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Department of Health and Human Services
Food and Drug Administration (FDA)
Center for Biologics Evaluation and Research (CBER)
Office of Biostatistics and Pharmacovigilance (OBPV)
Division of Pharmacovigilance (DPV)
PHARMACOVIGILANCE PLAN REVIEW MEMORANDUM
From: Deborah L. Thompson, MD, MSPH
Medical Officer, Pharmacovigilance Branch 3 (PB3) DPV, OBPV, CBER, FDA To: Ramachandra Naik, PhD
Chair, Review Committee Office of Vaccines Research and Review (OVRR), CBER, FDA
Through: Manette Niu, MD
Acting Branch Chief, PB3 DPV, OBPV, CBER, FDA Narayan Nair, MD Division Director, DPV OBPV, CBER, FDA Subject: Review of Revised Pharmacovigilance Plan
Sponsor: P f i z e r
Product: COMIRNATY (Pfizer-BioNTech COVID-19 Vaccine) BLA Number: 125742.45 Proposed Indication: Active immunization to prevent COVID-19 disease caused by SARS-CoV-2 in individuals 12 years of age.
Submission Date: December 16, 2021
Action Due Date: June 17, 2022 Deborah L.
Thompson -SDigitally signed by
Deborah L. Thompson -S
Date: 2022.05.06 09:12:56 -04'00'
Manette
T. Niu -SDigitally signed by Manette T. Niu -S Date: 2022.05.06 09:35:48 -04'00'
Narayan Nair -SDigitally signed by Narayan Nair -S Date: 2022.05.06 13:54:25 -04'00'
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1 Objective and Scope
The purpose of this review is to assess the adequacy of the sponsor’s revised pharmacovigilance plan (PVP) submitted under BLA supplement 125742/45, which proposes to extend use of Comirnaty to individuals 12 years of age and older (from the current 16 years and older licensed indication). This review provides recommendations for post-approval safety monitoring for use of Comirnaty in individuals 12 years of age and older, should it be approved, and identifies potential safety issues associated with the use of the vaccine in individuals 12 years of age and older that may need to be addressed through additional pharmacovigilance activities including postmarketing safety-related studies. 2 Product Information 2.1 Product Description Comirnaty* contains a nucleoside-modified messenger RNA (modRNA; 30 mcg per dose) that encodes the viral spike (S) glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is a PBS Sucrose formulation (purple cap) that must be diluted with 1.8 mL of sterile 0.9% Sodium Chloride Injection, USP prior to use to form the vaccine. Each 0.3 ml dose includes the following ingredients: lipids ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol), potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate dihydrate, and sucrose. There is also a Tris Sucrose formulation (gray cap; not diluted prior to use) in which the formulation buffer has been changed from phosphate buffered saline to Tris buffer without sodium chloride and potassium chloride while maintaining the same target pH. Excipients for the 30-mcg dose are ALC-0315, ALC-0159, DSPC, cholesterol, trometamol, trometamol hydrochloride, and sucrose. In addition, there is a Tris Sucrose product formulation that contains 10 mcg modRNA per dose for individuals 5 to 11 years of age. The Tris Sucrose formulation (10 mcg modRNA) for individuals 5 to 11 years of age is not interchangeable with Comirnaty or Pfizer-BioNTech COVID-19 Vaccine for ages 12 years and older. *Note: For purposes of this memo, Comirnaty is used interchangeably with Pfizer-BioNTech COVID-19 Vaccine and BNT162b2 (product used in clinical development program). 2.2 Indication and Dosing Regimen Comirnaty is approved for active immunization to prevent coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 in individuals 16 years of age. The vaccine is
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administered intramuscularly as a primary series of two doses (0.3 ml) given three
weeks apart. The product is currently authorized for use under an EUA for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 5 years of age and older. In addition, a third dose of the product is authorized for use under an EUA for individuals 5 years of age and older who have undergone solid organ transplant or who are diagnosed with conditions considered to have an equivalent level of immunocompromise. The EUA has also been amended to include booster doses for select populations. Reviewer comment: Please see Section 4 of this memo and the EUA letter of
authorization for additional details regarding EUA indications. 2.3 Proposed Indication The proposed BLA supplement indication for Comirnaty is active immunization to prevent COVID-19 disease caused by SARS-CoV-2 in individuals 12 years of age and older. Reviewer comment: Please see the final label submitted by the sponsor for the final
agreed upon language for the indication and dosing regimen. 3 Materials Reviewed
x Pharmacovigilance Plan, Version 1.4 (BLA 125742/45, Module 1.16, dated
December 15, 2021; received December 16, 2021)
x Pharmacovigilance Plan, Version 1.4.1, combined PVP for PBS Sucrose and Tris
Sucrose product formulations (BLA 125742/45/9, Module 1.16, dated April 29, 2022; received May 2, 2022)
x Cumulative Analysis of Post-Authorization Adverse Event Reports in Individuals
Aged Between 12 and 15 Year of Age (BLA 125742/45, Module 5.3.6, dated December 1, 2021; received December 16, 2021)
x Clinical Overview (BLA 125742/45, Module 2.5; received December 16, 2021)
x Draft Label (BLA 125742/45, Module 1.14; received December 16, 2021)
x Approval Letter for Comirnaty BLA 125742/0 (dated August 23, 2021) x Sponsor’s IR responses
o IR response regarding narratives and preferred terms (PTs) for death
reports (BLA 125742.45.3; received March 1, 2022)
o IR response regarding age eligibility for Pregnancy Registry Study (PMC
#10) (BLA 125742/45/10; received May 4, 2022)
x VAERS database and data mining
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4 Summary of Pertinent Regulatory History and Prior Marketed Experience
Pertinent regulatory history is shown in Table 1. Per the sponsor’s PVP, approximately
1,709,812,866 doses of BNT162b2 were shipped worldwide from receipt of the first temporary authorization for emergency supply on December 1, 2020 through September 30, 2021, including 270,020,505 doses shipped to the U.S. Per the sponsor’s Clinical Overview, as of December 2021, BNT162b2 (30 mcg) has received
temporary authorization for emergency use, conditional marketing authorization
approval, or full approval in >90 countries globally. As of March 8, 2022, more than 327
million doses of the Pfizer-BioNTech COVI D-19 Vaccine have been administered in the
U.S. (CDC COVID Data Tracker, accessed on March 9, 2022). Among all COVID-19
vaccines, 17,170,136 individuals aged 12-17 years have received at least one dose and 14,641,529 are fully vaccinated in the U.S. (CDC COVID Data Tracker, accessed on
March 9, 2022).
Table 1: Pertinent Regulatory History
Date Re
gulator y Action
April 29, 2020 IND for BNT162b2 became effective
July 7, 2020 Fast Track Designation granted for individuals 18 years
of age and older
December 11, 2020 EUA 27034 granted for active immunization to prevent
COVID-19 in individuals 16 years of a ge and older
May 10, 2021 FDA re-issued EUA letter to expand authorization for
use in individuals 12 through 15 years of age with
addition of following warning in Fact Sheet for
Healthcare Providers: “Syncope (fainting) may occur in association with administration of injectable vaccines, in particular adolescents. Procedures should be in place to avoid in
jury from faintin g.”
June 25, 2021 EUA Fact Sheet revised to add Warnings for myocarditis
and pericarditis following use of Pfizer-BioNTech COVID-19 Vaccine
August 12, 2021 EUA granted for third dose of BNT162b2 for individuals
12 years of age and older who have undergone solid organ transplant or who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise
August 23, 2021 Approval of original BLA 125742/0 for use of Comirnaty
in individuals aged 16 years and older which included safety related postmarketing requirements (PMRs # 4 - 9) for evaluation of the serious risks of myocarditis and pericarditis, and subclinical myocarditis, as well as postmarketing commitments (PMCs), including a pre
gnanc y registry stud y (C4591022, PMC #10 ) and an
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active safety surveillance study in the Veteran’s Affairs
Health S ystem (PMC #12 )
September 22, 2021 EUA granted for booster dose of Comirnaty or Pfizer-
BioNTech COVID-19 Vaccine at least six months after completing the primary series of this vaccine in individuals: 65 years of age and older; 18 through 64 years of age at high risk of severe COVID-19; and 18 through 64 years of age with frequent institutional or occupational exposure to SARS-CoV-2
October 20, 2021 EUA Letter of Authorization (LOA) clarified eligibility for
a booster dose of Comirnaty or Pfizer-BioNTech COVID-19 Vaccine and authorized administration of a single booster dose of Pfizer-BioNTech COVID-19 Vaccine as a heterologous booster dose following completion of primary vaccination with another authorized COVID-19 Vaccine
October 29, 2021 EUA expanded for use of product in children 5-11 years
of age and authorized manufacturing change to include additional formulation using a Tris Sucrose buffer instead of PBS
November 19, 2021 EUA expanded use of product as a single booster dose
in individuals 18 years and older at least 6-months after completing the primary series of this vaccine
(homolo gous booster ) and as a heterolo gous booster
December 9, 2021 EUA expanded use of product as a single booster dose
in individuals aged 16 and 17 years at least 6-months after completin
g the primar y series of this vaccine
December 16, 2021 BLA supplement approved to include a new 30-mcg
dose formulation of Comirnaty that uses a Tris Sucrose buffer instead of a PBS buffer
January 3, 2022 EUA LOA re-issued to authorize use of vaccine as a
single booster dose in individuals aged 12-15 years, lowered dosing interval for the homologous booster to at least 5-months after completion of the primary series, and authorized a third primary series dose of the vaccine at least 28-days following the 2-dose regimen for individuals aged 5-11 years who have undergone solid organ transplantation or who have an equivalent level of immunocompromise
March 29, 2022 EUA re-issued to authorize second booster dose to
individuals aged 50 years and older or individ XDOV
years of age with certain kinds of immunocompromise at least 4 months after receipt of the first booster dose of an
y FDA authorized or approved COVID-19 vaccine
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5 Summary of Sponsor’s Safety Database
5.1 Clinical Studies The sponsor evaluated the safety and immunogenicity of BNT162b2 among individuals 12-15 years of age in Phase 1/2/3 Study C4591001 SLYRWDO VWXG\ IRU LQGLYLGXDOV
years of age). Phase 1 was the dose finding portion of the study that evaluated dose levels for two vaccine candidates (BNT162b1 and BNT162b2) in the U.S. BNT162b2 (30 mcg dose) was selected to advance to a Phase 2/3 study which evaluated efficacy and safety of a 30 mcg two-dose series of BNT162b2 three-weeks apart and included 2264 randomized participants 12-15 years of age (1:1 randomization: 1134 vaccine recipients and 1130 saline placebo recipients; all adolescents were enrolled in the U.S.). Participants 12-15 years of age were unblinded when they became locally eligible for vaccination and wished to know their randomization status; placebo participants were offered BNT162b2 and unblinded follow-up continued for all study participants. The safety evaluation included assessment of reactogenicity and antipyretic use for 7-days after each dose via e-diary. Adverse events (AEs) were collected for up to 1-month post-dose 2 and serious AEs (SAEs) were collected for up to 6-months post-dose 2 (deaths were recorded to the end of the study). Myocarditis and pericarditis were AEs of special interest (AESIs). Cumulative safety data were reported from Dose 1 to at least
6-months after Dose 2 through the data cut-off (September 2, 2021). Follow-up will
continue for at least two years and/or end of study, except for those who enrolled in Study C4591031 for booster dose evaluation. Reviewer comment: Please see the clinical review memo for additional details regarding
the FDA clinical safety evaluation of BNT162b2 in individuals 12-15 years of age. 5.2 Adverse Events from the Clinical Safety Database The safety population included 2260 participants 12-15 years of age (1131 BNT162b2 recipients and 1129 placebo recipients; four study participants did not receive any study intervention and were excluded). For Phase 2/3, the median follow-up during the blinded placebo-controlled period was 4.4 months. From Dose 2 to the data cut-off date, most (n=740, 65.4%) of BNT162b2 group participants had a total follow-XS WLPH RI WR<10 months (blinded and unblinded). Most reactogenicity AEs were mild or moderate in severity and were self-limited. AEs from Dose 1 to unblinding were similar between BNT162b2 and placebo recipients (8.45% vs. 10.0%, respectively). The most frequently reported AEs in BNT162b2 recipients were lymphadenopathy (n=9, 0.8%), injection site pain (8, 0.7%), fatigue (8, 0.7%), pyrexia (6, 0.5%), depression (6, 0.5%), nausea (5, 0.4%), and headache (5, 0.4%). Psychiatric disorder AEs were similar between BNT162b2 and placebo recipients (1.5% vs 1.2%, respectively); depression was reported for 6 (0.5%) BNT162b2 recipients and 3 (0.3%) placebo recipients. Four study participants were hospitalized with suicidal ideation; all four were BNT162b2 recipients and had an ongoing past medical history of depression and/or anxiety. One BNT162b2 participant had an AE leading to study withdrawal (pyrexia of 40.4° C on Day 2 post-Dose 1; resolved on Day 4).
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From Dose 1 to the unblinding date, SAEs were reported for 10 (0.9%) BNT162b2 recipients (n=1131) and 2 (0.2%) placebo recipients (n=1129); there were no deaths reported. None of the SAEs were considered related to the product by study investigators. PTs reported for the SAEs among the 10 BNT162b2 recipients included suicidal ideation (n=4, 0.4%), depression (3, 0.3%), and one (0.1%) each of conversion disorder, anxiety, abdominal pain, constipation, anal abscess, and femur fracture. PTs reported for the SAEs among the 2 placebo recipients included appendicitis (n=2, 0.2%) and focal peritonitis (n=1, 0.1%). Multiple PTs could be reported for any individual subject. Among participants who originally received placebo and then received BNT162b2 after unblinding (n=1010) there were 6 (0.6%) participants who experienced SAEs from Dose 3 (first dose of BNT162b2) to the data cut-off. One participant experienced an SAE considered related to the product by study investigators (appendicitis on Day 4 after Dose 4 [Dose 2 of BNT162b2]). In addition, there was one SAE of myocarditis which occurred in a 16-year-old male who experienced chest pain on Day 3 after Dose 4 (2
nd
dose BNT162b2). This individual had a one-week history of fever, cough, rhinorrhea; a respiratory virus panel was PCR positive for rhinovirus (SARS-CoV-2 RNA PCR was negative). His chest pain resolved within 24-hours of receiving ketorolac and he was discharged home after 2-days of hospitalization; cardiology follow-up indicated that the condition had resolved. The study investigator did not consider the event related to the study intervention, although the sponsor commented that they consider it a reasonable possibility that the myocarditis event was related to BNT162b2 considering the prior reports of myocarditis/pericarditis among recipients of mRNA vaccines. Other SAEs among participants who originally received placebo and then received BNT162b2 after unblinding included one event each of traumatic renal injury, epilepsy, somnolence, and major depression; none of these SAEs were considered related to BNT162b2 by study investigators. No deaths were reported. Among other AEs of interest, lymphadenopathy was reported in nine BNT162b2 participants and two placebo participants during the blinded placebo-controlled follow-up period; events were mild or moderate in severity and most occurred in the arm and neck region. No cases of anaphylaxis, hyper sensitivity, or Bell’s palsy were reported
during the blinded placebo-controlled period. As of the data cut-off, there were no thromboembolic or intravascular coagulation events, autoimmune or demyelination events, meningitis, encephalitis, optic neuritis, Kawasaki’s disease, severe COVID-19 infection, multisystem inflammatory syndrome in children (MIS-C), or acute respiratory
distress syndrome events. Reviewer comment: Lymphadenopathy and myocarditis/pericarditis are labeled events.
Review of the sponsor’s clinical trial safety data among children 12-15 years of age did not reveal new safety concerns that need to be addressed in the PVP.
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5.3 Review of Sponsor’s Cumulative Analysis of Post-Authorization Adverse
Event Reports for Individuals Aged 12-15 Years
The sponsor submitted a cumulative analysis of post-authorization AE reports from the Pfizer global safety database for BNT162b2 among individuals aged 12-15 years (received through September 30, 2021). Among 629,525 total reports, there were a total of 3,320 (1,606 U.S.) reports concerning individuals 12-15 years of age, including 1,215 (36.6%) serious reports (259 U.S.) of which 18 (0.5%) were death reports (5 U.S.). Among all reports, there was a total of 10,050 AEs reported among individuals 12-15 years of age; the most frequently reported PTs (>5%) were pyrexia (17.4%), headache (15.7%), fatigue (10.4%), poor quality product administered (8.3%), nausea (8.1%), pain in extremity (6.8%), vomiting (5.9%), malais e (5.7%), dizziness (5.5%), and chest pain
(5.4%). The 5 U.S. death reports are summarized as follows:
x A columnist reported that a 13-year-old male experienced sudden death post-
dose 2
x 13-year-old male died 3-days post-dose 2; report indicated that the autopsy
result showed
x 13-year-old male died in his sleep 3-days post-dose 2; autopsy being performed,
and it was reported that information was being sent to CDC
x Reporter read a media headline that a 13-year-old (might have been a boy) died
in his sleep following an unknown dose of the Pfizer vaccine and that CDC was investigating
x 13-year-old female died of unknown cause post-dose 2
Reviewer comment: The five U.S. death reports received by the sponsor contained
limited clinical details. Four of the five reports seem to refer to the same unique 13-year-old male,
Review of the 13 foreign death reports, revealed that 10 reports contained limited clinical details with unknown/unclear causes of death. Two reports indicated septic shock in patients with multiple co-morbidities, including one report of an individual who experienced status epilepticus, multiorgan failure, pulmonary hemorrhage, and disseminated intravascular coagulation (DIC). One additional report concerned a 15-year-old female with a history of asthma, Barlow’s syndrome (i.e., mitral valve prolapse), and Marfan’s syndrome who experienced cardiac arrest and cerebral anoxia; cardiac MRI favored Takotsubo, and the report indicated that myocarditis was unlikely with infective and immunological work-up negative. This individual also had a positive
(b) (6)
(b) (6)
(b) (6)
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COVID-19 serology (anti-S, anti-N, and IgM), and the report mentioned a COVID-19
infection starting at the same time as vaccination; autopsy was not performed.
Among risks identified in the PVP, the sponsor’s search of the safety database through September 30, 2021 found 43 (1.3%; 8 U.S. reports) reports of anaphylactic reaction/shock (PVP: important identified risk) or anaphylactoid reaction/shock among individuals 12-15 years of age; all were serious events and there were no fatal events. No events were considered to be Vaccine-Associated Enhanced Disease (VAED), including Vaccine-Associated Enhanced Respiratory Disease (VAERD) (PVP: important potential risk) among individuals 12-15 years.
There were 180 reports of myocarditis and pericarditis (PVP: important identified risk) among individuals aged 12-15 years, including 154 (4.6%) reports of myocarditis and 61 (1.2%) reports of pericarditis (35 reports involved patients with both myocarditis and pericarditis). Among the 154 reports of myocarditis (26 U.S. reports), almost all (n=153, 99.4%) were serious; none reported a fatal outcome. The majority of reports were for males (n=131); the median age of patients was 14 years (range=12-15 years). Most cases occurred after the 2
nd dose (n=106, 68.8%); 36 (23.4%) cases occurred after the
1st dose and 12 (7.8%) cases occurred after an unknown dose. Time to onset was
reported for 108 cases; most events (n=101, 93.5%) occurred within 14-days post-vaccination. Most events had an outcome of resolved/resolving (n=79, 51.3%); 17 (11.0%) events were not resolved at the time of the report, and 58 (37.7%) events had an unknown outcome. Fourteen reports were classified by the sponsor as Brighton Collaboration (BC; version 1.5.0, July 16, 2021) level 1 (definitive case), nine were BC level 2 (probable case), 130 were BC level 4 (reported event but insufficient evidence to meet case definition), and one was BC level 5 (not a case). Among the 61 (1.2%) reports of pericarditis (4 U.S. reports), all were serious (no deaths). The majority of reports were for males (n=48, 78.7%); the median age of patients was 14 years (range=12-15 years). Most cases occurred after the 2
nd dose
(n=38, 62.3%); 14 (23.0%) cases occurred after the 1st dose and 9 (14.8%) cases
occurred after an unknown dose. Time to onset was reported for 32 cases; most events (n=28, 87.5%) occurred within 14-days post-vaccination. The outcome was unknown for most events (n=33, 54.1%); 18 (29.5%) events had an outcome of resolved/resolving, 1 (1.6%) event was resolved with sequelae, and 9 (14.8%) events were not resolved at the time of reporting. One report was classified by the sponsor as BC level 1 (BC version 1.0.0, July 15, 2021), four were BC level 2, and 56 were BC level 4. Among areas of the PVP considered as “Missing Information” (use of product in pregnancy/lactation, vaccine effectiveness, and use in pediatric individuals <5 years of age) there was one report concerning use of the product in pregnancy/lactation among individuals aged 12-15 years. This foreign report concerned a 12-year-old patient who experienced a miscarriage two weeks post-1
st dose. Regarding lack of vaccine
effectiveness, there were 29 reports (14 U.S. reports) among individuals 12-15 years of age, including 20 reports (19 serious) with the PT drug ineffective and 9 reports (all serious) with the PT vaccination failure; none were death reports.
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Among individuals <5 years of age (PVP: missing information), there were 56 reports (13 U.S. reports) including 14 (25.0%) serious reports; two (3.6%) reports included fatal outcomes. The two fatal reports were both foreign reports with limited information: one report of a 5-month-old male who died 15-days after his first dose and one report of a 2-year-old female who had been hospitalized since February 14, 2021, received her 2
nd
dose on February 25, 2021, and subsequently died on March 3, 2021. The most frequently reported PTs in the <5-year age group were product administered to patient of inappropriate age (n=21), off label use (n=17), product use issue (n=15), pyrexia (n=11), and fatigue, headache, myalgia, and nausea (n=4 each). Reviewer comment: Review of data from the sponsor’s safety database for individuals
12-15 years of age did not reveal new safety concerns that need to be addressed in the PVP. 6 Summary of FDA Post-Authorization Safety Data 6.1 Vaccine Adverse Event Reporting System (VAERS) Data
The Vaccine Adverse Event Reporting System (VAERS) was queried for AE reports following the Pfizer-BioNTech COVID-19 Vaccine, and the results are summarized below. Spontaneous surveillance systems su ch as VAERS are subject to many
limitations, including underreporting, stimulated reporting, variable report quality and accuracy, inadequate data regarding the numbers of doses administered, and lack of direct and unbiased comparison groups. Reports in VAERS may not be medically confirmed and are not verified by FDA. Also, there is no certainty that the reported event
was actually due to the vaccine.
As of March 9, 2022, VAERS received 676,758 reports (including 363,690 U.S. reports) for the Pfizer-BioNTech COVID-19 Vaccine, of which 8,971 U.S. reports were in children 5-11 years of age, 14,229 U.S. reports were in children 12-15 years of age, and 7,742 U.S. reports were in children 16-17 years of age. Among the 14,229 U.S. reports for children 12-15 years of age, 1,357 were non-fatal serious and 23 were death reports. Reviewer comment: The 23 death reports concerned 18 unique individuals. All death
reports were individually reviewed. There were four unique death reports that included
PTs for myocarditis/pericarditis; these reports are summarized in the myocarditis and
pericarditis section below. The other 14 unique death reports were reviewed to form a clinical impression of the event described in the report. For some reports there were limited clinical details provided with no additional medical records or autopsy reports available at the time of review. Clinical impressions of the events are summarized as follows: ruptured cerebral aneurysm (2), suicide (1), COVID-19 pneumonia (1), bilateral pulmonary emboli (described as “air bubbles not DVT”) (1), epithelioid sarcoma (1),
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acute intracerebral hemorrhage due to chronic small vessel vasculopathy of brain in
individual with Trisomy 18 (1), sudden death in individual with epilepsy and congenital microcephaly (1), unknown (1), static encephalopathy with intractable seizures and possible sepsis in individual with neuromuscular disorder and tracheostomy (1), hypertrophic cardiomyopathy in individual with recent COVID-19 infection (1), brainstem herniation from intracranial hemorrhage in individual positive for COVID-19 (1), stress
cardiomyopathy (1), and heart failure (1).
The above individual with was a 15-year-old male with
acne who experienced and then was
within 48 hours of his 2
nd dose of the Pfizer-BioNTech COVID-19
vaccine (VAERS #1382906).
The autopsy
report indicated and
The autopsy report
VAERS queries were run using the PT Report, which showed the top ten most frequently reported MedDRA PTs to be as follows (Note: A report may have one or more PTs; queries run on March 9, 2022):
x Most frequent PTs among all ages: SARS-CoV-2 test, headache, fatigue,
pyrexia, dizziness, pain, COVID-19, nausea, chills, and pain in extremity
x Most frequent PTs among individuals 17 years of age: dizziness, headache,
pyrexia, syncope, nausea, product administered to patient of inappropriate age, chest pain, fatigue, vomiting, and product storage error
x Most frequent PTs among individuals 12-15 years of age: dizziness, pyrexia,
headache, syncope, nausea, chest pain, product storage error, fatigue, vomiting, and product administered to patient of inappropriate age.
Reviewer comment: The most frequently reported PTs, including among individuals 12-
15 years of age, concern labeled events, PTs related to labeled events, product storage
or use issues, non-specific symptoms, or COVID-19 diagnosis/testing. The label contains instructions for storage/handling, product preparation, and administration. Review of the most frequently reported PTs did not identify new safety concerns.
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
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In addition, safety concerns identified from post-authorization safety surveillance data in
VAERS are summarized below. Anaphylaxis, myocarditis, and pericarditis are existing
safety concerns that are labeled events. Anaphylaxis: Post-authorization surveillance identified a risk of anaphylaxis, occurring at a rate
similar to reported rates of anaphylaxis following licensed preventive vaccines, primarily
in individuals with history of prior severe allergic reactions to other medications or foods.
1,2 Anaphylaxis is an important identified risk in the PVP and is included in the
label (Section 4 Contraindications, Section 5 Warnings and Precautions, 5.1 Management of Acute Allergic Reactions, Section 6.2 Postmarketing Experience). An automated VAERS query run on March 9, 2022 (which includes cases for which diagnosis and outcomes were not confirmed) for the PTs anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, and anaphylactoid shock returned a total of 7,582 reports, including 6,721 non-fatal serious reports and 58 death reports. Among U.S. reports, there have been a total of 1,589 reports, including 773 non-fatal serious
reports and 16 death reports. Among U.S. children aged 12-15 years, there were 43
total reports of anaphylactic/anaphylactoid reaction, including 14 non-fatal serious reports (no deaths). The estimated crude reporting rate for anaphylaxis after receipt of Pfizer-BioNTech COVID-19 vaccination among all ages in the U.S. is 4.9 cases per million doses administered based on the above VAERS data and 327,525,429 doses of Pfizer-BioNTech COVID-19 Vaccine administered among all ages in the U.S ( CDC
COVID Data Tracker , accessed on March 9, 2022). The estimated rate of anaphylaxis
following Pfizer-BioNTech COVID-19 vaccination is similar to estimated rates for other vaccines, including any influenza vaccine (1.53 cases per million doses), any tetanus diphtheria acellular pertussis vaccine (2 .07 cases per million doses), and measles
mumps rubella vaccine (5.14 cases per million doses).
3
Myocarditis and pericarditis :
Post-EUA safety surveillance reports received by FDA and CDC identified increased rates of myocarditis and pericarditis, particularly within 7 days following administration of the second dose of the 2-dose primary series. Reporting rates for medical chart-confirmed (i.e., verified to meet CDC case definition) myocarditis and pericarditis in VAERS have been higher among males under 40 years of age than among females and older males and have been highest in males 12 through 17 years of age (~70.2 verified cases per million doses within 7-days following dose 2 administration among males
ages 16-17 years and 45.7 verified cases per million doses within 7-days following dose
2 among males ages 12-15 years as per CDC presentation to the ACIP on January 5,
2022). Although some cases of vaccine-associated myocarditis/pericarditis have required intensive care support, available data from short-term follow-up suggest that most
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individuals have had resolution of symptoms with conservative management.
Information is not yet available about potential long-term sequelae and outcomes in affected individuals, or whether the vaccine might be associated initially with subclinical myocarditis (and if so, what are the long-term sequelae). A mechanism of action by which the vaccine could cause myocarditis and pericarditis has not been established.
Reviewer comment: CDC is conducting enhanc ed surveillance for VAERS case reports
using patient and healthcare provider survey s to assess functional status and clinical
outcomes among individuals reported to have developed myocarditis after mRNA
COVID-19 vaccination. Surveys are conducted at least 90 days after the onset of myocarditis symptoms. Preliminary data from this surveillance showed that among individuals aged 12-29 years who completed the survey (approximately 360 individuals), most reported no impact on their quality of life (measures included ability to perform
self-care and usual activities, mobility, pain, and anxiousness or depression) and did not report missing school or work (presented at ACIP meeting on February 4, 2022). Thirteen (4%) patients reported readmission to the hospital, including 8 of 13 (62%)
patients who were readmitted because of a concern with the heart. Seventy-one (20%)
patients were prescribed medication for their heart as of their last appointment with the provider. Among the healthcare providers who completed the survey (n=380), most (81%) indicated the patient was probably fully or fully recovered. There were no known vaccine-associated myocardi tis deaths. CDC has ongoing efforts to continue patient
follow-up and contact patients with myocarditis who were not yet recovered at the time of the survey. Myocarditis and pericarditis were added as important identified risks in the PVP and included in the label (Section 5 Warnings and Precautions, 5.2 Myocarditis and Pericarditis, Section 6.2 Postmarketing Experience). The Sponsor is conducting
additional post-author ization/postmarketing studies to assess known serious risks of
myocarditis and pericarditis as well as to identify an unexpected serious risk of
subclinical myocarditis. As of March 9, 2022, based on automated search of VAERS
(which includes cases for which diagnosis and outcomes were not confirmed), there have been a total of 15,932 reports of myocarditis and pericarditis (3,071 U.S.) following vaccination with the Pfizer-BioNTech COVID-19 Vaccine reported to VAERS, including 14,967 non-fatal serious reports (2,281 U.S.) and 206 death reports (53 U.S.). PTs included in the automated VAERS query were as follows: autoimmune myocarditis, autoimmune pericarditis, eosinophilic myocardi tis, hypersensitivity myocarditis, immune-
mediated myocarditis, myocarditis, pericarditis, pericarditis adhesive, pericarditis
constrictive, and pleuropericarditis.
Among individuals 12-15 years of age, summary statistics for U.S. VAERS reports of myocarditis/pericarditis following administration of the Pfizer-BioNTech COVID-19 Vaccine are as follows:
FDA-CBER-2022-5812-0500430
14
x 528 total U.S. reports, including 445 (84.2%) serious and 5 (0.9%) death reports
x 465 (88.1%) male and 63 (11.9%) female x Median age=14 years (range=12-15 years)
x Median onset post-vaccination=2 days* (range=0-238 days)
x 478 (90.5%) events occurred within a 0-7 day* risk window post-vaccination x By dose number: Dose 1=83 (15.7%) reports; Dose 2=354 (67.0%) reports; Dose
3=25 (4.7%) reports; Unknown/Missing Dose= 66 (12.5%) reports
*Based on calculated VAERS dates.
U.S. VAERS reports of myocarditis/pericarditis following the Pfizer-BioNTech COVID-19 Vaccine with an outcome of death among individuals 12-15 years of age (n=5 reports for 4 unique individuals) are summarized below:
x 1406840 (U.S.): 13-year-old male with past medical history (PMH) of
and then was found deceased 3-days post-dose 2. Autopsy report findings
Reviewer Comment:
Based on the
in
formation available in VAERS, it appears likely this individual died from
x 1505250 (U.S.): 13-year-old female with history of asthma,
experienced
EMS arrived and
cardioverted the individual who became responsive and started answering
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
FDA-CBER-2022-5812-0500431
15
questions; she subsequently experienced ventricular tachycardia, pulseless
ventricular tachycardia, and pulseless electrical activity and died
She had taken one dose of Dramamine the evening prior to the event.
The autopsy reported cause of death was
COVID-19 PCR testing was negative.
Reviewer Comment:
x 176
4974 (U.S.): 15-year-old male with PMH of experienced brief
unilateral shoulder pain 5-days post-dose 2; no chest pain, shortness of breath, or palpitations. The individual was swinging from a rope swing at a pond, flipping in the air, and landing in the water feet first. Individual surfaced, laughed, told his friends "Wow, that hurt!", then swam toward shore, underwater as was his usual routine; he did not re-emerge, and his body was retrieved by local authorities more than an hour later. He died 6-days post-dose 2. Autopsy report pertinent findings included the following:
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
FDA-CBER-2022-5812-0500432
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This
case was also sent for evaluation with
Hospital. Their report indicated
Reviewer Comment: This individual died from
This case had three independent
autop
sy evaluations. Autopsy findings noted
One autopsy evaluation indicated
x 1446789 (U.S.): 15-year-old male with PMH of autism, ADHD,
experienced coughing that began just prior to dose 2; he
was seen by his primary care provider 6-days post-dose 2 and chest x-ray showed fluid in the lungs and possible pneumonia. He did not improve on albuterol and antibiotics and subsequently developed decreased appetite, decreased urine output, a couple of episodes of post-tussive emesis with blood-tinged secretions, abdominal pain, increased coughing, and shortness of breath. He did not have a fever or rash. He fell and hit his head on a wall, couldn’t breathe, and was taken to the ED. He experienced cardiac arrest ×2 at the
hospital and was resuscitated, intubated and air transported to another hospital
for further care.
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
FDA-CBER-2022-5812-0500433
17
a
nd he died approximately 2.5 months after hospitalization.
Reviewer Comment: This individual with a history of autism, ADHD,
experienced acute decompensated heart failure with a
comp
licated hospital course. His symptoms began just prior to Pfizer-BioNTech
COVID-19 vaccine dose 2; noted that
He was evaluated for an
findings on autopsy included
Review of the above VAERS data, as well as ongoing review of VAERS data and the
sponsor’s periodic safety reports, did not identify new safety concerns among
individuals aged 12-15 years. Most AEs are labeled events, including anaphylaxis and myocarditis/pericarditis, and consistent with the known safety profile for this vaccine. No unusual frequency, clusters, or other trends for AEs were identified that would suggest a new safety concern.
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
(b) (6)
FDA-CBER-2022-5812-0500434
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6.2 Data Mining Findings
Data mining of the VAERS database using Empirica Signal1 with a data lock point of
March 4, 2022, revealed the following PTs and subgroups had an increased
disproportional reporting value (EB05 2) for the Pfizer-BioNTech COVID-19 Vaccine
(Table 2): Table 2: Preferred Terms with Disproportional Reporting in Empirica Signal for the Pfizer-BioNTech COVID-19 Vaccine
Preferred Term (PT) U.S.
EB05 U.S. Infant
(0-23.9
months)
EB05 U.S. Adult
65 years
EB05 U.S.
Female
EB05
Body height 2.17
Disease recurrence 2.05
Drug ineffective 2.29
Exposure via breast milk 17.41
Immunisation 2.24
Investi gation 2.16 2.25 2.04
Product preparation issue 2.18
Weight 2.02 2.13
Reviewer comment: There were no PTs with disproportionate reporting among children
(age 2-8.9 years) or teens (standard Empirica run for ages 9-18.9 years). Review of PTs
with an EB05 2 did not identify new safety concerns.
Reports concerning the PTs “body height” and “weight” generally refer to patient body measurements provided in VAERS reports or changes in weight/height. The PT
“investigation” is non-specific and generally refers to investigations performed as part of a work-up for signs or symptoms and does not represent an adverse event. Similarly, the PT “immunisation” refers to the patient having been immunized and does not represent an adverse event. The PT “product preparation issue” generally concerns reports with issues such as incorrect vaccine reconstitution or lack of reconstitution with
diluent and may not be associated with an adverse event.
1 Empirica Signal is a web-based platform that uses an automated approach to explore relationships in large datasets
by generating statistical scores for combinations of products and events from drug or vaccine databases. Data mining
is conducted to evaluate whether any events (i.e., MedDRA PTs) following use of a particular vaccine are
disproportionally reported compared to all vaccine reports in VAERS; the threshold for signal detection is an EB05 value 2. (EBO5 is the lower bound of the 90% confidence limit for the Empirical Bayesian Geometric Mean). The
data generated from Empirica Signal do not, by themselves, demonstrate causal associations, but the data might
serve as a signal for further investigation and can be useful for hypothesis generation and exploration of potential
concerns.
FDA-CBER-2022-5812-0500435
19
A cumulative VAERS query run on March 10, 2022 for “disease recurrence” following
the Pfizer-BioNTech COVID-19 Vaccine returned 2,647 total reports (289 U.S. reports). Among the 289 U.S. reports, 147 (50.9%) were non-fatal serious reports and 3 (1.0%) were death reports. Three U.S. reports (all non-fatal serious) concerned individuals 12-15 years of age. One report was regarding a 12-year-old male with a history of atrial fibrillation and AV node ablation procedure who experienced recurrence of heart rhythm
irregularity that began 9-days post-2
nd dose and was treated with metoprolol. Another
report concerned a 12-year-old female with “generally well-controlled epilepsy” (last
seizure 2020) who experienced status epilepticus starting 31 hours post-2nd dose; the
individual had symptoms of headache, fatigue, myalgias , and chills for approximately 16
hours before seizures began and was febrile to 101°F at time of arrival to the hospital. The third report was regarding a 13-year-old male with a history of epistaxis who experienced epistaxis, dizziness, and headache the same day post-1
st dose.
Use of the product during pregnancy and lactation is considered an area of “missing information” in the PVP that will additionally be monitored through post-authorization
safety studies, including a PMC Pregnancy Registry study. Review of VAERS data has not suggested patterns concerning for safety issues during pregnancy and lactation. Vaccine effectiveness is also an area considered as “missing information” in the PVP and is monitored through clinical trials, and post-authorization studies conducted by the sponsor.
7 Pharmacovigilance Plan 7.1 Summary of Pharmacovigilance Plan
The sponsor submitted a revised PVP (Version 1.4.1) which continues to include routine
pharmacovigilance, risk communication, and postmarketing observational and active surveillance safety studies (Table 3). There are also ongoing clinical trials. Table 3: Summary of Safety Concerns a nd Planned Pharmacovigilance Activities*
Safet
y Concern Actions Proposed
Important Identified Risks
Anaphylaxis x Communication of this important identified risk via
label (Sections 4 - Contraindications, 5.1 -
Management of Acute Allergic Reactions, Section
6.2 – Postmarketing Experience).
x C4591001: Phase 1/2/3, placebo-controlled,
randomized, observer-blind, dose-finding study to
evaluate the safety, tolerability, immunogenicity, and efficacy of SARS-CoV-2 RNA vaccine candidates against COVID-19 in healthy individuals.
x C4591009: A non-interventional post-approval
FDA-CBER-2022-5812-0500436
20
safety study of the Pfizer--BioNTech COVID-
19 vaccine in the United States.
x C4591011: Active safety surveillance of the Pfizer-
BioNTech COVID-19 Vaccine in the U.S.
Department of Defense population following Emergency Use Authorization.
x C4591012: Post-emergency use authorization
active safety surveillance study among individuals in the Veteran’s Affairs Health System receiving Pfizer-BioNTech Coronavirus Disease 2019 (COVID-19) Vaccine.
x C4591021: Post Conditional approval active
surveillance study among individuals in Europe receiving the Pfizer BioNTech Coronavirus Disease 2019 (COVID-19) vaccine.
Myocarditis and Pericarditis x Communication of this important identified risk via
label (Section 5.2 - Myocarditis and Pericarditis,
Section 6.2 - Postmarketing Experience).
x C4591009: A non-interventional post-approval
safety study of the Pfizer -BioNTech COVID-19
vaccine in the United States.
x C4591011: Active safety su rveillance of the Pfizer-
BioNTech COVID-19 Vaccine in the U.S. Department of Defense population following Emergency Use Authorization.
x C4591012: Post-emergency use authorization
active safety surveillance study among individuals in the Veteran’s Affairs Health System receiving Pfizer-BioNTech Coronavirus Disease 2019 (COVID-19) Vaccine.
x C4591021: Post Conditional approval active
surveillance study among individuals in Europe receiving the Pfizer BioNTech Coronavirus Disease 2019 (COVID-19) vaccine.
x C4591038 (formerly C4591021 substudy): Post
Conditional approval active surveillance study among individuals in Europe receiving the Pfizer-BioNTech Coronavirus Disease 2019 (COVID-19) Vaccine. Substudy to investigate natural history of post-vaccination myocarditis and pericarditis.
x C4591036: Pediatric Heart Network Study: Low
interventional cohort study of myocarditis associated with Comirnaty in persons less than 21 years of age.
x C4591031 substud
y B: A randomized, placebo-
FDA-CBER-2022-5812-0500437
21
controlled, observer-blind cross-over substudy to
evaluate the safety and tolerability of a booster WKLUG GRVH RI %17E 3DUWLFLSDQWV \HDUVRI DJH WR 30 years of age who have completed a
2-dose primary series of BNT162b2 (30 mcg doses) DW OHDVW PRQWKV PRQWKV IRU WKRVH -17 years
of age) prior to randomization will be enrolled.
x C4591007 substudy – Troponin group: A Phase 3
substudy of 750 participants 5 to <12 years of age (randomized 2:1 to receive BNT162b2 10 μg or
placebo) and 500 participants 12-<16 years of age
(open label receipt of BNT162b2 30 μg).
Important Potential Risks
Vaccine-Associated Enhanced Disease (VAED), including Vaccine-Associated Enhanced Respiratory Disease (VAERD) x C4591001: Phase 1/2/3, placebo-controlled,
randomized, observer-blind, dose-finding study to
evaluate the safety, tolerability, immunogenicity, and efficacy of SARS-CoV-2 RNA vaccine candidates against COVID-19 in healthy individuals.
x C4591008: HERO Together: A post-Emergency
Use Authorization observational cohort study to evaluate the safety of the Pfizer-BioNTech COVID-19 Vaccine in U.S. healthcare workers, their families, and their communities.
x C4591009: A non-interventional post-
approval safety study of the Pfizer--
BioNTech COVID-19 vaccine in the United States.
x C4591011: Active safety surveillance of the
Pfizer--BioNTech COVID-19 vaccine in the U.S.
Department of Defense population following
Emergency Use Authorization.
x C4591012: Post-emergency use authorization active
safety surveillance study among individuals in the
Veteran’s Affairs Health System receiving Pfizer--BioNTech Coronavirus Disease 2019 (COVID-19) vaccine.
x C4591021: Post Conditional approval active
surveillance study among individuals in
Europe receiving the Pfizer BioNTech
Coronavirus Disease 2019 (COVID-19)
vaccine.
Missin g Information
Use in pregnancy and
lactation x C4591015: A phase 2/3, placebo-controlled,
randomized, observer blind study to evaluate the
FDA-CBER-2022-5812-0500438
22
safety, tolerability, and immunogenicity of a SARS-
CoV-2 RNA vaccine candidate (BNT162b2) against COVID-19 in healthy pregnant women 18 years of age and older.
x C4591009: A non-interventional post-
approval safety study of the Pfizer--
BioNTech COVID-19 vaccine in the United States.
x C4591011: Active safety surveillance of the
Pfizer-BioNTech COVID-19 Vaccine in the U.S.
Department of Defense population following Emergency Use Authorization.
x C4591021: Post Conditional approval active
surveillance study among individuals in Europe receiving the Pfizer BioNTech Coronavirus Disease 2019 (COVID-19) vaccine.
x C4591022: Pfizer-BioNTech COVID-19 Vaccine
exposure during pregnancy: A non-interventional post-approval safety study of pregnancy and infant outcomes in the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy Registry.
Vaccine effectiveness
x C4591014: Pfizer-BioNTech COVID-19
BNT162b2 Vaccine Effectiveness Study - Kaiser Permanente Southern California.
x WI235284: Determining RSV Burden and
Outcomes in Pregnant Women and Older Adults
Requiring Hospitalization. COVID-19 Amendment for COVID VE/ Sub-study 6.
x WI255886: Avon Community Acquired
Pneumonia Surveillance Study: A Pan-pandemic
Acute Lower Respiratory Tract Disease Surveillance Study.
x BNT162-01 cohort 13: Immunogenicity of Pfizer-
BioNTech COVID-19 Vaccine in
immunocompromised subjects, including assessment of antibody responses and cell-mediated responses.
x C4591007 substudy – Lower dose evaluation
group: To study lower dose levels of BNT162b2 in individuals 12 through <18 years of age.
Use in pediatric individuals
<5 years of age Actions proposed in the PVP that are inclusive
of individuals <5 years of age include†:
x C4591007: Lower dose evaluation group:
FDA-CBER-2022-5812-0500439
23
Phase 1 open label dose-finding study to
evaluate safety, tolerability, and immunogenicity and Phase 2/3 placebo-controlled, observer blinded safety, tolerability, and immunogenicity, study of a SARS-CoV-2 RNA vaccine candidate against COVID-19 in healthy children <12 years of age.
x C4591009: A non-interventional post-
approval safety study of the Pfizer-BioNTech COVID-19 Vaccine in the United States.
x C4591021/ C 4591038 (C4591021 substudy): Post
Conditional approval active surveillance study among individuals in Europe receiving the Pfizer BioNTech Coronavirus Disease 2019 (COVID-19) vaccine. Substudy to investigate natural history of post-vaccination myocarditis and pericarditis.
x C4591023: Phase 1 open label dose-finding study
to evaluate safety, tolerability, and immunogenicity and phase 2/3 placebo-controlled, observer- blinded safety, tolerability, and immunogenicity
study of a SARS-CoV-2 mRNA vaccine candidate
against COVID-19 in healthy infants <6 months of age.
x C4591036: Pediatric Heart Network Study: Low
interventional cohort study of myocarditis associated with Comirnaty in persons less than 21 years of age.
*Adapted from sponsor’s Pharmacovigilance Plan, Version 1.4.1, Tables 52-57.
†Clinical trials (i.e., C4591001) that were originally included in the PVP to address
missing information on “Use in pediatric individuals <16 years of age” are also included in the PVP. 7.2 Summary of Post-Approval Safety Surveillance Studies
The sponsor’s proposed post- approval safety surveill ance studies are briefly
summarized in the sections below. In addition to PMR studies for
myocarditis/pericarditis included in the BLA 125742/0 approval letter, there were PMC studies, including a pregnancy registry study (PMC #10, C4591022) and an active safety surveillance study in the Veteran’s Affairs Health System (PMC #12, C4591012). The Sponsor also plans to conduct a vaccine effectiveness Study C4591014 entitled “Pfizer-BioNTech COVID-19 BNT162b2 Vaccine Effectiveness Study Kaiser
FDA-CBER-2022-5812-0500440
24
Permanente Southern California” (PMC #13). Please see the previous BLA (125742)
and EUA (27034) PVP review memos for additional details.
Reviewer comment: The pregnancy registry study (PMC #10, C4591022) includes
pregnant individuals aged 18 years and older. An IR was sent asking the sponsor to
include pregnant individuals of all ages in the study. The sponsor’s IR response (125742/45/10) indica ted that the pregnancy registry study protocol will be revised to
include pregnant individuals of all ages. The sponsor noted that the target enrollment sample size has been met in the exposed group of pregnant individuals who received Pfizer-BioNTech COVID-19 Vaccine, however, they will attempt to enroll individuals <18
years of age who may qualify for this group. An amended study protocol and statistical analysis plan (SAP) will be submitted by Ma y 20, 2022. Study C4591012 (PMC #12,
Veteran’s Affairs Health System study) includes various age subgroups, including 12-<18 years, although the focus is on the elderly. Study C4591014 (PMC #13, vaccine effectiveness study) includes all Kaiser Permanente Southern California members meeting vaccination eligibility to allow anal yses based on evolving age requirements.
Studies Included in BLA Approval Letter (125742/0) as Postmarketing Requirements (PMRs) under Section 505( o) of the Federal Food, Drug, and
Cosmetic Act (FDCA)
The sponsor is required to conduct the following studies under BLA approval of
Comirnaty to assess the known serious risks of myocarditis and pericarditis and to
identify an unexpected serious risk of subclinical myocarditis.
PMR #4, C4591009: A non-interventional post-approval safety study of the
Pfizer--
BioNTech COVID-19 mRNA vaccine in the United States
Objective: To assess the occurrence of safety events of interest, including myocarditis
and pericarditis, in the general U.S. population of all ages, pregnant women, the
immunocompromised, and persons with a prior history of COVID-19 within selected
data sources participating in the U.S. Sentinel System.
Study milestones in BLA (125742/0) approval letter: Final protocol submission: August 31, 2021 Monitoring report submission: October 31, 2022 Interim report submission: October 31, 2023 Study completion: June 30, 2025 Final study report submission: October 31, 2025 Reviewer comment: A final study protocol was submitted on August 30, 2021 (IND
19736.470 and EUA 27034.283). A protocol amendment was submitted on December 23, 2021 (IND 19736.617) which specified myocarditis/pericarditis as safety events of interest in the primary study objectives and included assessment of safety events following a third/booster dose of the Pfizer-BioNTech COVID-19 Vaccine.
While this
study includes individuals of all ages, including those aged 12-15 years, the protocol
FDA-CBER-2022-5812-0500441
25
indicates that safety analyses will be lim ited to individuals wit hin the age-approved
population for Pfizer-BioNTech COVID-19 Va ccine with age-based eligibility criteria
changing over the study period as the ages approved for vaccine use change.
PMR #5, C4591021: Post Conditional Ap proval Active Surveillance Study Among
Individuals in Europe Receiving the Pfizer-BioNTech Coronavirus Disease 2019
(COVID-19) Vaccine
Objective: To assess the potential increased risk of adverse events of special interest
(AESI), including myocarditis and pericarditis, after being vaccinated with at least one dose of the Pfizer-BioNTech COVID-19 Vaccine. Study milestones in BLA (125742/0) approval letter: Final Protocol Submission: August 11, 2021 Progress Report Submission: September 30, 2021 Interim Report 1 Submission: March 31, 2022 Interim Report 2 Submission: September 30, 2022 Interim Report 3 Submission: March 31, 2023 Interim Report 4 Submission: September 30, 2023 Interim Report 5 Submission: March 31, 2024 Study Completion: March 31, 2024 Final Report Submission: September 30, 2024 Reviewer comment: The final study protocol was submitted (BLA 125742.0.42 and IND
19336.464) and reviewed. A protocol amendment and SAP were received (IND 19736.619) on December 23, 2021 and have been reviewed. The protocol amendment includes the addition of myocarditis/pericarditis as outcomes separate from the cardiovascular composite endpoint, a sensitivity analysis to assess AESIs after 2
nd and
3rd vaccine doses, and additional stratification of the 0-19 years age group. The study
source population will include all individuals registered in each of the healthcare data sources who are eligible to receive the Pfizer-BioNTech COVID-19 Vaccine. This study is being conducted in Europe and va ccine eligibility will depend on European vaccine
eligibility criteria.
PMR #6, C4591021 Substudy (currently referred to as Study C4591038): Substudy
to describe the natural history of myocarditis and pericarditis following administration of COMIRNATY.
Objective: To describe the natural history of post-vaccination
myocarditis/pericarditis,
including recovery status, risk factors, and/or identification of serious cardiovascular
outcomes within one year of myocarditis/pericarditis diagnosis among individuals
vaccinated with BNT162b2 as well as individuals not vaccinated with a COVID-19
vaccine.
FDA-CBER-2022-5812-0500442
26
Study milestones in BLA (125742/0) approval letter:
Final Protocol Submission: January 31, 2022 Study Completion: March 31, 2024 Final Report Submission: September 30, 2024 Reviewer comment: This natural history substudy is being conducted in Europe and
vaccine eligibility will depend on European va ccine eligibility criteria. A final study
protocol was submitted on January 31, 2022 (IND 19736.656) and has been reviewed. The protocol includes an age category for individuals aged 0-17 years, including a subgroup for individuals aged 12-15 years (where feasible).
PMR #7, C4591036: Prospective cohort study with at least 5 years of follow-up for potential long-term sequelae of myocardi tis after vaccination (in collaboration
with Pediatric Heart Network [PHN]).
Objective: To characterize the clinical course, risk factors, resolution, long-term sequelae, and quality of life in children and young adults <21 years with acute post-vaccine myocarditis/pericarditis. Study milestones in BLA (125742/0) approval letter: Final Protocol Submission: November 30, 2021 Study Completion: December 31, 2026 Final Report Submission: May 31, 2027 Reviewer comment: This study includes individuals <21 years of age and is inclusive of
the population proposed for vaccine use in this BLA supplement. A final study protocol was received on November 29, 2021 (IND 19736.579) and has been reviewed.
PMR #8, C4591007 Substudy: Substudy to prospectively assess the incidence of subclinical myocarditis following admini stration of the second dose of
COMIRNATY in a subset of participants 5 through 15 years of age.
Objective: To obtain serum samples within the first ~4 days after
vaccination for
potential Troponin I testing in order to evaluate the frequency of subclinical myocarditis
amongst individuals 5 to 15 years of age.
Study milestones in BLA (125742/0) approval letter: Final Protocol Submission: September 30, 2021 Study Completion: November 30, 2023 Final Report Submission: May 31, 2024
FDA-CBER-2022-5812-0500443
27
Reviewer comment: This substudy includes participants in the age range of the proposed
BLA supplement (i.e., individuals 12-15 years of age) who are currently able to receive
vaccine under EUA. OBPV defers review of this study to OVRR. PMR #9, C4591031 substudy: Substudy to prospectively assess the incidence of subclinical myocarditis following administration of a third dose of COMIRNATY in a subset of participants 16 to 30 years of age. Objective: To obtain serum samples within the first ~4 days after
vaccination for
potential Troponin I testing in order to evaluate the frequency of subclinical myocarditis
amongst individuals 12 to 30 years of age following a third/booster vaccine dose.
Study milestones in BLA (125742/0) approval letter: Final Protocol Submission: November 30, 2021 Study Completion: June 30, 2022 Final Report Submission: December 31, 2022 Reviewer comment: The original BLA approval letter indicated this study would include
participants aged 16 to 30 years of age. The current PVP indicates this substudy has expanded the lower age range of participants to 12 years of age, consistent with the proposed indication for this BLA supplement. OBPV defers review of this study to OVRR. 8 DE Assessment of Sponsor’s Pharmacovigilance Plan This PVP assessment is focused on use of the Pfizer-BioNTech COVID-19 Vaccine in
individuals 12-15 years of age. Please see the original BLA PVP review memo and PVP addendum memo for additional details.
8.1 Important Identified Risk: Anaphylaxis
There were no reports of anaphylaxis following receipt of BNT162b2 in Study C4591001 among individuals 12-15 years of age during the blinded placebo-controlled period. Review of the sponsor’s data from their safety database through September 30, 2021 showed 43 (1.3%; 8 U.S.) reports of anaphy lactic reaction/shock or anaphylactoid
reaction/shock among individuals 12-15 years of age; all were serious events, and none were fatal. The majority (n=37, 86.0%) of anaphylaxis/anaphylactoid events occurred <24 hours after vaccination. A search of VAERS data (cumulative query run March 9, 2022) revealed 43 total U.S. reports among individuals aged 12-15 years, including 14 non-fatal serious/OMIC reports (no death reports). The important identified risk of anaphylaxis, which can be fatal or life-threatening, will be monitored through passive AE reporting and postmarketing safety studies. This safety concern is labeled in the following sections of the label:
x Section 4 Contraindications
FDA-CBER-2022-5812-0500444
28
x Section 5 Warnings and Precautions, 5.1 Management of Acute Allergic
Reactions
x Section 6.2 Postmarketing Experience
Reviewer comment: The proposed PVP is acceptable to monitor the risk of anaphylaxis.
8.2 Important Identified Risk: Myocarditis and Pericarditis
There was one SAE of myocarditis in Study C4591001 which occurred in a 16-year-old
male who experienced chest pain on Day 3 after Dose 4 (2nd dose BNT162b2). This
individual had a history one week prior of fever, cough, rhinorrhea, and positive PCR for
rhinovirus from a respiratory virus panel (SARS-CoV-2 RNA PCR was negative). His
chest pain resolved within 24-hours of receiving ketorolac and he was discharged home after 2-days of hospitalization. Through September 30, 2021, there were 180 reports of myocarditis and pericarditis retrieved from the sponsor’s safety database among individuals 12-15 years of age, including 154 reports (26 U.S.) of myocarditis and 61 reports (4 U.S.) of pericarditis (35 reports involved patients with both myocarditis and pericarditis); none had a fatal outcome. A VAERS search for U.S. reports among individuals aged 12-15 years revealed 528 reports, including 445 (84.2%) serious and 5 (0.9%) death reports for 4 unique individuals (described in Section 6.1; cumulative query run March 9, 2022).
Monitoring for myocarditis and pericarditis is ongoing and includes the following activities:
x Continued passive surveillance using VAERS
x Vaccine Safety Datalink (VSD) analyses for safety signals x Ongoing Sponsor passive surveillance using worldwide adverse events data
x Ongoing Sponsor voluntary surveillance studies
In addition, the approval letter for Comirnaty (125742/0) includes PMR safety studies under FDAAA Title IX to further characteri ze the serious risks of myocarditis and
pericarditis. This safety concern is labeled in the following sections of the label:
x Section 5 Warnings and Precautions, 5.2 Myocarditis and Pericarditis
x Section 6.2 Postmarketing Experience
Reviewer comment: The sponsor’s proposed PVP and FDA required postmarketing
studies are acceptable to monitor and further assess the risk of myocarditis and
pericarditis including long-term follow up.
8.3 Important Potential Risk: Vaccine-Associated Enhanced Disease (VAED),
including Vaccine-Associated Enhanced Respiratory Disease (VAERD)
No reports of VAED/VAERD have been identified in Study C4591001 or through post-authorization surveillance among individuals 12 -15 years of age. The important potential
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risk of VAED will be monitored through passive AE reporting and postmarketing safety
studies.
Reviewer comment: The proposed PVP is acceptable to monitor the potential risk of
VAED and VAERD.
8.4 Missing Information: Use in pregnancy and lactation Pregnant women were excluded from the pivotal clinical trial; non-interventional post-authorization studies to assess use of BNT162b2 in pregnancy are planned or ongoing. There were no known pregnant or breastfeeding individuals in the Study C4591001 among participants 12-15 years of age. Missing information regarding the use of the product during pregnancy and lactation will be monitored through passive AE reporting, a clinical trial, and postmarketing safety studies, including a PMC Pregnancy Registry study. Use in pregnancy and lactation will be communicated in product labeling (Section 8.1 Pregnancy and 8.2 Lactation), including a link to enroll in the pregnancy registry.
Reviewer comment: CDC recommends COVI D-19 vaccination for people who are
pregnant, breastfeeding, or trying to get pregnant now, or might become pregnant in the future.
4 CDC further states that evidence continues to build showing that COVID-19
vaccination before and during pregnancy is safe and effective and that data on the safety of receiving an mRNA COVID-19 vaccine, Moderna or Pfizer-BioNTech (Comirnaty), during pregnancy are reassuring.
4 Early data from three safety monitoring
systems (i.e., v-safe surveillance system, v- safe pregnancy regi stry, and VAERS) did
not find any safety concerns for people who received an mRNA COVID-19 vaccine late in pregnancy or for their babies.
4,5 Monitoring of COVID-19 vaccination during
pregnancy and lactation is ongoing. The proposed PVP is acceptable to monitor for use in pregnancy and lactation. 8.5 Missing Information: Vaccine effectiveness
The real-world vaccine effectiveness of the Pfizer-BioNTech COVID-19 Vaccine outside of clinical trials and over the course of the SARS-CoV-2 pandemic in larger and more diverse populations continues to evolve. Missing information regarding real-world vaccine effectiveness will be monitored through postmarketing real-world vaccine effectiveness studies. Data on vaccine efficacy in clinical trials will be communicated in
product labeling (Section 14 Clinical Studies).
Reviewer comment: Study C4591014 (PMC #13) entitled “Pfizer-BioNTech COVID-19
BNT162b2 Vaccine Effectiveness Study Kaiser Permanente Southern California” is
being conducted to evaluate vaccine effectiveness outside of clinical trials. The proposed PVP to monitor vaccine effectiveness is acceptable.
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8.6 Missing Information: Use in pediatric individuals <5 years of age
Use of BNT162b2 in pediatric individuals <5 years of age is being evaluated in clinical trials. Among individuals <5 years of age, cumulative post-authorization data from the sponsor’s safety database identified 56 reports (13 U.S. reports) including 14 serious reports; two reports included fatal outcomes (see Section 5.3 of this memo). Missing information regarding pediatric individuals <5 years of ag e will be monitored through
passive AE reporting and post-authorization/postmarketing safety studies. The lack of safety data will be communicated in product l abeling (Section 8.4 Pediatric Use).
Reviewer comment: The proposed PVP is acceptable to monitor use in individuals <5
years of age.
9 DPV Conclusions Based on review of available data, there were no new safety signals among participants 12-15 years of age who received BNT162b2 in Study C4591001. Review of the sponsor’s post-authorization safety data, VAERS data, and data mining findings did not reveal new safety concerns among individuals 12-15 years of age. The sponsor will conduct routine pharmacovi gilance and postmarketing observational
studies, which were previously identified in the August 23, 2021 approval letter for
Comirnaty BLA 125742/0 as FDAAA Title IX PMR safety studies (PMRs# 4 – 7) to assess the known serious risks of myocarditis and pericarditis. Also, the sponsor will
conduct PMC studies, including a pregnancy registry study (PMC #10, C4591022) and an active safety surveillance study in the Veteran’s Affairs Health System (PMC #12, C4591012). Furthermore, the sponsor will assess vaccine effectiveness in Study C4591014 (PMC #13) entitled “Pfizer-BioNTech COVID-19 BNT162b2 Vaccine Effectiveness Study Kaiser Permanente Southern California.” In addition, the safety of
BNT162b2 in individuals 12-15 years of age can be communicated through labeling.
10 DPV Recommendations
Should the product be approved in individuals 12-15 years of age, based on the review
of the clinical trial safety data, and the post-authorization safety data,
OBPV/DPV
recommends the following actions:
x Routine pharmacovigilance in accordance with adverse event reporting
regulations under 21 CFR 600.80, as per the sponsor’s revised PVP.
Additionally, following approval of Comirnaty 125742/0, the sponsor was also asked to submit reports of myocarditis and pericarditis as 15-day reports to VAERS.
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x Postmarketing requirement (PMR) safety studies under Section 505(o) of the
FDCA (amended by FDAAA, Title IX, Section 901), to assess the serious risk of myocarditis and pericarditis, as outlined in the BLA 125742/0 approval letter.
x Postmarketing commitment (PMC) safety studies , including a pregnancy
registry (C4591022) to assess whether pregnant women receiving the Pfizer-BioNTech COVID-19 Vaccine experience an increased risk of pregnancy and infant safety outcomes compared to comparator groups.
x Voluntary postmarketing studies : Post-EUA studies that continue as voluntary
studies will be followed through updates in periodic safety update reports (PSURs).
At this time, the available safety data do not suggest a safety concern that would require a Risk Evaluation and Mitigation Strategy (REMS). Please see the final version of the package insert submitted by the sponsor for the final agreed-upon language for the label.
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References
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2. Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine — United States, December 14–23, 2020. MMWR Morb
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4. COVID-19 Vaccines While Pregnant or Breastfeeding. Available at
https://www.cdc.gov/coronavirus/2019-
ncov/vaccines/recommendations/pregnancy.html#anchor 1628692520287; Accessed
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