02/2022 to certain people at the ANSM who had participated in the review of the Pfizer data. No response. 89 Christine COTTON – 05/04/2022 - ©

Whistleblower status • A whistleblower is a person who reports facts that seriously harm the general interest. Since 2016 (the “Sapin II” law), they benefit from a protective status against the risks incurred by their revelations. But, faced with insufficient legislation, a more protective bill has just been adopted by Parliament. • https://www.conseil-constitutionnel.fr/actualites/communique/decision-n-2022-838-dc-du-17-mars-2022-communique-de- presse 90 Christine COTTON – 05/04/2022 - ©

All-cause mortality inaccessible on Santé Publique France 92 Is there an OMERTA [code of silence] on the causes of death? Christine COTTON – 05/04/2022 - ©

Causes of death inaccessible on INSERM Is there an OMERTA on the causes of death? 93 https://www.cepidc.inserm.fr/inserm/html/index2.htm Christine COTTON – 05/04/2022 - ©

Source: https://www.assemblee-nationale.fr/dyn/15/rapports/ots/l15b3695_rapport-information.pdf OPECST report of 15/12/2020 The disease in December 2020 94 Christine COTTON – 05/04/2022 - ©

CCNE opinion Source: CCNE opinion: Ethical issues relating to Covid-19 vaccination of children and adolescents. Response to the referral by the Minister of Solidarity and Health of 09/06/2021 https://www.ccneethique.fr/sites/default/files/enjeux_ethiques_relatifs_a_la_vaccination_covid_08.06.21_0.pdf 95 Christine COTTON – 05/04/2022 - ©

The National Consultative Ethics Committee had advised against vaccination • In 12-16 year-olds, because of the low risk of severe forms and low individual benefit, and • In the under-12s, deemed ethically and scientifically unacceptable 96 Christine COTTON – 05/04/2022 - ©