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COVID -19Vaccine (BNT162 ,PF-07302048 )
BB-IND 019736
Agreed Pediatric Study Plan
PFIZER CONFIDENTIAL
Page 1of 22AGREED PEDIATRIC STUDY PLAN (PSP)
Product :COVID -19 Vaccine (BNT162, PF -07302048)
Dosage Form : Liquid formulation for intramuscular injection
IND # : 019736
Drug Class : Vaccine
Approved Indication : Not applicable
Proposed Initial Indication : Active immunization against COVI D-19 in individuals
≥16yearsof age
Proposed Supplemental Indication s: Active immunization against COVID -19in children
and adolescents 12through15years of age ; Active immunization against COVID -19 in
children and infants <12 yearsof age
Proposed General Plan :
Deferral of assessment in adolescents, children ,and infants 15 years of age and
younger
THIS DOCUMENT CONTAINS CONFIDENTIAL AND/OR TRADE SECRET I NFORMATION THAT IS DISCLOSED ONLY IN
CONNECTI ON WITH THE LI CENSING AND/OR REGI STRATION OF PRODUCTS FOR PFIZER INC OR ITS AFFILIATED
COMPANI ES. THIS DOCUMENT SHOULD NOT BE DI SCLOSED OR USED, I N WHOLE OR I N PART, FOR ANY OTHER
PURPOSE WITHOUT THE P RIOR WRITTEN CONSENT OF PFIZER INC.
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Page 2of 22TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 3
LIST OF ABBREVIATION S................................ ................................ ................................ ....4
1. OVERVIEW OF THE D ISEASE IN THE PEDIATRI C POPULATION ............................ 5
1.1. Pathophy siology of the Disease ................................ ................................ ................ 5
1.2. Clinical Presentation of SARS- CoV -2–Associated Disease in Adults and in
the Pediatric Population................................ ................................ ............................... 5
1.3. I ncidence and Prevale nce Overall and in the Pediatric Population........................... 6
1.4. Methods of Diagnosis ................................ ................................ ................................ 7
1.5. Currently Available Treatments and/or Prevention Strategies in the Pediatric
Population, I ncluding Neonates................................ ................................ ................... 7
1.6. Summary ................................ ................................ ................................ ................... 8
2. OVERVIEW OF THE D RUG OR BIOLOGICAL PRODUCT ................................ ........... 8
3. OVERVIEW OF PLANN ED EXTRAPOLATION OF EFFECTIVENESS TO
SPECIFIC PEDIATRI C POPUL ATIONS ................................ ................................ ........... 8
4. PL AN TO REQUEST D RUG -SPECIFIC WAIVER( S)................................ ....................... 8
5. PL AN TO REQUEST D EFERRAL OF PEDIATRI CSTUDIES ................................ ......... 8
6. TABULAR SUMMARY O F PLANNED NONCLINICA L AND CLINI CAL
STUDIES ................................ ................................ ................................ .............................. 9
6.1. Planned Nonclinical Studies ................................ ................................ ...................... 9
6.2. Planned Clinical Studies ................................ ................................ ............................ 9
7. AGE-APPROPRI ATE FORMULATION DEVEL OPMENT ................................ .............. 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 Safet y Data ................................ ................................ .......................... 13
9. CLINI CAL DATA TO SUPPORT DESI GN AND/O R INIT IATION OF STUD IES
IN PEDIATRIC PATIENTS...............................................................................................15
10. PL ANNED PEDIATRI C CLINICAL STUDIES ................................ .............................. 16
10.1. Pediatric Pharmacokinetic Studie s ................................ ................................ ........ 16
10.2. Clinical Effectiveness and Safet y Studies Planned ................................ ............... 16
10.2.1. Ongoing Pediatric Clinical Study ................................ ............................. 16
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Page 3of 2210.2.1.1. Study C4591001: Ages 12 Through 17 Years ........................ 16
10.2.2. Proposed Pediatric Clinical Studies................................ .......................... 16
10.2.2.1. Study C4591007: 11 y ears of age and younger ....................... 16
11. TI MELINE OF THE PEDI ATRI C DEVELOPMEN T PL AN................................ .......... 16
12. AGREEMENTS FOR P EDIATRIC STUDIES WI TH 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 in the Drug Product ................................ ................................ ...12
Table 4. Overview of Toxicity Testing Program ................................ ................................ 14
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Page 4of 22LIST OF ABBREVI ATIONS
Abbreviation Definition
ACE2 angiotensin -converting enzy me 2
A:G Albumin: Globulin ratio
CAS Chemical Abstracts Service
CBER Center for Biologics Evaluation and Research
COVID -19 coronavirus disease 2019
DART developmental and reproductive toxicity
DSPC 1,2-distearo yl-sn-glycero-3-phosphocholine
EUA Emergency Use Authorization
FDA US Food and Drug Administration
GLP Good Laboratory Practice
HCoV -229E human coron avirus 229E
HCoV -NL63 human coronavirus NL63
ICU intensive care unit
IFN interferon -gamma
IgG immunoglobulin G
IgM immunoglobulin M
IM intramuscular
IND investigational new drug
PSP pediatric stud y plan
LNP lipid nanoparticles
MIS-C multisy stem inflammatory syndrome in children
modRNA nucleoside -modified RNA
NAAT nucleic acid amplification test
NaCl sodium chloride
P2 S prefusion spike gl ycoprotein
PCR polymerase chain reaction
PLT platelet
RBC red blood cell
RDW red cell distribution width
RETI C reticulocy te
RNA ribonucleic acid
S spike protein
S1 spike protein S1 subunit
SARS -CoV -2 severe acute respiratory 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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Page 5of 221.OVERVIEW OF THE DISE ASE IN THE PEDIATRIC POPULATION
1.1.Pathophysiology of the Disease
SARS -CoV -2 is the causative agent of COVID -19. There are several other coronaviruses
alread y circulating in humans, such as HCoV- 229E or HCoV -NL63, very often as
asymptomatic infections or infections causing mild respiratory symptoms.1
SARS -CoV -2 uses adensely glycosylated S to bind to the angiotensin- converting enzy me 2
(ACE2) receptor of the human host cell, as found previously in SARS -CoV , to fuse the viral
and host cell membran es.2The distribution of the ACE2 receptor in pulmonary tissues
underlies the predominantly respiratory nature of COVID -19.3
1.2.Clinical Presentation of SARS -CoV -2–Associated Disease in Adults and in the
Pediatric Population
COVID -19 is generall y milder in children than adults, possibly because common risk factors
for severe COVID -19 in adults are generall y less prevalent in pediatric age groups. Like
adults, over half of children present with fever and dry cough.4Gastrointestinal sy mptoms,
including diarrhea and vomiting, which occur rarely in adults, occur more commonly in
children and may , in some cases, be the onl y presenting features.5Rhinorrhea and sore throat
may also be more prominent in children with SARS- CoV -2 infec tion, although this picture is
likely confounded b y coinfection with other respiratory pathogens common in children.5,6
Pulmonary involvement in sy mptomatic children is generall y mild.7In a systematic review
of the clinical characteristics and outcomes of SARS -CoV -2 infections in 7480 children from
around the world, mild (42.5%; 608/1432) or moderate (39.6%; 567/1432) signs of infection
were reported, and approximately 2% were admitted to pediatric intensive care.8
Nevertheless, severe cases, including those requiring intensive care support, have been
reported .9In a nationwide case series of 2135 pediatric patients with COVID -19 reported to
the Chinese Center for Disease Control and Prevention,10severe/critical disease defined b y a
combination of clinical, radiographic, 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 y ears of age g roups, respectivel y,
compared with 18.5% in adults.11,12In a retrospective review of 341 pediatric patients with a
definite diagnosis of COVID -19 reported to health authorities in China, severe or critical
disease was reported in 0.6% and 0.3%, respectively .13In an anal ysis of pediatric COVID -19
hospitalization data from 14 states in the US, although the cumulative rate of
COVID -19-associated hospitalization was lower among children (8.0 per 100,000
population) compared with that in adults (164.5), 33.2% were admitted to an intensive care
unit.14Common radiographic findings in severe disease are similar to those in adults and
include the presence of ground ‐glass opacities and segmental consolidation in bilateral lung
fields,7,15especiall y in the peripheral zones.15
In addition to the above, chi ldren may acquir e multisy stem inflammatory syndrome in
children (MIS-C), an emerging condition that appears to be temporally related to recent
exposure to SARS -CoV -2,frequentl y requires intensive care admission ,and may have a fatal
outcome.16,17MIS-C is a febrile hy perinflammatory condition with frequent evidence of
cardiac damage and dermatological, mucocutaneous, and gastrointestinal features.17MIS-C
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Page 6of 22can lead to shock and multiple organ failure requiring admission to an intensive care unit
(ICU).18The sy ndrome appears to have some overlap with Kawasaki disease shock
syndrome.19,20Compared with Kawasaki disease, patients with MI S-C are older, have more
cardiac injury ,and are more likely to be black, Hispanic, or of South Asian descent .21As of
30 June 2020, over 1000 cases have been reported .21As 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 s ystems,
63.9% of patients required I CU admission, and severe complications included cardiac
dysfunction (40.6%), shock (35.4%), m yocarditis (22.8%), coronary artery dilation or
aneury sm (18.6%), and acute kidney injury (18.4%).22Death rates of 2 %to 4% have been
reported .21MIS-C has been reported in many countries throughout North America, Europe,
Asia, and Latin America ,18including the US,16,17Italy,23and France.24
COVID -19 has been reported in neonates born to infected mothers.25,26There is limited
evidence that neonates acquire infection through intrauterine vertical transmission ;thus,
neonatal infection likely mostly occurs from postnatal contact .26Outcomes were generally
good in neonates, though assessment may be complex in neon ates where other conditions
may be relevant.25,26
1.3.Incidence and Prevalence Overall and in the Pediatric Population
In general ,COVID -19 affects pediatric populations less frequentl y as compared with other
age groups .11,27,28In the US ,individuals <17 years of age represent 10.9 % of reported cases
with 1.9% of cases reported in children 0-4 years of age, and 9.0% reported in children and
adolescents 5-17 yearsof age .29The 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–De cember 12, 2020, a total of 2,871,828 laboratory -confirmed cases of
COVID -19were reported in children, adolescents, and y oung adults aged 0 –24 years in the
United States. Among these cases, 16.3% were reported in children and adolescents aged 14 –
17 years old,7.9% were reported in children 11 –13 yearsold, 10.9% were reported in
children 5–10 years old, and 7.4% were reported in those 0–4 yearsold.Hospitalizations,
ICU admission, and death were available for 41.9%, 8.9%, and 49.1% of the cases
(respectively )and among children, adolescents, and y oung adults, 30,229 ( 2.5% )were
hospitalized, 1,973 (0.8%) required ICU admission, and 654(<0.1%) died . Children 0-4
years of age accounte d forthe largest percentage of hospitalizations (4.6%), and ICU
admissions (1.8%).31
In China, out of a series of 72,314 cases, children 0to 9 yearsof age represented only 0.9%
of COVID -19 cases ,while children and adolescents 10to 19 yearsof age represented 1.2%
of cases .32In the United Kingdom (UK), children and adolescents accounted for 9,944 out of
a total of 257 ,029 confirmed COVID -19 cases (3 .87%) (0.6 2% [0 -4 years of age],
0.70%[5-9 years of age], 0.81% [10- 14 years of age], to a maximum of 1.7 4% [15 -19 years
of age]) as of 30 July 2020.33However, these figures may be related to pediatric and
adolescent SARS -CoV -2 infections generally being as ymptomatic or mild, limiting
presentation to hospital or other medical care, as well as reduced diagnostic testing .1,9,10,34,35
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Page 7of 22An anal ysis conducted in the province of Shenz hen, China ,examined household contacts of
infected cases as well as primary subjects presenting with s ymptoms.36Children 0 to 9 years
of age represented 14.9% of cases identified as household contacts but only 2.1% of those
presenting with sy mptoms.36Children were as likely to be infected through household
exposure as an y other age group.36
1.4.Methods of Diagnosis
As in adults, the primary diagnostic method for children presenting with s ymptoms
suggestive of COVID -19 is by polymerase chain reaction (PCR), also termed nucleic acid
amplification test (NAAT), on respiratory tract secretions, ty picall y nasopharyngeal or
midturbinate nasal swabs, although the virus can be detected in other samples.1,34,35,37
Serological methods rel y on the development of immunoglobulin G (IgG) and/or
immunoglobulin M (IgM) to SARS -CoV -2 antigens following infection. Serological methods
are not useful diagnostics in acute 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 -approved vaccines for prevention of COVID- 19 in pediatric
populations. BNT162b2 has Emer gency Use Authorization (EUA) in the United States for
individuals 16 y ears of age and older. The Moderna COVID -19 vaccine has an EUA in the
United States for individuals 18 y ears of age and older.
For pediatric subjects with COVID- 19, the standard of c are is generall y supportive therap y,
as indicated for children infected 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 hospitalization for COVI D-19, and can be used under FDA EUA for
hospitalized p ediatric patients 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 imdevimab administered
together , are authorized for em ergency use for the treatment of mild to moderate COVID -19
in adults, as well as in pediatric patients at least 12 years of age and weighing at least 40 kg,
who have received positive results of direct SARS- CoV -2 viral testing and are at high risk
for prog ressing to severe COVID- 19 and/or hospitalization.40
Baricitinib in combination with remdesivir is authorized for emergency use for the treatment
of suspected or laboratory -confirmed COVID -19 in hospitalized adults and pediatric patients
2 years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or
extracorporeal membrane ox ygenation.40
Bamlanivimab is authorized 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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Page 8of 22testing who are 12 years of age and older weighing at least 40 kg, and who are at h igh risk
for progressing to severe COVID -19 and/or hospitalization.40
1.6.Summary
SARS -CoV -2 infection may be common in children and adolescents, but compared to adults,
severe disease and hospitalizations are rare. Nevertheless, severe disease may occur at any
age, and there is a unique severe pediatric manifestation of SARS -CoV -2 infection termed
MIS-C.These data indicate a need for a pediatric immunization strategy .
2.OVERVIEW OF THE DRUG OR BIOLOGICAL PRODU CT
BioNTech has developed RNA -based vaccine candidates using a platform approach that
enables the rapid development of vaccines against emerging viral diseases, including
COVID -19.BNT162b2 is based on a platform of nucleoside --modified messenger RNA
(modRNA) that expresses the SARS –CoV -2 full -length, P2 mutant, prefusion spike
glycoprotein (P2 S) (version 9) . The RNA is encapsulated in lipid nanoparti cles, which
enable entry of the RNA into host cells. The stabilized S antigen is expressed from the RNA
in the host cells and elicits virus neutralizing antibody and cell mediated immune responses.
BNT162b2 is currentl y authorized for Emergency Use .
Emerg ency Use Authorized Indication : Active immunization against COVI D-19 in
individuals ≥16yearsof age .
Proposed Initial Indication: Active immunization against COVI D-19 in individuals
≥16yearsof age .
Proposed Supplemental Indications: Active immunization against COVID -19in children
and adolescents 12through 15years of age; Active immunization against COVID- 19 in
children and infants yearsof age .
Planned Pediatric Clinical Studies are discussed in Table 1.
3. OVERVIEW OF PLANNED EXTRAPOLATION OF EFFECTIVENESS TO
SPECIFIC PEDIATRIC P OPULATIONS
No extrapolation is planned.
4.PLAN TO REQUEST DRUG -SPECIFIC WAIVER(S)
Not applicable.
5.PLAN TO R EQUEST DEFERRAL OF P EDIATRIC STUDIES
Pfizer and BioNTech propose to request a deferral of the evaluation of the COVID -19
vaccine in individuals ≤15 years of age (Attachment A) based on the following Criter iafor
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 co mplete .”
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Page 9of 22Adequate evidence of safety and efficacy has been established in the pivotal study C4591001
in individuals ≥16 y ears of age to allow Emergency Use Authori zation in that age group.
Study C4591001 includes subject s12 through 17 years of age . It wasappropriate to defer
studies in children 6 months to <12 y ears of age until adequate safet y and immunogenicit y
information wasavailable in 12 -through 15- year-old children and adolescents. I t would then
be appropriate to defer further age -de-escalation to <6 months until adequate safet y data is
available in 6 month through 11 -year-old children.
6. TABULAR SUMMARY OF P LANNED NONCLINICAL AND CLINIC AL
STUDIES
6.1. Planned Nonclinical Studies
No juvenile toxicity studies are planned because the current nonclinical and clinical data are
sufficient to support pediatric clinical studies in children .
6.2. Planned Clinical Studies
Pfizer and BioNTech request a deferral fora planned pediatric evaluation of the COVID -19
vaccine in adolescents, children , and infants ≤15 y ears of age (Table 1). Details for this
planned pediatric stud y can be found in Section 10.
Table 1.Table of Clinical Studies for COVID -19 Vaccine
PLANNED PEDIATRIC CLINICAL STUDIES
Pediatric Pharm acokinetic Studies
Age Group Type of Study Comments Deferral Request
Planned for the Study
(Y/N)
Not applicable
Clinical Studies Including Safety, and Effective ness
Age Group Type of Study Comments Deferral Request
Planned for the Study
(Y/N)
16 through 17 years Safety andeffectiveness Study C4591001 N
12 through 15 years Safety andeffectiveness Study C4591001 Y
5 through 11years Dose finding followed
bysafety and
effectivenessStudy C4591007 Y
6 months to <5 years Age de -escalating dose
finding followed by
safety and effectivenessStudy C4591 007 Y
< 6 months Dose finding followed
by safety and
effectivenessStudy C4591023 Y
7.AGE -APPROPRIATE FORM ULATION DEVELOPMENT
No formulation changes are planned for the pediatric development .
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Page 10of 227.1.Description of the drug product
The drug product is a preservative -free, sterile dispersion of RNA formulated in L NP in
aqueous cry oprotectant buffer for intramuscular ( IM)administration. The RNA drug
substance is the only active ingredient in the drug product. The product is a concentr ate for
solution at 0.5 mg/mL drug product.
The composition of RNA drug products for use in the planned clinical trials and the function
of the respective components are given in Table 2.
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Page 11of 22Table 2.Composition of Drug Products
Component Quality Standard Function
Drug substance In-house Active
ALC -0315aIn-house Functional lipid
ALC -0159bIn-house Functional lipid
DSPCcIn-house Structural lipid
Cholesterol Ph. Eur. Structural lipid
Sucrose NF/Ph. Eur. Cryoprotectant
NaCl USP/Ph. Eur. Buffer
KCl USP/Ph. Eur. Buffer
Na2HPO4 USP/Ph. Eur. Buffer
KH2PO4 NF/Ph. Eur. Buffer
Water for injection Ph. Eur. Solvent/Vehicle
aALC -0315 = ((4 -hydroxybutyl)azanediyl)bis(hexane- 6,1-diyl)bis(2 -hexyldecanoate).
bALC -0159 = 2 -[(polyethylene glycol) -2000] -N,N-ditetradecylacetamide.
cDSPC = 1,2 -distearoyl -sn-glycero -3-phosphocholine.
7.2.Description of the excipients
All excipients use d in the formulation of the drug product are listed in Table 3 .
The drug product contains the 2 functional lipids AL C-0315 and ALC -0159 and the
2structural lipids DSPC (1,2 -distearo yl-sn-glycero-3-phosphocholine) and cholesterol.
Physicochemical properties and the structures of the 4 lipids are shown in Table 3.
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Page 12of 22Table 3. Lipid Excipients in the Drug Product
Lipid
(CAS Number)Molecular
Weight [Da]Molecular
FormulaPhysical
State and
Storage
Condition Chemical Name (Synonyms) and Structure
ALC -0315
(not applicable)766 C48H95NO 5 Liquid (oil)
-20ºC(4-hydroxybutyl)azanediyl)bis(hexane- 6,1-
diyl)bis(2 -hexyldecanoate)
ALC -0159
(1849616 -42-7)~2400 -
2600C30H60NO(C 2
H4O)nOCH 3
n=45 -50Solid
-20ºC2-[(polyethylene glycol) -2000] -N,N-
ditetradecyclacetamide
DSPC
(816-94-4)790 C44H88NO 8P Solid
-20ºC1,2-Distearoyl -sn-glycero-
3-
phosphocholine
Cholesterol
(57-88-5)387 C27H46O Solid
-20ºC
7.3.Description of the diluent
For the dilution of drug products for IM injection, isotonic NaCl solution (0.9%) is sourced
as an approved medicinal product. The composition is according to the supplier’s
specifications.
8.NONCLINICAL STUDIES
8.1.Nonclinical Pharmacology
Nonclinical studies in mice and 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 antibod y response, Th1- type CD4+
T-cell response, and a CD8+IFNresponse. A ntigen -binding IgG and neutralizing antibody
responses were detectable as earl y as 14 d post -immunization, with substantial increases
observed in nonhuman primates after the second dose. BNT162b2 (V9) provided complete
protection from the presence of detectable viral RNA in the lungs compared to the saline
control with no clinical, radiological or histopathological evidence of vaccine -elicited disease
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Page 13of 22enhancement. A strong humoral response was also observed in an accessory study to the
GLP-compliant repeat -dose toxicology study with BNT162b2 (V8) in rats ( Study 38166 ).
Nonclinical development is further described in Module 2.4 of BB- IND 019736 (Nonclinical
Overview ).
For nonclinical mouse immunogenicit y studies, a pseudot ype neutralization assay has been
used as a surrogate of virus neutralization. For nonhuman primate nonclinical studies and for
clinical testing was performed using , qualified SARS -CoV -2 neutralization and SARS -CoV -
2 S1-binding IgG Luminex assay s (VR-MQR -10214 and VR-MQR -10211 ).
8.2.Nonclinical Safety Data
The nonclinical toxicity assessment of BNT162b2 ( BioNTech code number BNT162, Pfizer
code number PF -07302048) includes 2 GLP -compliant repeat -dose toxicity studies and a
developmental and reproductive toxicity (DART) study in Wistar Han rats outlined below in
Table 4 .The noncl inical safet y evaluation included 2 variants of BNT162b2: V8 and V9.
BNT162b2 (V9), the candidate granted EUA approval, differs from BNT162b2 (V8) onl y in
the presence of optimized codons to improve antigen expression, but the amino acid
sequences of the e ncoded antigens are identical. Two GL P repeat -dose toxicity studies for
BNT162b2 (V8) and BNT162b2 (V9), one stud y for each variant, have been completed. In
both studies, the nonclinical toxicology findings were similar between BNT162b2 (V9) and
BNT162b2 (V8). BNT162b2 (V9) was assessed for development and reproductive toxicity in
rats.
The IM route of exposure was selected as it is the intended route of clinical administration.
The selection of rats as the toxicology test species is consistent with the WHO guidance
documents on nonclinical evaluation of vaccines,44which recommend that vaccine toxicity
studies be conducted in a species in which an immu ne response is induced by the vaccine.
Generation of an immune response to BNT162b2 has been confirmed in rats in both repeat -
dose toxicity and DART studies. The Wistar Han rat is used routinel y for regulatory toxicity
studies, and there is an extensive hi storical safety database on this strain of rat.
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Page 14of 22Table 4. Overview of Toxicity Testing Program
StudyaStudy
(Sponsor)
No.Group/
Dose, µg RNATotal
Volume
(µL)bNo. of
Animals/
GroupStudy
Status
Repeat -Dose Toxicity
17-Day, 2 or 3 Dose
(1Dose/Week) IM Toxicity
With a 3 Week Recovery
Phase in Ratsc,d38166 Controle, 0
BNT162b2 (V8)i,
100200f
200f15/sex
15/sexCom pleted
17-Day, 3 Dose
(1 Dose/Week)
IM Toxicity With a
3 Week Recovery Phase in
Ratsg20GR142 Salineh, 0
BNT162b2 (V9)i, 3060
6015/sex
15/sexCom pleted
Developm ental and Reproductive
Toxicity
Com bined Fertility and
Developmental Study
(Including Teratogenicity
and Postnatal
Investigations) of
BNT162b1, BNT162b2 and
BNT162b3 by the IM route
in Rats20256434
(RN9391
R58)Salineh, 0
BNT162b2 (V9)i, 3060
6044F
44FCom pleted
a. All studies are GLP -compliant and were conducted in an OECD mutual acceptance of data -compliant
member state.
b. Doses w ere administered as 1 application at 1 site unless otherwise indicated.
c. Study also evaluated the BNT162a1, BNT162b1 and BNT162c1 vaccine candidates.
d. QW x3 (Days 1, 8, 15) for BNT162a1 , BNT162b1 , and BNT162b2 (V8) ; QW x2 (Days 1,8) for
BNT162c1 .
e. Phosphate buffered saline, 300 mM su crose.
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 acid sequence of the spike protein
antigen with two prefusion conformation -stabilizing amino acids in the stalk.
In both repeat dose toxicity studies, administration of BNT162b2 b y IM injection to male and
female Wistar Han rats once every week for a total of 3 doses was tolerated without evidence
ofsystemic toxicity . Expected immune responses to the vaccine were evident such as edema
and ery thema at the injection sites, transient elevation in body temperature, elevations in
WBCs and acute phase reactants ,and decreased A:G ratios. Injection site rea ctions were
common in all vaccine -administered animals and were greater after boost immunizations.
Changes secondary to inflammation included slight and transient reductions in body weights
and transient reductions in RETI C, PLT, and RBC mass parameters.41,42,43All changes in
hematology parameters and acute phase proteins were similar to control at the end of the
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Page 15of 22recovery phase for BNT162b2 with the exception of higher RDW and lower A:G ratios in
animals administered BNT162b2 (V9). Macroscopic pathology and organ weight changes
were also consistent with immune activation and inflammatory response and included
increased size of draining iliac l ymph nodes and increased size and weight of spleen.
Vaccine -related microscopic findings at the end of dosing for BNT162b2 were evident in
injection sites and surrounding tissues, in the draining iliac l ymph nodes, bone marrow,
spleen, and liver. Microscopic findings at the end of the dosing phase were partially
(recovery in progress) or completely recovered in all animal s at the end of the recovery phase
for BNT162b2. A robust immune response was elicited to the BNT162b2 vaccine antigen .
In the DART study , administration of BNT162b2 to female rats twice before the start of
mating and twice during gestation at the human c linical dose (30 µg RNA/dosing day ) was
associated with non -adverse effects (bod y weight, food consumption and effects localized to
the injection site) after each dose administration. However, there were no effects of
BNT162b2 administration on mating perf ormance, fertility , or any ovarian or uterine
parameters in the F0 female rats nor on embry o-fetal or postnatal survival, growth, or
development in the F1 offspring through the end of lactation . An immune response to the
vaccine was confirmed in F0 female rats prior to mating, at the end of gestation and at the
end of lactation and these responses were also detectable in the F1 offspring (fetuses and
pups).
Stand -alone safety pharmacology , genotoxicity , and carcinogenicity studies have not been
performed wi th the COVID -19 vaccine. This is consistent with the World Health
Organization guidance on the nonclinical safety assessment of vaccines.44
No nonclinical studies have been conducted in juvenile animals.
9.CLINICAL DATA TO SUP PORT DESIGN AND/OR I NITIATION OF STUDIES
IN PEDIATRIC PATIENT S
BNT162b2 has been studied in three clinical trials in adults. These are BNT162 -01, a
phase 1/2study in Germany , C4591001 (BNT162 -02), and C4591005 (BNT162 -05),a phase
1/2 safet y and immunogenicity study in Japan. Study C4591001 included a phase 1
component for candidate and dose selection, allowing progression to a large
placebo- controlled phase 2/3 safet y, immunogenicity and efficacy study conducted in theUS,
Argentina, Brazil, South Africa, Turkey and Germany . While t hese studies continue, t he
available clinical evidence demonstrates induction of strong immune responses and high VE,
suggesting the vaccine confers protection against COVID- 19 in individuals ≥16 y ears of age .
This evidence supported the granting of an EUA.
The observed safet y profile in clinical trials to date shows mostly mild reactogenicit y, low
incidence of severe or serious events, and no clinically concerning safet y observations. The
vaccine appears to be safe and well-tolerated across the safet y population and within
demographic subgroups based on age, sex, race/ethnicity , country , and baseline
SARS -CoV -2 status. The preponderance of severe cases of COVID -19 in the placebo group
relative to the BNT162b2 group (9 of 10) suggests no evidence of vaccin e-associated
enhanced disease ( VAED ).
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Page 16of 22Vaccine efficacy was high, ≥95% for participants without prior evidence of SARS -CoV -2
infection and >94% for those with and without prior infection, in the planned interim and
final anal yses. Observed VE was >93% across subgroups identified b y age, sex,
race/ethnicity , and country with the exception of “all others” race group (89.3% VE) and
Brazil (87.7% VE).
10.PLANNED PEDIATRIC CL INICAL 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: A ges 1 2Through 17Years
Approximately 600 individuals 16 through 17 y ears of age have been enrolled within the
Phase 3 C4591001 study .Data analy ses to be submitted will examine safety and
effectiveness endpoints.
Approximately 2000 individuals 12 through 15 y ears of age have been enrolled in the
Phase 3 C4591001 study .Data analy ses to be submitted will examine safety and
effectiveness endpoints to support an indication for use in individuals 12through 15 years of
age.
10.2.2. Propose d Pediatric Clinical Stud ies
10.2.2.1. Study C4591007 : 6 months to <12 years of age
Study C4591007 is a dose -finding , age de -escalating safetyandeffectiven ess study in
children 6 months to <12 years of age .
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
6months of age .
11.TIMELINE OF THE PEDIATRIC DEVELOPMENT PLAN
1.Formulation Development : Not applicable .
2. Nonclinical Studies: None.
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Page 17of 223.Clinical Studies:
PK Study :Not applicable .
Safety and Effectiveness Study :C4591007 (6 months to <12yearsofage)
Protocol submission date: 8 February 2021
Study initiation date: 24 March 2021
Estimated study completion date: 31 October 2023
Estimated final report submission date: 31 March 2024
Safety and Effectiveness Study : C4591023 ( < 6 months)
Estimated protocol submission date: 31 January 2022
Estimated study initiation date: 31 April 2022
Estimated study completion date: 31July2024
Estimated final report submission date: 31October 2024
4.Target Date for submission of supplemental BLA is October 2021 .
Target Date for submission of supplemental BLA for <12years of age isto be
determined.
12.AGREEMENTS FOR PEDIA TRIC STUDIES WITH OT HER REGULATORY
AUTHORITIES
BioNTech received approval from the European Medicines Agency for the Paediatric
Investigation Plan on 27 November 2020 (EMA Decision P/ 0480/2020). A deferral is
granted for studies from birth to less than 18 y ears of age.
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