Pfizer: Cumulative Analysis of Post-authorization Adverse Event Reports

BNT162b2

5.3.6 Cumulative Analysis of Post-authorization Adverse Event Reports

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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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

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

Term

AE

adverse event

AESI

adverse event of special interest

BC

Brighton Collaboration

CDC

Centers for Disease Control and Prevention

COVID-19

coronavirus disease 2019

DLP

data lock point

EUA

emergency use authorisation

HLGT

(MedDRA) High Group Level Term

HLT

(MedDRA) High Level Term

MAH

marketing authorisation holder

MedDRA

medical dictionary for regulatory activities

MHRA

Medicines and Healthcare products Regulatory Agency

PCR

Polymerase Chain Reaction

PT

(MedDRA) Preferred Term

PVP

pharmacovigilance plan

RT-PCR

Reverse Transcription-Polymerase Chain Reaction

RSI

reference safety information

TME

targeted medically event

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

SMQ

standardised MedDRA query

SOC

(MedDRA) System Organ Class

UK

United Kingdom

US

United States

VAED

vaccine-associated enhanced disease

VAERD

vaccine-associated enhanced respiratory disease

VAERS

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.

"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.

•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 processing colleagues. To date, Pfizer has onboarded approximately^(b' ⁽⁴' additional full-time employees (FTEs). More are joining each month with an expected total of more than (^^^^ 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.

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

Characteristics

Relevant cases (N=42086)

Gender:

Female

29914

Male

9182

No Data

2990

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

<17 18-30

31-50

51-64 65-74

>75

Unknown

175^a

4953 13886

7884 3098

5214 6876

Case outcome:

Recovered/Recovering

19582

Recovered with sequelae

520

Not recovered at the time of report

11361

Fatal

1223

Unknown

9400

a. in 46 cases reported age was <16-year-old and in 34 cases <12-year-old.

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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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

Cumulatively Through 28 February 2021

MedDRA SOC

MedDRA PT

AEs (AERP%) N = 42086

Blood and lymphatic system disorders

Lymphadenopathy

1972 (4.7%)

Cardiac disorders

Tachycardia

1098 (2.6%)

Gastrointestinal disorders

Nausea

5182 (12.3%)

Diarrhoea

1880 (4.5%)

Vomiting

1698 (4.0%)

General disorders and administration site conditions

Pyrexia

7666 (18.2%)

Fatigue

7338 (17.4%)

Chills

5514 (13.1%)

Vaccination site pain

5181 (12.3%)

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Table 2. Events Reported in >2% Cases

Cumulatively Through 28 February 2021

MedDRA SOC

MedDRA PT

AEs (AERP%) N = 42086

Pain

3691 (8.8%)

Malaise

2897 (6.9%)

Asthenia

2285 (5.4%)

Drug ineffective

2201 (5.2%)

Vaccination site erythema

930 (2.2%)

Vaccination site swelling

913 (2.2%)

Influenza like illness

835 (2%)

Infections and infestations

COVID-19

1927 (4.6%)

Injury, poisoning and procedural complications

Off label use

880 (2.1%)

Product use issue

828 (2.0%)

Musculoskeletal and connective tissue disorders

Myalgia

4915 (11.7%)

Pain in extremity

3959 (9.4%)

Arthralgia

3525 (8.4%)

Nervous system disorders

Headache

10131 (24.1%)

Dizziness

3720 (8.8%)

Paraesthesia

1500 (3.6%)

Hypoaesthesia

999 (2.4%)

Respiratory, thoracic and mediastinal disorders

Dyspnoea

2057 (4.9%)

Cough

1146 (2.7%)

Oropharyngeal pain

948 (2.3%)

Skin and subcutaneous tissue disorders

Pruritus

1447 (3.4%)

Rash

1404 (3.3%)

Erythema

1044 (2.5%)

Hyperhidrosis

900 (2.1%)

Urticaria

862 (2.1%)

Total number of events

93473

Important identified risks

Anaphylaxis

Important potential risks

Vaccine-Associated Enhanced Disease (VAED), Including Vaccine-associated Enhanced Respiratory Disease (VAERD)

Missing information

Use in Pregnancy and lactation

Use in Paediatric Individuals <12 Years of Age

Vaccine Effectiveness

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Table 4.

Topic

Important Identified Risk

Description

Important Identified Risk

Anaphylaxis

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

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 outcome^a: 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.

aDifferent clinical outcome may be reported for an event that occurred more than once to the same individual.

bThere 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

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

Vaccine-Associated Enhanced Disease (VAED), including Vaccine-Associated Enhanced Respiratory Disease

(VAERD)

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-19^a.

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: 413^a (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:

• •

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. 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)

• 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

Paediatric individuals <12 years of age

•Number of cases: 34^d (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:

■Whether the subject has received the series of two doses per the dosing regimen in local labeling;

■How many days have passed since the first dose (including unspecified number of days like" a few days", "some days", etc.);

■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 6 post 2nd dose

Day 7 post 2nd dose

Code only the events describing the SARS-CoV-2 infection

Code "Drug ineffective"

Code "Vaccination failure"

Scenario Not considered LOE

Scenario considered LOE as "Drug ineffective"

Scenario considered LOE as "Vaccination failure"

Lack of efficacy cases

•Number of cases: 1665^b(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 COVID-19 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.

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 COVID-19 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.

Table 7. AESIs Evaluation for BNT162b2

AESIs^a Category

Post-Marketing Cases Evaluation^b 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

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

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

•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): Adult^c (1078), Elderly^d (266) Child^e and Adolescent^f (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;

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Table 7. AESIs Evaluation for BNT162b2

AESIs^a Category

Post-Marketing Cases Evaluation^b Total Number of Cases (N=42086)

• Relevant event outcome^g: 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

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), Infant^h 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): COVID-19 (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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Table 7. AESIs Evaluation for BNT162b2

AESIs^a Category

Post-Marketing Cases Evaluation^b 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.

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);

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Table 7. AESIs Evaluation for BNT162b2

AESIs^a Category

Post-Marketing Cases Evaluation^b 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).

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), Infant^j and Child (1 each);

•Number of relevant events^k: 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, non-interventional 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

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Table 7. AESIs Evaluation for BNT162b2

AESIs^a Category

Post-Marketing Cases Evaluation^b 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: Immune-mediated/autoimmune disorders (SMQ) (Broad and Narrow) OR Autoimmune disorders HLGT (Primary Path) OR PTs Cytokine release syndrome; Cytokine storm; Hypersensitivity

•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 outcome^l: 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;

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Table 7. AESIs Evaluation for BNT162b2

AESIs^a Category

Post-Marketing Cases Evaluation^b 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

•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

AESIs^a Category

Post-Marketing Cases Evaluation^b 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; SARS-

CoV-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).

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

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

Renal AESIs

Search criteria: PTs Acute kidney injury; Renal failure.

•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

AESIs^a Category

Post-Marketing Cases Evaluation^b 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

•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).

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

Stroke

Search criteria: HLT Central nervous system haemorrhages and cerebrovascular accidents

•Number of cases: 275 (0.6% of the total PM dataset), of which 180 medically confirmed and 95 non-medically confirmed;

•Country of incidence: UK (81), US (66), France (32), Germany (21), Norway (14), Netherlands and Spain (11 each), Sweden (9),

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Table 7. AESIs Evaluation for BNT162b2

AESIs^a Category

Post-Marketing Cases Evaluation^b Total Number of Cases (N=42086)

(Primary Path) OR HLT Cerebrovascular venous and sinus thrombosis (Primary Path)

Israel (6), Italy (5), Belgium (3), Denmark, Finland, Poland and Switzerland (2 each); the remaining 8 cases originated from 8 different countries;

•Subjects' gender (n= 273): female (182), male (91);

•Subjects' age group (n=265): Adult (59), Elderly (205), Child^m

(1);

•Number of relevant events: 300, all serious;

•Most frequently reported relevant PTs (>1 occurrence) included:

o PTs indicative of Ischaemic stroke: Cerebrovascular accident (160), Ischaemic stroke (41), Cerebral infarction (15), Cerebral ischaemia, Cerebral thrombosis, Cerebral venous sinus thrombosis, Ischaemic cerebral infarction and Lacunal infarction (3 each) Basal ganglia stroke, Cerebellar infarction and Thrombotic stroke (2 each);

o PTs indicative of Haemorrhagic stroke: Cerebral haemorrhage (26), Haemorrhagic stroke (11), Haemorrhage intracranical and Subarachnoid haemorrhage (5 each), Cerebral haematoma (4), Basal ganglia haemorrhage and Cerebellar haemorrhage (2 each);

•Relevant event onset latency (n = 241): Range from <24 hours to 41 days, median 2 days;

•Relevant event outcome: fatal and resolved/resolving (61 each), resolved with sequelae (10), not resolved (85) and unknown (83).

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

Vasculitic Events

Search criteria: Vasculitides HLT

•Number of cases: 32 cases (0.08% of the total PM dataset), of which 26 medically confirmed and 6 non-medically confirmed;

•Country of incidence: UK (13), France (4), Portugal, US and Spain (3 each), Cyprus, Germany, Hungary, Italy and Slovakia and Costa rica (1 each);

•Subjects' gender: female (26), male (6);

•Subjects' age group (n=31): Adult (15), Elderly (16);

•Number of relevant events: 34, of which 25 serious, 9 non-serious;

•Reported relevant PTs: Vasculitis (14), Cutaneous vasculitis and Vasculitic rash (4 each), (3), Giant cell arteritis and Peripheral ischaemia (3 each), Behcet's syndrome and Hypersensitivity vasculitis (2 each) Palpable purpura, and Takayasu's arteritis (1 each);

•Relevant event onset latency (n = 25): Range from <24 hours to 19 days, median 3 days;

•Relevant event outcome: fatal (1), resolved/resolving (13), not resolved (12) and unknown (8).

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

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Table 7. AESIs Evaluation for BNT162b2

AESIs^a

Post-Marketing Cases Evaluation^b

Category

Total Number of Cases (N=42086)

a.For the complete list of the AESIs, please refer to Appendix 5;

b.Please note that this corresponds to evidence from post-EUA/conditional marketing authorisation approval data sources;

c.Subjects with age ranged between 18 and 64 years;

d.Subjects with age equal to or above 65 years;

e.Subjects with age ranged between 2 and 11 years;

f.Subjects with age ranged between 12 and less than 18 years;

g.Multiple episodes of the same PT event were reported with a different clinical outcome within some cases hence the sum of the events outcome exceeds the total number of PT events;

h.Subjects with age ranged between 1 (28 days) and 23 months;

i.Twenty-four additional cases were excluded from the analysis as they were not cases of peripheral facial nerve palsy because they described other disorders (stroke, cerebral haemorrhage or transient ischaemic attack); 1 case was excluded from the analysis because it was invalid due to an unidentifiable reporter;

j. This UK case report received from the UK MHRA described a 1-year-old subject who received the vaccine, and had left postauricular ear pain that progressed to left-sided Bell's palsy 1 day following vaccination that had not resolved at the time of the report;

k. If a case included both PT Facial paresis and PT Facial paralysis, only the PT Facial paralysis was considered in the descriptions of the events as it is most clinically important;

l. Multiple episodes of the same PT event were reported with a different clinical outcome within some cases hence the sum of the events outcome exceeds the total number of PT events

m. This UK case report received from the UK MHRA described a 7-year-old female subject who received the vaccine and had stroke (unknown outcome); no follow-up is possible for clarification. n. This PT not included in the AESIs/TME list was included in the review as relevant for ACCESS protocol criteria;

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5.3.6 Cumulative Analysis of Post-authorization Adverse Event Reports

3.1.4. Medication error

Cases potentially indicative of medication errors¹ that cumulatively occurred are summarized below.

•Number of relevant medication error cases: 2056² (4.9%) of which 1569 (3.7%) are medically confirmed.

•Number of relevant events: 2792

•Top 10 countries of incidence:

US (1201), France (171), UK (138), Germany (88), Czech Republic (87), Sweden (49), Israel (45), Italy (42), Canada (35), Romania (33), Finland (21), Portugal (20), Norway (14), Puerto Rico (13), Poland (12), Austria and Spain (10 each).

Medication error case outcomes:

•Fatal (7)³,

•Recovered/recovering (354, of which 4 are serious),

•Recovered with sequelae (8, of which 3 serious)

¹MedDRA (version 23.1) Higher Level Terms: Accidental exposures to product; Product administration errors and issues; Product confusion errors and issues; Product dispensing errors and issues; Product label issues; Product monitoring errors and issues; Product preparation errors and issues; Product selection errors and issues; Product storage errors and issues in the product use system; Product transcribing errors and communication issues, OR Preferred Terms: Accidental poisoning; Circumstance or information capable of leading to device use error; Circumstance or information capable of leading to medication error; Contraindicated device used; Deprescribing error; Device use error; Dose calculation error; Drug titration error; Expired device used; Exposure via direct contact; Exposure via eye contact; Exposure via mucosa; Exposure via skin contact; Failure of child resistant product closure; Inadequate aseptic technique in use of product; Incorrect disposal of product; Intercepted medication error; Intercepted product prescribing error; Medication error; Multiple use of single-use product; Product advertising issue; Product distribution issue; Product prescribing error; Product prescribing issue; Product substitution error; Product temperature excursion issue; Product use in unapproved therapeutic environment; Radiation underdose; Underdose; Unintentional medical device removal; Unintentional use for unapproved indication; Vaccination error; Wrong device used; Wrong dosage form; Wrong dosage formulation; Wrong dose; Wrong drug; Wrong patient; Wrong product procured; Wrong product stored; Wrong rate; Wrong route; Wrong schedule; Wrong strength; Wrong technique in device usage process; Wrong technique in product usage process.

²Thirty-five (35) cases were exclude from the analysis because describing medication errors occurring in an unspecified number of individuals or describing medication errors occurring with co suspects were determined to be non-contributory.

³All the medication errors reported in these cases were assessed as non-serious occurrences with an unknown outcome; based on the available information including the causes of death, the relationship between the medication error and the death is weak. .

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5.3.6 Cumulative Analysis of Post-authorization Adverse Event Reports

•Not recovered (189, of which 84 are serious),

•Unknown (1498, of which 33 are serious).

1371 cases reported only MEs without any associated clinical adverse event. The PTs most frequently reported (>12 occurrences) were: Poor quality product administered (539), Product temperature excursion issue (253), Inappropriate schedule of product administration (225), Product preparation error (206), Underdose (202), Circumstance or information capable of leading to medication error (120), Product preparation issue (119), Wrong technique in product usage process (76), Incorrect route of product administration (66), Accidental overdose (33), Product administered at inappropriate site (27), Incorrect dose administered and Accidental exposure to the product (25 each), Exposure via skin contact (22), Wrong product administered (17), Incomplete course of vaccination, and Product administration error (14 each) Product administered to patient of inappropriate age (12).

In 685 cases, there were co-reported AEs. The most frequently co- associated AEs (> 40 occurrences) were: Headache (187), Pyrexia (161), Fatigue (135), Chills (127), Pain (107), Vaccination site pain (100), Nausea (89), Myalgia (88), Pain in extremity (85) Arthralgia (68), Off label use (57), Dizziness (52), Lymphadenopathy (47), Asthenia (46) and Malaise (41). These cases are summarized in Table 8.

Table 8. ME PTs by seriousness with or without harm co-association (Through 28 February 2021)

Serious

Non-Serious

ME PTs

With Harm

Without Harm

With Harm

Without Harm

Accidental exposure to product

0

0

0

5

Accidental overdose

4

1

9

6

Booster dose missed

0

0

0

1

Circumstance or information capable of leading to medication error

0

0

5

11

Contraindicated product administered

1

0

0

2

Expired product administered

0

0

0

2

Exposure via skin contact

0

0

0

5

Inappropriate schedule of product administration

0

2

8

264

Incorrect dose administered

1

1

0

0

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5.3.6 Cumulative Analysis of Post-authorization Adverse Event Reports

Serious

Non-Serious

ME PTs

With Harm

Without Harm

With Harm

Without Harm

Incorrect route of product administration

2

6

16

127

Lack of vaccination site rotation

1

0

0

0

Medication error

0

0

0

1

Poor quality product administered

1

0

0

34

Product administered at inappropriate site

2

1

13

29

Product administered to patient of inappropriate age

0

4

0

40

Product administration error

1

0

0

3

Product dose omission issue

0

1

0

3

Product preparation error

1

0

4

11

Product preparation issue

1

1

0

14

4. DISCUSSION

Pfizer performs frequent and rigorous signal detection on BNT162b2 cases. The findings of these signal detection analyses are consistent with the known safety profile of the vaccine. This cumulative analysis to support the Biologics License Application for BNT162b2, is an integrated analysis of post-authorization safety data, from U.S. and foreign experience, focused on Important Identified Risks, Important Potential Risks, and areas of Important Missing Information identified in the Pharmacovigilance Plan, as well as adverse events of special interest and vaccine administration errors (whether or not associated with an adverse event). The data do not reveal any novel safety concerns or risks requiring label changes and support a favorable benefit risk profile of to the BNT162b2 vaccine.

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5. SUMMARY AND CONCLUSION

Review of the available data for this cumulative PM experience, confirms a favorable benefit: risk balance for BNT162b2.

Pfizer will continue routine pharmacovigilance activities on behalf of BioNTech according to the Pharmacovigilance Agreement in place, in order to assure patient safety and will inform the Agency if an evaluation of the safety data yields significant new information for BNT162b2.

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APPENDIX 1. LIST OF ADVERSE EVENTS OF SPECIAL INTEREST

1p36 deletion syndrome; 2-Hydroxyglutaric aciduria; 5'nucleotidase increased; Acoustic neuritis; Acquired C1 inhibitor deficiency; Acquired epidermolysis bullosa; Acquired epileptic aphasia; Acute cutaneous lupus erythematosus; Acute disseminated encephalomyelitis; Acute encephalitis with refractory, repetitive partial seizures; Acute febrile neutrophilic dermatosis; Acute flaccid myelitis; Acute haemorrhagic leukoencephalitis; Acute haemorrhagic oedema of infancy; Acute kidney injury; Acute macular outer retinopathy; Acute motor axonal neuropathy; Acute motor-sensory axonal neuropathy; Acute myocardial infarction; Acute respiratory distress syndrome; Acute respiratory failure; Addison's disease; Administration site thrombosis; Administration site vasculitis; Adrenal thrombosis; Adverse event following immunisation; Ageusia; Agranulocytosis; Air embolism; Alanine aminotransferase abnormal; Alanine aminotransferase increased; Alcoholic seizure; Allergic bronchopulmonary mycosis; Allergic oedema; Alloimmune hepatitis; Alopecia areata; Alpers disease; Alveolar proteinosis; Ammonia abnormal; Ammonia increased; Amniotic cavity infection; Amygdalohippocampectomy; Amyloid arthropathy; Amyloidosis; Amyloidosis senile; Anaphylactic reaction; Anaphylactic shock; Anaphylactic transfusion reaction; Anaphylactoid reaction; Anaphylactoid shock; Anaphylactoid syndrome of pregnancy; Angioedema; Angiopathic neuropathy; Ankylosing spondylitis; Anosmia; Antiacetylcholine receptor antibody positive; Anti-actin antibody positive; Anti-aquaporin-4 antibody positive; Anti-basal ganglia antibody positive; Anti-cyclic citrullinated peptide antibody positive; Anti-epithelial antibody positive; Anti-erythrocyte antibody positive; Anti-exosome complex antibody positive; Anti-GAD antibody negative; Anti-GAD antibody positive; Anti-ganglioside antibody positive; Antigliadin antibody positive; Anti-glomerular basement membrane antibody positive; Anti-glomerular basement membrane disease; Anti-glycyl-tRNA synthetase antibody positive; Anti-HLA antibody test positive; Anti-IA2 antibody positive; Anti-insulin antibody

increased; Anti-insulin antibody positive; Anti-insulin receptor antibody increased; Anti-insulin receptor antibody positive; Anti-interferon antibody negative; Anti-interferon antibody

positive; Anti-islet cell antibody positive; Antimitochondrial antibody positive; Anti-muscle specific kinase antibody positive; Anti-myelin-associated glycoprotein antibodies positive; Anti-myelin-associated glycoprotein associated polyneuropathy; Antimyocardial antibody positive; Anti-neuronal antibody positive; Antineutrophil cytoplasmic antibody increased; Antineutrophil cytoplasmic antibody positive; Anti-neutrophil cytoplasmic

antibody positive vasculitis; Anti-NMDA antibody positive; Antinuclear antibody

increased; Antinuclear antibody positive; Antiphospholipid antibodies

positive; Antiphospholipid syndrome; Anti-platelet antibody positive; Anti-prothrombin antibody positive; Antiribosomal P antibody positive; Anti-RNA polymerase III antibody

positive; Anti-saccharomyces cerevisiae antibody test positive; Anti-sperm antibody

positive; Anti-SRP antibody positive; Antisynthetase syndrome; Anti-thyroid antibody

positive; Anti-transglutaminase antibody increased; Anti-VGCC antibody positive; Anti-

VGKC antibody positive; Anti-vimentin antibody positive; Antiviral prophylaxis; Antiviral treatment; Anti-zinc transporter 8 antibody positive; Aortic embolus; Aortic thrombosis; Aortitis; Aplasia pure red cell; Aplastic anaemia; Application site thrombosis; Application site vasculitis; Arrhythmia; Arterial bypass occlusion; Arterial bypass thrombosis; Arterial thrombosis; Arteriovenous fistula thrombosis; Arteriovenous graft site

stenosis; Arteriovenous graft thrombosis; Arteritis; Arteritis

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