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COVID-19 Vaccine (BNT162, PF-07302048)
BB-IND 019736
Agreed Initial Pediatric Study Plan
PFIZER CONFIDENTIAL
Page 1 of 22
AGREED INITIAL PEDIATRIC STUDY PLAN ( iPSP)
Product : COVID-19 Vaccine (BNT162, PF-07302048)
Dosage Form : Liquid formulation for i ntramuscular injection
IND # : 019736
Drug Class : Vaccine
Approved Indication : Not applicable
Proposed Initial Indication : Active immunization again st COVID-19 in individuals
≥16 years of age Proposed Supplemental Indications: Active immunization again st COVID-19 in children
and adolescents 12 through 15 years of age; Active immunization against COVID-19 in
children and infants <12 years of age Proposed General Plan :
Deferral of assessment in adoles cents, children, and infants 15 years of age and
younger
THIS DOCUMENT CONTAINS CONFIDENTIAL AND/OR TRADE SECRET INFORMA TION THAT IS DISCLOSED ONLY IN
CONNECTION WITH THE LICENSING AND/OR REGISTRATION OF PRODUCTS F OR PFIZER INC OR ITS AFFILIATED
COMPANIES. THIS DOCUMENT SHOULD NOT BE DISCLOSED OR USED, IN W HOLE OR IN PART, FOR ANY OTHER
PURPOSE WITHOUT THE PRIOR WR ITTEN CONSENT OF PFIZER INC.
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BB-IND 019736
Agreed Initial Pediatric Study Plan
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TABLE OF CONTENTS
LIST OF TABLES .....................................................................................................................3
LIST OF ABBREVIATIONS ....................................................................................................4
1. OVERVIEW OF THE DISEASE IN THE PEDIATRIC POPULATION ........ ....................5
1.1. Pathophysiology of the Disease ................................................................................5
1.2. Clinical Presentation of SARS- CoV-2–Associated Disease in Adults and in
the Pediatric Population ...............................................................................................5
1.3. Incidence and Prevalence Over all and in the P ediatric Popu lation ...........................6
1.4. Methods of Diagnosis ................................................................................................7
1.5. Currently Available Treatment s and/or Prevention Strategie s in the Pediatric
Population, Including Neonates ...................................................................................7
1.6. Summary ...................................................................................................................8
2. OVERVIEW OF THE DRUG OR BIOLOGICAL PRODUCT ................. ..........................8
3. OVERVIEW OF PLANNED EXTRAPOLATION OF EFFECTIVENESS TO
SPECIFIC PEDIATRIC POPULATIONS ................................ ...........................................8
4. PLAN TO REQUEST DRUG-SPECIFIC WAIVER(S) .......................................................8
5. PLAN TO REQUEST DEFERRAL OF PEDIATRIC STUDIES .........................................8
6. TABULAR SUMMARY OF PLANNED NONCLINICAL AND CLINICAL
STUDIES ..............................................................................................................................9
6.1. Planned Nonclinical Studies ......................................................................................9
6.2. Planned Clinical Studies ................................. ...........................................................9
7. AGE-APPROPRIATE FORMULATION DEVELOPMENT ..............................................9
7.1. Description of the drug product ..............................................................................10
7.2. Description of the excipients ...................................................................................11
7.3. Description of the diluent ............................... .........................................................12
8. NONCLINICAL STUDIES .................................................................................................12
8.1. Nonclinical Pharmacology ................................. .....................................................12
8.2. Nonclinical Safety Data .................................. ........................................................13
9. CLINICAL DATA TO SUPPORT DESI GN AND/OR INITIATION OF STUDIES
IN PEDIATRIC PATIENTS ...............................................................................................15
10. PLANNED PEDIATRIC CLINICAL STUDIES ........................ ......................................16
10.1. Pediatric Pharmaco kinetic Studies ....................... .................................................16
10.2. Clinical Effectiveness a nd Safety Studies Planned ...............................................16
10.2.1. Ongoing Pediatric Clinical Study ...................... .......................................16
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10.2.1.1. Study C4591001: Ages 12 Through 17 Years ............ ............16
10.2.2. Proposed Pediatric C linical Studies ................... .......................................16
10.2.2.1. Study C4591007: 6 months to <12 years of age .....................16
10.2.2.2. Study C4591023: Less than 6 months of age ........... ...............16
11. TIMELINE OF THE PEDIATRIC DEVELOPMENT PLAN ................ ..........................16
12. AGREEMENTS FOR PEDIATRIC STUDIES WITH OTHER REGULATORY
AUTHORITIES ................................................... ...............................................................17
REFERENCES .................................................... ....................................................................18
LIST OF TABLES
Table 1. Table of Clinical Studies for COVID-19 Vaccine ..................................................9
Table 2. Composition of Drug Products .................................. ...........................................11
Table 3. Lipid Excipients i n the Drug Product .......................... .........................................12
Table 4. Overview of Toxicity Testing Program .......................... ......................................14
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LIST OF ABBREVIATIONS
Abbreviation Definition
ACE2 angiotensin-converting enzyme 2
A:G Albumin: Globulin ratio
CAS Chemical Abstracts Service
CBER Center for Biologics Evaluation and Research
COVID-19 coronavirus disease 2019
DART developmental a nd reproductive toxicity
DSPC 1,2-distearoyl-sn-glycero-3- phosphocholine
EUA Emergency Use Authorization
FDA US Food and Drug AdministrationGLP Good Laboratory Practice
HCoV-229E human coronavirus 229E
HCoV-NL63 human coronavirus NL63ICU intensive care unit
IFN interferon-gamma
IgG immunoglobulin G
IgM immunoglobulin MIM intramuscularIND investigational new drugiPSP
initial pediatric study plan
LNP lipid na noparticles
MIS-C multisystem inflamma tory syndrome in children
modRNA nucleoside-modified RNA
NAAT nucleic acid amplification test
NaCl sodium chloride
P2 S prefusion spike glycoprotein
PCR polymerase chain reaction
PLT platelet
RBC red blood cellRDW red cell distribution widthRETIC reticulocyteRNA ribonucleic aci
d
S spike protein
S1 spike protein S1 subunit
SARS-CoV-2 severe acute respi ratory syndrome coronavirus 2
Th1 Type 1 T helper cells
UK United Kingdom
US United States
VAED vaccine-associated enhanced disease
VE vaccine efficacy
WBC white blood cell
WHO World Health Organization
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1. OVERVIEW OF THE DISEASE IN THE PEDIATRIC POPULATION
1.1. Pathophysiology of the Disease
SARS-CoV-2 is the causative agent of COVID-19. There are severa l other coronaviruses
already circulating in humans, s uch as HCoV-229E or HCoV-NL63, very often as
asymptomatic infections or infec tions causing mild respiratory symptoms.1
SARS-CoV-2 uses a densely glycosylated S to bind to the angiote nsin-converting enzyme 2
(ACE2) receptor of the human hos t cell, as found previously in SARS-CoV, to fuse the viral
and host cell membranes.2 The distribution of the ACE2 rec eptor in pulmonary tissues
underlies the predominantly r espiratory nature of COVID-19.3
1.2. Clinical Presentation of SARS-CoV-2–Associated Disease in Adult s and in the
Pediatric Population
COVID-19 is generally milder i n children than adults, possibly because common risk factors
for severe COVID-19 in adults are generally less prevalent in p ediatric age groups. Like
adults, over half of children pr esent with fever and dry cough.4 Gastrointestinal symptoms,
including diarrhea and vomiting, whi ch occur rarely in adults, occur more commonly in
children and may, in some cases, b e the only presenting feature s.5 Rhinorrhea and sore throat
may also be more prominent in c hildren with SARS-CoV-2 infectio n, although this picture is
likely confounded by coinf ection with other respiratory pathoge ns common in children.5,6
Pulmonary involvement in symptomatic children is generally mild.7 In a systematic review
of the clinical characteristics and outcomes of SARS-CoV-2 infe ctions in 7480 children from
around the world, mild (42.5%; 608/1432) or moderate (39.6%; 567/1432) signs of infection
were reported, and a pproximately 2% were admitted to pediatric intensive care.8
Nevertheless, severe cases, i ncluding those requiring intensive care support, have been
reported.9 In a nationwide case series of 2135 pediatric patients with CO VID-19 reported to
the Chinese Center for Disease Control and Prevention,10 severe/critical disease defined by a
combination of clinical, radiogr aphic, and laboratory criteria was identified in 10.6%, 7.3%,
and 3.9% of patients within the <1, 1 to 5, and 6 to 18 years o f age groups, respectively,
compared with 18.5% in adults.11,12 In a retrospective review of 341 p ediatric patie nts with a
definite diagnosis of COVID-19 reported to healt h authorities i n China, severe or critical
disease was reported in 0.6% and 0.3%, respectively.13 In an analysis of pediatric COVID-19
hospitalization data from 14 sta tes in the US, although the cum ulative rate of
COVID-19-associated hospitaliza tion was lower among children (8.0 per 100,000
population) compared with tha t in adults (164.5), 33.2% were ad mitted to an intensive care
unit.14 Common radiographic findings in s evere disease are similar to those in adults and
include the presence of ground‐gl ass opacities and segmental co nsolidation in bilateral lung
fields,7,15 especially in the p eripheral zones.15
In addition to the above, children may acquire multisystem infl ammatory syndrome in
children (MIS-C), an emerging c ondition that appears to be temp orally related to recent
exposure to SARS-CoV-2, frequentl y requires intensive care admi ssion, and may have a fatal
outcome.16,17 MIS-C is a febrile hyperinfla mmatory condition with frequent e vidence of
cardiac damage and dermatological , mucocutaneous, and gastrointestinal features.17 MIS-C
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Agreed Initial Pediatric Study Plan
PFIZER CONFIDENTIAL
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can lead to shock and multiple organ failure requiring admission to an intensive care unit
(ICU).18 The syndrome appears to have som e overlap with Kawasaki diseas e shock
syndrome.19,20 Compared with Kawasaki disease , patients with MIS-C are older, have more
cardiac injury, and are more likely to be black, Hispanic, or o f South Asian descent.21 As of
30 June 2020, over 1000 cases have been reported.21 As of 29 July 2020, a total of 570 cases
were reported in the US to the CDC. Of these, 86.0% involved four or more organ systems,
63.9% of patients required ICU ad mission, and severe complicati ons included cardiac
dysfunction (40.6%), shock (35.4 %), myocarditis (22.8%), corona ry artery dilation or
aneurysm (18.6%), and acute kidney injury (18.4%).22 Death rates of 2% to 4% have been
reported.21 MIS-C has been reported in ma ny countries throughout North Ame rica, Europe,
Asia, and Latin America,18 including the US,16,17 Italy,23 and France.24
COVID-19 has been reported in neona tes born to infected mothers .25,26 There is limited
evidence that neonates acquire i nfection through intrauterine v ertical transmission; thus,
neonatal infection likely mostly occurs from postnatal contact.26 Outcomes were generally
good in neonates, though assessment may be comple x in neonates where other conditions
may be relevant.25,26
1.3. Incidence and Prevalence Overall and in the Pediatric Population
In general, COVID-19 affects pe diatric populations less frequently as compared with other
age groups.11,27,28 In the US, subjects individuals <17 years of age represent 10.9% of
reported cases with 1.9% of cases reported in childrensubjects 0-4 years of age, and 9.0%
reported in subjects children and adolescents 5-17 years of age.29 The hospitalization rate as
of 16 January 2021 in the US was 36.9/100,000 in children 0 to 4 years of age and
22/100,000 in children and adolescents 5 to 17 years of age, compared with 380.3/100,000 of the overall population.
30
Between March 1–December 12, 2020, a total of 2,871,828 laborat ory-confirmed cases of
COVID-19 were reported in ch ildren, adolescents, and young adul ts aged 0–24 years in the
United States. Among these cas es, 16.3% were reported in childr en and adolescents aged 14–
17 years old, 7.9% were reporte d in children 11–13 years old, 1 0.9% were reported in
children 5–10 years old, and 7.4% were reported in those 0–4 ye ars old. Hospitalizations,
ICU admission, and death were av ailable for 41.9%, 8.9%, and 49 .1% of the cases
(respectively) and among child ren, adolescents, and young adult s, 30,229 (2.5%) were
hospitalized, 1,973 (0.8%) required ICU admission, and 654 (<0. 1%) died. Children 0-4
years of age accounted for the largest percentage of hospitaliz ations (4.6%), and ICU
admissions (1.8%).
31
In China, out of a series of 72,314 cases, children 0 to 9 years of age represented only 0.9% of COVID-19 cases, while ch ildren and adolescents 10 to 19 year s of age represented 1.2%
of cases.
32 In the United Kingdom (UK), children and adolescents accounted for 9,944 out of
a total of 257,029 confirmed COVID- 19 cases (3.87%) (0.62% [0-4 years of age],
0.70% [5-9 years of age], 0.81% [10- 14 years of age], to a maxi mum of 1.74% [15-19 years
of age]) as of 30 July 2020.33 However, these figures ma y be related to pediatric and
adolescent SARS-CoV-2 infecti ons generally bein g asymptomatic o r mild, limiting
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presentation to hospital or other medical care, as well as redu ced diagnostic testing.1,9,10,34,35
An analysis conducted i n the province of S henzhen, China, exami ned household contacts of
infected cases as well as prima ry subjects presenting with symp toms.36 Children 0 to 9 years
of age represented 14.9% of cases identified as household conta cts but only 2.1% of those
presenting with symptoms.36 Children were as likely to be infected through household
exposure as any other age group.36
1.4. Methods of Diagnosis
As in adults, the primary diagnos tic method for children presenting with symptoms
suggestive of COVID-19 is by polym erase chain reaction (PCR), a lso termed nucleic acid
amplification test (NAAT), on res piratory tract secretions, typ ically nasopharyngeal or
midturbinate nasal swabs, alt hough the virus can be detected in other samples.1,34,35,37
Serological methods rely on the development of immunoglobulin G (IgG) and/or
immunoglobulin M (IgM) to SARS-Co V-2 antigens following infection. Serological methods
are not useful diagnostics in acu te disease but are useful for diagnosing prior infection.38
1.5. Currently Available Treatments and/or Prevention Strategies in the Pediatric
Population, Including Neonates
Currently, there are no FDA-appr oved vaccines for prevention of COVID-19 in pediatric
populations. BNT162b2 has Emergency U se Authorization (EUA) in the United States for
individuals 16 years of age and ol der. The Moderna COVID-19 va ccine has an EUA in the
United States for individuals 18 years of age and older.
For pediatric subjects with C OVID-19, the standard of care is g enerally supportive therapy,
as indicated for children infect ed with other known respiratory viruses.1
Remdesivir is approved for the treatment of children >12 years of age and >40 kg (as well as
adults) requiring hospitalizati on for COVID-19, and can be used under FDA EUA for
hospitalized pediatric pati ents weighing 3.5 kg to less than 40 kg or hospitalized pediatric
patients less than 12 years of age weighing at least 3.5 kg.39
A combination of two monoclonal antibodies, casirivimab and imd evimab administered
together, are authoriz ed for emergency use for the treatment of mild to moderate COVID-19
in adults, as well as in pediatri c patients at least 12 years of age and weighing at least 40 kg,
who have received positive results of direct SARS-CoV-2 viral t esting and are at high risk
for progressing to severe C OVID-19 and/or hospitalization.
40
Baricitinib in combination with remdesivir is authorized for em ergency use for the treatment
of suspected or laboratory-c onfirmed COVID-19 in hospitalized a dults and pediatric patients
2 years of age or older requi ring supplemental oxygen, invasive mechanical ventilation, or
extracorporeal membrane oxygenation.
40
Bamlanivimab is author ized for emergency use for the treatment of mild-to-moderate
COVID-19 in adult and pediatric patients with positive results of direct SARS-CoV-2 viral
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testing who are 12 years of age and older weighing at least 40 kg, and who are at high risk
for progressing to severe C OVID-19 and/or hospitalization.40
1.6. Summary
SARS-CoV-2 infecti on may be common in ch ildren and adolescents, but compared to adults,
severe disease and hospitalizations are rare. Nevertheless, sev ere disease may occur at any
age, and there is a unique severe pediatric manifestation of SA RS-CoV-2 infection termed
MIS-C. These data indicate a need for a pe diatric immunization strategy.
2. OVERVIEW OF THE DRUG OR BIOLOGICAL PRODUCT
BioNTech has developed RNA-base d vaccine candidates using a pla tform approach that
enables the rapid development of vaccines against emerging vira l diseases, including
COVID-19. BNT162b2 is based on a plat form of nucleoside--modifi ed messenger RNA
(modRNA) that expresses the SARS–CoV-2 full-length, P2 mutant, prefusion spike
glycoprotein (P2 S) (version 9). T he RNA is encapsulated in lip id nanoparticles, which
enable entry of the RNA into hos t cells. The stabilized S antig en is expressed from the RNA
in the host cells and elicits vi rus neutralizing antibody and c ell mediated immune responses.
BNT162b2 is currently authorized for Emergency Use.
Emergency Use Authorized Indication : Active immunization against COVID-19 in
individuals ≥16 years of age. Proposed Initial Indication: Active immunization again st COVID-19 in individuals
≥16 years of age. Proposed Supplemental Indications: Active immunization again st COVID-19 in children
and adolescents 12 through 15 years of age; Active immunization against COVID-19 in
children and infants years of age.
Planned Pediatric Clinical St udies are discussed in Table 1.
3. OVERVIEW OF PLANNED EXTRAPOLATION OF EFFECTIVENESS TO
SPECIFIC PEDIATRIC POPULATIONS
No extrapolation is planned. 4. PLAN TO REQUEST DRUG-SPECIFIC WAIVER(S)
Not applicable.
5. PLAN TO REQUEST DEFERRAL OF PEDIATRIC STUDIES
Pfizer and BioNTech propose to request a deferral of the evalua tion of the COVID-19
vaccine in individuals ≤15 years of age (Attachment A) based on the following Criteria for
Deferral (Section 505B(a)(4)(A)(i)(I) of the Act): “ Pediatric studies should be delayed until
additional safety or effectiveness data have been collected” and “The drug or biological
product will be ready for approval for use in adults before pediatric studies are complete.”
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Adequate evidence of safety a nd efficacy has been established i n the pivotal study C4591001
in individuals ≥16 years of age to allow Emergency Use Authorization in that age group.
Study C4591001 includes subjects 12 through 17 years of age. I t wasis appropriate to defer
studies in children 56 months to >11 years <12 years of age until adequate safety and
immunogenicity information iswas available in 12- through 15- year-old children and
adolescents. It would then be appr opriate to defer further age -de-escalation to <6 months
until adequate safety da ta is available in 56 month through 11-year-old children.
6. TABULAR SUMMARY OF PLANNED NONCLINICAL AND CLINICAL
STUDIES
6.1. Planned Nonclinical Studies
No juvenile toxicity studies a re planned because the current no nclinical and clinical data are
sufficient to support pediatric clinical studies in children.
6.2. Planned Clinical Studies
Pfizer and BioNTech request a de ferral for a planned pediatric evaluation of the COVID-19
vaccine in adolescents, children, and infants ≤15 years of age (Table 1). Details for this
planned pediatric study can be found in Section 10.
Table 1. Table of Clinical Stu dies for COVID-19 Vaccine
PLANNED PEDIATRIC CLINICAL STUDIES
Pediatric Pharmacokinetic Studies
Age Group Type o f Study Comments Deferral Request
Planned for the Study (Y/N)
Not applicable
Clinical Studies Including Safety, and Effectiveness
Age Group Type o f Study Comments Deferral Request
Planned for the Study
(Y/N)
16 through 17 years Safety and effectiveness Study C4591001 N
12 through 15 years Safety and effectiveness Study C4591001 Y 5 through 11 years Dose finding followed
by safety and
effectivenessStudy C4591007
Y
6 months to <5 years
Age de-escalating dose finding followed by safety and effectivenessStudy C4591007 Y
< 6 months
Ddose finding followed
by safety and
effectivenessStudy C4591023 Y
7. AGE-APPROPRIATE FORMULATION DEVELOPMENT
No formulation changes are planned for the pediatric developmen t.
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7.1. Description of the drug product
The drug product is a preservativ e-free, sterile dispersion of RNA formulated in LNP in
aqueous cryoprotectant buffer for intramuscular (IM) administra tion. The RNA drug
substance is the only active ingredient in the drug product. Th e product is a concentrate for
solution at 0.5 mg/mL drug product.
The composition of RNA drug products for use in the planned cli nical trials and the function
of the respective components are given in Table 2.
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Table 2. Composition of Drug Products
Component Quality Standard Function
Drug substance In-house Active
ALC-0315a In-house Functional lipid
ALC-0159b In-house Functional lipid
DSPCc In-house Structural lipid
Cholesterol Ph. Eur. Structural lipid
Sucrose NF/Ph. Eur. Cryoprotectan t
NaCl USP/Ph. Eur. Buffe r
KCl USP/Ph. Eur. Buffe r
Na2HPO4 USP/Ph. Eur. Buffe r
KH2PO4 NF/Ph. Eur. Buffe r
Water for injectio n Ph. Eur. Solvent/Vehicle
a ALC-0315 = ((4-hydroxybutyl)azaned iyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate).
b ALC-0159 = 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacet amide.
c DSPC = 1,2-distearoyl-sn-glycero-3- phosphocholine.
7.2. Description of t he excipients
All excipients used in the for mulation of the drug product are listed in Table 3.
The drug product contains the 2 functional lipids ALC-0315 and ALC-0159 and the
2 structural lipids DSPC (1,2-di stearoyl-sn-glycero-3-phosphoch oline) and cholesterol.
Physicochemical proper ties and the structure s of the 4 lipids a re shown in Table 3.
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Table 3. Lipid Excipients in the Drug Product
Lipid
(CAS Number) Molecular
Weight [Da] Molecular Formula Physical State and Storage Condition Chemical Name (Synonyms) and Structure
ALC-0315
(not applicable) 766 C 48H95NO 5 Liquid (oil)
-20ºC (4-hydroxybutyl)azanediyl)bis(hexane-6,1-
diyl)bis(2-hexyldecanoate)
ALC-0159
(1849616-42-7) ~2400-
2600 C30H60NO(C 2
H4O)nOCH 3
n=45-50 Solid
-20ºC 2-[(polyethylene glycol)-2000]-N,N-ditetradecy clacetamide
DSPC
(816-94-4) 790 C
44H88NO 8P Solid
-20ºC 1,2-Distearoyl-sn -glycero-3-
phosphocholine
Cholesterol (57-88-5) 387 C
27H46O Solid
-20ºC
7.3. Description of the diluent
For the dilution of drug products for IM injection, isotonic Na Cl solution (0.9%) is sourced
as an approved medicinal produc t. The composition is according to the supplier’s
specifications. 8. NONCLINICAL STUDIES
8.1. Nonclinical Pharmacology
Nonclinical studies in mice a nd nonhuman primates for BNT162b2 (V9), a nucleoside-
modified mRNA (modRNA) vaccine that encodes the SARS-CoV-2 full-length spike
glycoprotein (S), demonstrated a strong neutralizing antibody r esponse, Th1-type CD4
+
T-cell response, and a CD8+ IFN response. Antigen-binding IgG and neutralizing antibody
responses were detectable as ea rly as 14 d post-immunization, w ith substantial increases
observed in nonhuman primates after the second dose. BNT162b2 ( V9) provided complete
protection from the presence of detectable viral RNA in the lun gs compared to the saline
control with no clinical, radio logical or histopathological evi dence of vaccine-elicited disease
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enhancement. A strong humoral r esponse was also observed in an accessory study to the
GLP-compliant repeat-dose toxicology study with BNT162b2 (V8) i n rats ( Study 38166).
Nonclinical development is f urther described in Module 2.4 of B B-IND 019736 ( Nonclinical
Overview) .
For nonclinical mouse immunogenicity studies, a pseudotype neutralization assay has been
used as a surrogate of virus neutralization. For nonhuman prima te nonclinical studies and for
clinical testing was performed using, qualified S ARS-CoV-2 neut ralization and SARS-CoV-
2 S1-binding IgG Luminex assays ( VR-MQR-10214 and VR-MQR-10211 ).
8.2. Nonclinical Safety Data
The nonclinical toxicity assessmen t of BNT162b2 (BioNTech code number BNT162, Pfizer
code number PF-07302048) i ncludes 2 GLP-compliant repeat-dose t oxicity studies and a
developmental and reproductive toxicity (DART) study in Wistar Han rats outlined below in
Table 4. The nonclinical safety e valuation included 2 variants of BNT162b2: V8 and V9.
BNT162b2 (V9), the candidate gran ted EUA approval, differs from BNT162b2 (V8) only in
the presence of optimized codons t o improve antig en expression, but the amino acid
sequences of the encoded antigens are identical. Two GLP repeat -dose toxicity studies for
BNT162b2 (V8) and BNT162b2 (V9), one study for each variant, ha ve been completed. In
both studies, the nonclinical toxi cology findings were similar between BNT162b2 (V9) and
BNT162b2 (V8). BNT162b2 (V9) was a ssessed for development and r eproductive toxicity in
rats.
The IM route of exposure was sele cted as it is the intended route of clinical a dministration.
The selection of rats as the toxi cology test species is consist ent with the WHO guidance
documents on nonclinical evaluation of vaccines,44 which recommend that vaccine toxicity
studies be conducted in a species in which an immune response i s induced by the vaccine.
Generation of an immune response to BNT162b2 has been confirmed in rats in both repeat-
dose toxicity and DART studies. T he Wistar Han rat is used rout inely for regulatory toxicity
studies, and there is an extensive historical safety database o n this strain of rat.
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Table 4. Overview of Toxi city Testing Program
Studya Study
(Sponsor)
No. Group/
Dose, µg RNA Total
Volume
(µL)b No. of
Animals/
Group Study
Status
Repeat-Dose Toxicity
17-Day, 2 or 3 Dose
(1 Dose/Week) IM Toxicity With a 3 Week Recovery
Phase in Rats
c,d 38166 Controle, 0
BNT162b2 (V8)i,
100 200f
200f
15/sex
15/sex Completed
17-Day, 3 Dose
(1 Dose/Week) IM Toxicity With a
3 Week Recovery Phase in
Rats
g 20GR142 Salineh, 0
BNT162b2 (V9)i, 30 60
60 15/sex
15/sex Completed
Developmental and Reproductive Toxicity
Combined Fertility and Developmental Study (Including Teratogenicity
and Postnatal
Investigations) of BNT162b1, BNT162b2 and BNT162b3 by the IM route in Rats
20256434
(RN9391
R58) Salineh, 0
BNT162b2 (V9)i, 30 60
60 44 F
44 F Completed
a. All studies are GLP-compliant and were conducted in an OECD mutual acceptance of data-compliant
member state. b. Doses were administered as 1 application at 1 site unless ot herwise indicated.
c. Study also evaluated the BNT162a1, BNT162b1 and BNT162c1 vac cine candidates.
d. QW x 3 (Days 1, 8, 15) for BNT162a1, BNT162b1, and BNT162b2 (V8); QW x 2 (Days 1, 8) for
BNT162c1. e. Phosphate buffered saline, 300 mM sucrose.
f. One application (100 µL) at 2 sites for a total dose volume of 200 µL.
g. Study also evaluated BNT162b3.
h. Sterile saline (0.9% NaCl). i. BNT162b2 (V8) and BNT162b2 (V9) both encode the same amino a cid sequence of the spike protein
antigen with two prefusion conformation-stabilizing amino acids in the stalk.
In both repeat dose toxicity st udies, administration of BNT162b 2 by IM injection to male and
female Wistar Han rats once every week for a total of 3 doses w as tolerated w ithout evidence
of systemic toxicity. Expected immune responses to the vaccine were evident such as edema
and erythema at the injection s ites, transient elevation in bod y temperature, elevations in
WBCs and acute phase reactants, and d ecreased A:G ratios. Injec tion site reactions were
common in all vaccine-administere d animals and were greater aft er boost immunizations.
Changes secondary to inflammation include d slight and transient reductions in body weights
and transient reductions in RETI C, PLT, and RBC mass parameters .41,42,43 All changes in
hematology parameters and acute pha se proteins were similar to control at the end of the
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recovery phase for BNT162b2 with t he exception of higher RDW an d lower A:G ratios in
animals administered BNT162b2 (V9). Macroscopic pathology and o rgan weight changes
were also consistent with immune activation and i nflammatory re sponse and included
increased size of draining ili ac lymph nodes and increased size and weight of spleen.
Vaccine-related microscopic fi ndings at the end of dosing for B NT162b2 were evident in
injection sites and surroundi ng tissues, in the draining iliac lymph nodes, bone marrow,
spleen, and liver. Microscopic fi ndings at the end of the dosin g phase were partially
(recovery in progress) or complet ely recovered in all animals a t the end of the recovery phase
for BNT162b2. A robust immune respons e was elicited to the BNT1 62b2 vaccine antigen.
In the DART study, administration of BNT162b2 to female rats tw ice before the start of
mating and twice during gestation at the human clinical dose (3 0 µg RNA/dosing day) was
associated with non-adverse effects (body weight, food consumption and effects localized to
the injection site) after eac h dose administration. However, th ere were no effects of
BNT162b2 administration on mati ng performance, fertility, or an y ovarian or uterine
parameters in the F0 female rats nor on embryo-fetal or postnat al survival, growth, or
development in the F1 offspr ing through the end of lactation. A n immune response to the
vaccine was confirmed in F0 femal e rats prior to mating, at the end of gestation and at the
end of lactation and these responses were also detectable in th e F1 offspring (fetuses and
pups).
Stand-alone safety pharmacology, genotoxicity, and carcinogenicity studies have not been
performed with the COVID-19 vaccine . This is consistent with th e World Health
Organization guidance on the nonc linical safety assessment of vaccines.44
No nonclinical studies have been conducted in juvenile animals.
9. CLINICAL DATA TO SUPPORT DESIGN AND/OR INITIATION OF STUDIES
IN PEDIATRIC PATIENTS
BNT162b2 has been studied in three clinical trials in adults. These are BNT162-01, a
phase 1/2 study in Germany, C4591001 (BNT162-02), and C4591005 (BNT162-05), a phase
1/2 safety and immunogenicit y study in Japan. Study C4591001 included a phase 1
component for candidate and dos e selection, allowing progressio n to a large
placebo-controlled phase 2/3 saf ety, immunogenicity and efficacy study conducted in the US,
Argentina, Brazil, South Africa , Turkey and Ger many. While thes e studies continue, the
available clinical evidence de monstrates induction of strong immune responses and high VE,
suggesting the vaccine confers protection against COVID-19 in individuals ≥16 years of age.
This evidence supported the granting of an EUA.
The observed safety profile in c linical trials to date shows mo stly mild reactogenicity, low
incidence of severe or seri ous events, and no clinically concerning safety observations. The
vaccine appears to be safe and we ll-tolerated across the safety population and within
demographic subgroups based on a ge, sex, race/ethnicity, country, and baseline
SARS-CoV-2 status. T he preponderance of severe cases of COVID-1 9 in the placebo group
relative to the BNT162b2 group ( 9 of 10) suggests no evidence o f vaccine-associated
enhanced disease (VAED).
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Vaccine efficacy was high, ≥95% f or participants without prior evidence of SARS-CoV-2
infection and >94% for those w ith and without prior infection, in the planned interim and
final analyses. Observed VE was >93% across subgroups identifie d by age, sex,
race/ethnicity, and country with t he exception of “all others” race group (89.3% VE) and
Brazil (87.7% VE).
10. PLANNED PEDIATRIC CLINICAL STUDIES
10.1. Pediatric Pharmacokinetic Studies
Not applicable. 10.2. Clinical Effectiveness and Safety Studies Planned
10.2.1. Ongoing Pediatric Clinical Study
10.2.1.1. Study C4591001: Ages 12 Through 17 Years
Approximately 600 individuals 16 through 17 years of age have b een enrolled within the
Phase 3 C4591001 study. Data analyses to be submitted will exam ine safety and
effectiveness endpoints. Approximately 2000 individuals 12 through 15 years of age have been enrolled in the
Phase 3 C4591001 study. Data analyses to be submitted will exam ine safety and
effectiveness endpoints to suppor t an indication for use in ind ividuals 12 through 15 years of
age. 10.2.2. Proposed Pediatric Clinical Studies
10.2.2.1. Study C4591007: 6 months to ≤11<12 years of age and younger
Study C4591007 is a dose-finding, age de-escalating safety and effectiveness study in
children 6 months to ≤11<12 years of age and younger .
10.2.2.2. Study C4591023: Less than 6 months of age
Study C4591023 is a dose-finding safety and effectiveness study in infants less than
6 months of age
11. TIMELINE OF THE PEDIATRIC DEVELOPMENT PLAN
1. Formulation Development: Not applicable.
2. Nonclinical Studies: None.
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3. Clinical Studies:
PK Study: Not applicable.
Safety and Effectiveness Study: C4591007 (6 months to ≤11<12 years of age)
Estimated Pp rotocol submission date: 8 February 2021No later than March
2021
Estimated Ss tudy initiation date: No later than April 202124 March 2021
Estimated study completion date: To be determine d31 October 2023
Estimated final repor t submission date: To be determined31 March 2024
Safety and Effectiveness Study: C4591023 (< 6 months)
Estimated protocol submissi on date: 31 January 2022
Estimated study initiation date: 31 April 2022
Estimated study comple tion date: 31 July 2024
Estimated final report sub mission date: 31 October 2024
4. Target Date for submission of supplemental BLA is October 2021.
Target Date for submission of supplemental BLA for <12 years of age is to be
determined.
12. AGREEMENTS FOR PEDIATRIC STUDIES WITH OTHER REGULATORY
AUTHORITIES BioNTech received approval from the European Medicines Agency f or the Paediatric
Investigation Plan on 27 Novemb er 2020 (EMA Decision P/0480/2020). A deferral is
granted for studies from birth to less than 18 years of age.
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