Document text
BNT162b2
Module 1.6.3 Correspondence Regarding Meetings
CONFIDENTIAL
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1.6.3 CORRESPONDENCE REGARDING MEETINGS
The following is a brief summary of the significant meetings and communications between
Pfizer and FDA regarding IND 19736. Copies of these correspondences are also provided.
Key US Regulatory Interactions
Date Regulatory Communication Additional Information
26 June 2020 FDA Type C Meeting
CRMTS #12645
The purpose of this Type C Meeting
was to present the proposed Clinical
Development Program, including the
revised Phase 1/2/3 Study C4591001,
intended to support licensure in the
US and globally as well as potential
use of the candidate vaccine under an
Emergency Use Authorization, if
authorized by HHS.
Pfizer/BioNTech Meeting Request and
Briefing Document Submitted 11 June
2020 (SN 0015)
Pfizer/BioNTech response to CBER’s
June 25, 2020 preliminary meeting
responses and Meeting Minutes
Submitted 09 July 2020 (SN 0028)
FDA Meeting Summary (Including
Preliminary Meeting responses)
Received 15 July 2020
FDA Teleconference Summary
Received 06 July 2020
14 October 2020 Request for Proprietary and
Non-proprietary Name
Review The purpose of this request was for the
Agency to consider a new proprietary
name: COMIRNATY.
Request for Proprietary Name Review
submitted 14 October 2020 (SN 0108)
Proprietary Name Acceptable At this
Time Letter Received from FDA 20 November 2020
FDA-CBER-2021-5683-1147650
BNT162b2
Module 1.6.3 Correspondence Regarding Meetings
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14 August 2020 FDA Type C Meeting CRMTS #12714
The purpose of this Type C Meeting
was to describe the proposed CMC
and facilities information package
intended to support licensure in the
US and globally as well as potential
use of the candidate vaccine under an
Emergency Use Authorization, if
authorized by HHS.
Pfizer/BioNTech Meeting Request and
Briefing Document Submitted 13 July
2020 (SN 0031)
FDA Written Responses Received 14
August 2020
Response to FDA August 14 and
September 18, 2020 Information
Request Submitted 08 October 2020
(SN 0102)
14 August 2020 Request for Comments and
Advice (Nonclinical) The purpose of this Request for
Comments and Advice was to seek
FDA feedback and approval on
sufficiency of the planned nonclinical
absorption, disposition, metabolism,
and excretion (ADME) and toxicology
packages and timing of study data
submissions to support the BLA for
the COVID-19 Vaccine (BNT162, PF-
07302048).
Request for Comments & Advice
Submitted 27 July 2020 (SN 0045)
FDA Comments Regarding Request
for Advice on Sufficiency of
Nonclinical Package for BLA
Received on 14 August 2020
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23 September 2020 FDA Type C Meeting CRMTS# 12822
The purpose of this Type C Meeting
was to describe the proposed CMC
and facilities information package
intended to support licensure in the
US and globally as well as the
facilities utilized for the potential use
of the candidate vaccine under an
Emergency Use Authorization, if
authorized by HHS.
Pfizer/BioNTech Briefing Document
Submitted 02 September 2020 (SN
0074)
Response to Type C Facilities
Meeting, September 23, 2020
Response to CBER October 1, 2020
Information Request Submitted 14
October 2020 (SN 0106)
FDA Meeting Summary (Including
Preliminary Meeting responses)
Received 14 October 2020 28 September 2020 Request for Comments and
Advice (Clinical, Nonclinical,
Pre-Authorization Safety Pre-
BLA) The purpose of this Request for
Comments and Advice was to seek
CBER feedback regarding the
practical (not data related)
aspects of the planned BLA
submission.
Request for Comments & Advice
Submitted 15 September 2020 (SN
0084)
FDA Comments Regarding Planned
BLA Received 28 September 2020
Response to CBER September 28,
2020 Information Request (Practical
aspects of the planned BLA
submission) Submitted 16 October
2020 (SN 0112)
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CONFIDENTIAL
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27 November 2020 Request for Comments and
Advice (C4591001 Placebo
Subjects) The purpose of this Request for
Comments and Advice was to seek
CBER feedback regarding
administration of BNT162b2 to
participants in C4591001 who
originally received placebo.
Request for Comments & Advice
Submitted 18 November 2020 (SN
0139)
FDA Comments Regarding
Administration of BNT162b2 to
Participants in C4591001 Who
Originally Received Placebo (Placebo
Cross-Over) Received 27 November
2020
Request for Comments & Advice
Submitted 21 January 2021 (SN 0188)
FDA Comments Regarding the
Follow-up of BNT162b2 Recipients
Who Originally Received Placebo
Received 29 January 2021
Response to FDA 29 January 2021 IR
(Regarding Follow-up of BNT162b2
Recipients Who Originally Received
Placebo) Submitted 08 February 2021
(SN 0205)
Follow-up to 8 February 2021
Response to FDA 29 January 2021
Comments – Question for the Agency
Submitted 15 March 2021 (SN 0243)
FDA Comments Regarding a Follow-
Up Question on Pfizer’s Response
Regarding Follow-Up of Placebo
Crossover Subjects Received 02 April 2021
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CONFIDENTIAL
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01 February 2021 Email Correspondence
Regarding content of
Nonclinical Package and
Timelines of Rolling BLA The purpose of this Request was to
seek Agency Feedback regarding the
nonclinical package to include in the
BLA and the timelines regarding
submission of nonclinical, CMC and
clinical information to the rolling BLA
for Pfizer-BioNTech COVID-19
Vaccine.
Email Correspondence on January 13,
2021 and January 22, 2021 between
Dr. Ramachandra Naik (CBER) and
Ms. Elisa Harkins Tull (Pfizer)
FDA Comments Regarding Content of
Nonclinical Package and Timelines of
Rolling BLA Received 01 February 2021
09 March 2021 Request for Comments and
Advice (Proposal for Clinical
and Post-Authorization Safety
Data Package for Biologics
License Application) The purpose of this Request for
Comments and Advice was to seek
CBER feedback regarding the Clinical
and Post-Authorization Safety
Questions submitted in lieu of a pre-
BLA meeting.
Request for Comments & Advice
Submitted 04 February 2021 (SN
0200)
FDA Comments Regarding the
Proposal for Clinical and Post-EUA
Safety Data Package for BLA
Received 09 March 2021
FDA Comments Regarding CMC
Contents of the BLA and Additional
Comments on Clinical/Statistical and
CMC/Facilities Information to be
Included in the BLA Received 31
March 2021
FDA Clarification to a Few of the
Comments Sent on March 9, 2021
Regarding the Proposal for Clinical
and Post-EUA Safety Data Package for BLA Received 01 April 2021
FDA-CBER-2021-5683-1147654
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CONFIDENTIAL
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Response to FDA 09 and 31 March
2021 IR (regarding the proposal for
clinical and post -EUA safety data
package for BLA) Submitted 07 April
2021 (SN 0278)
Additional Response to CBER
Comments Received on 09 March
2021, 31 March 2021, and 01 April
2021, Regarding eSUB/CDISC data
Submitted 14 April 2021 (SN 0285)
FDA Teleconference Summary
Received 26 April 2021
31 March 2021 Request for Comments and
Advice (Plans for Submitting
the CMC Portions of the
BLA) The purpose of this Request for
Comments and Advice was to seek
CBER feedback regarding the strategy
for submitting the contents related to
chemistry, manufacturing, and
controls (CMC).
Request for Comments & Advice
Submitted 01 March 2021 (SN 0229)
FDA Comments Regarding CMC
Contents of the BLA and Additional
Comments on Clinical/ Statistical and
CMC/ Facilities Information to be
Included in the BLA Received 31
March 2021
Response to FDA 31 March 2021 IR
(regarding CMC package for BLA)
Submitted 07 April 2021 (SN 0278)
FDA Teleconference Summary
Received 26 April 2021
FDA-CBER-2021-5683-1147655
COVID -19Vaccine (BNT16 2;PF-0730204 8)
BB-IND 019736
1.6.1 Meeting Request
PFIZER CONFIDENTIAL
Page 1COVID -19 V accine (BNT162, PF-07302048)
BB-IND 019736
Type C Meeting Request
June 2020
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1.6.1 Meeting Request
PFIZER CONFIDENTIAL
Page 2TABLE OF CONTENTS
1.PRODUCT DESCRI PTIONAND APPLICATION NUM BER ................................ ........... 3
2.CHEMI CAL NAME AND S TRUCTURE ................................ ................................ ............ 4
3.PROPOSED I NDICATION (S)................................ ................................ .............................. 5
4.TYPE OF MEETING BEI NG REQUESTED ................................ ................................ .......5
5. PURPOSE OF THE MEETIN G ................................ ................................ ............................ 5
6.SPECIFIC OBJECTIVES /OUTCOMES EXPECTED ................................ ......................... 5
7.PRELIMINARY AGENDA, PRESENTER, TIME ................................ .............................. 5
8.SPECIFIC QUESTIONS GROUPED BY DI SCIPLINE................................ ...................... 6
9.SPONSOR ATTENDEES ................................ ................................ ................................ .....8
10.AGENCY STAFF ................................ ................................ ................................ ................ 9
11.ANTICI PATED DATE OF SUPPORTING DOCUMENT ATION ................................ ...9
12.SUGG ESTED MEETING DATES AND TIME ................................ ................................ .9
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Page 31.PRODUCT DESCRI PTION AND APPLICATIO N NUMBER
Pfizer and BioNTech are developing an investigational vaccine intended toprevent
Coronavirus D isease 2019 ( COVI D-19 )caused by the virus ,SARS -CoV-2. The goal of the
development program is to r apidly develop and license a vacc ine for use in adu lts ≥18years
of age,followed by a pediatric indication. The vaccine isbased on SARS -CoV-2 spike
(S)glycoprotein antigens encoded in RNA and formulated in lipid nanoparticles (LNPs),
referred to as COVID -19 Vaccine (BioNTech code number BNT162, Pfizer code number
PF-07302048 ).Initially ,four different clinical candidates were considered based on
evaluation of emerging preclinical and clinical data . An Investigational New Drug
Application (IND) for the COVID -19 V accine was submitted to the US FDA on
April 22,2020. On April 29,2020 Pfizer was notified by CBER that there were no clinical
hold issues identified and the evaluation of this vaccine in the US could proceed. The
COVID -19candidate vaccine formulation sare investigational medicinal products (IMPs)
andhave not been submitted for marketing approval in any country . A Request for Fast
Track Designation was submitted on May 15,2020 (Serial Number 0005) and is currentl y
under review b y CBER.
BioNTech is conducting a German first-in-human ( FIH)dose level -finding Phase 1/2 study
(BNT162 -01) to gather safet y and immunogenicity data to enable evaluation of each of the
vaccines individuall y to inform the overall clinical development of a COVID -19 Vaccine.
This study is not conducted under the IND b ut is being conducted under a German Clinical
Trial Agreement (CTA) . The protocol for this study has been provided previously in
Module 5 (Module 5.3.5.1 Clinical Study Protocol BNT162-01 ).
Pfizer and BioNTech are conducting a large Phase 1/2 clinical stu dy in the US (C4591001)
using a flexible and stepwise study design to evaluate the safet y and immunogenicity of the
same proph ylactic COVID -19vaccine candidates also being evaluated in the German stud y,
using a range of dosage levels and dosing regimens, with the in tent to select the most
appropriate final vaccine candidate for Phase 3 development. To gather appropriate dose
level information quickly, some dose levels evaluated in German or US studies were not the
same. In addition, Pfizer has chosen not to evaluate currently unmodified RNA (uRNA )or
self-amplify ing RNA (saRNA )candidate sin the US study . The protocol for this study is
providedin Module 5 (Module 5.3.5.1 Clinical Study Protocol C4591001).
On May 15, 2020 (Serial Number 000 7),Pfizer submitted the sy nopsis for a Phase 2/3
randomized, placebo -controlled, observer -blinded study of the efficacy and safet y of oneor
more COVID -19 vaccine candidate sin individuals ≥18 y ears of age (Module 5.3.5.1 Clinical
Study Synopsis C4591002). On May 29,2020, following their review, CBER provided
comments and information requests on this s ynopsis via email. These comments have been
considered and addressed in Response to CBER May 29,2020 Comments and I nformation
Requests provided in Module 1.11.3 , and are also addresse d inBriefing Document included
with this meeting request.
Upon further consideration, specificall y stud y site logistics and protocol efficiencies, a
decision has been taken to incorporate this efficacy study design as an amendment tothe
ongoing Phase 1/2 study (C4591001) to create a Phase 1/2/3 study . Reference is made to
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1.6.1 Meeting Request
PFIZER CONFIDENTIAL
Page 4CBER’s May 29, 2020 feedback regarding the efficacy study synopsis. CBER’s feedback has
been considered will be addressed in a revised Phase 1/2/3 study protocol for C4591001.
Adescript ion ofthe revised protocol design, including pla ns for incorporation of P hase 2/3
based on CBER’s May 29,2020 feedback from CBER, is provided in the briefing document
included wi th this request .Itis Pfizer’s intent to initiate the Phase 2/3 portion of the study in
July 2020.
The purpose of this Ty pe C Meeting is to present the proposed Clinical Development
Program, including the revised Phase 1/2/3 Study C4591001, intended to support licensure in
the US and globally as well as potential use of the candi date vaccine under an Emergency
Use Authorization, if authorized by HHS .This Type C meeting package will explain our
rationale to select a nucleoside -modified RNA ( modRNA )vaccine candidate and dose level
to progress into the Phase 3 part of Study C459100 1. A separate meeting will be requested in
the near future to present the CMC and facilities data package proposed for licensure .
2. CHEMICAL NAME AND STRUCTURE
BioNTech has developed three RNA -LNP platforms with different features, as follows :
nonmodified u ridine containing mRNA (uRNA) ,with high intrinsic adjuvanticity ;
nucleoside -modified mRNA (modRNA) , with blunted innate immune sensor activating
capacity and thus augmented antigen expression; and
self-amplifying mRNA (saRNA) , from which higher amounts o f protein per injected
RNA template c ould be produced and thus immunogenicity enhanced .
The RNA -based vaccines are formulated in the same LNPs . Each platform RNA encode s
either a full -length SARS -CoV -2 S glycoprotein, the P2 mutant S gly coprotein (P2 S), and/or
the receptor binding domain (RBD) of the S gly coprotein. Each candidate is also given a V
number that indicates the specific version of the optimized insert genomic sequence.
BNT162 vaccine candidates based on these platforms have been (or may be) tested at the
follow ing dose ranges in the German Study BNT162 -01 and/or US S tudy C4591001 :
BNT162a1 (RBL 063.3) uRNA encoding RBD (V5) : 0.1to 3 µg, German study only
BNT162b1 (RBP020.3) modRNA encoding RBD (V5): 1 to 100µg
German stud y (1, 10, 30, 50 , 60 µg) and US study (10, 20, 30, 100 µg)
BNT162b2 (RBP020.2) modRNA encoding P2 S (V9) : 1to 100 µg
German stud y (1, 10 , 30, 100 µg) and US study (10, 20, 30 µg)
BNT162c2 (RBS004.2) saRNA encoding P2 S (V9) : 0.1 to 3 µg, German study only.
Dosing with BNT162a 1 and BNT162c2 is currently not planned in the US study ;
accordingl y, thesehave been removed from Study C4591001 in protocol Amendment 3.
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Page 53. PROPOSED INDICATION(S )
The proposed indication for the COVID -19 Vaccine is:
Active immunization against COVID -19inadults ≥18 years of age.
Full clinical development of the COVID -19 V accine for a pediatric indication will also be
pursued . The proposed indication for the pediatri c population is:
Active immunization against COVID -19in children 12 months to 17 yearsof age.
The COVID -19 V accine will also be evaluated in pregnant women . Currently , these
evaluations are planned for 2021. The proposed indication would be:
Active immunization against COVI D-19 in pregnant women 18- 45 years of age .
4. TYPE OF MEETING BEING REQUE STED
This is a Ty pe Cmeeting request ; Pfizer respectfully requests a meeting with CBER by the
end of June 2020.
5.PURPOSE OF THE M EETING
The purpose of this Ty pe C Meeting is to present the proposed Clinical Development
Program, including the p roposed revis ions toongoing Study C4591001, as well as high level
pediatric and maternal immunization plans. It is our intention to complete an efficacy study
within C4591001 to support Traditional Approval ;
Specific CBER
feedback is requ ested on the clinical data requirements to support
Traditional Approval , as well as requirements for use under an Em ergency Use Authorization
should one be authorized by HHSand FDA.
6.
SPECIFIC OBJECTIVES/ OUTCOMES EXPECTED
To obtain rapid CB ER feedback on the questions included herein .
7. PRELIMINARY AGENDA , PRESENTER, TIME
Introduction –10 minutes
Discussion – 45 minutes
Closure – 5 minutes
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Page 68.SPECIFIC QUESTIONS G ROUPED BY DISCIPLINE
Clinical
1)Does CBER have an y comments on the overall Clinical Development Plan and timeline
propos edto support
Traditional Approval ?Specificall y,
a)Does CBER agree with the proposed revisions to the ongoing Phase 1/2 US Study
C4591001 that would add a Phase 2/3 efficacy phase to the study , to evaluate efficacy
in an expanded number of participants? Does CBER agree with the proposed Phase 3
safet y, immunogenicity ,and efficacy endpoints and case defini tions?
b)
c)Does CBER agree with the proposed plan for progression of vaccine candidates from
Phase 2 to Phase 3?
d)Does CBER agree with the proposed inclusion of global sites (eg ,EU, South
America, Turkey )inthe efficacy phase of the study with at least 30% of participants
coming from US assuming current state of the pandemic ?
2) Does CBER agree that revised Study C4591001 is adequate to serve as t he single pivotal
study to demonstrat e adequate safety , immunogenicity ,and efficacy of the candidate
vaccine for the proposed indication and may be used to support
Tradit ional Approval ?
3) Does CBER agree with Pfizer/BioNTech’s plans to evaluate the BNT162b3 candidate
expressing the RBD domain with a short transmembrane tail and two amino acids added
to the signal peptide for more homogenous cleavage in Stud y C4591001, as des cribed in
Section 6.2?
Regulatory
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PFIZER CONFIDENTIAL
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Traditional Approval
1)Does CBER agree that the proposed stud y design, including aPhase 2/3 efficacy portio n,
and the planned persisten ceevaluations from Phase 1 sentinel and P hase 2 cohorts are
adequate to support Traditional Approval?
2)Does CBER agre e that the planned clinical lot consistency study may be conducted in
parallel with the planned Phase 3 efficac y stud y and results submitte d as a post -approval
commitment under the Traditional Approval Pathway ?
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Page 8Emergency Use Authorization
1)The Sponsor is currentl y manufacturing vaccine at -risk and is targeting to have
US-manufactured and released vaccine doses of approx imately available b y
year-end 2020 with initial deliveries projected for late November . Does CBER agree that
the proposed
?The Emergency Use Authorization request package could be submitted for
CBER review in parallel with the initia l BLA.
Pediatric andMaternal I mmunization Study Plans
1)Does CBER have an y comments on the high -level pediatric study plan? Does CBER
agree
?
2) Does CBER agree with the proposed inclusion of global sites (eg, EU, South America,
Turkey ) in the pediatric study with at least 30% of participants coming from US?
3)Does CBER have an y comments on thepropos ed plan for evaluating maternal
immunization?
4)The developmental and reproductive toxicology (DART) study will be initiated
. Does CBER agree that the results of the DART study
can be provided during review of the initial BLA
?
Please refer to the Pre -IND Briefing Document included i n the submission for backgro und
information on the questions.
9.SPO NSOR ATTENDEES
Mark Boaz Program Director, Vaccine Research and Development, Pfizer Inc.
Donna Boyce Vice President, Global Regulatory Affairs, Vaccines, Pfizer Inc.
Carmel Devlin Global R egulatory Portfolio Lead, Gl obal Regulatory Affairs, Vaccines,
Pfizer Inc.
Philip R. Dormitzer, MD, PhD Vice President and Chief Scientific Officer, Viral Vaccines, Vaccines
Research and Development, Pfizer Inc.
, PhD Regulatory Consultant for BioNTech SE
William C. Gruber, MD Senior Vice President, Vaccine Clinic al Research and Development, Pfizer Inc.
Elisa Harkins Global Regulatory Lead, Global Regulatory Affairs, Vaccines, Pfizer Inc.
Kathrin U. Jansen, PhD Senior Vice President and H ead, Vaccine Research and De velopment,
Pfizer Inc.
Luis Jodar, PhD Vaccines Chief Medical and Scientific Affairs Officer, Pfizer Inc.
Nicholas Kitchin, MD Senior Director, Vaccines Clinical Research and Development, Pfizer Ltd.
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PFIZER CONFIDENTIAL
Page 9Kenneth Koury Head of Statistics and Modeling, Vaccine Clinical Research and
Development, Pfi zer Inc.
Stephen Lockhart, MD Head EU/AP, Vaccines Clinical Research and Development, Pfizer Ltd.
David Swerdlow , MD Senior Director, Medical Development and Clinical/Scientif ic Affairs,
Pfizer Inc.
Ruben Rizzi, PhD Regulatory Affairs Strategist, BioNTech SE
Satrajit Roychoudhury, PhD Senior Director, Statistical Research and Data Science Center, Pfiz er Inc.
Ugur Sahin, MD, PhD Chief Executive Officer, BioNTech, SE
10.AGENCY STAFF
Pfizer respectfull y requests participation of appropriate personnel from the Division of
Vaccine s and Related Drug Products, the Office of Biostatistics and Epidemiology and the
Division of Bacterial, Parasitic and Allergenic Products .
11.ANTICIPATED D ATE OF SUPPORTING DOCUM ENTATION
The Type C Briefing Document is included in th issubmission.
12.SUGGESTED ME ETING DATES AND TIME
A meeting is requested by the end of June, morning or earl y afternoon time ifpossible.
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Document Approval Record
Document Name:
Document Title:
Signed By: Date(GMT) Signing Capacity
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Module 1.6.2 Meeting Background Materials
PFIZER CONFIDENTIAL
Page 1COVID -19 V accine (BNT162, PF-07302048)
BB-IND 019736
Type C Meeting Briefing Document
June 2020
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Page 2TABLE OF CONTENTS
LIST OF TABLES ................................ ................................ ................................ ..................... 3
ABBREVIAT IONS ................................ ................................ ................................ ................... 4
1. EXECUTIVE SUMMARY ................................ ................................ ................................ ...6
2. PRODUCT I DENTIFIC ATION AND APPLICATIO N................................ ....................... 7
2.1. Chemical Name and Structure ................................ ................................ ................... 7
2.2. Dosage Form, Route of Administration, and Dosing Regimen ................................ 8
2.3. Proposed Indication ................................ ................................ ................................ ...8
3. PURPOSE OF MEETIN G................................ ................................ ................................ .....8
4. PROPOSED AGENDA A ND LIST OF PARTICI PANTS ................................ ................... 8
4.1. Proposed Agenda ................................ ................................ ................................ .......8
4.2. L ist of Pfizer Inc. and BioNTech SE Participants ................................ ..................... 9
5. LIST OF SPECIFIC QUESTIONS FOR DISCUS SION................................ ...................... 9
6. CLINI CAL DEVELOPM ENT PL AN................................ ................................ ................. 12
6.1. I ntroduction ................................ ................................ ................................ ............. 12
6.1.1. Background on the Target Indication ................................ ......................... 12
6.1.2. Rationale for Development................................ ................................ ......... 12
6.2. Status of Ongoing and Planned Clinical Studies ................................ ..................... 12
6.2.1. Ongoing German Phase 1/2 FIH Clinical Study BNT162 -01 .................... 13
6.2.2. Ongoing US Phase 1/2 Clinical Study C4591001 ................................ ......15
6.2.2.1. Current Status in Stage 1 ................................ ........................... 16
6.2.2.2. Proposed Amendment to Replace Stage 3 of Protocol ............. 16
6.2.3. Clinical L ot Consistency Study ................................ ................................ ..24
6.3. Pediatric Plan ................................ ................................ ................................ ........... 24
6.4. Pregnancy ................................ ................................ ................................ ................ 25
7. REGULATORY PATHWA YS................................ ................................ ........................... 26
.................... ......................... 26
.............. ............................... 27
.................. ........................... 27
7.2. Emergency Use Authorization ................................ ................................ ................ 29
7.3. Traditional Approval ................................ ................................ ............................... 29
8. SUMMARY ................................ ................................ ................................ ......................... 30
9.REFERENCES ................................ ................................ ................................ .................... 32
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Page 3LIST OF TABLES
Table 1. Number of Participants Vaccinated in Study BNT162 -01 as of June
8, 2020 ................................ ................................ ................................ ......12
Table 2. Number of Participants Vaccinated in Study C4591001 as of June
8, 2020 ................................ ................................ ................................ ......13
Table 3. Additional Planned Clinical Studies................................ ......................... 13
Table 4. Current versus Revised Study C4591001 Sections ................................ ..16
Table 5. Bayesian Sequential Design with Four Interim Analyses
(VE Threshold =20%) ................................ ................................ .............. 23
Table 6. Bayesian Sequential Design with Four Interim Analyses
(VE Threshold =30%) ................................ ................................ .............. 24
Table 7. ................................ ....27
Table 8. Clinical Data for Traditional Approval Pathway ................................ ......29
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Page 4ABBREVIATIONS
Abbreviation Definition
AE adverse event
BLA Biologics License Application
CBER (USFood and Drug Administration) Center for Biologics Evaluation and Research
CI confidence interval
CMC chemistry, manufacturing, and controls
CoV Coronav irus
COVID -19 Coronavirus Disease 2019
CRP C-reactive protein
CTA Clinical Trial Agreement
DART developmental and reproductive toxicology (study)
DBP diastolic blood pressure
DMC Data Monitoring Committee
ECMO extracorporeal membrane oxygenation
EU European Union
FiO 2 fraction of inspired oxygen
GLP Good Laboratory Practice
FIH first- in-human
HHS (US Department of) Health and Human Services
HR heart rate
IM intramuscular(ly)
IMP investigative medicinal product
iPSP initial Pediatric Study Plan
IND Investigational New Drug application
LL lower limit (of confidence interval)
LNP lipid nanoparticle
mNG mNeonGreen
modRNA nucleoside modified messenger RNA
mRNA messenger RNA
NAAT nucleic acid amplification test
NHP non-human primate
PaO 2 arterial oxygen pressure
P/B prime/ boost: dosing regimen ofa priming immunization and a boost erimmunization
POS probability of trial success
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Page 5Abbreviation Definition
RNA -LNP RNA lipid nanoparticle
RR respiratory rate
saRNA self-amplifying messenger RNA
SAE serious adverse event
SARS severe acute respiratory syndrome
SARS -CoV-2 SARS Coronavirus -2; virus causing the disease COVID -19
sBLA supplemental Biologics License Application
SBP systolic blood pressure
S glycoprotein Spike glycoprotein
SpO 2 peripheral oxygen saturation
TdaP Tetanus toxoid, low dose diphtheria toxoid, acellular pertussis (vaccine)
uRNA non-modified uridine containing mRNA
US United States
VE vaccine efficacy
WHO World Health Organization
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Page 61.EXECUTIVE SUMMARY
Pfizer and BioNTech are developing an investigational vaccine intended toprevent
Coronavirus D isease 2019 ( COVI D-19 )caused by the virus ,SARS -CoV-2. The goal of the
development program is to rapidly develop and license a vaccine for use in adults ≥18years
of age ,followed by a pediatric indication. The vaccine isbased on SARS -CoV-2 spike
(S)glycoprotein antigens encoded in RNA and formulated in lipid nanoparticles (LNPs),
referred to as COVID -19 Vaccine (BioNTech code number BNT162, Pfizer code number
PF-07302048 ).Initially ,four different clinical candidates were considered based on
evaluation of emerging preclinical and clinical data . An Investigational New Drug
Application (IND) for the COVID -19 V accine was submitted to the US FDA on
April 22,2020. On April 29,2020 Pfizer was notified by CBER that there we re no clinical
hold issues identified and the evaluation of this vaccine in the US could proceed. The
COVID -19candidate vaccine formulation sare investigational medicinal products (IMPs)
and have not been submitted for marketing approval in any country . ARequest for Fast
Track Designation was submitted on May 15,2020 (Serial Number 0005) and is currentl y
under review b y CBER.
BioNTech is conducting a German first-in-human ( FIH)dose level -finding Phase 1/2 study
(BNT162 -01) to gather safet y and immunogenicity data to enable evaluation of each of the
vaccines individuall y to inform the overall clinical development of a COVID -19 Vaccine.
This study is not conducted under the IND but is being conducted under a German Clinical
Trial Agreement (CTA) . The protocol for this study has been provided previously in
Module 5 (Module 5.3.5.1 Clinical Study Protocol BNT162-01 ).
Pfizer and BioNTech are conducting a large Phase 1/2 clinical study in the US(C4591001)
using a flexible and stepwise study design to evaluate the safet y and immunogenicity of the
same proph ylactic COVID -19vaccine candidates also being evaluated in the German stud y,
using a range of dosage levels and dosing regimens, with the intent to select the most
appropriate final vaccine candidate for P hase 3 development. To gather appropriate dose
level information quickly, some dose levels evaluated in German or US studies were not the
same. In addition, Pfizer has chosen not to evaluate currently unmodified RNA (uRNA )or
self-amplify ing RNA (saRNA )candidate sin the US study . The protocol for this study is
provided in Module 5 ( Module 5.3.5.1 Clinical Study Protocol C4591001 ).
On May 15, 2020 (Serial Number 000 7),Pfizer submitted the sy nopsis for a Phase 2/3
randomized, placebo -controlled, ob server -blinded study of the efficacy and safet y of oneor
more COVID -19 vaccine candidate sin individuals ≥18 y ears of age (Module 5.3.5.1 Clinical
Study Synopsis C4591002). On May 29,2020, following their review, CBER provided
comments and information requests on this s ynopsis via email. These comments have been
considered and addressed in Response to CBER May 29,2020 Comments and I nformation
Requests provided in Module 1.11.3 , and ar e also addressed in this B riefing D ocument .
Upon further consideration, specificall y stud y site logistics and protocol efficiencies, a
decision has been taken to incorporate this efficacy study design as an amendment tothe
ongoing Phase 1/2 stud y (C4591001) to create a Phase 1/2/3 study . Reference is made to
CBER’s May 29, 2020 feedback regarding the efficacy study synopsis. CBER’s feedback has
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Page 7been considered and will be addressed in a revised Phase 1/2/3 study protoco lfor C4591001.
Adescriptio n ofthe revised protocol design, including plans for incorporation of P hase 2/3
based on CBER’s May 29,2020 feedback, is provided herein. It is Pfizer’s intent to initiate
the Phase 2/3 portion of the study in July 2020.
The purpose of this Ty pe C Meeting is to present the proposed Clinical Development
Program, including the revised Phase 1/2/3 Study C4591001, intended to support licensure in
the US and globally ,as well as potential use of the candidate vaccine under an E mergency
Use Authorization if authorized by HHS .This Type C meeting package will explain our
rationale to select a nucleoside -modified RNA ( modRNA )vaccine candidate and dose level
to progress into the Phase 3 part of Study C4591001. A separate meeting will be requested in
the near future to present the CMC and facilities data package proposed for licensure .
2.PRODUCT IDENTIFICATI ON AND APPLICATION
2.1.Chemical Name and Structure
BioNTech has developed three RNA -LNP platforms with different features, as follows :
nonmodified uridine containing mRNA (uRNA) ,with high intrinsic adjuvanticity ;
nucleoside -modified mRNA (modRNA) , with blunted innate immune sensor activating
capacity and thus augmented antigen expression; and
self-amplifying mRNA (saRNA) , from which higher amounts of protein per injected
RNA template c ould be produced and thus immunogenicity enhanced .
The RNA -based vaccines are formulated in the same LNPs . Each platform RNA encode s
either a full -length SARS -CoV -2 S glycoprotein, the P2 mutant S gly coprotein (P2 S),and/or
the receptor binding domain (RBD) of the S gly coprotein. Each candidate is also given a V
number that indicates the specific version of the optimized insert genomic sequence.
BNT162 vaccine candidates based on these platforms have been (or may be)tested at the
follow ing dose ranges in the German Study BNT162 -01 and/or US S tudy C4591001 :
BNT162a1 (RBL 063.3) uRNA encoding RBD (V5) : 0.1to 3 µg, German study only
BNT162b1 (RBP020.3) modRNA encoding RBD (V5): 1 to 100µg
German stud y (1, 10, 30, 50 , 60 µg) and US study (10, 20, 30, 100 µg)
BNT162b2 (RBP020.2) modRNA encoding P2 S (V9) : 1to 100 µg
German stud y (1, 10 , 30, 100 µg) and US study (10, 20, 30 µg)
BNT162c2 (RBS004.2) saRNA encoding P2 S (V9) : 0.1 to 3 µg, German study only.
Dosing with BNT162a1 and BNT162c2 is currently not planned in the US study ;
accordingl y, thesehave been removed from Study C4591001 in protocol Amendment 3.
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Page 82.2.Dosage Form, Route of Administration, and Dosing Regimen
Thevaccine candi dates being evaluated in c linical studies are liquid formulation sstored
frozen at -80 °C in a 2 ml Type 1 glass vial to be thawed on the day of administration and
stored at 2 -8 °C until administration ,as described in Module 3.2 of the IND. The Sponsor
intends to commercialize the current formulation and initially plans to provide a single vial
from which multiple doses (depending on final dose level) would be drawn. The multi -dose
vial presentation is planned to be preservative -free.
The ca ndidate vaccine is administered intramuscularly (IM) in the upper arm (musculus
deltoideus) using single dose or prime/boost (P/B) regimens. Thecurrently planned P/B
regimen is twoinjection sgiven at 0 and 21 day s.
2.3.Proposed Indication
The proposed indication for the COVID -19 Vaccine is:
Active immunization against COVID -19in adults ≥18 years of age.
Full clinical development of the COVID -19 V accine for a pediatric indication will also be
pursued (see Section 6.3). The proposed indication for the pediatric population is:
Active immunization against COVID -19in children 12 months to 17 yearsof age.
The COVID -19 V accine will also be evaluated in pregnant women (seeSection 6.4).
Currently , these evaluations are planned for 2021. The proposed indication would be:
Active immuniz ation against COVI D-19 in pregnant women 18- 45 years of age .
3.PURPOSE OF MEETING
The purpose of this Ty pe C Meeting is to present the proposed Clinical Development
Program, including the p roposed revisions toongoing Study C4591001, as well as high -level
pediatric and maternal immunization plans. It is our intention to complete an efficacy study
within C4591001 to support Traditional Approval ;
. Specific CBER
feedback is requested on the clinical data requirements to suppor t
Traditional Approval ,as well as requirements for use under an Emergency Use Authorization
should one be authorized by HHSand FDA.
4.PROPOSED AGENDA AND LIST OF PARTICIPANTS
4.1.Proposed Agenda
Introduction –10 minutes
Discussion –
45 minutes
Closure – 5 minutes
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Page 94.2.List of Pfizer Inc. and BioNTech SE Participants
Mark Boaz Program Director, Vaccine Research and Development, Pfizer Inc.
Donna Boyce Vice President, Global Regulatory Affairs, Vaccines, Pfizer Inc.
Carmel Devlin Global Regulatory Portfolio Lead, Global Regulatory Affairs, Vaccines,
Pfizer Inc.
Philip R. Dormitzer, MD, PhD Vice President and Chief Scientific Officer, Viral Vaccines, Vaccines
Research and Development, Pfizer Inc.
, PhD Regulatory Consultant for BioNTech SE
William C. Gruber, MD Senior Vice President, Vaccine Clinical Research and Development, Pfizer Inc.
Elisa Harkins Global Regulatory Lead, Global Regulatory Affairs, Vaccines, Pfizer Inc.
Kathrin U. Jansen, PhD Senior Vice President and Head, Vaccine Research and Development,
Pfizer Inc.
Luis Jodar, PhD Vaccines Chief Medical and Scientific Affairs Officer, Pfizer Inc.
Nicholas Kitchin, MD Senior Director, Vaccines Clinical Research and Development, Pfizer Ltd.
Kenneth Koury , PhD Head of Statistics and Modeling, Vaccine Clinical Research and
Development, Pfizer Inc.
Stephen Lockhart, MD Head EU/AP, Vaccines Clinical Research and Development, Pfizer Ltd.
David Swerdlow , MD Senior Director, Medical Development and Clinical/Scientific Affairs,
Pfizer Inc.
Ruben Rizzi, PhD Regulatory Affairs Strategist, BioNTech SE
Satrajit Roychoudhury, PhD Senior Director, Statistical Research and Data Science Center, Pfiz er Inc.
Ugur Sahin, MD, PhD Chief Executive Officer, BioNTech SE
5.LIST OF SPE CIFIC QUESTIONS FOR DISCUSSION
Clinical
1)Does CBER have an y comments on the overall Clinical Development Plan and timeline
propos edto support
Traditional Approval ?Specificall y,
a)Does CBER agree with the proposed revisions to the ongoing Phase 1/2 US Study
C4591001 that would add a Phase 2/3 efficacy phase to the study , to evaluate efficacy
in an expanded number of participants? Does CBER agree with the proposed Phase 3
safet y, immunogenicity ,and efficacy endpoints and case definition s?
b)
c)Does CBER agree with the proposed plan for progression of vaccine candidates from
Phase 2 to Phase 3?
d) Does CBER agree with the proposed inclusion of global sites (eg ,EU, South
America, Turkey )inthe efficacy phase of the study with at least 30% of participants
coming from the US assuming current state of the pandemic ?
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Page 102) Does CBER agree that revised Study C4591001 is adequate to serve as t he single pivotal
study to demonstrate adequate safety , immunogenicity ,and efficacy of the candidate
vaccine for the proposed indication and may be used to support
Traditional Approval ?
3) Does CBER agree with Pfizer/BioNTech’s plans to evaluate the BNT162b3 candidate
expressing the RBD domain with a short transmembrane tail and two amino acids added
to the signal peptide for more hom ogenous cleavage in Stud y C4591001, as described in
Section 6.2?
Regulatory
3
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Page 11Traditional Approval
1)Does CBER agree that the proposed stud y design, including aPhase 2/3 efficacy portion,
and the planned persistence evaluations from Phase 1 sentinel and P hase 2 cohorts are
adequate to support Traditional Approval?
2)Does CBE R agree that the planned clinical lot consistency study may be conducted in
parallel with the planned Phase 3 efficacy study and results submitted as a post -approval
commitment under the Traditional Approval Pathway ?
Emergency Use Authorization
1)The Sponsor is currentl y manufacturing vaccine at -risk and is targeting to have
US-manufactured and released vaccine doses of approx imately available by
year-end 2020 with initial deliveries projected for late November . Does CBER agree that
?The Emer gency Use Authorization request package could be submitted for
CBER review in parallel with the initia l BLA.
Pediatric and Maternal Immunization Study Plans
1)Does CBER have an y comments on the high -level pediatric study plan? Does CBER
agree
?
2)Does CBER agree with the proposed inclusion of global sites (eg ,EU, South America,
Turkey ) in the pediatric study with at least 30% of participants coming from US?
3)Does CBER have an y comments on thepropos ed plan for evaluating maternal
immunization?
4)The developmental a nd reproductive toxicology (DART) study will be initiated
Does CBER agree that the results of the DART study
can be provided during review of the initial BLA
?
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Page 126.CLINICAL DEVELOPMENT PLAN
6.1. Introduction
6.1.1. Background on the T arget Indication
SARS -CoV -2 infections and the resulting COVID -19disease have spread globally .On
March 11 , 2020 the World Health Organization (WHO) characterized the COVID -19
outbreak as pandemic . At the time of this communication, the number of confirmed cases
exceeds 7 million and continues to rise globall y.
There are currently no vaccines to prevent SARS -CoV -2 infections or the disease it causes,
COVID -19 (Habibzadeh & Stoneman 2020 ).
6.1.2. Rationale for D evelopment
The rational efor development of BNT162 candidate vaccines based on mRNA technology
was covered in the Clinical Overview with the initial I ND application ( Module 2.5).
6.2.Status of Ongoing and Planned Clinical Studies
German Stud y BNT162 -01 is theFIH, Phase 1/2 dose level -finding study ,in which all
participants are 18 -55 years of age and receive active vaccine; the number of participants
who have received dose 1 and dose 2 of the first three candidates tested (BNT162b1 ,
BNT162a1 ,and BNT162c2) isshown in Table 1.
Table 1. Number of Participants Vaccinated in Study BNT162- 01 as of June 8 , 2020
BNT162b1 BNT162a1 BNT162c2
Dose 1 Dose 2 Dose 1 Dose 2 Dose 1
0.1 µg dose level N=12 Timepoint not reached N=6
0.3 µg dose level N=12 N=12 -
1 µg dose level N=12 N=12 - - -
3 µg dose level N=6 Not applicable -
10 µg dose level N=12 N=11
30 µg dose level N=12 N=12
50 µg dose level N=12 N=12
60 µg dose level N=12 Not applicable
Not applicable = decision made by Safety Review Committee not to administer dose 2 .
US Study C4591001 is a randomized and placebo -controlled study ,in which participants in
Stage 1 are randomized 4:1 to receive active vaccine or placebo; the number of participants
who have received dose 1 and dose 2 of the first two candidate stested (BNT162b1 and
BNT162b2 ) are shown in Table 2.
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Page 13Table 2. Number of Participants Vaccinated in Study C4591001 as of June 8 ,2020
BNT162b1 Placebo
Dose 1 Dose 2 Dose 1 Dose 2
18-55 years of age
10 µg dose level N=12 N=12 N=3 N=3
30 µg dose level N=12 N=12 N=3 N=3
100 µg dose level N=12 Not applicable N=3 Not applicable
65-85 years of age
10 µg dose level - - - -
20 µg dose level - - - -
30 µg dose level - - - -
BNT162b 2 Placebo
Dose 1 Dose 2 Dose 1 Dose 2
18-55 years of age
10 µg dose level N=2 - - -
20 µg dose level - - - -
30 µg dose level - - - -
65-85 years of age
10 µg dose level - - - -
20 µg dose level - - - -
30 µg dose level - - - -
Not applicable = decision made by Internal Revie w Committee not to administer d ose 2 .
Pfizer/B ioNTech intend to evaluate a slightl y modified BNT162b1 candidate expressing the
RBD domain with a short transmembrane tail and two amino acids added to the sig nal
peptide for more homogenous cleavage (BNT162b3) in Study C4591001. BNT162b3 in mice
has shown superior immunogenicity to BNT162b1. I t will be assessed in non -human
primates ( NHP )and may replace BNT162b1 during its early evaluation in the Phase 2
porti on of the Phase 2/3 study after confirmation of a similar (to BNT162b1 or BNT162b 2)
safet y/tolerability profile expected for this modRNA/LNP platform. Pfizer plans to modify
the protocol accordingl y once a decision is made. This decision is planned by end June 2020.
Additional planned studies are listed in Table 3.
Table 3.Additional Planned Clinical Studies
Lot consistency study Refer to Section 6.2.3
Pediatric study Refer to Section 6.3
Maternal immunization study Refer to Section 6.4
6.2.1. Ongoing German Phase 1/2 FIH Cli nical Study BNT162 -01
BioNTech is currently conducting a German FIH dose level -finding Phase 1/2 study
(BNT162 -01) to gather safet y and immunogenicity data for each of the vaccine candidates
noted above individually ,andto inform the overall clinical development of a COVID -19
Vaccine. Th is study is not under an IND but is being conducted under a German CTA . The
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Page 14protocol for this study has been provided previously in Module 5 ( Module 5.3.5.1 Clinical
Study Protocol BNT162-01 ).
In Study BNT162 -01, 60 participants have been administered a first dose of candidate
BNT162 b1 in fivecohorts of 12 participants each atdoses of 1, 10, 30, 50 and 60 µ g.
Eleven participants have received a second dose of 10 µgand 12each a second dose at 1 µg ,
30 µg,and 50 µg.Most participants report mild or moderate flu -like s ymptoms and/or
injection site reactions . Approximately 25% of participants have re ported fever. Onset of
systemic or local symptoms may begin around 6 h ours post vaccinatio n but they more
typicall y present 10-12 hours post administration, with fever usually starting 16 -24 h ours
post vaccination . All events resolve spontaneously or with simple medical management,
primarily acetaminophen , typicall y within 24 -48 h ours of onset. No serious adverse events
(SAEs) have been reported. There was some increase in frequency and intensity of sy mptoms
from the 1 µg to 10 µg cohorts ; for 10 µg to 60 µg there is no clear dose dependency . On
laboratory examination, transitory depression of the ly mphocy te count and mild elevation of
CRP are seen, consistent with the expected mode of action for the modRNA platform with no
associated clinical consequence. Overall tolerability of P/Bdosing is comparable at each
dose level. No participants have withdrawn from the study due to related events. Overall the
risk-benefit for this candidate within the dose range explored remains unchanged.
In Study BNT162 -01, 6 participants have been administered the vaccine candidate
BNT162 a1at the 3µgdose. All participants reported flu -like s ymptoms within 24 hours of
dosing, mostly of moderate intensity . One participant experienced vomiting and a second
participant experienced an episode of h ypotension , but this was not an SAE . A more marked
elevatio n to CRP was noted, with a similar pattern of transient ly mphocy te depression to that
described above for the BNT162 b1candidate . All events resolved; however, some
participants remain edsymptomatic for a number of day s. No SAEs have been reported and
no participants withdrew due to adverse events (AEs) . Subsequently , 12participants have
been dosed at 0.3 µg and demonstrate a similar pattern of reactogenicity asdescribed for the
BNT162 b1candidate at the 1 µ g to 10 µg dose s, with almost exclusively mild effects
reported to date. Twelve participants have recently been dosed at 0. 1µg.
BNT162a1 and BNT162b1 represent different mRNA platforms (unmodified and modified
mRNA, respectivel y) andencode the same antigen (RBD) . The difference in the
reactogenicity profile between BNT162 a1 and BNT162 b1candidates highlights that the
reactogenicity profile is dependent on the t ype of RNA platform (eg,unmodified versus
modified). Given the extensive clinical experiences with regard to safet y and tolerability of
the R NA platforms in the context of oncology programs (see Module 2.5Clinical Overview )
it is not anticipated that changes to the viral antigen sequence expressed b y the RNA
platform will affect the safet y and tolerability profile .
As of June 8, 2020 , dosing with BNT162b2 in the German S tudy BNT162 -01 is planned to
commence imminently ,and the first 6 subjects have been dosed with BNT162c2.
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Page 156.2.2. Ongoing US Phase 1/2 Clinical Study C4591001
Pfizer and BioNTech are currentl y conducting a large Phase 1/2 clinica l study (C4591001) in
the US .The current protocol for this study is provided in Module 5 ( Module 5.3.5.1 Clinical
Study Protocol C4591001 ). The stud y currently consists of three stages. Stage 1 is to identify
preferred vaccine candidate(s), dose level(s), number of doses, and schedule of
administration; Stage 2 is an expanded -cohort stage; and Stage 3 is a final candidate/dose
large -scale stage. Of note, Pfizer/BioNTech have de -selected evaluation of the BNT162a1
and BNT162c 2candidates for Study C45 91001. As noted in S ection 6.2, however,
Pfizer/BioNTech reserve the option to include an additional modRNA candidate similar to
BNT162b1 ,a very slightly modified vaccine candidate BNT162b3.
Two amendments to the protocol for stud y C4591001 have been submitted to BB -IND 19736
as follows. A summary of the change sincluded in these amendments is located in the
Protocol Amendment Summary of Changes Table within Module 5.3.5.1 Clinical Study
Protocol C4591001.
Protocol A mendment 1 was submitted on May 15, 2020 (Serial Number 0006). CBER
acknowledged acceptance of the changes included in this protocol amendment via email
to Pfizer on May 28, 2020.
Protocol Amendme nt 2 was submitted on June 2, 2020 (Serial Number 001 4). This
submission also included 3 documents supportive of the changes made in this amendment
(C4591001 Protocol Amendment 2 Briefing Document; C4591001 I RC 29May 2020
Safety Tables BNT162b1 Stage 1, 2 D ose, 21 Days Apart – 18- 55 Years of Age ;
C4591001 I RC 29May 2020 Safety Listings BNT162b1 Stage 1, 2 Dose, 21 Day s Apart –
18-55 Years of Age ).CBER acknowledged acceptance of the revised plan for enrollment
and dosing of elderl y subjects included in this protocol amendment via email to Pfizer on
June 3 , 2020.
Protocol Amendment 3 is being finalized in parallel with this Brie fing Document and
includes CBER requested revisions, following review of Amendment 2, to remove
BNT162b3 and BNT 162a1from the C4591001 Protocol.
Pfizer also previously submitted a sy nopsis for review for a large P hase 2/3 study
(C4591002) on May 15, 2020 (Serial Number 0007). This study was designed to allow
further down -selection of candidate vaccines in the P hase 2 portion of the study and
investigate the efficacy of BNT162 vaccine candidates ( Module 5.3.5.1 Clinical Study
Synopsis C4591002 ). On May 29, 2020 , following their review, CBER provided comments
and information requests onthissynopsis via email. The Respon se to CBER May 29, 2020
Comments and I nformation Requests is provided in Mo dule 1.11.3.
Pfizer now proposes to replace Stage 3 of C4591001 in its entirety with the Phase 2/3
components previously outlined as C4591002, with changes based on CBER review .
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Page 166.2.2.1. C urrent Status in Stage 1
A total of 45participants have been enrolled and received a first dose of the BNT162 b1
vaccine candidate (modRNA encoding RBD ) or placebo. Of these, 12 participants received
10 µg, 12 received 30 µg, 12 received 100 µg ,and 9 rece ived placebo. A second dose of
10µg (12), 30µg (12) or placebo (6)has been administered to 30participants. A n expected
degree of reactogenicity for the modRNA platform is evident, with local and sy stemic
reactions similar to those reported in German Study BNT162-01. Reactogenicity is generall y
transient and of mild or moderate intensit y. Grade 3 reactogenicit y events have been reported
by5participants: 3 after a single dose of 100 µg, 1 after the second dose of 10 µg ,and 1 after
the second dose of 3 0 µg. This, alongside an apparent increase in reactogenicity after the
second dose of 30 µg, led to the Internal Review Committee (I RC) to decid enot to give a
second dose at 100 µg. No grade 4 reactogenicit y has been reported. No stopping rules have
been met and no SAEs have been reported to date.
Dosing with candidate BNT162 b2 beganon June 8, 2020 .
6.2.2.2. Proposed Amendment to Replace Stage 3 of P rotocol
Itis proposed to replace Stage 3 of the current protocol with a Phase 2 b/3 section similar to
that proposed in the submitted sy nopsis C4591002.
Toavoid confusion over terminology about sections of the study used in the initial protocol
and in protocol Amendment 3, the sections are summarized in Table 4.
Table 4. Current versus Revised Study C4591001 Section s
Current Revised
Section
nameNumber of
participantsRandomi zation
(active :placebo)Age group s
(years)Section
nameNumber of
participantsRandomi zation
(active :placebo)Age group s
(years)
Stage 1 15/cohort 4:1 18-55
65-85Phase 1 15/cohort 4:1unblinded 18-55
65-85
Stage 2 225/cohort 4:1 Stratified:
18-55
56-85Phase 2a
(if needed )225/cohort 4:1unblinded Stratified:
18-55
56-85
Stage 3 3000/age group 1:1 Stratified:
18-55
56-85Phase 2b/3a19,642 total 1:1blinded Stratified :
18-55
>55
aAnticipated 3000 in Phase 2b, will contribute to the 19,642 total for efficacy.
Stage 1 is renamed Phase 1 . It is unchanged since Amendment 2. Itisa classical Phase 1
stage with escalating dose levels in small cohorts in two different age groups.
As reactogenicit y is dependent on the type of mRNA platform (ie ,unmodified, modified, or
self-amplify ing),and both the unmodified ( uRNA, BNT162a1) and self-amplify ing (saRNA ,
BNT162c1) platforms have been de -selected for progression in the US study already ,it is
proposed that in the future aPhase 1 dose level escalation will not be required for new
candidates encoding different Sglycoprotein sequences ifbased on a the platform ty pe that
has alread y been in studied Phase 1 (ie,modRNA) .As an example, a new candidate
BNT162b3 encodes a revised RBD antigen, but otherwise is the same modRNA platform as
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Page 17BNT162b1 .If BNT162b1 in Phase 1 leads to a selected dose level to proceed into P hase 2
for both y ounger and older adults, this same dose level would be appropriate to take directl y
into Phase 2 for both age groups for BNT162b3 .
A vaccine candidate will be considered Phase 2- ready if, as determined by the I RC, safet y
(reactogenicit y and AEs) and immunogenicit y (binding and neutralizing antibody responses)
are both considered acceptable in the Phase 1 sentinel cohorts (ie ,12 participants enrolled to
recei veactive vaccine per dose level and age category ) through 7 day s after dose 2. As
described below, progression may be to Phase 2aor directl y to Phase 2b. In our submission
accompan ying Protocol Amendment 2, we committed that these data ,including Th1/ Th2
profile data for the platform ( ie, modRNA and a single dose level), will be part of the
package submitted for CBER r eview prior to initiation of Phase 2a or Phase 2b.
Stage 2 is renamed Phase 2a. This step allows further examination of safety and
immunogenicit y in larger numbers of participants ( up to 225;180 active, 45 placebo) and is
likely to be particularl y useful where it is not possible to define a single dose level from
Phase 1 data to proceed into later development.
In Phase 1 and Phase 2a the emphasis is on rapid understanding of safet y and
immunogenicit y for selection and deselection of dose levels to progress for further clinical
development . To achieve this, most participants receive a ctive vaccine ,with a randomization
ratio of 4:1 active :placebo . Additionally ,although the study is observer -blinded, the S ponsor
is unblinded to facilitate rapid decision making. If it is clear from Phase 1 , or from the
German Stud y BNT162 -01,that a dose level can be selected ,then a candidate vaccine may
progress directly to Phase 2b .
A vaccine candidate studied in Phase 2a will be considered Phase 3 -ready if, as determined
by the IRC, the following are both considered acceptable in the 90 participan ts enrolled to
receive active vaccine per dose level and age category :
Safety (reactogenicity andAEs)through 7 day s after dose 2; and
Immunogenicit y (binding andneutralizing antibody responses) through 21 day s after dose 1.
These data will be submitted for CBER review prior to initiation of Phase 3.
Stage 3 is renamed Phase 2b/3. Themain purpose of Phase 2b/3 is to provide pivotal
assessment of efficacy . For this purpose, we anticipate enroll ment of at least 20,000 subjects,
with the possibility of enrolling more if required according to observed rates of disease. For
that reason, thePhase 2b/3 section will be observer-blinded at site ,and the Sponsor staff will
also be blinded except for named unblinded staff. The randomization ratio will be 1:1
active :placebo to optimize power to detect efficacy .
If a vaccine candidate progresses directly from Phase 1 to Phase 2b/3, the following data will
be anal yzed by defined unblinded staff for the first 90 participants enrolle d to receive active
vaccine per age category per dose level (if more than one dose level enters Phase 2b/3):
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Page 18Safety (reactogenicity andAEs)through 7 day s after dose 2; and
Immunogenicit y (binding andneutralizing antibody responses) through 21 day s afte r dose 1.
(Post -dose 2 immunogenicity data will not be required for decision making to progress but
will be submitted to the IND once available .)
These data will be reviewed b y the unblinded external Data Monitoring Committee (DMC)
to determine suitability of the candidate to continue being studied in Phase 2b and through
Phase 3 and will be submitted for CBER review. Enroll ment, which is anticipated to be rapid,
may continue during the accrual, anal ysis, and submission of these data. To assure the safet y
of study participants in this period, the DMC will review unblinded safet y data weekly and, if
an untoward safet y finding arises, will have the authority to pause further enrol lment whilst it
is assessed.
In Phase 2b , 6000 participants (3000 active, 3000 placebo) will be enrolled . It is intended that
this should include around 50% younger adults 18 -55 years of age and 50% older adults
>55years of age , although the ratio may depend on when enrol lment of older adults can start.
The safety data from the fir st 3000 subjects in P hase 2b and immunogenicity data from a
total of approximately 300 subjects ( number to be confirmed ;combined from earlier phases,
German stud y BNT162 -01, and subsets from Phase 2b)
. Safety data from the remaining 3000 subjects would be submitted
within 60 day s of the initial application. The Phase 2b anal ysiswill be undertaken b y defined
unblinded staff and resulting decisions on risk -benefit t o continue taken b y the study
governance committee. Enrol lment will continue in Phase 3 in parallel with the P hase 2b
analysis.
It is anticipated that Phase 2b/3 will commence in July 2020.
6.2.2.2.1. Rational e for Phase 2b/3 Enroll ment
A broad adult population will be enrolled, comparable to that for which a vaccine is required.
Of note ,adults aged ≥ 18 years will be enrolled with no upper age limit.
Inorder to perfor mthestudy at sites where SARS -CoV -2 is circulating ,the study will b e
performed at sites across the US where there is evidence of rec ent disease activity . We will
also plan to include sites in the EU (possibly Germany , UK, Sweden, Netherlands) and
Turkey . We anticipate at least 30% of participants being enrolled in the US ,and enrol lment
will commence in the US .
Participants will be ge nerally healthy at the time of enrol lment, but those with pre -existing
stable disease, defined as disease not requiring significant change in therapy or
hospitalization for worsening disease during the 6 weeks before enrollment, can be included .
Immunocompromised persons will be excluded as vaccine immunogenicit y is not y et defined
in such conditions. I n a large clinical trial of adults ≥ 65 years of age this has resulted in a bout
half of enrolled participants having “at-risk” conditions such as chr onic cardiopulmonary
disease, chronic renal disease, diabetes ,etc. (Suaya et al. 2018). Healthcare workers and
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Page 19other front -line workers and care staff will be eligible, as will be participants in long -term
care facilities.
Particip ants will not be screened at entry for SARS -CoV -2 infection or for antibody evidence
of prior infection. This is for two reasons. Firstl y, screening at entry would severel y impact
the ability to perform a large efficacy assessment. Secondly , such screening will not be
possible in a routine immunization program and so it is important to assess immunogenicit y
and safet y in such participants . It will be possible to identify previously infected participant
based on baseline immunogenicity assay s and to identify most participants infected at entry
by presentation with COVID- 19 before completing study vaccination. The primary anal ysis
will exclude participants with evidence of previous infection or presentation with COVI D-19
before 14 day s after the last dose of s tudy vaccine.
Age groups will be stratified by age between younger adults 18-55 years of age andolder
adults >55years of age . It is possible that enrollment may commence in the younger stratum,
as data to support progression in this age group may be available before data to support
progression in older adults.
6.2.2.2.2. Rationale for E fficacy Assessments and Case Definitions
The case definitions for COVID -19 were described in the Clinical Overview for the initial
IND (Module 2.5) as participants in all stages may be followed for COVID- 19 for up to
24months. The case definitions for COVID -19 and severe COVID -19have been modified in
accordance with CBER’s suggestions.
Subjects with the following s ymptoms, which trigger either an illness visit or a telehealth
visit with self -swabbing, andSARS -CoV -2 NAAT -positive at Pfizer’s central laboratory or
locally with a validated nucleic acid amplification test (NAAT) are defined as having
COVID -19:
Fever;
New or increased cough;
New or increased shortness of breath;
Chills;
New or increased muscle pain;
New loss of taste or smell;
Sore throat ;and/or
Diarrhea and vomiting .
Diarrhea and vomiting have been added to this list as requested b y CBER as there have been
reports of presentation with gastrointestinal s ymptoms alone (Pan et al. 2020). Consideration
was given to adding nausea as a defining s ymptom, but as nausea is too common for many
people in daily life,it has not been included.
Note that microbiological diagnosis may be b y NAAT perform ed at Pfizer’s central
laboratory or a locall y performed NAAT using a validated method. The use of local results
may be particularl y important for sites outside the US, due to transport limitations during the
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Page 20current pandemic . It will also be important whe re participants present to emergency
healthcare without contact with the investigator site.
The sample tested for b y NAAT will generally be mid -turbinate swabs as COVID -19 most
commonly presents with respiratory symptoms and these are readily provided for self-
swabbing. However, positive NAAT testing from other samples will be considered to
contribute to defining a case. This is most likely to be the case for local testing as emergency
room procedures may vary in which samples are taken in suspected cases. For example ,
saliva or other upper respiratory tract samples may be acquired, and stool samples may be
taken if gastrointestinal sy mptoms are prominent.
A definition for severe disease was added based on reports of factors associated with poor
outcomes (Richardson S et al. 2020 ; Guan W -j et al. 2020 ).In addition, we have taken
account of CBER’s comments on the definition and updated it such that p articipants with
confirmed COVID -19 and the following will be defined as having severe COVID -19:
Clinical signs at rest indicative of severe s ystemic illness ( RR≥30 per minute, HR≥125
per minute , SpO 2 ≤93% on room air at sea level ,or PaO 2/FiO 2<300 mm Hg) ;
Respiratory failure (defined as needing high -flow oxy gen, noninvasive ventilation,
mechanical ventilation, or ECMO) ;
Evidence of s hock ( SBP <90 mm Hg, D BP <60 mm Hg, or requiring vasopressors) ;
Significant acute renal, hepatic, or neurologic d ysfunction ;
Admission to an intensive care unit; or
Death.
6.2.2.2.3. Analyses During Phase 2b/3
Objectives, estimands and endpoints were presented in the sy nopsis for a Phase 2/3
randomized, placebo -controlled, observer -blinded study of the efficacy and safet y of one or
more COVID -19 V accine candidates in individuals ≥18 years of age (C4591002 ). At
CBER’s suggestion , additional objectives and associated estimands and endpoints will be
included to assess safety , immunogenicit y,and efficacy in subjects with evidence of prior
infection at baseline.
Three types of anal yses are proposed during the Phase 2b/3 portion of the study :
Phase 2b safet y and immunogenicity anal ysis to support continuation of a vaccine
candidate/dose level in Phase 3 ;
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(b) (4)
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Page 21Efficacy interim and final analy ses to support T raditional Approval .
Phase 2b safety and immunogenicity analysis to support continuation of a vaccine
candidate/dose level in Phase 3
If a vaccine candidate progresses directly from Phase 1 to Phase 2b/3, the following data will
be anal yzed by defined unblinded staff for the first 90 participants enrolled to receive active
vaccine per age category per dose level (if more than one dose level enters Phase 2b/3):
Safety (reactogenicity , AEs) through 7 days after dose 2; and
Immunogenicit y (binding , neutralizing antibody responses) through 21 days after dose 1.
(Post -dose 2 immunogenicity data will not be required for decision making to progress
but will be submitted to the IND once available .)
These dat a will be reviewed by the unblinded external DMC to determine suitability of the
candidate to continue being studied in Phase 3 and will be submitted for CBER review .
Enro llment will continue while this analy sis is performed .
Phase 2b safety and immunogen icity analysis
It is anticipated that up to 3000 subjects (1500 active, 1500 placebo) will have completed a
1-month post -dose 2 visit in September 2020 for at least one candidate vaccine ,and that
clinical data together with immunogenicit y (including virus neutralizing assay results) on a
subset would be available within a few weeks. As enrol lment would continue during this
analysisat a substantial rate, this could be supplemented by safet y data on an additional
3000 participants (1500 active, 1500 pl acebo) within 60 day s. This analy sis would be
performed and reported by a defined unblinded team separate from staff managing the
clinical study as blinded assessment of efficacy would continue.
Efficacy interim and final analyses
Theprimary efficacy analysiswill be efficacy against COVI D-19 at least 14 day s after the
last dose of vaccine in participants without evidence of prior SARS -CoV -2 infection at
baseline, as such infection induces strong neutralizing antibody responses likely to prevent
further infection (Okba et al. 2020 ).
Pfizer acknowledges C BER’s position that the criterion of success for efficacy should be
based on demonstrating vaccine efficacy (VE) >30% , and a statistical framework
corresponding to this criterion is described below. Pfizer’s preference, however, is to retain a
criterion based on demonstrating VE >20%in the protocol because results from this study
will be used to seek licensure from other global regulatory authoritie swho may accept a
threshold of 20% for VE.We acknowledge that CBER may ultimately require VE >30% for
USlicensure. We look forward to additional discussions and alignment with CBER on this
topic prior to unblinding.
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Page 22Also, as shown below, using VE >30% rather than VE >20% requires approximately 50%
more cases (under current design assumptions) , which is likely to extend the length and /or
increase the complexity of the study . From a practical perspective, both approaches would
require an observed VE of approximately 50% to meet the respective success criteria , based
on the proposed number of cases. For these reasons, Pfizer maintains that the original
threshold is appropriate .
Given the large number of cases required, uncertainty in the rate of ca se accrual ,as well as
the true level of vaccine efficacy and the likely need to provide data to CBER as the study
progresses, Pfizer proposes that a more flexible statistical framework be considered since it
may be more appropriate for this setting than the more traditional frequentist approach
described previously .Specificall y, Bayesian sequential designs provide a formal framework
for updating information about the vaccine effect as new data are observed, and consequ ently
these designs are well suited to interim analy ses with accumulating information. R esults of
Bayesian anal yses may also be easier to interpret than frequentist anal yses as they provide
direct probabilistic statements about the unknown VE using the posterior distribution . The
posterior distribution drives key decisions at each interim analy sis, such as stopping for study
success or futility . Predictive probabilities can also be obtained from the posterior, such as
the probability that the study will be successful if it continues to completion. These measures
are more informative than confidence intervals , and they can provide the probability of
interest corresponding to various thresholds for VE.
Themaximum number of cases is specified to be N=110 (corresponding to a VE t hreshold of
20%; Table 5) or N=150 (corresponding to a VE threshold of 30% ; Table 6 ). Stopping for
success will not occur before accruing at least 40% of the target or maximum number of
cases, and the number of interim analy ses is limited to four based on practical considerations.
Bayesian sequential design swith interim anal ysesare p roposed, although t he boundaries for
efficacy and futility in Table 5and Table 6 may be further modified to ensure good operating
characteristics (t ype I error and power).
Bayesian approaches require specification of a prior distribution for the possible values of the
unknown vaccine effect, thereb y accounting for uncertaint y in its value. A minimally
informative beta prior, Beta(0.700102, 1) ,is propo sedfor θ (= (1- VE)/(2 -VE). The prior is
centered at 0.4118 (VE=30%) which can be considered pessimistic. The prior allows
considerable uncertainty ;the 95% interval for θ is (0.005, 0.964) and the corresponding 95%
interval for VE is (-26.2, 0.995).
Decision c riteria based on VE threshold = 20%
Study success is defined as demonstrating eff icacy of a candidate vaccine. The study will be
deemed successful at the final anal ysis if the posterior probability of VE > 20% is at least
0.975. This value is chosen based on power and simulated ty pe I error considerations. An
observed estimate of VE ≥47.2 % (case split 38:72 for vaccine: placebo) is required to meet
this criterion.
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Page 23The stopping criteria for futility are based on the posterior predictive probability of trial
success (POS) at the end of the study . POS incorporates accumulated complete data, as well
as the uncertainty associ ated with future cases. The study will be stopped early for futility if
demonstrating VE at the end of the study is unlikely (ie,POS <5% ).
The stopping criteria for success at an interim analy sis are based on the posterior probabilit y
at the current numbe r of cases. If this probability is greater than the success threshold at an
interim analy sis, the study will stop for overwhelming efficacy . The success threshold for
each interim anal ysis is specified as 99%, that is, P(VE ≥2 0%|data) >0.99.
Efficacy and futility boundaries are calculated in a nonbinding way .
Table 5 summarizes the design with four interim anal yses using a VE threshold of 20%.
Table 5. Bayesian Sequential Design with Four Interim Analyses
(VE Threshold = 20%)
Interi m
AnalysisTiming of Interim Analysis
(Information Fraction)Stop for
EfficacyStop for
FutilityEfficacy Boundaries Futility Boundaries
1 22/110 (1/5) No Yes NA VE ≤-20% and Y ≥12
2 44/110 (2/5) Yes Yes VE ≥62.5% and Y ≤12 VE ≤16.7% and Y ≥20
3 66/110 (3/5) Yes Yes VE ≥56.5% and Y ≤20 VE ≤26.3% and Y ≥28
4 88/110 (4/5) Yes No VE ≥53.3% and Y ≤28 NA
Boundaries are provided in terms of VE and number of cases in the active vaccine arm (Y) .
With assumptions of true VE of 60% after the last dose of investigational product, a total of
approximately 110 first confirmed COVID -19illness cases will be sufficient to demonstrate
VE >20%. This would be achieved with 7857 evaluable participants per gr oup or 9821
vaccine recipients randomized in a 1:1 ratio with placebo, based on the assumption of a 1.0%
incidence rate in the placebo group, and 20% of the participants being non -evaluable or
having serological evidence of prior infection with SARS -CoV -2. Pfizer may inve stigate the
possibility of enrolling a larger number of participants to accrue the cases in shorter time .
Decision c riteria based on VE threshold = 30%
Using the threshold proposed by CBER , the study would be deemed successful at the final
analysis if the posterior probability of VE > 30% is at least 0.975. One hundred and fift y
(150) would be accrued, and an observed estimate of VE ≥50 % (case split 50:100 for
vaccine:placebo) would be required to meet this criterion.
The stopping criteria for futility are based on the posterior predictive POS at the end of the
study . The study will be stopped earl y for futility if demonstrating VE at the end of the study
is unlikely (ie,POS <5% ).
The stopping criteria for s uccess at an interim analysis are based on the posterior probabilit y
at the current number of cases. If this probability is greater than the success threshold at an
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Page 24interim analy sis, the study will stop for overwhelming efficacy . The success threshold for
each interim anal ysis is specified as 99%, that is, P(VE ≥3 0%|data) >0.99.
Table 6 summarizes the design with four interim anal yses using a VE threshold of 30%.
Table 6. Bayesian Sequential Design with Four Interim Analyses
(VE Threshold = 30%)
Interi m
AnalysisTiming of Interim Analysis
(Information Fraction)Stop for
EfficacyStop for
FutilityEfficacy Boundaries Futility Boundaries
1 30/150 (1/5) No Yes NA VE ≤0% and Y ≥15
2 60/150 (2/5) Yes Yes VE ≥63.6% and Y ≤16 VE ≤28.6 % and Y ≥25
3 90/150 (3/5) Yes Yes VE ≥59.5% and Y ≤26 VE ≤36.4 % and Y ≥35
4 120/150 (4/5) Yes No VE ≥55.4% and Y ≤37 NA
Boundaries are provided in terms of VE and number of cases in the active vaccine arm (Y).
6.2.3. Clinical Lot Consistency Study
TheBNT162 vaccine candidate active antigenic components are manufactured in a
controlled chemical process and the LNPs contain defined components . To fulfill CBER’s
clinical lot consistency study requirement , a randomized safety and immunogenicity study
willcompare three lots of the vaccine candidate manufactured with a process suitable for
large -scale manufacture and will be performed in 2021 . The primary immunogenicity
endpoint will be antigen -specific IgG. The number of participants will be based upon
emerging data on vaccine immunogenicit y and assay characteristics .Due to the urgency of
the current pandemic and the desire to have a US- licensed vaccine as quickly as possible, the
Sponsor proposes that this study be conducted as a post -approval commitment.
6.3.Pediatric Plan
Within family clusters children were noted to be infected as often as adults (Bi et al. 2020 ).
Pediatric and adolescent SARS -CoV -2 infections have generall y been as ymptomatic or mild
(Lu et al. 2 020; Liu et al. 2020 ; Zimmermann & Curtis 2020 ; Qiu et al. 2020 ),which is likely
the reason wh y far fewer cases were identified in these age groups than in adults
(Wu&McGoogan 2020 ; Guan et al. 2020 ; Richardson et al. 2020 ). However, some infected
children have required intensive care support (Lu et al. 2020 ).There is a lso a possible
relationship between SARS- CoV -2 infection and a Kawasaki -like s yndrome (Verdoni et al.
2020 ). The role of children and adolescents in transmission is unknown, but more common
seasonal coronaviruses are frequently found in the upper respiratory tract of sy mptomatic and
non-symptomatic children (Zimmermann & Curtis 2020 ),suggesting that transmission might
be common.
In accordance with regulations, w e intend to submit an initial Pediatric Study Plan ( iPSP )in
July 2020 , at about the time we plan to start rapid enrollment of participants into the
Phase 2/3 component of Study C4591001 and at which point we expect to be moving
forward in adults with a specific vaccine candidate at a defined dose -level. The iPS P will
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Page 25outline the planned pediatric studies in children 12 months through 17 y ears of age which
will proceed in a st epwise manner.
Currently , a waiver is planned for children <12months of age to avoid interfering with
delivery of existi ng vaccine schedules which are of known public health importance
(Nelson 2020 ),and due to the infrequency and general mild and self -limiting nature of
disease in children in the first y ear of life ( Lu et al. 2020 ; Liu et al. 2020 ; Zimmermann &
Curtis 2020 ; Qiu et al. 2020 ; Wu& McGoogan 2020 ; Guan et al. 2020 ; Richardson et al.
2020 ).
Safety will be demonstrated in approximately 3000 pediatric
subjects. Licensure via Traditional Approval in the pediatric population will therefore be
dependent on Trad itional Approval of the adult indication (following demonstration of
clinical endpoint e fficacy) . Details of the pediatric study plan will be included in the iPSP .
6.4.Pregnancy
COVID -19 infections have been described in pregnant women, generall y with good
outcomes following Caesarean section (Yu et al. 2020 ).Neonatal infection has followed in
some but generall y without adverse outcome s (Yu et al. 2020 ; Zeng et al. 2020).
Nonetheless, i t would be desirable to protect women with a vaccine during the second half of
pregnancy and this may also have the advantage of protecting neonates from COVI D-19,
even though neonatal disease has not generally been severe. Therefore, the Sponsor plans to
seek licensure for use in pregnant women 18 -45 years of age. Licensure will be sought based
on demonstration of adequate safety and effectiveness sed
.
Before starting a stud y of vaccination in pregnancy, results from a DART study will be
submitted . The results of this would also be reassuring for advising women following
accidental exposure in early pregnancy , which is very likely to occur in the event of a large -
scale general population immunization program.
A two -stepsafety and immunogenicit y stud y is anticipated, bridging to immunogenicit y data
in age-matched non -pregnant adults in Study C4591001 . Initiall y up to 40 pregnant women
18-40 years of age would be randomized to receive a first dose of COVID -19 vaccine o r
TdaP (Tetanus toxoid, low dose di phtheria toxoid , acellular pertussis vaccine )between
270/7 and 35 6/7 weeks gestation and a second dose 3 weeks later, with the control group
receiving placebo.
In a second step ,the study would expand to 200 participants randomized to two doses of
COVID -19 vaccine candidate or TdaP followed b y placebo. Numbers may be adjusted based
on assay characteristics and risk of safet y events. Consideration would be given to including
some participants to receive their f irst dose from 24 0/7 gestational age.
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Page 26In addition to safet y, reactogenicit y,and immunogenicity assessments in maternal
participants we would record pregnancy and neonatal outcome, with cord blood and 6- month
infant blood for SARS -CoV -2 serology . Mothers and neonates would be followed for up to
6months after birth for SAEs and clinical COVID -19 episodes.
Similar to the pediatric population, licensure for use in pregnancy would follow Traditional
Approval of the candidate vaccine in adult subjects following demonstration of acceptable
clinical efficacy .
A pregnancy register capturing maternal, birth , and infant outcomes will be created for
inadvertentl y exposed pregnant women during development but particularly for anticipated
exposures in pregnancy durin g post -approval use of the vaccine.
7.REGULATORY PATHWAYS
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Page 297.2. Emergency Use Authorization
. The Emergency Use Auth orization request package could be submitted for CBER
review in parallel with the initial BLA.
7.3. Tr aditional Approval
The clinical data anticipated for Traditional Approval application in 2021 for the first
BNT162 candidate is summarized in Table 8. The timeline for clinical development and
regulatory submissions is shown below.
Table 8.Clinical Data for Traditional Approval Pathway
Study Safety 1- month post -dose 2
(active/placebo)Immunogenicity
(active)Efficacy
(total)
Traditional Approval based
onfinal efficacy analysisC4591001 Phase 1 24/6a24aNA
C4591001 Phase 2a 180/45b180bNA
C4591001 Phase 2b/3 9821/9821c9821d(subset) 19,642c
110 casese
a Half 18 -55 years of age, half 65 -85 years of age .
bHalf 18 -55 years of age, half 56 -85 years of age, if Phase 2a is performed .
cStratified to 18 -55and >55years of age. Not equal by age, depends on enro llment capability in older adults.
dSubset sizes for immunogenicity will depend on assay characteristics and Phase 1 data.
e110 cases at final analysis but interim efficacy analyses at 44, 66, and 88 cases .
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Page 308.SUMMARY
In summary , the Sponsor respectfull y requests CBER feedback on the following :
The overall Clinical Development Plan and timeline proposed to support
Traditional Approval.
The a dequacy of S tudy C4591001 to serve as thesingle pivotal study to dem onstrate
safet y, immunogenicity ,and efficacy of the candidate vaccine for the proposed indication
and the use of Study C4591001 to support Traditional Approval .
Pfizer/BioNTech’s plans to evaluate the BNT162b3 candidate expressing the RBD
domain with a short transmembrane tail and two amino acids added to the signal peptide
for more homogenous cleavage in Study C4591001, as described in Section 6.2.
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Page 31The proposal that study success criteria usin g the identified protective threshold may be
defined in parallel with the Phase 2/3 study ,as long as the stud y will continue fully
blinded .
Providing a dditional safety data for 1 500 vaccinated participants ( additional 3000 vaccine
and placebo combined), that is split approximately equally across cohorts 18- 55 and
>55years of age during review, within 60 day s of BLA submission .
Conducting the planned clinical lot consistency study in parallel with the planned Phase 3
efficacy study and submitt ing the results as a post -approval commitment.
The adequacy ofthe proposed stud y design, including Phase 2 b/3 efficacy portion, and
the planned persistence evaluations to support Traditional Approval .
Pediatric Study Plans.
Maternal Immunization Study Plans.
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Page 329.REFERENCES
(All references are available upon request)
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Nelson R. COVID -19 disrupts vaccine delivery . The Lancet Infectious Dis 2020;20:546.
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Page 33Okba NM, Muller MA, Li W, et al. SARS -CoV -2 specific antibod y responses in COVID -19
patients. MedRXiv .Posted March 20, 2020. doi: 10.1101/2020.03.18.20038059.
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Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and
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of SARS -CoV -2. Nature. Posted May 26, 2020. doi: 10.1038/s41586 -020-2381 -y.
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pneumococcal conjugate vaccine against vaccine -type community -acqui red pneumonia in at -
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Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the
Italian epicentre of the SARS- CoV -2 epidemic: an observational cohort study . The Lancet.
Posted May 13, 2020 . doi:10.1016/S0140 -6736(20)31103-X.
Vogel AB, Lambert L, Kinnear E, et al. Self -amplify ing RNA vaccines give equivalent
protection against influenza to mRNA vaccines but at much lower doses. Mol Ther
2018;26(2):446 -55.
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Page 34Wu Z, McGoogan. Characteristics of and important lessons from the coronavirus disease
2019 (COVID -19) outbreak in China: summary of a report of 72 314 cases from the Chinese
Center for Disease Control and Prevention. JAMA 2020 ;323(13):1239 -42.
XieX, Muruato A, Lokugamage KG, et al. An infectious cDNA clone of SARS -CoV -2.
Cell Host & Microbe 2020; 27:841-8.
Yu N, L i W, Kang Q, et al. Clinical features and obstetric and neonatal outcomes of pregnant
patients with COVID -19 in Wuhan, China: a retrospective, single -centre , descriptive study .
The Lancet Infectious Diseases. Posted March 25, 2020. doi:10.1016/S1473 -3099(20)30176-6.
Zeng L, Xia S, Yuan W, et al. Neonatal earl y-onset infection with SARS -CoV -2 in 33
neonates born to mothers with COVI D-19 in Wuhan, China. JAMA Pediatrics
Posted March 26, 2020. doi:10.1001/jamapediatrics.2020.0878.
Zhau X, Chen D, Szabla R, et al. Broad and differential animal ACE2 receptor usage b y
SARS -CoV -2. bioRxiv. Posted April 20, 2020. doi:10.1101/2020.04.19.048710 .
Zhou P, Yang X, Wang X, et al. A pneumonia outbreak associated with a new coronavirus of
probable bat origin. Nature 2020;579 :270-3.
Zimmermann P, Curtis N. Coronavirus infections in children including COVID -19: an
overview of the epidemiology , clinical features, diagnosis, treatment and prevention options
in children. Ped Infect Dis J 2020;39:355 -68.
Zost SJ, Gilchuk P, Chen RE, et al. Rapid isolation and profiling of a diverse panel of human
monoclonal antibodies targeting the SARS -CoV -2 spike protein. bioRxiv. Posted May 13, 2020.
doi:10.1101/2020.05.12.091462 .
Zou L, Ruan F, Huang M, et al. SARS- CoV -2 Viral load in upper respiratory specimens of
infected patients. N Engl J Med 2020;382:1177 -9.
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Document Approval Record
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Page 1COVID -19 Vaccine (BNT162, PF -07302048)
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Response to CBER 25 June 2020 Preliminary Type C Meeting
Comments and Requests /Meeting Minutes
July 8, 2020
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Page 2TABLE OF CONTENTS
1. INTRODUCTION ................................ ................................ ................................ ................. 4
2. CBER REQUESTS AND SPONSOR RESPONSES ................................ ............................ 4
2.1. Clinical ................................ ................................ ................................ ...................... 4
2.1.1. Sponsor Clinical Question 1 ................................ ................................ ......... 4
2.1.1.1. Sponsor Clinical Question 1a ................................ ...................... 4
2.1.2. Sponsor Clinical Question 1b ................................ ................................ .......6
2.1.2.1. CBER Clinical Request 1b(i) ................................ ...................... 6
2.1.2.2. CBER Clinical Request 1b(ii) ................................ ..................... 7
2.1.3. Sponsor Clinical Question 1c ................................ ................................ .......7
2.1.3.1. CBER Clinical Request 1c ................................ .......................... 7
2.1.4. Sponsor Clinical Question 1d ................................ ................................ .......8
2.1.5. Sponsor Clinical Question 2 ................................ ................................ ......... 9
2.1.6. Sponsor Clinical Question 3 ................................ ................................ ......... 9
2.1.6.1. CBER Clinical Request 3a ................................ .......................... 9
2.1.6.2. CBER Clinical Request 3b................................ ........................ 10
2.2. Regulatory Comments ................................ ................................ ............................. 10
...10
...10
...10
...11
...11
...12
...12
...12
2.2.2. Traditional Approval ..................................................................................13
2.2.2.1. Sponsor Traditional Approval- Related Question 1 ................... 13
2.2.2.2. Sponsor Traditional Approval- Related Question 2 ................... 14
2.2.3. Emergency Use Authorization (EUA) ................................ ........................ 14
2.2.3.1. Sponsor EUA- Related Question 1 ................................ ............. 14
2.2.4. Pediatric and Maternal Immunization (P&MI) Study Plans ....................... 15
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Page 32.2.4.1. Sponsor P&MI Study Plans- Related Question 1 ....................... 15
2.2.4.2. Sponsor P&MI Study Plans- Related Question 2 ....................... 16
2.2.4.3. Sponsor P&MI Study Plans-Related Question 3 ....................... 16
2.2.4.4. Sponsor P&MI Study Plans- Related Question 4 ....................... 17
2.3. Additional FDA Comments ................................ ................................ .................... 18
2.3.1. Additional FDA Comment 1 ................................ ................................ ......18
2.3.2. Additional FDA Comment 2 ................................ ................................ ......18
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Page 41.INTRODUCTION
Reference is made to BB -IND 19736 for the COVID -19 Vaccine (BNT162; PF -07302048)
that Pfizer and BioNTech are developing for the prevention of COVID -19 in adults ≥18years
of age. On 26 June 2020, a Ty pe C meeting was held to gain CBER feedback regarding
Pfizer /BioNTech ’sproposed Clinical Development Program , including revis ions to the
ongoing Study C4591001, as well as high- level pediatric and maternal immunization plans .
CBER feedback was also requested regarding t he clinical data requirements to support
Traditional Approval, as well as requirements for use under an Emergency
Use Authorization.
CBER provided preliminary meeting responses to Pfizer /BioNTech ’s pre -meeting questions,
along with additional comments and requests , via email on 25 June 2020. On 26 June 2020,
in advance of the meeting, Pfizer requested to walk th rough each item during the meeting for
clarity . The information below provides minutes of the discussion between CBER and
Pfizer/BioNTech per item during the Ty pe C Meeting. The Sponsor’s original questions, as
well as C BER’s pre-meeting comme nts and requests are noted in bold italics andfollowed b y
the discussion per topic.
At the start of the meeting Pfizer/BioNTech acknowledged CBER’s feedback regarding
based
upon CBER’s feedback we pl an to seek Traditional Approval so we will focus the meeting
on what will be required for that.
2.CBER REQUESTS AND SPONSOR RESPONSES
2.1.Clinical
2.1.1. Sponsor Clinical Question 1
Does CBER have any comments on the overall Clinical Development Plan and timeline
proposed to support
Traditional Approval? Specifically,
2.1.1.1.
Sponsor Clinical Question 1a
Does CBER agree with the proposed revisions to the ongoing Phase 1/2 US Study
C4591001 that would add a Phase 2/3 efficacy phase to the study, to evaluate efficacy in an
expanded number of participants? Does CBER agree with the proposed Phase 3 safety,
immunogenicity, and efficacy endpoints and case definitions?
FDA Response to Clinical Question 1a
We agree with your general proposal to add a Phase 2/3 efficacy phase to the study
[C4591001] and evaluate efficacy in an expanded number of participants.
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Page 52.1.1.1.1. CBER Clinical Request 1a(i)
We note that you state, “the Phase 2b/3 section will be observer- blinded at site, and the
Sponsor staff will also be blinded except for named unblinded staff.” We request that the
blinding procedures be updated in the revised protocol, with appropriate justifications
included, to ensure study integrity.
Meeting Discussion
Pfizer/BioNTech acknowledged CBER’s request and agreed to make the update to the
protocol for stud y C4591001. Weinformed CBER that the submission of the updated
protocol for stud y C4591001 is anticipated for the end of next week. [Post-meeting Note:
Protocol C4591001 Amendment 4 including this update was submitted on 02 July 2020
(SN00 25)].
2.1.1.1.2. CBER Clinical Request 1a(ii)
We recommend the case definition described below, which is similar to your proposed
primary efficacy endpoint case definition, to standardize e valuation of efficacy across
COV ID-19 vaccine studies. You may choose to evaluate the standardized case definition as
your primary efficacy endpoint or as a secondary endpoint to be analyzed with or without
formal hypothesis testing. We recommend defining a positive case as virologic
confirmation by RT -PCR for SARS -CoV-2, along with any symptom for COVID -19 as
listed by the CDC (https://www.cdc.gov/coronavirus/2019 -ncov/symptoms -
testing/symptoms.html): fever or chills , cough, shortness of breath or difficul ty breathing,
fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion
or runny nose, nausea or vomiting, diarrhea.
Meeting Discussion
Pfizer/BioNTech acknowledged CBER’s request. Weproposed to retain our case definition
as currently described in the protocol for study C4591001 and add the CDC case definition as
a secondary endpoint in the updated protocol . CBER agreed. [Post-meeting Note: Protocol
C4591001 Amendment 4 including this change was submitted on 02 July 2020 (SN0025)].
2.1.1.1.3. CBER Clin ical Request 1a(i ii)
We acknowledge your agreement to modify your case definition for severe COVID -19 as
previously requested.
Meeting Discussion
There was no discussion o fthis item during the meeting.
2.1.1.1.4. CBER Clin ical Request 1a(iv)
Please propose a study stopping rule for severe disease as an indicator of enhanced disease
to be assessed by the DMC with each prespecified interim analysis. An acceptable
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Page 6approach would be to pause study enrollment for further data review, as well as
notification of OVRR, if the number of severe COVID -19 cases is greater among vaccine
versus placebo recipients. You may propose alternative rules based on reasonable
statistical criteria.
Meeting Discussion
Pfizer/BioNTech acknowledged CBER’s comment and st ated that a stopping rule will be
provided in the updated C4591001 protocol for CBER’s review. CBER agreed with this
approach. [Post-meeting Note: Protocol C4591001 Amendment 4 including th e stopping rule
was submitted on 02 July 2020 (SN0025)].
2.1.1.1.5. CBER Clin ical Request 1a(v)
The briefing document did not include defined safety and immunogenicity endpoints for
Phase 3. However, we agree in general with the safety and immunogenicity endpoints
described in the previously submitted Phase 3 protocol synopsis (in a mendment 7,
sequence 0007, dated May 15, 2020), including the plan to assess the serologic response at
baseline, 14 days, and 1, 6, 12, and 24 months after completion of vaccination in all study
subjects in Phase 3. The immunologic assays described in item 2.13.1 of your responses to
CBER comments dated May 29, 2020 are appropriate, provided the assay validation data to
be submitted prior to the testing of Phase 3 samples are acceptable.
Meeting Discussion
Pfizer/BioNTech sought clarification on the applicability of this request to the initial BLA
since we would now be seeking Traditional Approval. We explained that while these would
be supportive data, for example, for subsequent immunobridging, they will probably not be
relevant for the initial BLA filing and licensure which will likely be based upon efficacy
data, and hence would not be required in the initial BLA . CBER agreed. We also stated that
the
immunogenicit y sampling beyond 1 month post -dose 2 to a subset of participants in Phase
2b/3.
It was also agreed that Pfizer will provide CBER the assay validation data prior to testing of
Phase 3 samples.
2.1.2. Sponsor Clinical Question 1b
Does CBER agree with the proposed study success criteria for Phase 3
?
2.1.2.1. CBER Clinical Request 1b(i)
As communicated previously, we do not agree with a success criterion defined as the lower
limit of VE being >20%. To ensure that a widely deployed vaccine is more than modestly
effective, we request that the success criterion be defined equivalent to a primary efficacy
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Page 7endpoint point estimate of at least 50% and the lower limit of the alpha -adjust ed 95% CI
around that point estimate being >30%. In principle, the four interim analyses proposed in
Table 6 of the briefing document, using a VE threshold of 30%, would be acceptable if the
criteria were adjusted to preserve the type I error rate at 2.5%. In addition, the proposed
efficacy boundaries are based solely on case split, which presumes that the numbers of
evaluable subjects and duration of follow -up in both groups are equivalent. Please clarify
how you plan to adjust the boundaries for potential difference in numbers of evaluable
subjects.
Meeting Discussion
On 24 June 2020 Pfizer provided a set of slides to CBER via email that were utilized for the
discussion of this topic (See Attachment A ). With reference to slide numbers 8 and 9 Pfizer
explained how we intend to potentially identify vaccine efficacy at 32 cases. CBER convey ed
that conceptuall y, the design seems appropriate, however they will review this carefull y and
provide post -meeting feedback on this topic. [Post-meeting Note:Protocol C4591001
Amendment 4 was submitted on 02 July 2020 (SN0025)].
2.1.2.2. CBER Clinical Request 1b(ii)
Given that current COVID -19 epidemiology is permissive for conducting clinical disease
endpoint efficacy trials,
.
approval will need
to be based on demonstration of clinical disease endpoint efficacy.
Meeting Discussion
Acknowledged b y Pfizer/BioNTech at the start of the meeting.
2.1.3. Sponsor Clinical Question 1c
Does CBER agree with the proposed plan for progre ssion of vaccine candidates from
Phase 2 to Phase 3?
2.1.3.1. CBER Clinical Request 1c
We agree with the proposal that includes review of unblinded safety data through 7 days
after dose 2 and immunogenicity data through 21 days after dose 1 of each vaccine
candidate by the internal review committee. With the submission of these data to CBER,
we request that you include a summary of the data that includes the rationale for dose
selection.
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Page 8Meeting Discussion
On 26 June 2020 Pfizer provided 2 tables to CBER vi a email that were utilized for the
discussion of this topic (See Attachment B ). Pfizer explained that we are getting a much
better understanding of the dosage from the US and German studies , have eliminated some of
the initial candidates, and that going fo rward the dose levels are likely to be 10 or 20 mcg.
We anticipate being able to have a decision on the Ph2b/3 candidate which would be either
BNT162 b1 or BNT162 b2, and the dosage decision should be made b y July 17th. Pfizer
representatives walked through the tables provided with details regarding when relevant
nucleoside -modified mRNA (modRNA) platform data from US Study C4591001 will
become available for decisions and for submission to CBER, including plans to provide
CBER data in real time. BioNTech representatives added information regarding when
additional data will also be available from German Study BNT162-01.
Pfizer further explained that the intention is to make the decision on candidate and dosage
based on data from the sentinel subject s in Stage 1such that we are read y to have 1 vaccine
candidate, at 1 dose level, to start Phase 2b/ 3 and enroll rapidl ywhile there are still
significant cases in the US, to be able to potentially identify vaccine efficacy as earl y as
when 32 cases have accrued, as described during the discussion of the statistical design.
Pfizer/BioNTech offered to send further information regarding data availability from both
studies to CBER to assist in their review. CBER convey ed that they will review and provide
post-meetin g feedback on this topic.
[Post Meeting Note: On 30 June 2020 Pfizer provided additional information via email for
clarification and timing around the data to be provided to CBER in advance of Phase 2b/3
study start planned for 20 July 2020. This informati on was also submitted to BB- IND 19736
on 1 J uly2020 ( Module 1.12.14 Request for Comments and Advice SN0024 ).]
2.1.4. Sponsor Clinical Question 1d
Does CBER agree with the proposed inclusion of global sites (e.g., EU, South America,
Turkey) in the efficacy phase of the study with at least 30% of participants coming from
the US assuming current state of the pandemic?
FDA Response to Cl inical Question 1d
We agree with the proposal to include global sites in the efficacy phase of the study, with at
least 30% of parti cipants coming from the US.
Meeting Discussion
There was no discussion on this item during the meeting.
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Page 92.1.5. Sponsor Clinical Question 2
Does CBER agree that revised Study C4591001 is adequate to serve as the single pivotal
study to demonstrate adequate safety, immunogenicity, and efficacy of the candidate
vaccine for the proposed indication and may be used to support
Traditional Approval?
FDA Response to Clinical Question 2
Please see our responses to your other questions. We agree that a single, well -designed and
well-conducted clinical disease endpoint efficacy study that is able to meet our requested
pre-specified success criterion would likely provide substantial evidence of effectiveness
and an adequately sized safety database to supp ort licensure of your product via the
Traditional Approval Pathway.
.
Meeting Discussion
Acknowledged b y Pfizer/BioNTech at the start of the meeting.
2.1.6. Sponsor Clinical Question 3
Does CBER agree with Pfizer/BioNTech’s plans to evaluate the BNT162b3 candidate
expressing the RBD domain with a short transmembrane tail and two amino acids added
to the signal peptide for more homogeneous cleavage in Study C4591001, as described in
Section 6.2?
FDA Response to Clinical Question 3
We agree that the clinical data from BNT162b1, which uses the same nucleoside -modified
mRNA (modRNA) platform as your new BNT162b3 vaccine candidate, could support the
useof BNT162b3 in the proposed Phase 1/2/3 study. As previously communicated on June
3, 2020, you may submit a revised protocol to include the new vaccine candidate with
supportive CMC and nonclinical data.
2.1.6.1. CBER Clinical Request 3 a
Please provide the CMC drug substance and drug product information for the BNT162b3
clinical lot and the non -clinical immunogenicity data for this new vaccine candidate
(including assessment of Th1/Th2 markers and cellular responses) to the IND prior to the
initiation of the Phase 2 portion of your Study C4591001. In addition, please provide a
summary of CMC comparability between BNT162b1 and BNT162b3.
Meeting Discussion
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Page 10Pfizer/BioNTech acknowledged CBER’s request and convey ed that a CMC amendment to
provide information for BNT1 62b3 is planned to be submitted to CBER next week. [Post -
meeting Note: The CMC amendment was submitted to BB -IND 19736 on 29 June 2020 (SN
0021)].
2.1.6.2. CBER Clinical Request 3 b
We note that if Phase 1 evaluation of BNT162b1 leads to a selected dose level to pro ceed
into Phase 2 for both younger and older adults, you plan to take BNT162b3 directly to
Phase 2 for both age groups at the same dose selected for BNT162b1. However, your
rationale for inclusion of BNT162b3 is that it has shown superior immunogenicity to
BNT162b1 in mice, which suggests that the immunologic response to these vaccine
candidates, and by extension the optimal dose, might not be the same. As such, we request
that if you introduce BNT162b3 directly into Phase 2 based on a dose chosen for
BNT16 2b1, you introduce it into the Phase 2a portion of your study, rather than the Phase
2b portion, so that the safety and immunogenicity of that dose level can be evaluated in a
smaller group prior to dosing 3,000 subjects.
Meeting Discussion
Pfizer/BioNTec h acknowledged CBER’s request.
2.2.Regulatory Comments
Meeting Discussion
Acknowledged b y Pfizer/BioNTech at the start of the meeting.
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Page 11Meeting Discussion
Acknowledg ed by Pfizer/BioNTech at the start of the meeting.
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Page 13Meeting Discussion
Acknowledged b y Pfizer/BioNTech at the start of the meeting.
2.2.2. Traditional Approval
2.2.2.1. Sponsor Traditional Approval- Related Question 1
Does CBER agree that the proposed study design, including a Phase 2/3 efficacy portion,
and the planned persistence evaluations from Phase 1 sentinel and Phase 2 cohorts are
adequate to support Traditional Approval?
2.2.2.1.1. CBER Traditional Approval -Related Request 1a
We agree that the proposed study design may be adequa te to support Traditional Approval
using the success criteria specified in our response to Question 1.b, contingent on our
review and assessment of the submitted data. It is not clear from your briefing material
what you mean by the planned persistence eva luations from Phase 1 sentinel and Phase 2
cohorts.
Meeting Discussion
Pfizer explained that all subjects in Stage 1 will be followed for 24 months. For Phase 2 /3 it
is still intended to follow subjects for 24 months. However, if we achieve sufficient cases to
be successful sooner, we may need to vaccinate subjects receiving placebo. These subjects
would still be followed for safet y but the persistence evaluations wou ld be impacted. CBER
acknowledged understanding and agreement.
2.2.2.1.2. CBER Traditional Approval -Related Request 1b
Ideally, your BLA submission would include blinded 6 -month safety data from at least 3,000
subjects who have received the vaccine at the dose intend ed for licensure. Please comment on
how many subjects from whom you anticipate to provide 6 -month safety data in your licensure
application (including in the initial submission and potentially in a safety update submitted
during our review) in the event that an interim efficacy analysis meets the study success
criterion. Further discussion may be needed on the acceptability of the safety database,
depending on the data you plan to have available.
Meeting Discussion
Pfizer explained that we would have 1-month safety data from at least 3,000 subjects who
have received the vaccine at the dose intended for licensure, but we would only have
6-month safet y data from a few subjects enrolled near the start of the C4591001 study .
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Page 142.2.2.1.3. CBERTraditional Approval -Relat ed Request 1c
We agree with your plan to continue to follow subjects through Month 24 to enable
assessment of longer -term safety and durability of vaccine efficacy. Please discuss your
contingency plans for continuing longer -term follow up and analysis of safety and
effectiveness outcomes in the event that early demonstration of efficacy sufficient to
support wide use of the vaccine raises ethical arguments to break the blind and offer
vaccine to placebo recipients.
Meeting Discussion
Discussed in the cont ext of Traditional Approval Reques t 1a (See above Section 2.2.2.1.1 ).
2.2.2.2. Sponsor Traditional Approval- Related Question 2
2.2.2.2.1. CBER Traditional Approval -Related Request 2
Clinical lot consistency studies are traditionally performed as a component of the Phase 3
efficacy study. Data from these studies are used to support product consistency in the clinic
and are typically designed using three independently manufactured lots. Data from these
studies are used to support product licensure and therefore should be included in the BLA. If
you are not able to complete a lot to lot consistency study as part of your Phase 3 study, please
propose an analytic al comparability study to support the consistent manufacture and quality of
the product batches used in your Phase 3 study.
Meeting Discussion
Pfizer/BioNTech acknowledged CBER ’s comment and convey ed that a Ty pe C Meeting to
discuss Chemistry , Manufacturi ng and Controls is planned for the end of July . We will
provide a proposal within the context of that meeting.
2.2.3. Emergency Use Authorization (EUA)
2.2.3.1. Sponsor EUA -Related Question 1
The Sponsor is currently manufacturing vaccine at- risk and is targeting to have
US-manufactured and released vaccine doses of approximately available by
year-end 2020 with initial deliveries projected for late November. Does CBER agree that
The
Emergency Use Authorization request package could be submitted for CBER review i n
parallel with the initial BLA.
FDA Response to EUA -Related Question 1
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Page 15Meeting Discussion
Pfizer/BioNTech requested clarification of our understanding that clinical efficacy data are
needed to support Emergency Use Authorization. CBER con firmed that a signal of efficacy
is needed to support Emergency Use Authorization.
Pfizer expressed agreement with CBER and explained that this is the reason we are planning
to start the efficacy phase of the study in July , we are attempting to demonstrate efficacy as
soon as possible while we are still able to in the US.
2.2.4. Pediatric and Maternal Immunization (P&M I) Study Plans
2.2.4.1. Sponsor P&MI Study Plans -Related Question 1
Does CBER have any comments on the high -level pediatric study plan? Does CBER agree
that
FDA Response to P&MI Study Plans -Related Question 1
We have the following comments on the high -level pediatric study plan.
2.2.4.1.1. CBER P&MI Study Plan -Related Request 1a
Please provide a statutory rationale to support the planned waiver for children less than
12months of age. We disagree with your statement that COVID- 19 is generally mild and
self-limiting in children in the first year of life as sever al large pediatric case series have
demonstrated a higher proportion of severe disease in children less than 12 months of age
versus other pediatric age groups (Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID -19
Among Children in China. Pediatrics. 2020;145(6):e20200702. Coronavirus Disease 2019
in Children — United States, February 12 –April 2, 2020. MMWR Morb Mortal Wkly Rep
2020;69:422–426. DOI: http://dx.doi.org/10.15585/mmwr.mm6914e4)
Meeting Discussion
Pfizer/BioNTech acknowledged CBER’s comment and will provide pediatric plans for
CBER review in the Pediatric Study Plan that we plan to submit mid -July.
2.2.4.1.2. CBER P&MI Study Plans -Related Request 1b
It is premature to agree on the applicability of immunobridging studies to infer
effectiveness for all pediat ric age groups; clinical disease endpoint efficacy studies may be
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Page 16required for some age groups pending better understanding of SARS -CoV-2 immunology
and pathogenesis.
Meeting Discussion
Pfizer/BioNTech acknowledged CBER’s comment and will provide pediatric plans for
CBER review in the Pediatric Study Plan that we plan to submit mid -July.
2.2.4.2. Sponsor P&MI Study Plans -Related Question 2
Does CBER agree with the proposed inclusion of global sites (eg, EU, South America,
Turkey) in the pediatric study with at least 30% of participants coming from US?
FDA Response to P&MI Study Plans -Related Question 2
We agree with the proposal to include global sites in the pediatric study, with at least 30%
of participants coming from the US.
Meeting Discussion
There was no discussion of this item during the meeting.
2.2.4.3. Sponsor P&MI Study Plans -Related Question 3
Does CBER have any comments on the proposed plan for evaluating maternal
immunization?
FDA Response to P&MI Study Plans -Related Question 3
We acknowledge your plans to assess your product in pregnant women, and we would
encourage an ongoing dialogue regarding inclusion of pregnant women in your planned
studies and how safety and effectiveness data obtained with your vaccine may be used.
Please note that initiation of studies in this population is contingent on our review of data
to support the safety of this approach, particularly your planned DART study. We have the
following comments and requests for clarification:
2.2.4.3.1. CBER P&MI Study Plans -Related Request 3a
Please provide a detailed proposal for how you intend to label the data from studies
conducted in pregnant women (or the subanalyses of the data from pregnant women, if
they are included in broader studies).
Meeting Discussion
Pfizer/BioNTech acknowledged CBER’s r equest and will defer this discussion for a later
date.
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Page 172.2.4.3.2. CBER P&MI Study Plans -Related Request 3b
Please clarify whether you intend to seek an indication for vaccination during pregnancy
to protect the infant from SARS CoV -2 infection. Please note that cord blood immune
assays are unlikely to be adequate to support this indication in the absence of establishing
a biomarker reasonably likely to predict protection.
Meeting Discussion
Pfizer/BioNTech acknowledged CBER’s request and will defer this discussion for a later
date.
2.2.4.3.3. CBER P&MI Study Plans Request 3c
With respect to other vaccines recommended for administration during pregnancy (i.e.,
Tdap and influenza vaccines), please comment on the potential for immunologic
interference and discuss your plans to ad dress this issue.
Meeting Discussion
Pfizer/BioNTech acknowledged CBER’s request and will defer this discussion for a later
date.
2.2.4.3.4. CBER P&MI Study Plans Request 3d
Further discussion on your proposed immunobridging study may be needed after you
provide responses to our questions above to clarify your intentions for labeling of data
from this study and claims related to the data, and after more data are available to
determine the acceptability of immune markers that you would propose for
immunobridging.
Meeting Discussion
Pfizer/BioNTech acknowledged CBER’s request and will defer this discussion for a later
date.
2.2.4.4. Sponsor P&MI Study Plans -Related Question 4
. Does CBER agree that the results of the DART study can be
provided during review of the initial BLA
?
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Page 18FDA Response to P&MI Study Plans -Related Question 4
We agree that the results of the DART study can be provided during review of the initial
BLA that will include data from Study C4591001.
.
Meeting Discussion
Pfizer convey ed that we plan to start the DART study in July and anticipate that we will be
able to submit the results of it while the [Traditional Approval] BLA is under review.
2.3.Additional FDA Comments
2.3.1. Additional FDA Comment 1
Consistent with the FDA Gui dance for Industry on Enhancing the Diversity of Clinical
Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs
(https://www.fda.gov/media/127712/download), we encourage you to adopt enrollment and
retention practices that enhan ce inclusiveness so that the clinical trial population reflects
the diversity of the people who will be using the vaccine, if approved. Specifically, racial
and ethnic minority persons should be represented in clinical trials. We suggest that
clinical tria l sites include geographic locations with a higher concentration of racial and
ethnic minorities to recruit a diverse study population.
Meeting Discussion
There was no discussion of this item during the meeting. Pfizer/BioNTech acknowledge
CBER’s comment.
2.3.2. Additional FDA Comment 2
All study data generated from trials initiated after December 17, 2016, that will be
submitted with applications for new drugs/biologics must be in conformance with the
standards listed in the FDA Data Standards Catalog. As you intend to initiate your Phase
1/2/3 clinical trial in the near future, we request that you provide as soon as possible, a
Study Data Standardization Plan (SDSP) with CBER appendix proposing the specific use
of the Clinical Data Interchange Standards Consortium (CDISC), including Study Data
Tabulation Model (SDTM) and Analysis Data Model (ADaM) formats. We also request
that the associated annotated case report form (aCRF) for SDTM be provided. Please refer
to the CDISC Vaccine Therapeutic Area User Gui de (TAUG) and Guidance for Industry
“Submitting Study Datasets for Vaccines to the Office of Vaccines Research and Review”
for details on standardizing your data.
Meeting Discussion
There was no discussion of this item during the meeting. Pfizer/BioNTech acknowledge
CBER’s comment.
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COVID-19 Design Details
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FDA-CBER-2021-5683-1147719
Design 1: Bayesian Sequential Design with Four
Interim Analyses (VEThreshold=20%)
Interim
AnalysisTiming of Interim
Analysis (Information
Fraction)Stop for
EfficacyStop for
FutilityEfficacy Boundaries Futility Boundaries
1 22/110 (1/5) No Yes NA VE≤-20% and Y ≥12
2 44/110 (2/5) Yes Yes VE ≥62.5% and Y ≤12 VE ≤16.7% and Y ≥20
3 66/110 (3/5) Yes Yes VE ≥56.5% and Y ≤20 VE≤26.3% and Y ≥28
4 88/110 (4/5) Yes No VE≥53.3% and Y ≤28 NA
Final 110/110 VE≥47.2% and Y ≤38
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FDA-CBER-2021-5683-1147720
Design 1: Operating Characteristics
Interim
AnalysisTiming of
Interim
Analysis
(Information
Fraction)Stop for
EfficacyStop
for
FutilityCumulative Probability of
Stopping for EfficacyCumulative Probability of
Stopping for FutilityVE= 20% VE= 55% VE= 60% VE= 20% VE= 55% VE= 60%
1 22/110 (1/5) No Yes 0% 0% 0% 22.9% 1.8% 0.1%
2 44/110 (2/5) Yes Yes 1.4% 36.0% 50.0% 52.8% 4.1% 1.9%
3 66/110 (3/5) Yes Yes 2.2% 54.8% 70.9% 72.9% 5.9% 2.5%
4 88/110 (4/5) Yes No 2.7% 69.2% 84.5% - - -
Final 110/110 3.8% 90.2 99.0% - - -
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FDA-CBER-2021-5683-1147721
Design 2: Bayesian Sequential Design with Four
Interim Analyses (VEThreshold=30%)
Interim
AnalysisTiming of Interim
Analysis (Information
Fraction)Stop for
EfficacyStop for
FutilityEfficacy Boundaries Futility Boundaries
1 30/150 (1/5) No Yes NA VE ≤0% and Y ≥15
2 60/150 (2/5) Yes Yes VE ≥63.6% and Y ≤16 VE ≤28.6 % and Y ≥25
3 90/150 (3/5) Yes Yes VE ≥59.5% and Y ≤26 VE ≤36.4 % and Y ≥35
4 120/150 (4/5) Yes No VE≥55.4% and Y ≤37 NA
Final 150/150 VE≥50.0% and Y ≤50
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FDA-CBER-2021-5683-1147722
Design 2: Operating Characteristics
Interim
AnalysisTiming of
Interim
Analysis
(Information
Fraction)Stop for
EfficacyStop for
FutilityCumulative Probability of
Stopping for EfficacyCumulative Probability of
Stopping for FutilityVE= 30% VE= 55% VE= 60% VE= 30% VE= 55% VE= 60%
1 30/150 (1/5) No Yes 0% 0% 0% 21.2% 2.3% 1.1%
2 60/150 (2/5) Yes Yes 1.4% 28.1% 43.5% 53.7% 6.3% 2.6%
3 90/150 (3/5) Yes Yes 2.0% 42.6% 62.1% 75.1% 10.0% 3.9%
4 120/150 (4/5) Yes No 2.7% 60.3% 80.7% - - -
Final 150/150 4.1% 84.3% 98.0% - - -
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FDA-CBER-2021-5683-1147723
Design 3: Calibrated Bayesian Sequential Design
with Four Interim Analyses (VEThreshold=30%)
Interim
AnalysisTiming of Interim
Analysis (Information
Fraction)Stop for
EfficacyStop for
FutilityEfficacy Boundaries*, ** Futility Boundaries
1 32/164 No Yes NA VE≤11.8% and Y ≥15
2 62/164 Yes Yes VE≥ 70.8% and Y ≤14 VE≤27.8 % and Y
≥26
3 92/164 Yes Yes VE≥62.7% and Y ≤25 VE≤36.8 % and Y
≥36
4 120/164 Yes No VE≥60.5% and Y ≤34 NA
Final 164/164 VE≥50.9% and Y ≤54*Using efficacy boundary at interim: , P(VE≥30%|data) >0.9975
**Using success criteria at the final analysis: , P(VE ≥30%|data) >0.98.
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FDA-CBER-2021-5683-1147724
Design 4: Operating Characteristics
Interim
AnalysisTiming of
Interim
Analysis
(Information
Fraction)Stop for
EfficacyStop for
FutilityCumulative Probability of
Stopping for EfficacyCumulative Probability of
Stopping for FutilityVE= 30% VE= 55% VE= 60% VE= 30% VE= 55% VE= 60%
1 32/164 No Yes 0% 0% 0% 31.5% 4.4% 2.1%
2 62/164 Yes Yes 0.2% 9.4% 18.4% 62.7% 9.6% 4.3%
3 92/164 Yes Yes 0.5% 26.0% 44.7% 81.4% 13.9% 5.9%
4 120/164 Yes No 0.6% 35.4% 57.9% - - -
Final 164/164 2.2% 78.8% 96.2% - - -
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FDA-CBER-2021-5683-1147725
Design 4: Frequentist Sequential Design with Four
Interim Analyses (VEThreshold=30%)
Interim
AnalysisTiming of Interim
Analysis (Information
Fraction)Stop for
EfficacyStop for
FutilityEfficacy Boundaries* Futility Boundaries
1 32/164 Yes Yes VE≥81.5% and Y ≤5 VE≤11.8% and Y ≥15
2 62/164 Yes Yes VE≥ 70.8% and Y ≤14 VE≤27.8 % and Y ≥26
3 92/164 Yes Yes VE≥62.7% and Y ≤25 VE≤36.8 % and Y ≥36
4 120/164 Yes No VE≥57.1% and Y ≤36 NA
Final 164/164 VE≥52.3% and Y ≤53*Efficacy boundary is calculated using Gamma(-2) family
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FDA-CBER-2021-5683-1147726
Design 4: Operating Characteristics
Interim
AnalysisTiming of
Interim
Analysis
(Information
Fraction)Stop for
EfficacyStop for
FutilityCumulative Probability of
Stopping for EfficacyCumulative Probability of
Stopping for FutilityVE= 30% VE= 55% VE= 60% VE= 30% VE= 55% VE= 60%
1 32/164 Yes Yes 0.1% 3.9% 7.2% 31.5% 4.4% 2.1%
2 62/164 Yes Yes 0.3% 11.0% 20.4% 54.6% 7.1% 3.2%
3 92/164 Yes Yes 0.6% 27.5% 46.7% 76.3% 10.4% 4.2%
4 120/164 Yes No 1.1% 48.7% 72.0% - - -
Final 164/164 1.9% 72.9% 92.4% - - -
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FDA-CBER-2021-5683-1147727
1Harkins Tull, Elisa
From: Harkins Tull, Elisa
Sent: Friday, June 26, 2020 12:51 PM
To: Naik, Ramachandra
Subject: IND 19736 Type C Meeting - Tables for use in meeting
Importance: High
Dear Ram,
Would you mind to kindly distribute these tables to your colleagues who are attending the meeting today? They are just
intended as a tool to help discuss data availability. We thought this would be more clear than just describing verbally.
Best regards,
Elisa
Projected serological Data following dose 1 Projected number of subje
Post Dose 1 By 17-Jul-20
Construct Age Cohort Dose Level IgG Neut BNT162b1 total
18-55 10ug completed completed 18-55yrs
18-55 30ug completed completed 65-85yrs
BNT162b1 18-55 20ug 30-Jul BNT162b2 total
18-55yrs
65-85 10ug 9-Jul 11-Jul 65-85yrs
65-85 20ug 16-Jul 17-Jul Grand Total
65-85 30ug 16-Jul 18-Jul
18-55 10ug 9-Jul 11-Jul
18-55 20ug 15-Jul 17-Jul
18-55 30ug 23-Jul
BNT162b2
65-85 10ug 30-Jul 3-Aug
65-85 20ug 15-Jul 17-Jul
65-85 30ug 16-Jul
Elisa Harkins Tull
Senior Director
Global Regulatory Affairs - Vaccines
Pfizer, Inc.
090177e19452f592\Final\Final On: 09-Jul-2020 18:40 (GMT)
FDA-CBER-2021-5683-1147728
2500 Arcola Road
Collegeville, PA 19426
Mobile – 215-280-5503
Fax – 845-474-3500
090177e19452f592\Final\Final On: 09-Jul-2020 18:40 (GMT)
FDA-CBER-2021-5683-1147729
U.S. Food & Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993
w ww.fda.gov
Our Reference: Type C Meeting Request: IND 19736, Amendment 15; CRMTS 12645
MEETING SUMMARY
Date: July 15, 2020
BioNTech RNA Pharmaceuticals GmbH
Attention: Elisa HarkinsPfizer, Inc.500 Arcola RoadCollegeville, PA 19436
Dear Ms. Harkins:
Attached is a copy of the memorandum summarizing your June 26, 2020, IND meeting
(teleconference) with CBER. This memorandum constitutes the offic ial record of the
teleconference. If your understanding of the teleconference outc omes differs from
those expressed in this summa ry, it is your responsibility to c ommunicate with CBER as
soon as possible. Please include a reference to IND 19736, Amendment 15; CRMTS 12 645 in your future
submissions related to the subject product. If you have any questions, please contact me at 301-796-2640.
Sincerely,
Ramachandra S. Naik, PhD
Primary ReviewerDivision of Vaccines and Related Products ApplicationsOffice of Vaccines Research and ReviewCenter for Biologics Evaluation and Research
Ramachandra Naik
-SDigitally signed by Ramachandra Naik -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=2001232361, cn=Ramachandra Naik -S Date: 2020.07.15 11:37:05 -04'00'
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Page 2 – IND 19736, Amendment 15; CRMTS 12645 – Elisa Harkins
Meeting Summary
(Includes Preliminary Meeting Responses)
Meeting ID #: CRMTS 12645
Submission type & #: IND 19736, Amendment 15
Product name: Human Coronavirus mRNA Vaccines (SARS-CoV-2 Spike
Protein; BNT162a1 (uRNA; variant RBL063.3); BNT162b1 (modRNA; variant RBP020.3); BNT162b2 (modRNA; variant RBP020.2); and BNT162c2 (saRNA; variant RBS004.2)) in Lipid Nanoparticles (ALC-0315, ALC-0159, DSPC and Cholesterol)
Proposed indication: Active immunization against COVID-19 in adults 18 years of age and older
Sponsor: BioNTech RNA Pharmaceuticals GmbHSponsor Agent: Pfizer, Inc.
Meeting type: Type C
Meeting category: IND - Other
Meeting date & time: June 26, 2020, 1:30 – 3:00 PM
Meeting format: Teleconference
Meeting Leader: Ramachandra Naik, PhD
RPM: Ramachandra Naik, PhD
Preliminary Meeting Responses Sent: June 25, 2020
FDA Attendees:Nabil Al-Humadi, PhD OVRR/DVRPAMaria Allende, MD OVRR/DVRPABrenda Baldwin, PhD OVRR/DVRPAAnissa Cheung, MSc OVRR/DVPCarmen Collazo, PhD OVRR/DVRPADennis Cato, MD OBE/DISNicolette Devore, PhD ODKaren Farizo, MD OVRRDoran Fink, MD, PhD OVRR/DVRPASara Gagneten, PhD OVRR/DVPMartin (Dave) Green, PhD OVRR/DVRPAMarion Gruber, PhD OVRRLei Huang, PhD OBE/DBBhanu Kannan OBE/DISPhilip Krause, MD OVRRRobin Levis, PhD OVRR/DVPTsai-Lien Lin, PhD OBE/DBCarrie Mampilly OCBQ/DISValerie Marshall OVRRLoris McVittie, PhD OVRR/DVRPARamachandra Naik, PhD OVRR/DVRPAManuel Osorio, PhD OD
FDA-CBER-2021-5683-1147731
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Keith Peden, PhD OVRR/DVP
Douglas Pratt, MD OVRR/DVRPAJeff Roberts, MD OVRRDavid Rouse ODElizabeth Sutkowski, PhD OVRR/DVRPAStephanie Troy, MD OVRR/DVRPAJerry Weir, PhD OVRR/DVPSusan Wollersheim, MD OVRR/DVRPA
Sponsor Attendees:
Mark Boaz Program Director, Vaccine Research and Development,
Pfizer Inc.
Donna Boyce Vice President, Global Regulatory Affairs, Vaccines,
Pfizer Inc.
Carmel Devlin Global Regulatory Portfolio Lead, Global Regulator y
Affairs, Vaccines, Pfizer Inc.
Philip R. Dormitzer, MD, PhD Vice President and Chief Scientific Officer, Viral
Vaccines, Vaccines Research and Development, Pfizer Inc.
, PhD Regulatory Consultant for BioNTech SE
William C. Gruber, MD Senior Vice President, Vaccine Clinical Re search and
Development, Pfizer Inc.
Elisa Harkins Global Regulatory Lead, Global Regulatory Affairs,
Vaccines, Pfizer Inc.
Kathrin U. Jansen, PhD Senior Vice President and Head, Vaccine Re search and
Development, Pfizer Inc.
Luis Jodar, PhD Vaccines Chief Medical and Scientific Affairs Of ficer,
Pfizer Inc.
Nicholas Kitchin, MD Senior Director, Vaccines Clinical Research and
Development, Pfizer Ltd.
Kenneth Koury, PhD Head of Stati stics and Modeling, Vaccine Clin ical
Research and Development, Pfizer Inc.
Stephen Lockhart, MD Head EU/AP, Vaccines Clinical Research and
Development, Pfizer Ltd.
David Swerdlow, MD Senior Director, Medical Development and
Clinical/Scientific Affairs, Pfizer Inc.
Ruben Rizzi, PhD Regulatory Affairs Strategist, BioNTech SE
Satrajit Roychoudhury, PhD Senior Director, Statistical Research and Data Science
Center, Pfizer Inc.
Ugur Sahin, MD, PhD Chief Executive Officer, BioNTech SE
Background and Objectives:
The Sponsor submitted a meeting request on June 11, 2020, to gain CBER feedback
regarding (1) the proposed Clinical Development Program, includ ing revisions to the
ongoing Study C4591001, as well as high-level pediatric and mat ernal immunization
plans, and (2) the clinical data requirements to support Traditional
(b) (4)
(b) (6), (b) (4)
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Approval, as well as requirements for use under an Emergency Us e Authorization. The
pre-meeting materials were submitted on June 11, 2020.
FDA provided its preliminary meeting responses to the Sponsor’s questions on
June 25, 2020. After reviewing the preliminary meeting responses , the Sponsor notified
FDA on June 26, 2020, of its decision to proceed with the agend a as planned. In
addition, on June 24, 2020, Pfizer sent a slide deck (Attachment 1; page 20), to facilitate
the discussion, that describes their Phase 3 designs with 4 inter im analyses with VE
threshold = 20% or 30%, and their operating characteristics. O n June 26, 2020, Pfizer
sent two tables (Attachment 2; pag e 24) with Projected available s erological data
following dose 1 and Projected number of subjects receiving 1 o r 2 doses by July 17,
2020. This slide deck/information was presented at the meeting.Sponsor Questions:ClinicalSponsor Question 1:
Does CBER have any comments on the overall Clinical Development Plan and timeline
proposed to support Traditional Approval? Specifically,
Sponsor Question 1.a:
Does CBER agree with the proposed revisions to the ongoing Phas e 1/2 US Study
C4591001 that would add a Phase 2/3 efficacy phase to the study , to evaluate efficacy
in an expanded number of participants? Does CBER agree with the proposed Phase 3
safety, immunogenicity, and efficacy endpoints and case definit ions?
FDA Preliminary Meeting Response to Sponsor Question 1.a:We agree with your general proposal to add a Phase 2/3 efficacy phase to the study
and evaluate efficacy in an expanded number of participants.
i. We note that you state, “the Phase 2b/3 section will be observer-blinded at
site, and the Sponsor staff will also be blinded except for name d unblinded
staff.” We request that the blinding procedures be updated in the revised
protocol, with appropriate justifications included, to ensure s tudy integrity.
Meeting Discussion for Sponsor Question 1.a.i:
Pfizer stated that they acknowledge CBER’s concern regarding bl inding
and the ethical dilemma regarding breaking the blind and offering vaccine
to placebo recipients in the event of early demonstration of eff icacy
sufficient to support wide use of the vaccine. They will include their
justification in the revised protocol and submit for CBER review . CBER
acknowledged.
(b) (4)
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ii. We recommend the case definition described below, which is s imilar to your
proposed primary efficacy endpoint case definition, to standard ize evaluation
of efficacy across COVID-19 vaccine studies. You may choose to evaluate
the standardized case definition as your primary efficacy endpo int or as a
secondary endpoint to be analyzed with or without formal hypoth esis testing.
We recommend defining a positive case as virologic confirmation by RT-PCR
for SARS-CoV-2, along with any symptom for COVID-19 as listed b y the CDC
(https://www.cdc.gov/coronavirus/2019-ncov/symptoms-
testing/symptoms.html ):
xFever or chills
xCough
xShortness of breath or difficulty breathing
xFatigue
xMuscle or body aches
xHeadache
xNew loss of taste or smell
xSore throat
xCongestion or runny nose
xNausea or vomiting
xDiarrhea
Meeting Discussion for Sponsor Question 1.a.ii:
Pfizer indicated that they would keep their definition for COVID -19
described in the briefing document. However, they proposed to i nclude
OVRR’s recommended definition using the symptoms listed on the C DC
website as a secondary efficacy endpoint analysis without formal hypothesis testing. CBER agreed.
iii. We acknowledge your agreement to modify your case definition for severe
COVID-19 as previously requested.
Meeting Discussion for Sponsor Question 1.a.iii:There was no discussion of this question during the meeting. T his
response is now considered final.
iv. Please propose a study stopping rule for severe disease as an indicator of
enhanced disease to be assessed by the DMC with each prespecifi ed interim
analysis. An acceptable approach would be to pause study enroll ment for
further data review, as well as notification of OVRR, if the number of severe COVID-19 cases is greater among vaccine versus placebo recipients . You
may propose alternative rules based on reasonable statistical c riteria.
Meeting Discussion for Sponsor Question 1.a.iv:Pfizer understood and stated that they would include the alterna tive
stopping rules in the revised protocol. CBER acknowledged.
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v. The briefing document did not include defined safety and immu nogenicity
endpoints for Phase 3. However, we agree in general with the s afety and
immunogenicity endpoints described in the previously submitted Phase 3
protocol synopsis (in amendment 7, sequence 0007, dated May 15, 2020),
including the plan to assess the serologic response at baseline , 14 days, and
1, 6, 12, and 24 months after completion of vaccination in all study subjects in
Phase 3. The immunologic assays described in item 2.13.1 of you r
responses to CBER comments dated May 29, 2020 are appropriate, p rovided
the assay validation data to be submitted prior to the testing of Phase 3
samples are acceptable.
Meeting Discussion for Sponsor Question 1.a.v:Pfizer stated that they
collecting samples at baseline, 1- , 6-, 12-,
and 24- month timepoints for immunogenicity assessments, but the y may
only conduct the assays in an immunogenicity subset of the stud y
population. They believe that in principle, the serological data are not required for BLA filing and for lic ensure under Traditional Appr oval
pathway.
CBER acknowledged and stated that although data from serological
assessment at the above-stated timepoints will not be required for primary
efficacy endpoints or for licensure under a Traditional pathway, these data will be important/useful, e.g., for immunobridging to population s not
included in the efficacy trial. Pfizer acknowledged, and stated that for
these reasons, they will collect samples at various timepoints, and they
will keep these sample collections in the protocol. However, t hey commit
to validating the immunological assays before testing these sampl es.
CBER asked how many different age groups Pfizer will have for a dults.
Pfizer replied that currently they stratify by age only two groups – 18-55years of age and >55 years of age. Currently, there are no plans foradditional subgroups. They plan to enroll 30,000 subjects split equally
between age groups, 18-55 and >55 years of age, and half of them will
receive placebo.
CBER asked when Pfizer will complete qualification and validati on of the
immunological assays and asked if the assays are adequately qual ified to
measure the immune response (e.g., antigen-binding IgGs and viru s
(b) (4)
(b) (4)
(b) (4)
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neutralization titers) from Phase 1 studies. Pfizer stated that the ir assay to
measure antigen-binding IgG antibodies (for determining which case s
were infected before vaccination so they can be excluded from t he primary
efficacy analysis) has already been qualified. The virus neutraliz ation
assay
. Both of these immunological assa ys are
robust, and Pfizer can provide the details to CBER, if needed. Pfizer
asked if that is acceptable. Pfizer also stated that they are pla nning to
initiate the Phase 3 study on July 20, 2020. CBER stated that th e plan for
validating the assays is acceptable but stressed that the assays n eed to
be validated prior to assessing the samples from the Phase 3 effic acy
study. Pfizer understood.
Sponsor Question 1.b:
?
FDA Preliminary Meeting Response to Sponsor Question 1.b:As communicated previously, we do not agree with a success criterion defined as the lower limit of VE being >20%. To ensure that a widely deployed vaccine is more
than modestly effective, we request that the success criterion b e defined equivalent
to a primary efficacy endpoint point estimate of at least 50% and the lower limit of the alpha-adjusted 95% CI around that point estimate being >30%. In principle, the
four interim analyses proposed in Table 6 of the briefing docum ent, using a VE
threshold of 30%, would be acceptable if the criteria were adjus ted to preserve the
type I error rate at 2.5%. In addition, the proposed efficacy bo undaries are based
solely on case split, which presu mes that the numbers of evalua ble subjects and
duration of follow-up in both groups are equivalent. Please cl arify how you plan to
adjust the boundaries for potential difference in numbers of eval uable subjects.
Given that current COVID-19 epidemiology is permissive for cond ucting clinical
disease endpoint efficacy trials,
Meeting Discussion for Sponsor Question 1.b.:Pfizer stated that they agree with defining the success criterio n to be equivalent
to a primary efficacy endpoint point estimate of at least 50% and the lower limit of the alpha-adjusted 95% CI around that point estimate being >30% . Also, they
acknowledged CBER’s comment regarding controlling the type I er ror rate at
2.5%. CBER indicated conceptual agreement with Pfizer’s study des igns 3 and 4
included in the slide deck sent to CBER on June 24, 2020, which control the
overall type I error at nominal l evel; however, CBER had not fully evaluated and
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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discussed those designs interna lly. Therefore, CBER will provide comments on
those designs in the meeting summary, as post-meeting notes. P fizer
acknowledged.
Regarding boundaries for efficacy, Pfizer stated that they will calculate
boundaries in terms of VE for number of person-years in evaluab le population,
and VE analysis based on that population. CBER acknowledged and wi ll provide
feedback, if any, on the protocol when submitted.Post-meeting Comment:
The proposed study designs 3 and 4 included in the slide deck s ent to CBER on
June 24, 2020 are acceptable.
Sponsor Question 1.c.:Does CBER agree with the proposed plan for progression of vacci ne candidates from
Phase 2 to Phase 3?
FDA Preliminary Meeting Response to Sponsor Question 1.c:We agree with the proposal that includes review of unblinded safety data through 7 days after dose 2 and immunogenicity data through 21 days after dose 1 of each vaccine candidate by the internal review committee. With the submission of these data to CBER, we request that you include a summary of the data that includes the
rationale for dose selection.
Meeting Discussion for Sponsor Question 1.c:Pfizer explained that in the initial IND submission, they propos ed to evaluate
multiple doses and dosing regimens of 4 vaccine candidates in th eir Phase 1/2
study. However, they have plans to eliminate some of the vaccine candidates.
They are planning to initiate the Phase 2b/3 study on July 20, 2 020, and will
select only one construct, at one dose level. By that time, a to tal of 252 subjects
will have received 1 dose and 180 subjects will have received 2 doses (all doses)
of BNT162b1 or BNT162b2, and safety data on these subjects will be available.
Pfizer has decided to eliminate the 50 Pg and the 100 Pg doses, and they believe
they will go forward with either 10 Pg or 20Pg of one of the two vaccine
candidates, based on their safety profile. Post-dose 1 immunogen icity data for
10Pg and 30 Pg of BNT162b1 in younger adults (18-55 years of age), for 10 Pg
and 20 Pg of BNT162b1 in older adults (65-85 years of age), for 10 P g and 20 P g
of BNT162b2 in younger adults, and for 20 Pg of BNT162b2 in older adults, will
be available by July 17, 2020. As reactogenicity is benign in old er adults
compared with that in younger adults, Pfizer feels comfortable do sing older
adults based on the safety and tolerability profile of these dos es in the younger
adults.
CBER acknowledged Pfizer’s plan to initiate the Phase 2b/3 study on
July 20, 2020, but stated that further internal discussion is n eeded on whether
the proposed clinical immunogeni city data that will be availabl e then are sufficient
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to support Phase 2b/3 initiation or whether additional clinical i mmunogenicity
data will be required. CBER asked when the immunogenicity data will be
available to Pfizer and to CBER for review. Pfizer replied that antigen-binding
IgG data will be available on July 13, 2022, and virus neutralization data will be available by July 17, 2020. Pfizer will include all available i mmunogenicity data
for the modRNA platform (BNT162b1 and BNT162b2). This includes T-cell (CD4
and CD8) data from the German study from all 12 subjects. All a ssays used in
these evaluations are the same as those that are/will be used by Pfizer to
analyze the serum samples from this study.
CBER acknowledged and expressed the need to discuss internally and provide
feedback to Pfizer in post-meeting notes. Pfizer acknowledged.
Post-meeting Comment:CEBR held a follow-up teleconference on July 6, 2020, to clarif y Pfizer’s plans
for the Phase 2b/3 portion of the study and the clinical data, non-clinical data,
and immunogenicity assay information that would be submitted to support
those plans. A summary of that teleconference will be provided in a separate
communication.
Sponsor Question 1.d:Does CBER agree with the proposed inclusion of global sites (e. g., EU, South America,
Turkey) in the efficacy phase of the study with at least 30% of participants coming from
the US assuming current state of the pandemic?
FDA Preliminary Meeting Respons e to Sponsor Question 1.d:
We agree with the proposal to include global sites in the effic acy phase of the study,
with at least 30% of participants coming from the US.
Meeting Discussion for Sponsor Question 1.d:There was no discussion of this question during the meeting. Thi s response is
now considered final.
Sponsor Question 2:Does CBER agree that revised Study C4591001 is adequate to serv e as the single
pivotal study to demonstrate adequate safety, immunogenicity, an d efficacy of the
candidate vaccine for the proposed indication and may be used to support
Traditional Approval?
FDA Preliminary Meeting Response to Sponsor Question 2:Please see our responses to your other questions. We agree tha t a single, well-
designed and well-conducted clinical disease endpoint efficacy study that is able tomeet our requested pre-specified success criterion would likely provide substantial
evidence of effectiveness and an adequately sized safety database to support licensure of your product via the Traditional Approval Pathway.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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Page 10 – IND 19736, Amendment 15; CRMTS 12645 – Elisa Harkins
Meeting Discussion for Sponsor Question 2:
There was no discussion of this question during the meeting. Thi s response is
now considered final.
Sponsor Question 3:Does CBER agree with Pfizer/BioNTech’s plans to evaluate the BN T162b3 candidate
expressing the RBD domain with a short transmembrane tail and t wo amino acids
added to the signal peptide for more homogeneous cleavage in Stud y C4591001, as
described in Section 6.2?
FDA Preliminary Meeting Response to Sponsor Question 3:We agree that the clinical data from BNT162b1, which uses the s ame nucleoside-
modified mRNA (modRNA) platform as your new BNT162b3 vaccine ca ndidate,
could support the use of BNT162b3 in the proposed Phase 1/2/3 s tudy. As
previously communicated on June 3, 2020, you may submit a revised protocol to include the new vaccine candidate with supportive CMC and noncl inical data.
Please provide the CMC drug substance and drug product information for the BNT162b3 clinical lot and the non-clinical immunogenicity data for this new vaccine
candidate (including assessment of Th1/Th2 markers and cellular responses) to the
IND prior to the initiation of the Phase 2 portion of your Stud y C4591001. In
addition, please provide a summar y of CMC comparability between BNT162b1 and
BNT162b3.
We note that if Phase 1 evaluation of BNT162b1 leads to a selec ted dose level to
proceed into Phase 2 for both younger and older adults, you pla n to take BNT162b3
directly to Phase 2 for both age groups at the same dose select ed for BNT162b1.
However, your rationale for inclusion of BNT162b3 is that it has shown superior
immunogenicity to BNT162b1 in mice, which suggests that the imm unologic
response to these vaccine candidates, and by extension the opti mal dose, might not
be the same. As such, we request that if you introduce BNT162b 3 directly into
Phase 2 based on a dose chosen for BNT162b1, you introduce it i nto the Phase 2a
portion of your study, rather than the Phase 2b portion, so that the safety and immunogenicity of that dose level can be evaluated in a smaller group prior to dosing 3,000 subjects.
Meeting Discussion for Sponsor Question 3.:There was no discussion of this question during the meeting. Thi s response is
now considered final.
(b) (4)
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Regulatory
(b) (4)
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(b) (4)
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Meeting Discussion for Sponsor Ques tion 7:
There was no discussion of this question during the meeting. Thi s response is
now considered final.
Traditional Approval
Traditional Approval-related Sponsor Question 1:
Does CBER agree that the proposed study design, including a Pha se 2/3 efficacy
portion, and the planned persistence evaluations from Phase 1 sentinel and Phase 2 cohorts are adequate to support Traditional Approval?
FDA Preliminary Meeting Response to Traditional Approval-related Sponsor Question 1:We agree that the proposed study design may be adequate to support Traditional Approval using the success criteria specified in our response to Question 1.b, contingent on our review and assessment of the submitted data. I t is not clear from
(b) (4)
(b) (4)
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your briefing material what you mean by the planned persistence evaluations from
Phase 1 sentinel and Phase 2 cohorts.
Ideally, your BLA submission would include blinded 6-month safe ty data from at
least 3,000 subjects who have received the vaccine at the dose intended for
licensure. Please comment on how many subjects from whom you an ticipate to
provide 6-month safety data in your licensure application (incl uding in the initial
submission and potentially in a safety update submitted during our review) in the
event that an interim efficacy analysis meets the study success criterion. Further
discussion may be needed on the acceptability of the safety dat abase, depending on
the data you plan to have available. We agree with your plan to continue to follow subjects through M onth 24 to enable
assessment of longer-term safety and durability of vaccine efficacy. Please discuss
your contingency plans for continuing longer-term follow up and analysis of safety
and effectiveness outcomes in the event that early demonstratio n of efficacy
sufficient to support wide use o f the vaccine raises ethical ar guments to break the
blind and offer vaccine to placebo recipients.
Meeting Discussion for Traditional Approval-related Sponsor Ques tion 1:
Pfizer stated that all subjects in the Stage 1 sentinel groups will be followed for
24 months. Serological assessment is planned for the 24-month time point in Phase 2b/3. For long term e ffectiveness, the subjects will be followed for
COVID-19 cases for the full 24-month period. Pfizer will addres s in the protocol
the ethical dilemma regarding breaking the blind and offering vac cine to placebo
recipients in the event of early demonstration of efficacy suffici ent to support wide
use of the vaccine. CBER acknowledged.
CBER asked how many subjects Pfizer is expecting to have 6-month safety data
from at the time of submission of the BLA. Pfizer stated that they are confident to
have 3,000 subjects in the vaccine group, and they will have ab undant 7-day
safety and 30-day immunogenicity data. However, Pfizer expressed concern that
if their BLA is filed in October 2020, they will have very litt le 6-month safety data.
CBER acknowledged and stated that this issue needs further discu ssion.
Traditional Approval-related Sponsor Question 2:Does CBER agree that the planned clinical lot consistency study may be conducted in
parallel with the planned Phase 3 efficacy study and results su bmitted as a post-
approval commitment under the Traditional Approval Pathway?
FDA Preliminary Meeting Response to Traditional Approval-related Sponsor Question 2:Clinical lot consistency studies are traditionally performed as a component of the
Phase 3 efficacy study. Data from these studies are used to su pport product
consistency in the clinic and are typically designed using thre e independently
manufactured lots. Data from these studies are used to support product licensure
FDA-CBER-2021-5683-1147743
Page 15 – IND 19736, Amendment 15; CRMTS 12645 – Elisa Harkins
and therefore should be included in the BLA. If you are not able to complete a lot to
lot consistency study as part of your Phase 3 study, please pro pose an analytical
comparability study to support the consistent manufacture and q uality of the product
batches used in your Phase 3 study.
Meeting Discussion for Traditiona l Approval-related Sponsor Ques tion 2:
Pfizer stated that they will pr opose an analyt ical comparabilit y study to support
the consistent manufacture and quality of the product batches in their Phase 3
study. Pfizer is planning to submit a Type C meeting request o n July 13, 2020 to
obtain CBER feedback regarding facilities and other CMC informa tion. CBER
acknowledged.
Emergency Use Authorization (EUA)
EUA-related Sponsor Question 1:The Sponsor is currently manufacturing vaccine at-risk and is t argeting to have US-
manufactured and released vaccine doses of approximately available by
year-end 2020 with initial deliveries projected for late Novemb er. Does CBER agree that
? The Emergency Use Authorization request package coul d be submitted for
CBER review in parallel with the initial BLA.
FDA Preliminary Meeting Response to EUA-related Sponsor Question 1:
Meeting Discussion for EUA-related Sponsor Question 1:Pfizer asked whether clinical efficacy data would be considered to support an
EUA in the event that declining COVID-19 disease activity precludes or significantly delays meeting the pre-specified study success cr iteria. CBER
replied that the totality of data, including the clinical disease efficacy data, would
be considered in the context of th e specific circumstances of a ny EUA request.
Pfizer acknowledged.
Pediatric and Maternal Immunization (P&MI) Study Plans
P&MI Study Plans-related Sponsor Question 1:Does CBER have any comments on the high-level pediatric study p lan? Does CBER
agree
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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FDA Preliminary Meeting Response to P&MI Study Plans-related Spo nsor
Question 1:
We have the following comments on the high-level pediatric stud y plan:
a. Please provide a statutory rationale to support the planned w aiver for children
less than 12 months of age. We disagree with your statement th at COVID-19 is
generally mild and self-limiting in children in the first year of life as several large pediatric case series have demonstrated a higher proportion of s evere disease in
children less than 12 months of age versus other pediatric age groups (Dong Y,
Mo X, Hu Y, et al. Epidemiology of COVID-19 Among Children in C hina.
Pediatrics. 2020;145(6):e20200702. Coronavirus Disease 2019 in C hildren —
United States, February 12–April 2, 2020. MMWR Morb Mortal Wkly Rep
2020;69:422–426. DOI: http://dx.doi.org/10.15585/mmwr.mm6914e4 )
b. It is premature to agree on th e applicability of immunobridgi ng studies to infer
effectiveness for all pediatric age groups; clinical disease endpoint efficacy studies may be required for some age groups pending better unde rstanding of
SARS-CoV-2 immunology and pathogenesis.
Meeting Discussion for P&MI Study Plans-related Sponsor Question 1:
Pfizer stated that they are planning to submit the Pediatric St udy Plan (PSP) on
July 15, 2020. They will include details of the deferred studi es (and
immunobridging) and justification of waiver in the PSP. CBER ackn owledged.
P&MI Study Plans-related Sponsor Question 2:
Does CBER agree with the proposed inclusion of global sites (eg , EU, South America,
Turkey) in the pediatric study with at least 30% of participant s coming from US?
FDA Preliminary Meeting Response to P&MI Study Plans-related Spo nsor
Question 2:We agree with the proposal to include global sites in the pedia tric study, with at least
30% of participants coming from the US.
Meeting Discussion for P&MI Study Plans-related Sponsor Question 2:
There was no discussion of this question during the meeting. Thi s response is
now considered final.
P&MI Study Plans-related Sponsor Question 3:Does CBER have any comments on the proposed plan for evaluating maternal
immunization?
FDA Preliminary Meeting Response to P&MI Study Plans-related Spo nsor
Question 3:We acknowledge your plans to assess your product in pregnant women, and we would encourage an ongoing dialogue regarding inclusion of preg nant women in
FDA-CBER-2021-5683-1147745
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your planned studies and how safety and effectiveness data obta ined with your
vaccine may be used. Please note that initiation of studies in th is population is
contingent on our review of data to support the safety of this approach, particularly
your planned DART study. We have the following comments and req uests for
clarification:
a. Please provide a detailed proposal for how you intend to labe l the data from
studies conducted in pregnant women (or the subanalyses of the data from
pregnant women, if they are included in broader studies).
b. Please clarify whether you intend to seek an indication for v accination during
pregnancy to protect the infant from SARS CoV-2 infection. Pleas e note that
cord blood immune assays are unlikely to be adequate to support this indication
in the absence of establishing a biomarker reasonably likely to predict protection.
c. With respect to other vaccines recommended for administration during
pregnancy (i.e., Tdap and influenza vaccines), please comment on the potential
for immunologic interference and discuss your plans to address this issue.
d. Further discussion on your proposed immunobridging study may be needed after
you provide responses to our questions above to clarify your in tentions for
labeling of data from this study and claims related to the data, and after more data are available to determine the acceptability of immune mar kers that you
would propose for immunobridging.
Meeting Discussion for P&MI Study Plans-related Sponsor Question 3:
Pfizer stated that they will submit information related to maternal immunization
studies later. CBER acknowledged.
P&MI Study Plans-related Sponsor Question 4:The developmental and reproductive toxicology (DART) study will be initiated
. Does CBER agree that the res ults of the DART
study can be provided during review of the initial BLA
?
FDA Preliminary Meeting Response to P&MI Study Plans-related Spo nsor
Question 4:We agree that the results of the DART study can be provided duri ng review of the
initial BLA that will include data from Study C4591001.
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
(b) (4)
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Meeting Discussion for P&MI Study Plans-related Sponsor Question 4:
Pfizer stated that they will submit the DART study protocol for CBER review in
July 2020, and they plan to submit the DART study results during the review of
the BLA. CBER acknowledged.
FDA Questions/Comments sent in Preliminary Meeting Response:
FDA Comment 1:
Consistent with the FDA Guidance for Industry on Enhancing the Diversity of Clinical
Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs
(https://www.fda.gov/media/127712/download ), we encourage you to adopt enrollment
and retention practices that enhance inclusiveness so that the clinical trial population
reflects the diversity of the people who will be using the vacc ine, if approved.
Specifically, racial and ethnic minority persons should be repr esented in clinical trials.
We suggest that clinical trial sites include geographic locatio ns with a higher
concentration of racial and ethnic minorities to recruit a dive rse study population.
Meeting Discussion for FDA Comment 1:There was no discussion of this FDA comment during the meeting. This response is
now considered final.
FDA Comment 2:All study data generated from trials initiated after December 1 7, 2016, that will be
submitted with applications for new drugs/biologics must be in conformance with the
standards listed in the FDA Data Standards Catalog (https://www.fda.gov/ForIndustry/DataStandards/StudyDataStandard s/default.htm ).
As you intend to initiate your Phase 1/2/3 clinical trial in th e near future, we request that
you provide as soon as possible, a Study Data Standardization Plan (SDSP) with CBER appendix (https://www.phuse.eu/documents//sop/wp/phuse-tp001-st udy-data-
standardization-plan-v1-8409.docx) proposing the specific use o f the Clinical Data
Interchange Standards Consortium (CDISC), including Study Data Tabulation Model
(SDTM) and Analysis Data Model (ADaM) formats. We also request that the associated
annotated case report form (aCRF) for SDTM be provided. Please r efer to the CDISC
Vaccine Therapeutic Area User Guide (TAUG) and Guidance for Indu stry “Submitting
Study Datasets for Vaccines to the Office of Vaccines Research and Review”
(https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceCo mplianceRegulato
ryInformation/Guidances/General/UCM605147.pdf ) for details on standardizing your
data.
Meeting Discussion for FDA Comment 2:There was no discussion of this FDA comment during the meeting. This response is
now considered final.
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Additional FDA Comment:
1. Post Meeting Comments:
Please refer to the Post meeting comments provided regarding Spon sor Questions
1.b and 1.c that are located below the meeting discussion sectio ns (above).
FDA-CBER-2021-5683-1147748
Page 20 – IND 19736, Amendment 15; CRMTS 12645 – Elisa Harkins
Attachment 1:
Slide deck that describes Pfizer’s Phase 3 designs with 4 interi m analyses with VE
threshold = 20% or 30%, and their operating characteristics.
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FDA-CBER-2021-5683-1147750
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FDA-CBER-2021-5683-1147751
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FDA-CBER-2021-5683-1147752
Page 24 – IND 19736, Amendment 15; CRMTS 12645 – Elisa Harkins
Attachment 2:
Projected available serological data following dose 1 and Projected number of
subjects receiving 1 or 2 doses by July 17, 2020.
FDA-CBER-2021-5683-1147753
Teleconference Summary
Meeting date & time: July 6, 2020, 2:00 – 3:00 PM
Submission: IND 19736
Product name: Human Coronavirus mRNA Vaccines (SARS-CoV-2 Spike
Protein; BNT162a1 (uRNA; variant RBL063.3); BNT162b1 (modRNA; variant RBP020.3); BNT162b2 (modRNA; variant RBP020.2); and BNT162c2 (saRNA; variant RBS004.2)) in Lipid Nanoparticles (ALC-0315, ALC-0159, DSPC and Cholesterol)
Proposed indication: Active immunization against COVID-19 in adults 18 years of age and older
Sponsor: BioNTech RNA Pharmaceuticals GmbH/Pfizer. Inc.Sponsor Agent: Pfizer, Inc.
FDA Attendees: Maria Allende, MD OVRR/DVRPASarah Browne, MD OVRR/DVRPACarmen Collazo, PhD OVRR/DVRPADoran Fink, MD, PhD OVRR/DVRPASara Gagneten, PhD OVRR/DVPMarion Gruber, PhD OVRRLei Huang, PhD OBE/DBRobin Levis, PhD OVRR/DVPKeith Peden, PhD OVRR/DVPDouglas Pratt, MD OVRR/DVRPAElizabeth Sutkowski, PhD OVRR/DVRPAStephanie Troy, MD OVRR/DVRPAJerry Weir, PhD OVRR/DVPSusan Wollersheim, MD OVRR/DVRPA
Pfizer Participants:
Donna Boyce Vice President, Global Regulatory Affairs, Vaccines,
Pfizer Inc.
Carmel Devlin Global Regulatory Portfolio Lead, Global Regulatory
Affairs, Vaccines, Pfizer Inc.
Philip R. Dormitzer, MD, PhD Vice President and Chief Scientific Officer, Viral
Vaccines, Vaccines Research and Development, Pfizer Inc.
Kathrin U. Jansen, PhD Senior Vice President and Head, Vaccine R esearch and
Development, Pfizer Inc.
FDA-CBER-2021-5683-1147754
Background and Objectives:
After June 26, 2020 Type C meeting, CBER received clarification information from
Pfizer’s Donna Boyce regarding the construct and doses Pfizer i s planning to use in
Phase 3 (The same information was later submitted to IND 19736, i n amendment 24
dated July 1, 2020). This information suggested, as discussed du ring the Type C
meeting, that Pfizer will use either BNT162b1 and BNT162b2, at either a 10 or 20 μgdose. However, the clinical protocol amendment 4 submitted on July 2, 2020, includes the third candidate, i.e., BNT162b3, and the email sent by Pfize r’s Donna Boyce on July
6, 2020, suggested that Pfizer may select a 30 μg dose (The same in formation was later
submitted to IND 19736, in amendment 26 dated July 8, 2020). CBER requested a
teleconference with Pfizer to obtain clarification regarding the construct and doses
Pfizer is planning to use in Phase 3 as knowing this helps us to provide appropriate
advice and response to Pfizer’s questions.
Teleconference summary:
Pfizer stated it is too late for them to introduce BNT162b3, an d therefore, they will
remove this vaccine candidate from consideration for their stud y. They plan to make
the decision by July 17, 2020, if they will move forward with ei ther BNT162b1 or
BNT162b2 and which dose level they will select.
CBER stated that less immunogenicity data have been submitted fo r older subjects as
compared with younger subjects, and post-dose 2 immunogenicity data will be available
only for the 10 μg dose of BNT162b1. In addition, Pfizer has not su bmitted details on
the methodology or assays that used to measure antigen-binding I gG and authentic
virus neutralization titers, to make sure that the data generat ed by using these assays
are acceptable. Pfizer stated that they will submit the qualif ication reports for both
assays next week. CBER acknowledg ed. Pfizer stated that they will submit complete
post-dose 2 safety and immunogenicity data (including the CMI d ata) for the 10 μg dose
from the German study by July 10, 2020. CBER acknowledged. Pf izer indicated that
the immune responses from subjects from the German study are co nsistent with the
immune responses from subjects in the US study. Pfizer also indic ated that the immune
responses are tightly distributed, post-dose 2 safety data from subjects that received 30
Pg vaccine candidate also look promising, and that they believe that the risk-benefit
considerations could favor moving forward with 10 Pg, 20 Pg or 30 Pg doses, depending
on the construct. CBER asked, for BNT162b2, as post-dose 2 immuno genicity data are
available for only 10 μg dose, how Pfizer will choose the 20 μg or 30 μg dose to study in
Phase 3 in the absence of post-dose 2 immunogenicity data. Pfi zer replied that based
on quality of the post-dose 2 immunogenicity data for 10 μg dos e, they believe that
post-dose 2 immunogenicity data for the other doses (20 μg or 3 0 μg) will be better,
whether it is BNT162b1 or BNT162b2, based on the (same) platfor m, and T-cell
response will be same. CBER noted that Pfizer plans to analyze data for the first 360 subjects enrolled in the
Phase 2b/3 portion of the study, and enrollment may continue during this period. CBER asked how many subjects will be enrolled in Phase 2b/3 before da ta from the planned
interim assessment in the first 360 enrolled subjects (which will consist of post-dose 2
FDA-CBER-2021-5683-1147755
safety and post-dose 1 immunogenicity). Pfizer stated that the y plan on enrolling 1,400
subjects/week. So, by the time of the interim assessment in the first 360 subjects,
which would take 4-5 weeks, they may have already vaccinated close to 4,000 subjects
given the 1:1 randomization. They will make sure to have overs ight by IRC and DMC.
CBER also asked about the timing of the submission of the NHP c hallenge study data.
Pfizer asked if submission of the data from the NHP challenge study is necessary before initiating the Phase 3 study, as they understood the dat a to be “nice to have”
rather than “must have.” CBER stated that the animal challenge s tudy data may not be
absolutely necessary but would help to compensate for the relatively small amount of clinical immunogenicity data being proposed to support Phase 2b/3 initiation. Pfizer stated that the data from the NHP challenge study (including vi ral load and CAT scan)
will be submitted by July 17, 2020; lung pathology information will be submitted later.
CBER acknowledged.
CBER indicated that if Pfizer s ubmits much of this information o n July 17, 2020 with the
plan of initiating Phase 3 trial on July 22, 2020, CBER may not have adequate time for
reviewing the submitted information. Pfizer responded that the y will provide the
information to support Phase 2b/3 initiation as soon as it beco mes available. Pfizer
stated that they will submit the qualification reports for the two assays by the end of this
week, and they will submit preliminary data (viral load and CT scans) from the macaque
challenge studies by July 17, 2020. They will also submit the s afety and
immunogenicity data (including CMI data from 12 subjects in the German study) per the
schedule they previously communicated.Pfizer asked if CBER could instruct Pfizer, based on the planned av ailable safety and
immunogenicity data, if they can enroll younger and older adults concurrently in Phase
2b/3, or if they will need to enroll younger adults first and old er adults later. CBER
stated that we would need to at least receive the assay qualifi cation data first to assess
the quality of the immunogenicity data, before providing an ans wer. CBER stressed
again that the animal challenge study data is important given t he smaller size of safety
and immunogenicity data from Phase 1. CBER committed to take all data into consideration, review and discuss internally the upcoming submis sions, and provide
feedback later. Pfizer agreed.
Post-meeting Comment:
Pfizer submitted the Qualification Information (assay method/man ual and qualification
report) for the Luminex Assay for Quantitation of IgG Antibodie s and the Virus
neutralization assay, in amendment 30 dated July 10, 2020, and it is under CBER
review.
Ramachandra
Naik -SDigitally signed by Ramachandra Naik -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=2001232361, cn=Ramachandra Naik -S Date: 2020.07.15 12:30:35 -04'00'
FDA-CBER-2021-5683-1147756
COVID -19 Vaccine (BNT162, PF -07302048)
IND #19736
Request for Proprietary & Non -Proprietary Name Revie w
PFIZER CONFIDENTIAL
Page 1REQUEST FOR PROPRIETARY &
NON- PROPRIETARY NAM E REVIEW
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FDA-CBER-2021-5683-1147757
COVID -19 Vaccine (BNT162, PF -07302048)
IND #19736
Request for Proprietary & Non -Proprietary Name Revie w
PFIZER CONFIDENTIAL
Page 2TABLE OF CONTENTS
1. APPLICANT CONTACT INFORMATION ................................ ................................ ......... 3
2. PROPOSED PRI MARY AND ALTERNATE PROPRI ETARY NAMES .......................... 3
3. INTENDED PRONUNCI ATION................................ ................................ ......................... 3
4. DERIVATION OF PROPRI ETARY NAME ................................ ................................ ........ 3
5. INTENDED MEANING OF PROPRIETARY NAME MODIFIERS ................................ ..3
6. PROPOSED ESTABLISHED NAME ................................ ................................ .................. 3
7. PHARMACOL OGIC/ TH ERAPEUTI C CATEGORY ................................ ........................ 3
8. PROPOSED I NDICATI ON FOR USE ................................ ................................ ................. 3
9. PRESCRI PTION STAT US................................ ................................ ................................ ...3
10. DOSAGE FORM, PRO DUCT STRENGTH(S) ................................ ................................ .4
11. ROUTE OF ADMINIS TRATION ................................ ................................ ...................... 4
12. US UAL DOSAGE, FREQUENC Y OF ADMINI STRATION, MAXIMUM
DAILY DOSE ................................ ................................ ................................ ....................... 4
13. DOSING IN SPECIF IC POPULATIONS ................................ ................................ ........... 4
14. INSTRUCTI ONS FOR USE ................................ ................................ ............................... 4
15. STORAGE REQUIREMENT ................................ ................................ ............................. 4
16. HOW SUPPLIED AND PACKAGING CONFIGURA TION................................ ............ 4
17. LIKELY CARE ENVI RONMENT(S) FOR DI SPENSING AND USE ............................. 4
18. DELIVERY SYSTEM, MEA SURI NG DEVICE ................................ ............................... 5
19. ASSESSMENTS OF P ROPRI ETARY NAME, PAC KAGING, AND/OR
LABELING ................................ ................................ ................................ ........................... 5
090177e1953f5675\Approved\Approved On: 14-Oct-2020 15:08 (GMT)
FDA-CBER-2021-5683-1147758
COVID -19 Vaccine (BNT162, PF -07302048)
IND #19736
Request for Proprietary & Non -Proprietary Name Revie w
PFIZER CONFIDENTIAL
Page 31.APPLICANT CONTACT IN FORMATION
Name and title of contact Elisa Harkins, Senior Director, Global Regulatory
Affairs, Pfizer, Inc. –Authorized US Agent for:
BioNTech RNA Pharmaceut icals GmbH
Company Name Pfizer, I nc.
Address 500 Arcola Road
Collegeville, PA 19426
Phone number 215-280-5503
Fax number 845-474-3500
Email address [email protected]
2.PROPOSED PRIMARY AND ALTERNATE PROPRIETA RY NAMES
The primary proposed proprietary name for Agency consideration is COMIRNATY .
The trademark application serial number is 88942267 (filed b y BioNTech SE) for
COMI RNATY . The application was filed at the United States Patent and Trademark Office
on June 1, 2020 by BioNTech SE. The Notice of Allowance has not y et issued.
Should this name not be found acceptable, an alternate name will be provided at that time.
3.INTENDED PRONUNCIATI ON
koh-MER’ nah- tee
4.DERIVATION OF PROPRI ETARY NAME
The proposed proprietary nam e COMI RNATY is an invented word with no inherent
meaning .
5.INTENDED MEANING OF PROPRIETARY NAME MOD IFIERS
Not applicable.
6.PROPOSED ESTABLISHED NAME
Pfizer -BioNTech COVID-19 vaccine
7.PHARMACOLOGIC/ THERA PEUTIC CATEGORY
Prophy lactic vaccine.
8.PROPOSED INDICATION FOR USE
Active immunization against COVI D-19.
9.PRESCRIPTION STATUS
To be administered b y a qualified healthcare professional.
090177e1953f5675\Approved\Approved On: 14-Oct-2020 15:08 (GMT)
FDA-CBER-2021-5683-1147759
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IND #19736
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PFIZER CONFIDENTIAL
Page 410.DOSAGE FORM, PRODUCT STRENGTH(S)
Concentrate for solution for injection.
5-Dose Vial is supplied as a white to off- white sterile frozen liquid, packaged in a clear glass
2 mL vial with a rubber stopper, aluminum overseal and flip off cap.
A single vial will be used to prepare a diluted dosing solution that is used to prepare doses for
multiple individuals. The concentrat ed solution in the vial requires dilution with sterile 0.9%
Sodium Chloride I njection, USP. After dilution, the vials contain a sufficient volume to
supply 5 doses, where each 0.3 mL dose contains 30 µgvaccine for intramuscular injection.
11.ROUTE OF ADMINI STRATION
For intramuscular injection only .
12.USUAL DOSAGE, FREQUE NCY OF ADMINISTRATIO N, MAXIMUM DAILY
DOSE
Administered intramuscularly as a series of two 30 µg doses of the diluted vaccine solution
(0.3 mL each) according to the following schedule: A single 0.3 mL dose followed by a
second 0.3 mL dose 21 day s later.
13.DOSING IN SPECIFIC P OPULATIONS
No specific information will be provided for modifications that ar e dependent on renal and/or
hepatic function. There will be no gender -based modifications.
14.INSTRUCTIONS FOR USE
After thawing, each vial of vaccine must be diluted with 1.8 mL sterile 0.9% Sodium
Chloride I njection, USP. After dilution, the vial contains f ive 30 µg doses of 0.3 mL per
dose. Individual 0.3 mL doses should be withdrawn from the vial and administered
intramuscularl y in the deltoid muscle of the non -dominant arm.
15. STORAGE REQUIREMENT
Vaccine vials must be immediately stored between -80 ºC and -60ºC (-112 ºF to -76ºF),
protected from light and kept in the original packaging until read y for use.
16. HOW SUPPLIED AND PAC KAGING CONFIGURATION
The vaccine will be supplied frozen in -80ºC thermal containers with dry ice, in cartons each
containing 195 vials.
17.LIKELY CARE ENVIRONM ENT(S) FOR DISPENSING AND USE
This vaccine will be administered by a qualified healthcare professional.
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IND #19736
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PFIZER CONFIDENTIAL
Page 518.DELIVERY SYSTEM, MEA SURING DEVICE
After dilution, each 0.3 mL dose of vaccine should be withdrawn from the vial with a
commerciall y available disposable sterile syringe with appropriate graduations and delivered
with a needle appropriate for intramuscular injection.
19.ASSESSMENTS OF PROPR IETARY NAME, PACKAGI NG, AND/OR
LABELING
The Sponsor has evaluated the proposed primary proprietary name of COMI RNATY for this
vaccine and considers the name safe, not misleading, or over-promising. However, no
information of this nature is included in the current application.
090177e1953f5675\Approved\Approved On: 14-Oct-2020 15:08 (GMT)
FDA-CBER-2021-5683-1147761
U.S. Food & Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20903
www.fda.gov
Our Reference: IND 19736 PROPRIETARY NAME
ACCEPTABLE AT THIS TIME
BioNTech RNA Pharmaceuticals GmbH
Attention: Ms. Elisa HarkinsPfizer, Inc.500 Arcola RoadCollegeville, PA 19426
Dear Ms. Harkins:Please refer to your Investigational New Drug Application (IND) submitted under section
505(i) of the Federal Food, Drug, and Cosmetic Act (FDCA) for “ Human Coronavirus
mRNA Vaccine (SARS-CoV-2 Spike Protein; BNT162b2 (modRNA; varia nt RBP020.2))
in Lipid Nanoparticles (ALC-0315, ALC-0159, DSPC and Cholestero l).”
We also refer to your amendment submitted and received on October 14, 2020,
requesting a proprietary name review for COMIRNATY.In consultation with the Center for Biologics Evaluation and Re search’s Advertising and
Promotional Labeling Branch (CBER/APLB), we conclude that, unde r the FDCA and
applicable regulations, COMIRNATY is Acceptable at this time .
Please provide a request for a re-review of your proposed proprietary name
COMIRNATY within 14 days following submission of your Biologics License Application.
If you have any questions, please contact the Regulatory Projec t Manager,
Ramachandra Naik, PhD, at 301-796-2640.
Sincerely,
Loris D. McVittie, PhD
Deputy Director - RegulatoryDivision of Vaccines and
Related Products Applications
Office of Vaccines
Research and Review
Center for Biologics
Evaluation and Research Loris D.
Mcvittie -SDigitally signed by Loris D. Mcvittie -S DN: c=US, o=U.S. Government, ou=HHS, ou=FDA, ou=People, 0.9.2342.19200300.100.1.1=1300064781, cn=Loris D. Mcvittie -S Date: 2020.11.20 09:30:51 -05'00'
November 20, 2020
FDA-CBER-2021-5683-1147762
COVID-19Vaccine (BNT16 2;PF-0730204 8)
BB-IND 01973 6
1.6.1 Meeting Request
PFIZER CONFIDENTIAL
Page 1COVID -19 V accine (BNT162, PF-07302048)
BB-IND 019736
Type C Meeting Request
July 2020
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FDA-CBER-2021-5683-1147763
COVID-19Vaccine (BNT16 2;PF-0730204 8)
BB-IND 01973 6
1.6.1 Meeting Request
PFIZER CONFIDENTIAL
Page 2TABLE OF CONTENTS
1.PRODUCT DESCRI PTIONAND APPLICATION NUM BER ................................ ........... 3
2.CHEMI CAL NAME AND S TRUCTURE ................................ ................................ ............ 3
3.PROPOSED I NDICATION (S)................................ ................................ .............................. 4
4.TYPE OF MEETING BEI NG REQUESTED ................................ ................................ .......4
5. PURPOSE OF THE MEETIN G ................................ ................................ ............................ 4
6.SPECIFIC OBJECTIVES /OUTCOMES EXPECTED ................................ ......................... 4
7.PRELIMINARY AGENDA, PRESENTER, TIME ................................ .............................. 5
8.SPECIFIC QUESTIONS GROUPED BY DI SCIPLINE................................ ...................... 5
9.SPONSOR ATTENDEES ................................ ................................ ................................ .....5
10.AGENCY STAFF ................................ ................................ ................................ ................ 7
11.ANTICI PATED DATE OF SUPPORTING DOCUMENT ATION ................................ ...7
12.SUGG ESTED MEETING DATES AND TIME ................................ ................................ .7
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BB-IND 01973 6
1.6.1 Meeting Request
PFIZER CONFIDENTIAL
Page 31.PRODUCT DESCRI PTION AND APPLICATIO N NUMBER
Pfizer and BioNTech are developing an investigational vaccine intended toprevent
Coronavirus D isease 2019 ( COVI D-19 )caused by the virus ,SARS -CoV-2. The goal of the
development program is to rapidly develop and license a vacc ine for use in adu lts ≥ 18 years
of age ,followed by a pediatric indication. The vaccine isbased on SARS -CoV-2 spike
(S)glycoprotein antigens encoded in RNA and formulated in lipid nanoparticles (LNPs),
referred to as COVID -19 Vaccine (BioNTech code number BNT162, Pfizer code number PF -
07302048 ).
An Investigational New Drug Application (IND) for the COVID -19 Vaccine was submitted
to the US FDA on April 22,2020. On April 29,2020 Pfizer was notified by CBER that there
were no clinical hold issues identified ,and the evaluation of this vaccine in the US could
proceed. The COVID -19candidate vaccine formulation s are investigational medicinal
products (IMPs) and have not been sub mitted for marketing approval in any country . A
Request for Fast Track Designation was submitted on Ma y 15, 2020 (Serial Number 0005)
and was granted on July 7, 2020 .
BioNTech is conducting a German first-in-human ( FIH)dose level -finding Phase 1/2 study
(BNT162 -01; 2020 -001038 -36) to gather safet y and immunogenicit y data to enable
evaluation of each of th e vaccines individuall y to inform the overall clinical development of
a COVID -19 vaccine. This study is not conducted under the IND but is being conducted
under a German Clinical Trial A uthorization (CTA) . The protocol for this study has been
provided previousl y in Module 5 (Module 5.3.5.1 Clinical Study Protocol BNT162-01 ).
Pfizer and BioNTech are conducting a large Phase 1/2 cl inical study in the US (C4591001) to
evaluate the safet y and immunogenicit y of the prophy lactic COVID- 19 vaccine candidates
using a range of dosage levels and dosing regimens, with the intent to select the most
appropriate final vaccine candidate for Phase 3 development. To gather appropriate dose
level information quickly, some dose levels evaluated in German or US studies were not the
same. In addition, Pfizer has chosen not to evaluate currently unmodified RNA (uRNA) or
self-amplify ing RNA (saRNA) candid ates in the US study . The protocol for this study is
provided in Module 5 (Module 5.3.5.1 Clinical Study Protocol C4591001). Pfizer and
BioNTech plan to convert this study to a large Phase 2b/3 safet y and efficacy study by the
end of July 2020.
AType C Me eting was held on June 26, 2020 present ingthe proposed Clinical Development
Program intended to support Tr
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