Pfizer rapport.pdf

BNT162b2 5.3.6 Cumulative Analysis of Post-authorization Adverse Event Reports

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5.3.6 CUMULATIVE ANALYSIS OF POST-AUTHORIZATION ADVERSE EVENT REPORTS OF PF-07302048 (BNT162B2) RECEIVED THROUGH 28-FEB-2021

Report Prepared by: Worldwide Safety Pfizer The information contained in this document is proprietary and confidential. Any disclosure, reproduction, distribution, or other dissemination of this information outside of Pfizer, its Affiliates, its Licensees, or Regulatory Agencies is strictly prohibited. Except as may be otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such information in confidence and not to disclose it to others (except where required by applicable law), nor to use it for unauthorized purposes.

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TABLE OF CONTENTS LIST OF TABLES.....................................................................................................................3 LIST OF FIGURES ...................................................................................................................3 APPENDICES ...........................................................................................................................3 LIST OF ABBREVIATIONS....................................................................................................4 1. INTRODUCTION .................................................................................................................5 2. METHODOLOGY ................................................................................................................5 3. RESULTS ..............................................................................................................................6 3.1. Safety Database .........................................................................................................6 3.1.1. General Overview.........................................................................................6 3.1.2. Summary of Safety Concerns in the US Pharmacovigilance Plan ...............9 3.1.3. Review of Adverse Events of Special Interest (AESIs) .............................16 3.1.4.

Medication error .........................................................................................26 090177e196ea1800\Approved\Approved On: 30-Apr-2021 09:26 (GMT)

4. DISCUSSION ......................................................................................................................28 5. SUMMARY AND CONCLUSION ....................................................................................29

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LIST OF TABLES Table 1.

General Overview: Selected Characteristics of All Cases Received During the Reporting Interval.....................................................................7

Table 2.

Events Reported in ≥2% Cases...................................................................8

Table 3.

Safety concerns ...........................................................................................9

Table 4.

Important Identified Risk..........................................................................10

Table 5.

Important Potential Risk ...........................................................................11

Table 6.

Description of Missing Information .........................................................12

Table 7.

AESIs Evaluation for BNT162b2.............................................................16

Table 8.

ME PTs by seriousness with or without harm co-association (Through 28 February 2021) ....................................................................27

LIST OF FIGURES

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Figure 1.

Total Number of 13vPnC AEs by System Organ Classes and Event Seriousness .................................................................................................8

APPENDICES APPENDIX 1 LIST OF ADVERSE EVENTS OF SPECIAL INTEREST ............................30

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LIST OF ABBREVIATIONS Acronym AE AESI BC CDC COVID-19 DLP EUA HLGT HLT MAH MedDRA MHRA PCR PT PVP RT-PCR RSI TME SARS-CoV-2 SMQ SOC UK US VAED VAERD VAERS

Term adverse event adverse event of special interest Brighton Collaboration Centers for Disease Control and Prevention coronavirus disease 2019 data lock point emergency use authorisation (MedDRA) High Group Level Term (MedDRA) High Level Term marketing authorisation holder medical dictionary for regulatory activities Medicines and Healthcare products Regulatory Agency Polymerase Chain Reaction (MedDRA) Preferred Term pharmacovigilance plan Reverse Transcription-Polymerase Chain Reaction reference safety information targeted medically event severe acute respiratory syndrome coronavirus 2 standardised MedDRA query (MedDRA) System Organ Class United Kingdom United States vaccine-associated enhanced disease vaccine-associated enhanced respiratory disease vaccine adverse event reporting system

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1. INTRODUCTION Reference is made to the Request for Comments and Advice submitted 04 February 2021 regarding Pfizer/BioNTech’s proposal for the clinical and post-authorization safety data package for the Biologics License Application (BLA) for our investigational COVID-19 Vaccine (BNT162b2). Further reference is made to the Agency’s 09 March 2021 response to this request, and specifically, the following request from the Agency.

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“Monthly safety reports primarily focus on events that occurred during the reporting interval and include information not relevant to a BLA submission such as line lists of adverse events by country. We are most interested in a cumulative analysis of post-authorization safety data to support your future BLA submission. Please submit an integrated analysis of your cumulative post-authorization safety data, including U.S. and foreign post-authorization experience, in your upcoming BLA submission. Please include a cumulative analysis of the Important Identified Risks, Important Potential Risks, and areas of Important Missing Information identified in your Pharmacovigilance Plan, as well as adverse events of special interest and vaccine administration errors (whether or not associated with an adverse event). Please also include distribution data and an analysis of the most common adverse events. In addition, please submit your updated Pharmacovigilance Plan with your BLA submission.” This document provides an integrated analysis of the cumulative post-authorization safety data, including U.S. and foreign post-authorization adverse event reports received through 28 February 2021. 2. METHODOLOGY Pfizer is responsible for the management post-authorization safety data on behalf of the MAH BioNTech according to the Pharmacovigilance Agreement in place.

Data from BioNTech are included in the report when applicable. Pfizer’s safety database contains cases of AEs reported spontaneously to Pfizer, cases reported by the health authorities, cases published in the medical literature, cases from Pfizer-sponsored marketing programs, non-interventional studies, and cases of serious AEs reported from clinical studies regardless of causality assessment. The limitations of post-marketing adverse drug event reporting should be considered when interpreting these data: •

Reports are submitted voluntarily, and the magnitude of underreporting is unknown. Some of the factors that may influence whether an event is reported include: length of time since marketing, market share of the drug, publicity about a drug or an AE, seriousness of the reaction, regulatory actions, awareness by health professionals and consumers of adverse drug event reporting, and litigation.

•

Because many external factors influence whether or not an AE is reported, the spontaneous reporting system yields reporting proportions not incidence rates. As a result, it is generally not appropriate to make between-drug comparisons using these

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proportions; the spontaneous reporting system should be used for signal detection rather than hypothesis testing.

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•

•

In some reports, clinical information (such as medical history, validation of diagnosis, time from drug use to onset of illness, dose, and use of concomitant drugs) is missing or incomplete, and follow-up information may not be available.

•

An accumulation of adverse event reports (AERs) does not necessarily indicate that a particular AE was caused by the drug; rather, the event may be due to an underlying disease or some other factor(s) such as past medical history or concomitant medication.

Among adverse event reports received into the Pfizer safety database during the cumulative period, only those having a complete workflow cycle in the safety database (meaning they progressed to Distribution or Closed workflow status) are included in the monthly SMSR. This approach prevents the inclusion of cases that are not fully processed hence not accurately reflecting final information. Due to the large numbers of spontaneous adverse event reports received for the product, the MAH has prioritised the processing of serious cases, in order to meet expedited regulatory reporting timelines and ensure these reports are available for signal detection and evaluation activity. The increased volume of reports has not impacted case processing for serious reports, and compliance metrics continue to be monitored weekly with prompt action taken as needed to maintain compliance with expedited reporting obligations. Non-serious cases are entered into the safety database no later than 4 calendar days from receipt. Entrance into the database includes the coding of all adverse events; this allow for a manual review of events being received but may not include immediate case processing to completion. Non-serious cases are processed as soon as possible and no later than 90 days from receipt.

Pfizer has also taken a multiple actions to help alleviate the large increase of adverse event reports. This includes significant technology enhancements, and process and workflow solutions, as well as increasing the number of data entry and case (b) (4) processing colleagues. To date, Pfizer has onboarded approximately additional fulltime employees (FTEs). More are joining each month with an expected total of more than (b) (4) additional resources by the end of June 2021.

3. RESULTS 3.1. Safety Database 3.1.1. General Overview It is estimated that approximately (b) (4) doses of BNT162b2 were shipped worldwide from the receipt of the first temporary authorisation for emergency supply on 01 December 2020 through 28 February 2021. Cumulatively, through 28 February 2021, there was a total of 42,086 case reports (25,379 medically confirmed and 16,707 non-medically confirmed) containing 158,893 events. Most cases (34,762) were received from United States (13,739), United Kingdom (13,404) Italy (2,578), Germany (1913), France (1506), Portugal (866) and Spain (756); the remaining 7,324 were distributed among 56 other countries. CONFIDENTIAL Page 6

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Table 1 below presents the main characteristics of the overall cases. Table 1.

General Overview: Selected Characteristics of All Cases Received During the Reporting Interval

Gender:

Age range (years): 0.01 -107 years Mean = 50.9 years n = 34952

Characteristics Female Male No Data ≤ 17 18-30 31-50 51-64 65-74 ≥ 75 Unknown

Relevant cases (N=42086) 29914 9182 2990 175a 4953 13886 7884 3098 5214 6876

Case outcome:

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a.

Recovered/Recovering Recovered with sequelae Not recovered at the time of report Fatal Unknown in 46 cases reported age was <16-year-old and in 34 cases <12-year-old.

19582 520 11361 1223 9400

As shown in Figure 1, the System Organ Classes (SOCs) that contained the greatest number (≥2%) of events, in the overall dataset, were General disorders and administration site conditions (51,335 AEs), Nervous system disorders (25,957), Musculoskeletal and connective tissue disorders (17,283), Gastrointestinal disorders (14,096), Skin and subcutaneous tissue disorders (8,476), Respiratory, thoracic and mediastinal disorders (8,848), Infections and infestations (4,610), Injury, poisoning and procedural complications (5,590), and Investigations (3,693).

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Figure 1. Total Number of BNT162b2 AEs by System Organ Classes and Event Seriousness

Table 2 shows the most commonly (≥2%) reported MedDRA (v. 23.1) PTs in the overall dataset (through 28 February 2021), Table 2.

Events Reported in ≥2% Cases

MedDRA SOC

MedDRA PT

Cumulatively Through 28 February 2021 AEs (AERP%) N = 42086

Blood and lymphatic system disorders Lymphadenopathy

1972 (4.7%)

Tachycardia

1098 (2.6%)

Cardiac disorders Gastrointestinal disorders Nausea Diarrhoea Vomiting General disorders and administration site conditions Pyrexia Fatigue Chills Vaccination site pain

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5182 (12.3%) 1880 (4.5%) 1698 (4.0%) 7666 (18.2%) 7338 (17.4%) 5514 (13.1%) 5181 (12.3%)

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Table 2.

Events Reported in ≥2% Cases

MedDRA SOC

MedDRA PT

Cumulatively Through 28 February 2021 AEs (AERP%) N = 42086

Pain Malaise Asthenia Drug ineffective Vaccination site erythema Vaccination site swelling Influenza like illness

3691 (8.8%) 2897 (6.9%) 2285 (5.4%) 2201 (5.2%) 930 (2.2%) 913 (2.2%) 835 (2%)

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Infections and infestations COVID-19 Injury, poisoning and procedural complications Off label use Product use issue Musculoskeletal and connective tissue disorders Myalgia Pain in extremity Arthralgia Nervous system disorders Headache Dizziness Paraesthesia Hypoaesthesia Respiratory, thoracic and mediastinal disorders Dyspnoea Cough Oropharyngeal pain Skin and subcutaneous tissue disorders Pruritus Rash Erythema Hyperhidrosis Urticaria Total number of events

1927 (4.6%) 880 (2.1%) 828 (2.0%) 4915 (11.7%) 3959 (9.4%) 3525 (8.4%) 10131 (24.1%) 3720 (8.8%) 1500 (3.6%) 999 (2.4%) 2057 (4.9%) 1146 (2.7%) 948 (2.3%) 1447 (3.4%) 1404 (3.3%) 1044 (2.5%) 900 (2.1%) 862 (2.1%) 93473

3.1.2. Summary of Safety Concerns in the US Pharmacovigilance Plan Table 3.

Safety concerns

Important identified risks

Anaphylaxis

Important potential risks

Vaccine-Associated Enhanced Disease (VAED), Including Vaccine-associated Enhanced Respiratory Disease (VAERD) Use in Pregnancy and lactation Use in Paediatric Individuals <12 Years of Age Vaccine Effectiveness

Missing information

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Table 4.

Important Identified Risk

Topic

Description

Important Identified Risk Anaphylaxis

Post Authorization Cases Evaluation (cumulative to 28 Feb 2021) Total Number of Cases in the Reporting Period (N=42086) Since the first temporary authorization for emergency supply under Regulation 174 in the UK (01 December 2020) and through 28 February 2021, 1833 potentially relevant cases were retrieved from the Anaphylactic reaction SMQ (Narrow and Broad) search strategy, applying the MedDRA algorithm. These cases were individually reviewed and assessed according to Brighton Collaboration (BC) definition and level of diagnostic certainty as shown in the Table below:

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Brighton Collaboration Level Number of cases BC 1 290 BC 2 311 BC 3 10 BC 4 391 BC 5 831 Total 1833 Level 1 indicates a case with the highest level of diagnostic certainty of anaphylaxis, whereas the diagnostic certainty is lowest for Level 3. Level 4 is defined as “reported event of anaphylaxis with insufficient evidence to meet the case definition” and Level 5 as not a case of anaphylaxis. There were 1002 cases (54.0% of the potentially relevant cases retrieved), 2958 potentially relevant events, from the Anaphylactic reaction SMQ (Broad and Narrow) search strategy, meeting BC Level 1 to 4: Country of incidence: UK (261), US (184), Mexico (99), Italy (82), Germany (67), Spain (38), France (36), Portugal (22), Denmark (20), Finland, Greece (19 each), Sweden (17), Czech Republic , Netherlands (16 each), Belgium, Ireland (13 each), Poland (12), Austria (11); the remaining 57 cases originated from 15 different countries.

Relevant event seriousness: Serious (2341), Non-Serious (617); Gender: Females (876), Males (106), Unknown (20); Age (n=961) ranged from 16 to 98 years (mean = 54.8 years, median = 42.5 years); Relevant even outcomea: fatal (9)b, resolved/resolving (1922), not resolved (229), resolved with sequelae (48), unknown (754); Most frequently reported relevant PTs (≥2%), from the Anaphylactic reaction SMQ (Broad and Narrow) search strategy: Anaphylactic reaction (435), Dyspnoea (356), Rash (190), Pruritus (175), Erythema (159), Urticaria (133), Cough (115), Respiratory distress, Throat tightness (97 each), Swollen tongue (93), Anaphylactic shock (80), Hypotension (72), Chest discomfort (71), Swelling face (70), Pharyngeal swelling (68), and Lip swelling (64). Conclusion: Evaluation of BC cases Level 1 - 4 did not reveal any significant new safety information. Anaphylaxis is appropriately described in the product labeling as are non-anaphylactic hypersensitivity events. Surveillance will continue. a Different clinical outcome may be reported for an event that occurred more than once to the same individual. b There were 4 individuals in the anaphylaxis evaluation who died on the same day they were vaccinated.

Although these patients experienced adverse events (9) that are potential symptoms of anaphylaxis, they all had serious underlying medical conditions, and one individual appeared to also have COVID-19 pneumonia, that likely contributed to their deaths

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Table 5.

Important Potential Risk

Topic

Description

Important Potential Risk VaccineAssociated Enhanced Disease (VAED), including VaccineAssociated Enhanced Respiratory Disease (VAERD)

Post Authorization Cases Evaluation (cumulative to 28 Feb 2021) Total Number of Cases in the Reporting Period (N=42086) No post-authorized AE reports have been identified as cases of VAED/VAERD, therefore, there is no observed data at this time. An expected rate of VAED is difficult to establish so a meaningful observed/expected analysis cannot be conducted at this point based on available data. The feasibility of conducting such an analysis will be re-evaluated on an ongoing basis as data on the virus grows and the vaccine safety data continues to accrue. The search criteria utilised to identify potential cases of VAED for this report includes PTs indicating a lack of effect of the vaccine and PTs potentially indicative of severe or atypical COVID-19a.

Since the first temporary authorization for emergency supply under Regulation 174 in the UK (01 December 2020) and through 28 February 2021, 138 cases [0.33% of the total PM dataset], reporting 317 potentially relevant events were retrieved: Country of incidence: UK (71), US (25), Germany (14), France, Italy, Mexico, Spain, (4 each), Denmark (3); the remaining 9 cases originated from 9 different countries; Cases Seriousness: 138; Seriousness criteria for the total 138 cases: Medically significant (71, of which 8 also serious for disability), Hospitalization required (non-fatal/non-life threatening) (16, of which 1 also serious for disability), Life threatening (13, of which 7 were also serious for hospitalization), Death (38). Gender: Females (73), Males (57), Unknown (8); Age (n=132) ranged from 21 to 100 years (mean = 57.2 years, median = 59.5); Case outcome: fatal (38), resolved/resolving (26), not resolved (65), resolved with sequelae (1), unknown (8); Of the 317 relevant events, the most frequently reported PTs (≥2%) were: Drug ineffective (135), Dyspnoea (53), Diarrhoea (30), COVID-19 pneumonia (23), Vomiting (20), Respiratory failure (8), and Seizure (7).

Conclusion: VAED may present as severe or unusual clinical manifestations of COVID-19. Overall, there were 37 subjects with suspected COVID-19 and 101 subjects with confirmed COVID-19 following one or both doses of the vaccine; 75 of the 101 cases were severe, resulting in hospitalisation, disability, life-threatening consequences or death. None of the 75 cases could be definitively considered as VAED/VAERD. In this review of subjects with COVID-19 following vaccination, based on the current evidence, VAED/VAERD remains a theoretical risk for the vaccine. Surveillance will continue. a. Search criteria: Standard Decreased Therapeutic Response Search AND PTs Dyspnoea; Tachypnoea; Hypoxia; COVID 19 pneumonia; Respiratory Failure; Acute Respiratory Distress Syndrome; Cardiac Failure; Cardiogenic shock; Acute myocardial infarction; Arrhythmia; Myocarditis; Vomiting; Diarrhoea; Abdominal pain; Jaundice; Acute hepatic failure; Deep vein thrombosis; Pulmonary embolism; Peripheral Ischaemia; Vasculitis; Shock; Acute kidney injury; Renal failure; Altered state of consciousness; Seizure; Encephalopathy; Meningitis; Cerebrovascular accident; Thrombocytopenia; Disseminated intravascular coagulation; Chillblains; Erythema multiforme; Multiple organ dysfunction syndrome; Multisystem inflammatory syndrome in children.

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Table 6.

Description of Missing Information

Topic

Description

Missing Information

Post Authorization Cases Evaluation (cumulative to 28 Feb 2021) Total Number of Cases in the Reporting Period (N=42086)

Use in Pregnancy and lactation

• •

Number of cases: 413a (0.98% of the total PM dataset); 84 serious and 329 non-serious; Country of incidence: US (205), UK (64), Canada (31), Germany (30), Poland (13), Israel (11); Italy (9), Portugal (8), Mexico (6), Estonia, Hungary and Ireland, (5 each), Romania (4), Spain (3), Czech Republic and France (2 each), the remaining 10 cases were distributed among 10 other countries.

Pregnancy cases: 274 cases including: • •

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•

•

•

270 mother cases and 4 foetus/baby cases representing 270 unique pregnancies (the 4 foetus/baby cases were linked to 3 mother cases; 1 mother case involved twins). Pregnancy outcomes for the 270 pregnancies were reported as spontaneous abortion (23), outcome pending (5), premature birth with neonatal death, spontaneous abortion with intrauterine death (2 each), spontaneous abortion with neonatal death, and normal outcome (1 each). No outcome was provided for 238 pregnancies (note that 2 different outcomes were reported for each twin, and both were counted). 146 non-serious mother cases reported exposure to vaccine in utero without the occurrence of any clinical adverse event. The exposure PTs coded to the PTs Maternal exposure during pregnancy (111), Exposure during pregnancy (29) and Maternal exposure timing unspecified (6). Trimester of exposure was reported in 21 of these cases: 1st trimester (15 cases), 2nd trimester (7), and 3rd trimester (2). 124 mother cases, 49 non-serious and 75 serious, reported clinical events, which occurred in the vaccinated mothers. Pregnancy related events reported in these cases coded to the PTs Abortion spontaneous (25), Uterine contraction during pregnancy, Premature rupture of membranes, Abortion, Abortion missed, and Foetal death (1 each).

Other clinical events which occurred in more than 5 cases coded to the PTs Headache (33), Vaccination site pain (24), Pain in extremity and Fatigue (22 each), Myalgia and Pyrexia (16 each), Chills (13) Nausea (12), Pain (11), Arthralgia (9), Lymphadenopathy and Drug ineffective (7 each), Chest pain, Dizziness and Asthenia (6 each), Malaise and COVID-19 (5 each). Trimester of exposure was reported in 22 of these cases: 1st trimester (19 cases), 2nd trimester (1 case), 3rd trimester (2 cases). 4 serious foetus/baby cases reported the PTs Exposure during pregnancy, Foetal growth restriction, Maternal exposure during pregnancy, Premature baby (2 each), and Death neonatal (1). Trimester of exposure was reported for 2 cases (twins) as occurring during the 1st trimester.

Breast feeding baby cases: 133, of which: • •

116 cases reported exposure to vaccine during breastfeeding (PT Exposure via breast milk) without the occurrence of any clinical adverse events; 17 cases, 3 serious and 14 non-serious, reported the following clinical events that occurred in the infant/child exposed to vaccine via breastfeeding: Pyrexia (5), Rash (4), Infant irritability (3), Infantile vomiting, Diarrhoea, Insomnia, and Illness (2 each), Poor feeding infant, Lethargy, Abdominal discomfort, Vomiting, Allergy to vaccine, Increased appetite, Anxiety, Crying, Poor quality sleep, Eructation, Agitation, Pain and Urticaria (1 each).

Breast feeding mother cases (6): • 1 serious case reported 3 clinical events that occurred in a mother during breast feeding (PT Maternal exposure during breast feeding); these events coded to the PTs Chills, Malaise, and Pyrexia • 1 non-serious case reported with very limited information and without associated AEs.

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Table 6. Topic

Description

Missing Information

Post Authorization Cases Evaluation (cumulative to 28 Feb 2021) Total Number of Cases in the Reporting Period (N=42086) • In 4 cases (3 non-serious; 1 serious) Suppressed lactation occurred in a breast feeding women with the following co-reported events: Pyrexia (2), Paresis, Headache, Chills, Vomiting, Pain in extremity, Arthralgia, Breast pain, Scar pain, Nausea, Migraine, Myalgia, Fatigue and Breast milk discolouration (1 each). Conclusion: There were no safety signals that emerged from the review of these cases of use in pregnancy and while breast feeding.

Use in Paediatric Individuals <12 Years of Age

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Description of Missing Information

• • • • • • •

Paediatric individuals <12 years of age Number of cases: 34d (0.1% of the total PM dataset), indicative of administration in paediatric subjects <12 years of age; Country of incidence: UK (29), US (3), Germany and Andorra (1 each); Cases Seriousness: Serious (24), Non-Serious (10); Gender: Females (25), Males (7), Unknown (2); Age (n=34) ranged from 2 months to 9 years, mean = 3.7 years, median = 4.0; Case outcome: resolved/resolving (16), not resolved (13), and unknown (5). Of the 132 reported events, those reported more than once were as follows: Product administered to patient of inappropriate age (27, see Medication Error), Off label use (11), Pyrexia (6), Product use issue (5), Fatigue, Headache and Nausea (4 each), Vaccination site pain (3), Abdominal pain upper, COVID-19, Facial paralysis, Lymphadenopathy, Malaise, Pruritus and Swelling (2 each).

Conclusion: No new significant safety information was identified based on a review of these cases compared with the non-paediatric population. Vaccine Effectiveness

Company conventions for coding cases indicative of lack of efficacy: The coding conventions for lack of efficacy in the context of administration of the COVID-19 vaccine were revised on 15 February 2021, as shown below: • PT “Vaccination failure” is coded when ALL of the following criteria are met: o The subject has received the series of two doses per the dosing regimen in local labeling. o At least 7 days have elapsed since the second dose of vaccine has been administered. o The subject experiences SARS-CoV-2 infection (confirmed laboratory tests). • PT “Drug ineffective” is coded when either of the following applies: o The infection is not confirmed as SARS-CoV-2 through laboratory tests (irrespective of the vaccination schedule). This includes scenarios where LOE is stated or implied, e.g., “the vaccine did not work”, “I got COVID-19”. o It is unknown: ƒ Whether the subject has received the series of two doses per the dosing regimen in local labeling; ƒ How many days have passed since the first dose (including unspecified number of days like” a few days”, “some days”, etc.); ƒ If 7 days have passed since the second dose; o The subject experiences a vaccine preventable illness 14 days after receiving the first dose up to and through 6 days after receipt of the second dose.

Note: after the immune system as had sufficient time (14 days) to respond to the vaccine, a report of COVID-19 is considered a potential lack of efficacy even if the vaccination course is not complete. Summary of the coding conventions for onset of vaccine preventable disease versus the vaccination date:

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Table 6.

Description of Missing Information

Topic

Description

Missing Information

Post Authorization Cases Evaluation (cumulative to 28 Feb 2021) Total Number of Cases in the Reporting Period (N=42086) 1st dose (day 1-13) From day 14 post 1st dose to Day 7 post 2nd dose day 6 post 2nd dose Code only the events Code “Drug ineffective” Code “Vaccination failure” describing the SARS-CoV-2 infection Scenario Not considered Scenario considered LOE as Scenario considered LOE as LOE “Drug ineffective” “Vaccination failure”

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Lack of efficacy cases •

Number of cases: 1665b (3.9 % of the total PM dataset) of which 1100 were medically confirmed and 565 non medically confirmed;

•

Number of lack of efficacy events: 1665 [PT: Drug ineffective (1646) and Vaccination failure (19)f].

•

Country of incidence: US (665), UK (405), Germany (181), France (85), Italy (58), Romania (47), Belgium (33), Israel (30), Poland (28), Spain (21), Austria (18), Portugal (17), Greece (15), Mexico (13), Denmark (8), Canada (7), Hungary, Sweden and United Arab Emirates (5 each), Czech Republic (4), Switzerland (3); the remaining 12 cases originated from 9 different countries.

•

COVID-19 infection was suspected in 155 cases, confirmed in 228 cases, in 1 case it was reported that the first dose was not effective (no other information).

•

COVID-19 infection (suspected or confirmed) outcome was reported as resolved/resolving (165), not resolved (205) or unknown (1230) at the time of the reporting; there were 65 cases where a fatal outcome was reported.

Drug ineffective cases (1649) •

Drug ineffective event seriousness: serious (1625), non-serious (21)e;

•

Lack of efficacy term was reported: o after the 1st dose in 788 cases o after the 2nd dose in 139 cases o in 722 cases it was unknown after which dose the lack of efficacy occurred.

•

Latency of lack of efficacy term reported after the first dose was known for 176 cases: o Within 9 days: 2 subjects; o Within 14 and 21 days: 154 subjects; o Within 22 and 50 days: 20 subjects;

•

Latency of lack of efficacy term reported after the second dose was known for 69 cases: o Within 0 and 7 days: 42 subjects; o Within 8 and 21 days: 22 subjects; o Within 23 and 36 days: 5 subjects.

•

Latency of lack of efficacy term reported in cases where the number of doses administered was not provided, was known in 409 cases: o Within 0 and 7 days after vaccination: 281 subjects. o Within 8 and 14 days after vaccination: 89 subjects. o Within 15 and 44 days after vaccination: 39 subjects.

According to the RSI, individuals may not be fully protected until 7 days after their second dose of vaccine, therefore for the above 1649 cases where lack of efficacy was reported after the 1st dose or the

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Table 6.

Description of Missing Information

Topic

Description

Missing Information

Post Authorization Cases Evaluation (cumulative to 28 Feb 2021) Total Number of Cases in the Reporting Period (N=42086) 2nd dose, the reported events may represent signs and symptoms of intercurrent or undiagnosed COVID19 infection or infection in an individual who was not fully vaccinated, rather than vaccine ineffectiveness. Vaccination failure cases (16) •

Vaccination failure seriousness: all serious;

•

Lack of efficacy term was reported in all cases after the 2nd dose:

•

Latency of lack of efficacy was known for 14 cases: o Within 7 and 13 days: 8 subjects; o Within 15 and 29 days: 6 subjects. COVID-19 (10) and Asymptomatic COVID-19 (6) were the reported vaccine preventable infections that occurred in these 16 cases.

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Conclusion: No new safety signals of vaccine lack of efficacy have emerged based on a review of these cases.

a. From a total of 417 cases, 4 cases were excluded from the analysis. In 3 cases, the MAH was informed that a 33-year-old and two unspecified age pregnant female patients were scheduled to receive bnt162b2 (PT reported Off label use and Product use issue in 2 cases; Circumstance or information capable of leading to medication error in one case). One case reported the PT Morning sickness; however, pregnancy was not confirmed in this case. b. 558 additional cases retrieved in this dataset were excluded from the analysis; upon review, 546 cases cannot be considered true lack of efficacy cases because the PT Drug ineffective was coded but the subjects developed SARS-CoV-2 infection during the early days from the first dose (days 1 – 13); the vaccine has not had sufficient time to stimulate the immune system and, consequently, the development of a vaccine preventable disease during this time is not considered a potential lack of effect of the vaccine; in 5 cases the PT Drug ineffective was removed after data lock point (DLP) because the subjects did not develop COVID19 infection; in 1 case, reporting Treatment failure and Transient ischaemic attack, the Lack of efficacy PT did not refer to BNT162b2 vaccine; 5 cases have been invalidated in the safety database after DLP; 1 case has been deleted from the discussion because the PTs reported Pathogen resistance and Product preparation

issue were not indicative of a lack of efficacy. to be eliminated. c. Upon review, 31 additional cases were excluded from the analysis as the data reported (e.g. clinical details, height, weight, etc.) were not consistent with paediatric subjects d. Upon review, 28 additional cases were excluded from the analysis as the data reported (e.g. clinical details, height, weight, etc.) were not consistent with paediatric subjects. e. Different clinical outcomes may be reported for an event that occurred more than once to the same individual f. In 2 cases the PT Vaccination failure was replaced with Drug ineffective after DLP. Another case was not included in the discussion of the Vaccination failure cases because correct scheduling (21 days apart between the first and second dose) cannot be confirmed.

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3.1.3. Review of Adverse Events of Special Interest (AESIs) Please refer to Appendix 1 for the list of the company’s AESIs for BNT162b2. The company’s AESI list takes into consideration the lists of AESIs from the following expert groups and regulatory authorities: Brighton Collaboration (SPEAC), ACCESS protocol, US CDC (preliminary list of AESI for VAERS surveillance), MHRA (unpublished guideline). The AESI terms are incorporated into a TME list and include events of interest due to their association with severe COVID-19 and events of interest for vaccines in general. The AESI list is comprised of MedDRA PTs, HLTs, HLGTs or MedDRA SMQs and can be changed as appropriate based on the evolving safety profile of the vaccine. Table 7 provides a summary review of cumulative cases within AESI categories in the Pfizer safety database. This is distinct from safety signal evaluations which are conducted and included, as appropriate, in the Summary Monthly Safety Reports submitted regularly to the FDA and other Health Authorities.

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Table 7.

AESIs Evaluation for BNT162b2

a

AESIs Category

Post-Marketing Cases Evaluationb Total Number of Cases (N=42086)

Anaphylactic Reactions Search criteria: Anaphylactic reaction SMQ (Narrow and Broad, with the algorithm applied), selecting relevant cases according to BC criteria Cardiovascular AESIs Search criteria: PTs Acute myocardial infarction; Arrhythmia; Cardiac failure; Cardiac failure acute; Cardiogenic shock; Coronary artery disease; Myocardial infarction; Postural orthostatic tachycardia syndrome; Stress cardiomyopathy; Tachycardia

Please refer to the Risk ‘Anaphylaxis’ included above in Table 4.

• •

• • • •

•

Number of cases: 1403 (3.3% of the total PM dataset), of which 241 are medically confirmed and 1162 are non-medically confirmed; Country of incidence: UK (268), US (233), Mexico (196), Italy (141), France (128), Germany (102), Spain (46), Greece (45), Portugal (37), Sweden (20), Ireland (17), Poland (16), Israel (13), Austria, Romania and Finland (12 each), Netherlands (11), Belgium and Norway (10 each), Czech Republic (9), Hungary and Canada (8 each), Croatia and Denmark (7 each), Iceland (5); the remaining 30 cases were distributed among 13 other countries; Subjects’ gender: female (1076), male (291) and unknown (36); Subjects’ age group (n = 1346): Adultc (1078), Elderlyd (266) Childe and Adolescentf (1 each); Number of relevant events: 1441, of which 946 serious, 495 non-serious; in the cases reporting relevant serious events; Reported relevant PTs: Tachycardia (1098), Arrhythmia (102), Myocardial infarction (89), Cardiac failure (80), Acute myocardial infarction (41), Cardiac failure acute (11), Cardiogenic shock and Postural orthostatic tachycardia syndrome (7 each) and Coronary artery disease (6); Relevant event onset latency (n = 1209): Range from <24 hours to 21 days, median <24 hours; CONFIDENTIAL Page 16

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Table 7.

AESIs Evaluation for BNT162b2

AESIsa Category

Post-Marketing Cases Evaluationb Total Number of Cases (N=42086) •

Relevant event outcomeg: fatal (136), resolved/resolving (767), resolved with sequelae (21), not resolved (140) and unknown (380);

Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue

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COVID-19 AESIs Search criteria: Covid-19 SMQ (Narrow and Broad) OR PTs Ageusia; Anosmia

• •

• • • •

• •

Number of cases: 3067 (7.3% of the total PM dataset), of which 1013 are medically confirmed and 2054 are non-medically confirmed; Country of incidence: US (1272), UK (609), Germany (360), France (161), Italy (94), Spain (69), Romania (62), Portugal (51), Poland (50), Mexico (43), Belgium (42), Israel (41), Sweden (30), Austria (27), Greece (24), Denmark (18), Czech Republic and Hungary (17 each), Canada (12), Ireland (11), Slovakia (9), Latvia and United Arab Emirates (6 each); the remaining 36 cases were distributed among 16 other different countries; Subjects’ gender: female (1650), male (844) and unknown (573); Subjects’ age group (n= 1880): Adult (1315), Elderly (560), Infanth and Adolescent (2 each), Child (1); Number of relevant events: 3359, of which 2585 serious, 774 non-serious; Most frequently reported relevant PTs (>1 occurrence): COVID19 (1927), SARS-CoV-2 test positive (415), Suspected COVID-19 (270), Ageusia (228), Anosmia (194), SARS-CoV-2 antibody test negative (83), Exposure to SARS-CoV-2 (62), SARS-CoV-2 antibody test positive (53), COVID-19 pneumonia (51), Asymptomatic COVID-19 (31), Coronavirus infection (13), Occupational exposure to SARS-CoV-2 (11), SARS-CoV-2 test false positive (7), Coronavirus test positive (6), SARS-CoV-2 test negative (3) SARS-CoV-2 antibody test (2); Relevant event onset latency (n = 2070): Range from <24 hours to 374 days, median 5

days; Relevant event outcome: fatal (136), not resolved (547), resolved/resolving (558), resolved with sequelae (9) and unknown (2110).

Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue Dermatological AESIs Search criteria: PT Chillblains; Erythema multiforme

• • • • •

Number of cases: 20 cases (0.05% of the total PM dataset), of which 15 are medically confirmed and 5 are non-medically confirmed; Country of incidence: UK (8), France and Poland (2 each), and the remaining 8 cases were distributed among 8 other different countries; Subjects’ gender: female (17) male and unknown (1 each); Subjects’ age group (n=19): Adult (18), Elderly (1); Number of relevant events: 20 events, 16 serious, 4 non-serious

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BNT162b2 5.3.6 Cumulative Analysis of Post-authorization Adverse Event Reports

Table 7.

AESIs Evaluation for BNT162b2

AESIsa Category

Post-Marketing Cases Evaluationb Total Number of Cases (N=42086) • • •

Reported relevant PTs: Erythema multiforme (13) and Chillblains (7) Relevant event onset latency (n = 18): Range from <24 hours to 17 days, median 3 days; Relevant event outcome: resolved/resolving (7), not resolved (8) and unknown (6).

Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue.

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Haematological AESIs Search criteria: Leukopenias NEC (HLT) (Primary Path) OR Neutropenias (HLT) (Primary Path) OR PTs Immune thrombocytopenia, Thrombocytopenia OR SMQ Haemorrhage terms (excl laboratory terms

• •

• • • •

• •

Number of cases: 932 (2.2 % of the total PM dataset), of which 524 medically confirmed and 408 non-medically confirmed; Country of incidence: UK (343), US (308), France (50), Germany (43), Italy (37), Spain (27), Mexico and Poland (13 each), Sweden (10), Israel (9), Netherlands (8), Denmark, Finland, Portugal and Ireland (7 each), Austria and Norway (6 each), Croatia (4), Greece, Belgium, Hungary and Switzerland (3 each), Cyprus, Latvia and Serbia (2 each); the remaining 9 cases originated from 9 different countries; Subjects’ gender (n=898): female (676) and male (222); Subjects’ age group (n=837): Adult (543), Elderly (293), Infant (1); Number of relevant events: 1080, of which 681 serious, 399 non-serious; Most frequently reported relevant PTs (≥15 occurrences) include: Epistaxis (127), Contusion (112), Vaccination site bruising (96), Vaccination site haemorrhage (51), Petechiae (50), Haemorrhage (42), Haematochezia (34), Thrombocytopenia (33), Vaccination site haematoma (32), Conjunctival haemorrhage and Vaginal haemorrhage (29 each), Haematoma, Haemoptysis and Menorrhagia (27 each), Haematemesis (25), Eye haemorrhage (23), Rectal haemorrhage (22), Immune thrombocytopenia (20), Blood urine present (19), Haematuria, Neutropenia and Purpura (16 each) Diarrhoea haemorrhagic (15); Relevant event onset latency (n = 787): Range from <24 hours to 33 days, median = 1 day; Relevant

event outcome: fatal (34), resolved/resolving (393), resolved with sequelae (17), not resolved (267) and unknown (371).

Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue Hepatic AESIs Search criteria: Liver related investigations, signs and symptoms (SMQ) (Narrow and Broad) OR PT Liver injury

• •

• •

Number of cases: 70 cases (0.2% of the total PM dataset), of which 54 medically confirmed and 16 non-medically confirmed; Country of incidence: UK (19), US (14), France (7), Italy (5), Germany (4), Belgium, Mexico and Spain (3 each), Austria, and Iceland (2 each); the remaining 8 cases originated from 8 different countries; Subjects’ gender: female (43), male (26) and unknown (1); Subjects’ age group (n=64): Adult (37), Elderly (27); CONFIDENTIAL Page 18

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Table 7.

AESIs Evaluation for BNT162b2

AESIsa Category

Post-Marketing Cases Evaluationb Total Number of Cases (N=42086) • •

• •

Number of relevant events: 94, of which 53 serious, 41 non-serious; Most frequently reported relevant PTs (≥3 occurrences) include: Alanine aminotransferase increased (16), Transaminases increased and Hepatic pain (9 each), Liver function test increased (8), Aspartate aminotransferase increased and Liver function test abnormal (7 each), Gamma-glutamyltransferase increased and Hepatic enzyme increased (6 each), Blood alkaline phosphatase increased and Liver injury (5 each), Ascites, Blood bilirubin increased and Hypertransaminasaemia (3 each); Relevant event onset latency (n = 57): Range from <24 hours to 20 days, median 3 days; Relevant event outcome: fatal (5), resolved/resolving (27), resolved with sequelae (1), not resolved (14) and unknown (47).

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Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue Facial Paralysis Search criteria: PTs Facial paralysis, Facial paresis

• •

• • • • • •

Number of cases: 449i (1.07% of the total PM dataset), 314 medically confirmed and 135 non-medically confirmed; Country of incidence: US (124), UK (119), Italy (40), France (27), Israel (20), Spain (18), Germany (13), Sweden (11), Ireland (9), Cyprus (8), Austria (7), Finland and Portugal (6 each), Hungary and Romania (5 each), Croatia and Mexico (4 each), Canada (3),Czech Republic, Malta, Netherlands, Norway, Poland and Puerto Rico (2 each); the remaining 8 cases originated from 8 different countries; Subjects’ gender: female (295), male (133), unknown (21); Subjects’ age group (n=411): Adult (313), Elderly (96), Infantj and Child (1 each); Number of relevant eventsk: 453, of which 399 serious, 54 non-serious; Reported relevant PTs: Facial paralysis (401), Facial paresis (64); Relevant event onset latency (n = 404): Range from <24 hours to 46 days, median 2 days; Relevant event outcome: resolved/resolving (184), resolved with sequelae (3), not resolved (183) and unknown (97);

Overall Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue. Causality assessment will be further evaluated following availability of additional unblinded data from the clinical study C4591001, which will be unblinded for final analysis approximately mid-April 2021. Additionally, noninterventional post-authorisation safety studies, C4591011 and C4591012 are expected to capture data on a sufficiently large vaccinated population to detect an increased risk of Bell’s palsy in vaccinated individuals. The timeline for conducting these analyses will be established based on the size of the vaccinated population captured in the study data sources by the first interim reports (due 30 June CONFIDENTIAL Page 19

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Table 7.

AESIs Evaluation for BNT162b2

AESIsa Category

Post-Marketing Cases Evaluationb Total Number of Cases (N=42086) 2021). Study C4591021, pending protocol endorsement by EMA, is also intended to inform this risk.

Immune-Mediated/Autoimmune AESIs Search criteria: Immunemediated/autoimmune disorders (SMQ) (Broad and Narrow) OR Autoimmune disorders HLGT (Primary Path) OR PTs Cytokine release syndrome; Cytokine storm; Hypersensitivity

• •

• • •

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•

• •

Number of cases: 1050 (2.5 % of the total PM dataset), of which 760 medically confirmed and 290 non-medically confirmed; Country of incidence (>10 cases): UK (267), US (257), Italy (70), France and Germany (69 each), Mexico (36), Sweden (35), Spain (32), Greece (31), Israel (21), Denmark (18), Portugal (17), Austria and Czech Republic (16 each), Canada (12), Finland (10). The remaining 74 cases were from 24 different countries. Subjects’ gender (n=682): female (526), male (156). Subjects’ age group (n=944): Adult (746), Elderly (196), Adolescent (2). Number of relevant events: 1077, of which 780 serious, 297 non‑serious. Most frequently reported relevant PTs (>10 occurrences): Hypersensitivity (596), Neuropathy peripheral (49), Pericarditis (32), Myocarditis (25), Dermatitis (24), Diabetes mellitus and Encephalitis (16 each), Psoriasis (14), Dermatitis Bullous (13), Autoimmune disorder and Raynaud’s phenomenon (11 each); Relevant event onset latency (n = 807): Range from <24 hours to 30 days, median <24 hours. Relevant event outcomel: resolved/resolving (517), not resolved (215), fatal (12), resolved with sequelae (22) and unknown (312).

Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue Musculoskeletal AESIs Search criteria: PTs Arthralgia; Arthritis; Arthritis bacterialn; Chronic fatigue syndrome; Polyarthritis; Polyneuropathy; Post viral fatigue syndrome; Rheumatoid arthritis

• •

• • • •

•

Number of cases: 3600 (8.5% of the total PM dataset), of which 2045 medically confirmed and 1555 non-medically confirmed; Country of incidence: UK (1406), US (1004), Italy (285), Mexico (236), Germany (72), Portugal (70), France (48), Greece and Poland (46), Latvia (33), Czech Republic (32), Israel and Spain (26), Sweden (25), Romania (24), Denmark (23), Finland and Ireland (19 each), Austria and Belgium (18 each), Canada (16), Netherlands (14), Bulgaria (12), Croatia and Serbia (9 each), Cyprus and Hungary (8 each), Norway (7), Estonia and Puerto Rico (6 each), Iceland and Lithuania (4 each); the remaining 21 cases originated from 11 different countries; Subjects’ gender (n=3471): female (2760), male (711); Subjects’ age group (n=3372): Adult (2850), Elderly (515), Child (4), Adolescent (2), Infant (1); Number of relevant events: 3640, of which 1614 serious, 2026 non-serious; Reported relevant PTs: Arthralgia (3525), Arthritis (70), Rheumatoid arthritis (26), Polyarthritis (5), Polyneuropathy, Post viral fatigue syndrome, Chronic fatigue syndrome (4 each), Arthritis bacterial (1); Relevant event onset latency (n = 2968): Range from <24 hours to 32 days, median 1 day; CONFIDENTIAL Page 20

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Table 7.

AESIs Evaluation for BNT162b2

AESIsa Category

Post-Marketing Cases Evaluationb Total Number of Cases (N=42086) •

Relevant event outcome: resolved/resolving (1801), not resolved (959), resolved with sequelae (49), and unknown (853).

Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue. Neurological AESIs (including demyelination) Search criteria: Convulsions (SMQ) (Broad and Narrow) OR Demyelination (SMQ) (Broad and Narrow) OR PTs Ataxia; Cataplexy; Encephalopathy; Fibromyalgia; Intracranial pressure increased; Meningitis; Meningitis aseptic; Narcolepsy

• •

• • •

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•

• •

Number of cases: 501 (1.2% of the total PM dataset), of which 365 medically confirmed and 136 non-medically confirmed. Country of incidence (≥9 cases): UK (157), US (68), Germany (49), Mexico (35), Italy (31), France (25), Spain (18), Poland (17), Netherlands and Israel (15 each), Sweden (9). The remaining 71 cases were from 22 different countries. Subjects’ gender (n=478): female (328), male (150). Subjects’ age group (n=478): Adult (329), Elderly (149); Number of relevant events: 542, of which 515 serious, 27 non‑serious. Most frequently reported relevant PTs (˃2 occurrences) included: Seizure (204), Epilepsy (83), Generalised tonic-clonic seizure (33), Guillain-Barre syndrome (24), Fibromyalgia and Trigeminal neuralgia (17 each), Febrile convulsion, (15), Status epilepticus (12), Aura and Myelitis transverse (11 each), Multiple sclerosis relapse and Optic neuritis (10 each), Petit mal epilepsy and Tonic convulsion (9 each), Ataxia (8), Encephalopathy and Tonic clonic movements (7 each), Foaming at mouth (5), Multiple sclerosis, Narcolepsy and Partial seizures (4 each), Bad sensation, Demyelination, Meningitis, Postictal state, Seizure like phenomena and Tongue biting (3 each); Relevant event onset latency (n = 423): Range from <24 hours to 48 days, median 1 day; Relevant events outcome: fatal (16), resolved/resolving (265), resolved with sequelae (13), not resolved (89) and

unknown (161);

Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue Other AESIs Search criteria: Herpes viral infections (HLT) (Primary Path) OR PTs Adverse event following immunisation; Inflammation; Manufacturing laboratory analytical testing issue; Manufacturing materials issue; Manufacturing production issue; MERS-CoV test; MERS-CoV test negative; MERS-CoV test positive; Middle East respiratory syndrome; Multiple organ dysfunction syndrome; Occupational exposure to communicable disease; Patient

• •

• •

Number of cases: 8152 (19.4% of the total PM dataset), of which 4977 were medically confirmed and 3175 non-medically confirmed; Country of incidence (> 20 occurrences): UK (2715), US (2421), Italy (710), Mexico (223), Portugal (210), Germany (207), France (186), Spain (183), Sweden (133), Denmark (127), Poland (120), Greece (95), Israel (79), Czech Republic (76), Romania (57), Hungary (53), Finland (52), Norway (51), Latvia (49), Austria (47), Croatia (42), Belgium (41), Canada (39), Ireland (34), Serbia (28), Iceland (25), Netherlands (22). The remaining 127 cases were from 21 different countries; Subjects’ gender (n=7829): female (5969), male (1860); Subjects’ age group (n=7479): Adult (6330), Elderly (1125), Adolescent, Child (9 each), Infant (6);

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Table 7.

AESIs Evaluation for BNT162b2

AESIsa Category

Post-Marketing Cases Evaluationb Total Number of Cases (N=42086)

isolation; Product availability issue; Product distribution issue; Product supply issue; Pyrexia; Quarantine; SARS-CoV-1 test; SARS-CoV-1 test negative; SARSCoV-1 test positive

• •

• •

Number of relevant events: 8241, of which 3674 serious, 4568 non‑serious; Most frequently reported relevant PTs (≥6 occurrences) included: Pyrexia (7666), Herpes zoster (259), Inflammation (132), Oral herpes (80), Multiple organ dysfunction syndrome (18), Herpes virus infection (17), Herpes simplex (13), Ophthalmic herpes zoster (10), Herpes ophthalmic and Herpes zoster reactivation (6 each); Relevant event onset latency (n =6836): Range from <24 hours to 61 days, median 1 day; Relevant events outcome: fatal (96), resolved/resolving (5008), resolved with sequelae (84), not resolved (1429) and unknown (1685).

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Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue Pregnancy Related AESIs Search criteria: PTs Amniotic cavity infection; Caesarean section; Congenital anomaly; Death neonatal; Eclampsia; Foetal distress syndrome; Low birth weight baby; Maternal exposure during pregnancy; Placenta praevia; Pre-eclampsia; Premature labour; Stillbirth; Uterine rupture; Vasa praevia Renal AESIs Search criteria: PTs Acute kidney injury; Renal failure.

For relevant cases, please refer to Table 6, Description of Missing Information, Use in Pregnancy and While Breast Feeding

• • • • • • • •

Number of cases: 69 cases (0.17% of the total PM dataset), of which 57 medically confirmed, 12 non-medically confirmed; Country of incidence: Germany (17), France and UK (13 each), US (6), Belgium, Italy and Spain (4 each), Sweden (2), Austria, Canada, Denmark, Finland, Luxembourg and Norway (1 each); Subjects’ gender: female (46), male (23); Subjects’ age group (n=68): Adult (7), Elderly (60), Infant (1); Number of relevant events: 70, all serious; Reported relevant PTs: Acute kidney injury (40) and Renal failure (30); Relevant event onset latency (n = 42): Range from <24 hours to 15 days, median 4 days; Relevant event outcome: fatal (23), resolved/resolving (10), not resolved (15) and unknown (22).

Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue. Respiratory AESIs Search criteria: Lower respiratory tract infections NEC (HLT)

•

Number of cases: 130 cases (0.3% of the total PM dataset), of which 107 medically confirmed;

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Table 7.

AESIs Evaluation for BNT162b2

AESIsa Category

Post-Marketing Cases Evaluationb Total Number of Cases (N=42086)

(Primary Path) OR Respiratory failures (excl neonatal) (HLT) (Primary Path) OR Viral lower respiratory tract infections (HLT) (Primary Path) OR PTs: Acute respiratory distress syndrome; Endotracheal intubation; Hypoxia; Pulmonary haemorrhage; Respiratory disorder; Severe acute respiratory syndrome

•

• • • •

•

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•

Countries of incidence: United Kingdom (20), France (18), United States (16), Germany (14), Spain (13), Belgium and Italy (9), Denmark (8), Norway (5), Czech Republic, Iceland (3 each); the remaining 12 cases originated from 8 different countries. Subjects’ gender (n=130): female (72), male (58). Subjects’s age group (n=126): Elderly (78), Adult (47), Adolescent (1). Number of relevant events: 137, of which 126 serious, 11 non-serious; Reported relevant PTs: Respiratory failure (44), Hypoxia (42), Respiratory disorder (36), Acute respiratory distress syndrome (10), Chronic respiratory syndrome (3), Severe acute respiratory syndrome (2). Relevant event onset latency (n=102): range from < 24 hours to 18 days, median 1 day; Relevant events outcome: fatal (41), Resolved/resolving (47), not recovered (18) and unknown (31).

Conclusion: This cumulative case review does not raise new safety issues. Surveillance will continue. Thromboembolic Events Search criteria: Embolism and thrombosis (HLGT) (Primary Path), excluding PTs reviewed as Stroke AESIs, OR PTs Deep vein thrombosis; Disseminated intravascular coagulation; Embolism; Embolism venous; Pulmonary embolism

• •

• • • •

• •

Number of cases: 151 (0.3% of the total PM dataset), of which 111 medically confirmed and 40 non-medically confirmed; Country of incidence: UK (34), US (31), France (20), Germany (15), Italy and Spain (6 each), Denmark and Sweden (5 each), Austria, Belgium and Israel (3 each), Canada, Cyprus, Netherlands and Portugal (2 each); the remaining 12 cases originated from 12 different countries; Subjects’ gender (n= 144): female (89), male (55); Subjects’ age group (n=136): Adult (66), Elderly (70); Number of relevant events: 168, of which 165 serious, 3 non-serious; Most frequently reported relevant PTs (>1 occurrence) included: Pulmonary embolism (60), Thrombosis (39), Deep vein thrombosis (35), Thrombophlebitis superficial (6), Venous thrombosis limb (4), Embolism, Microembolism, Thrombophlebitis and Venous thrombosis (3 each) Blue toe syndrome (2); Relevant event onset latency (n = 124): Range from <24 hours to 28 days, median 4 days; Relevant event outcome: fatal (18), resolved/resolving (54), resolved with sequelae (6), not resolved (49) and unknown (42).