EMA/596333/2021

Committee for Medicinal Products for Human Use (CHMP)

Assessment report on the annual renewal of the

conditional marketing authorisation

Procedure no.: EMEA/H/C/005735/R/0046

Invented name: COMIRNATY

Common name: COVID-19 mRNA vaccine (nucleoside-modified)

Marketing authorisation holder (MAH): BioNTech Manufacturing GmbH

Note
Assessment report as adopted by the CHMP with all information of a commercially confidential
nature deleted.

Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands

Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us
Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union
Steps taken for the assessment

Description Date

Start of procedure: 19 Jul 2021

CHMP and PRAC Rapporteurs Joint Assessment Report 17 Aug 2021

CHMP and PRAC members comments 23 Aug 2021

Updated CHMP and PRAC Rapporteurs Joint Assessment Report N/A

PRAC endorsed relevant sections of the assessment report 02 Sep 2021

Request for supplementary information 16 Sep 2021

MAH responses to (RfSI) received on 21 Sep 2021

CHMP and PRAC Rapporteurs' joint assessment report 28 Sep 2021

PRAC endorsed relevant sections of the assessment report 30 Sep 2021

CHMP and PRAC members comments N/A

Updated CHMP and PRAC Rapporteurs joint assessment report N/A

Opinion 14 Oct 2021

Procedure resources

CHMP Rapporteur: Filip Josephson

PRAC Rapporteur: Menno van der Elst

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Table of contents

1. Background information on the annual renewal ...................................... 4

2. Specific Obligations ................................................................................. 4

2.1. Specific Obligations adopted by the CHMP at time of initial marketing authorisation ...... 4
2.2. Outstanding Specific Obligations – Status report for period covered ............................ 5
2.3. Overall conclusion on Specific Obligations .............................................................. 11

3. Additional scientific data provided relevant for the assessment of the

benefit/risk balance .................................................................................. 12
3.1. Quality .............................................................................................................. 12
3.2. Clinical efficacy .................................................................................................. 12
3.3. Clinical safety .................................................................................................... 12
3.4. Pharmacovigilance inspections ............................................................................. 37

4. Risk management plan .......................................................................... 37

5. Changes to the Product Information...................................................... 37

6. Request for Supplementary Information - RfSI ..................................... 38

6.1. Other concerns .................................................................................................. 38

7. Assessment of the MAH responses to the RfSI ...................................... 38

7.1. Other concerns .................................................................................................. 38

8. Overall conclusions and benefit-risk balance ......................................... 39

8.1. Specific Obligations (SOBs) ................................................................................. 39
8.2. Benefit-risk Balance ............................................................................................ 40

9. Recommendations ................................................................................. 42

10. EPAR changes ...................................................................................... 43

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1. Background information on the annual renewal
The European Commission issued on 21 December 2020, a conditional marketing authorisation (MA)
for Comirnaty. This implied that, pursuant to Article 14-a of Regulation (EC) No 726/2004 and Article 5
of Commission Regulation (EC) No 507/2006, the marketing authorisation holder (MAH) has to
complete ongoing studies, or to conduct new studies, as listed in Annex II.E of the MA, the so-called
Specific Obligations (SOBs). These data form the basis of the renewal of the conditional MA.

A conditional MA is valid for one year and may be renewed annually upon request by the MAH.
Therefore, pursuant to Article 14-a of Regulation (EC) No 726/2004 and Article 6(2) of Commission
Regulation (EC) No 507/2006, the MAH BioNTech Manufacturing GmbH, submitted to the Agency on 18
June 2021 an application for renewal of the conditional marketing authorisation for Comirnaty. The
expiry date of the MA is 21 December 2021.

The period covered by this annual renewal is 21 December 2020 to 29 April 2021.

2. Specific Obligations

2.1. Specific Obligations adopted by the CHMP at time of initial marketing

authorisation

Number Description Due date

SOB 001 In order to complete the characterisation of the active substance July 2021
and finished product, the MAH should provide additional data.
SOB 002 In order to ensure consistent product quality, the MAH should July 2021
provide additional information to enhance the control strategy,
including the active substance and finished product specifications.
SOB 003 In order to confirm the consistency of the finished product March 2021
manufacturing process, the MAH should provide additional
validation data.
SOB 004 In order to confirm the purity profile and ensure comprehensive July 2021
quality control and batch-to-batch consistency throughout the
lifecycle of the finished product, the MAH should provide additional
information about the synthetic process and control strategy for
the excipient ALC-0315.
SOB 005 In order to confirm the purity profile and ensure comprehensive July 2021
quality control and batch-to-batch consistency throughout the
lifecycle of the finished product, the MAH should provide additional
information about the synthetic process and control strategy for
the excipient ALC-0159.
SOB 006 In order to confirm the efficacy and safety of Comirnaty, the MAH Dec 2023
should submit the final Clinical Study Report for the randomized,
placebo-controlled, observer-blind study C4591001.

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2.2. Outstanding Specific Obligations – Status report for period covered

SOB Number Description (scope) Due date Date of Date of Current

indicated in submission resolution (if status
Annex II applicable)

Specific In order to complete the characterisation of the active substance and July 2021 02/08/2021 Not
Obligation 1 finished product, the MAH should provide additional data. Fulfilled
(SO1)
SO1 (a) Additional data is to be provided to further characterise the truncated July 2021 02/08/2021 Ongoing
and modified mRNA species present in the finished product. Data are
expected to cover batches used in clinical trials (for which the
characterisation data could be available earlier) and the PPQ batches.
These data should address results from ion pairing RP-HPLC addressing
5’cap levels and presence of the poly(A) tail. These data should further
address the potential for translation into Assessment report
EMA/707383/2020 Page 37/140 truncated S1S2 proteins/peptides or
other proteins/peptides. Relevant protein/peptide characterization data
for predominant species should be provided. Any homology between
translated proteins (other than the intended spike protein) and human
proteins that may, due to molecular mimicry, potentially cause an
autoimmune process should be evaluated.
SO1 (b) The analysis of the main peak of the RNA integrity test representing the July 2021 02/08/2021 Ongoing
full-length RNA, should be also undertaken addressing 5’cap levels and
presence of the poly (A) tail.

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SOB Number Description (scope) Due date Date of Date of Current
indicated in submission resolution (if status
Annex II applicable)

SO1 (c) Additional data for the active substance are to be provided to confirm July 2021 02/08/2021 Ongoing
the identities of the observed Western Blot (WB) bands obtained by the
in vitro expression assay. Protein heterogeneity, resulting in broad
bands on the WB and uncertainties in the theoretical intact molecular
weight of the spike protein, is assumed to be due to glycosylation.
Therefore, to further confirm protein identities, enzymatic
deglycosylation of the expressed proteins followed by WB analysis
should be performed. Correlation with the calculated molecular weights
of the intact S1S2 protein should be demonstrated
Specific In order to ensure consistent product quality, the MAH should provide July 2021 02/08/2021 Not
Obligation 2 additional information to enhance the control strategy, including the Fulfilled
(SO2) active substance and finished product specifications.

SO2 (a) The active substance and finished product specifications acceptance July 2021 02/08/2021 Ongoing
limits should be reassessed and revised as appropriate, as further data
becomes available from ongoing clinical trials and in line with
manufacturing process capability and stability data of the product.
Comprehensive data should be provided comprising batch analyses of a
suitable number of commercial batches as well as analyses of batches
that have been used in the (ongoing) clinical trials.
SO2 (b) Poly(A) tail length is considered a critical attribute, which should be July 2021 02/08/2021 Ongoing
controlled on each batch, even though comparable results were obtained
until now. An active substance specification to control poly(A) length
should be introduced. A suitable method should be developed, and
appropriate acceptance criteria should be set.

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SOB Number Description (scope) Due date Date of Date of Current
indicated in submission resolution (if status
Annex II applicable)

SO2 (c) The poly(A) tail percentage is considered a critical attribute, but July 2021 02/08/2021 Ongoing
uncertainties remain on the suitability of the method. Additional data
should be provided to support the suitability of the method used for
%poly(A) tail or an alternative suitable assay should be developed and
introduced. The %poly(A) tail should be characterised following any
future active substance process changes.
SO2 (d) Since mRNA integrity and polydispersity are CQAs for the efficacy of the July 2021 02/08/2021 Ongoing
medicinal product, the finished product acceptance criteria for these
parameters should be revised as further data becomes available from
ongoing clinical trials and in line with manufacturing process capability.

SO2 (e) Additional data should be provided to support the suitability of the July 2021 02/08/2021 Ongoing
method used for potency determination or an alternative suitable assay
for this purpose should be developed and introduced. Then the finished
product acceptance criteria for potency should be revised accordingly.

SO2 (f) Lipid-related impurities should be further evaluated. An appropriate July 2021 26/07/2021 Ongoing
control strategy should be introduced, suitably justified and provided for
assessment during Q2 2021.

Specific In order to confirm the consistency of the finished product March 2021 29/03/2021 20/05/2021 Fulfilled
Obligation 3 manufacturing process, the MAH should provide additional validation
(SO3) data.
SO3 (a) Full commercial scale finished product PPQ-batches will be manufactured March 2021 29/03/2021 20/05/2021 Fulfilled
at the commercial facility Pfizer Puurs, Belgium. The applicant should
provide the summary report on the completed commercial scale process
validation activities.

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SOB Number Description (scope) Due date Date of Date of Current
indicated in submission resolution (if status
Annex II applicable)

SO3 (b) The applicant should perform testing of future process validation-batches March 2021 29/03/2021 20/05/2021 Fulfilled
of finished product according to the extended comparability testing
protocol and the results should be provided for assessment.

Specific In order to confirm the purity profile and ensure comprehensive quality July 2021 06/01/2021 Not
Obligation 4 control and batch-to-batch consistency throughout the lifecycle of the Fulfilled
(SO4) finished product, the MAH should provide additional information about 26/07/2021
the synthetic process and control strategy for the excipient ALC-0315.

SO4 (a) A detailed description of the chemical synthesis of ALC-0315 (e.g. January 2021 06/01/2021 27/01/2021 Fulfilled
information on reagents and process conditions) should be provided.

SO4 (b) Differences in the manufacturing process between two suppliers should July 2021 26/07/2021 Ongoing
be described and possible impact on impurity profile should be discussed
by July 2021.

SO4 (c) Information and justification of quality control of starting materials (e.g. July 2021 26/07/2021 Ongoing
general synthetic route, supplier and specifications) and solvents should
be provided.
SO4 (d) Information and justification on critical steps and intermediates July 2021 26/07/2021 Ongoing
(including specifications) should be provided.
SO4 (e) Specified impurities should be further evaluated and appropriate July 2021 26/07/2021 Ongoing
specification limits for individual impurities should be included when
more data are available. Acceptance criteria for specified and un-
specified impurities should be added to the specification for ALC-0315
and should also be evaluated during stability studies.

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SOB Number Description (scope) Due date Date of Date of Current
indicated in submission resolution (if status
Annex II applicable)

SO4 (f) The specification limit for total impurities should be re-evaluated as July 2021 26/07/2021 Ongoing
more batch data becomes available and revised, as appropriate.

SO4 (g) The specification limit for assay should be tightened based on the July 2021 26/07/2021 Ongoing
provided batch data to improve the quality control strategy of the
finished product.
SO4 (h) Detailed method validation reports for assay, impurities, and residual July 2021 26/07/2021 Ongoing
solvents for ALC-0315 should be provided.
SO4 (i) Results of stability studies in accordance with ICH guidelines should be July 2021 26/07/2021 Ongoing
provided.
Specific In order to confirm the purity profile and ensure comprehensive quality July 2021 06/01/2021 Not
Obligation 5 control and batch-to-batch consistency throughout the lifecycle of the Fulfilled
(SO5) finished product, the MAH should provide additional information about 26/07/2021
the synthetic process and control strategy for the excipient ALC-0159.

SO5 (a) A detailed description of the chemical synthesis of ALC-0159 (e.g. January 2021 06/01/2021 27/01/2021 Fulfilled
information on reagents and process conditions) should be provided.

SO5 (b) Information and quality control of starting materials (e.g. general July 2021 26/07/2021 Ongoing
synthetic route, supplier and specifications) and solvents should be
provided. Relevant acceptance criteria for molecular weight and
polydispersity should be included in the specification for the starting
material carboxy-MPEG.
SO5 (c) Information and justification of critical steps and intermediates July 2021 26/07/2021 Ongoing
(including specifications) should be provided.

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SOB Number Description (scope) Due date Date of Date of Current
indicated in submission resolution (if status
Annex II applicable)

SO5 (d) The specification limit for assay should be tightened based on batch data July 2021 26/07/2021 Ongoing
in order to provide a more stringent quality control of the finished
product.
SO5 (e) Specified impurities should be further evaluated and appropriate July 2021 26/07/2021 Ongoing
specification limits for individual impurities should be included when
more data are available. Acceptance criteria for specified and un-
specified impurities should be added to the specification for ALC-0159
and should also be evaluated during stability studies.
SO5 (f) The specification limit for total impurities should be re-evaluated as July 2021 26/07/2021 Ongoing
more batch data are available and revised, as appropriate.
SO5 (g) Acceptance criteria for tetrahydrofuran should be added to the January 2021 06/01/2021 27/01/2021 Fulfilled
specification for ALC-0159, unless otherwise justified, as it is included as
a solvent in step 2 of the synthesis.
SO5 (h) Detailed method validation reports for assay, impurities and residual July 2021 26/07/2021 Ongoing
solvents for ALC-0159 should be provided.

SO5 (i) Results of stability studies in accordance with ICH guidelines should be July 2021 26/07/2021 Ongoing
provided.

Specific In order to confirm the efficacy and safety of Comirnaty, the MAH should December Pending
Obligation 6 submit the final Clinical Study Report for the randomized, placebo- 2023
(SO6) controlled, observer-blind study C4591001.

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SOB 1: Quality: Characterisation

The due date for this SOB was July 2021 and a variation application EMEA/H/C/005735/II/0056/G is
under assessment. An interim report was submitted within a PAM-ANX procedure in March 2021 and
monthly status reports submitted in January, February and May 2021.

SOB 2: Quality: Control strategy

The due date for this SOB was July 2021 and a variation application EMEA/H/C/005735/II/0056/G is
under assessment. An interim report was submitted within a PAM-ANX procedure in March 2021 and
monthly status reports submitted in January, February and May 2021.

SOB 4: Quality: Process and control strategy for the excipient ALC-0315

The due date for this SOB was July 2021 and a variation application EMEA/H/C/005735/II/0054/G is
under assessment. Interim reports were submitted in January and April 2021.

SOB 5: Quality: Process and control strategy for the excipient ALC-0159

The due date for this SOB was July 2021 and a variation application EMEA/H/C/005735/II/0054/G is
under assessment. Interim reports were submitted in January and April 2021.

SOB 6: Clinical

In order to confirm the efficacy and safety of Comirnaty, the MAH should submit the final Clinical Study
Report for the randomized, placebo-controlled, observer-blind study C4591001.

Interim results from study C4591001 were included in the initial Marketing Authorisation Application
for Comirnaty, and the study design and results were extensively assessed during the approval
procedure. The study is still ongoing according to plan, and final results are expected in December
2023.

CHMP comment:

Specific Obligations 1,2, 4, 5 and 6 are ongoing and progressing according to plan.

The CHMP issued an opinion on the 20th of May 2021 concluding that Specific Obligation 003 had been
fulfilled, and therefore deleted from the Annex II.

2.3. Overall conclusion on Specific Obligations

During the period covered by this annual renewal, several aspects for all quality SOBs have been
addressed.

SOB 004 and SOB 005 relating to the novel excipients are partially fulfilled. The data to fulfil the
remaining parts of these SOBs have been submitted in variation EMEA/H/C/005735/II/0054/G and are
currently under assessment by the CHMP. A Request for Further Information has been adopted on 14

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October 2021.

Similarly, data to fulfil SOB 001 (characterisation) and SOB 002 (control strategy & specifications)
have been submitted in variation EMEA/H/C/005735/II/0056/G and are currently under assessment by
the CHMP. A Request for Further Information has been adopted on 14 October 2021.

Therefore, overall SOB 001, SOB 002, SOB 004 and SOB 005 are not fulfilled at the time point of the
present assessment report; nevertheless, the MAH has been compliant in providing the data in
response to these SOBs in line with the imposed deadlines, and therefore, the overall status of
compliance is satisfactory.

Regarding SOB003: In order to confirm the consistency of the finished product manufacturing process,
the MAH should provide additional validation data, the due date for this SOB was March 2021 and the
SOB was fulfilled with the variation EMEA/H/C/005735/II/0023/G (approved on 20 May 2021).

During the period covered by this annual renewal interim data on the clinical SOB 006 have been
submitted that overall are compliant in terms of adherence to deadlines and in terms of acceptability of
data submitted. The available clinical evidence includes a tolerable safety profile and high vaccine
efficacy against COVID-19 in individuals ≥12 years of age.

3. Additional scientific data provided relevant for the

assessment of the benefit/risk balance

3.1. Quality

For several of the remaining Quality SOBs the due date was July 2021 and variations
EMEA/H/C/005735/II/0054/G and EMEA/H/C/005735/II/0056/G are currently under assessment.

3.2. Clinical efficacy

Since approval of Comirnaty the MAH has submitted efficacy and safety data for children 12-15 years
of age, and approval of an indication in this age group was obtained on May 31, 2021.
(EMEA/H/C/005735/II/0030). For further details on the efficacy of Comirnaty, please see the initial
marketing authorisation approval.

3.3. Clinical safety

The MAH submitted the Addendum to the Clinical Overview (ACO), covering the period from 21
December 2020 until 29 April 2021.

Worldwide Marketing Authorisation Status

BNT162b2 received a first temporary authorisation for emergency supply under regulation 174 in the
UK on 1 December 2020 and in EEA countries on 21 December 2021. Up to the DLP (29 April 2021), it
is currently conditionally approved in 42 countries (including EEA).

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Actions Taken for Safety Reasons During the Period Covered Since the Initial Marketing
Authorisation

Issue Country Action Taken Date

Compared to the global supply of BNT162b2, an increased Hong Vaccination in 24

complaints rate for leakages was observed by the MAH in Kong and Hong Kong March
Hong Kong, with 19 vials with leakages reported from 3 Macau and Macau was 2021
different vaccination sites in the country; overall 26 vials stopped on 24
with leakages and/or loose caps were reported. All vials March 2021
were from 1 batch, the only batch in use for vaccination in and was
Hong Kong and Macau. During the investigation, it became resumed with
apparent that the root cause of the reported product a vaccine
quality complaints is a combination of the container batch from a
closure process (crimping) at 1 single CMO and of the different CMO
specific transport conditions on dry ice that are required on 3 April
for BNT162b2. Vaccination in Hong Kong and Macau was 2021
stopped as soon as the issue became apparent (24 March
2021). A total of 2 batches have been affected (including
the one being used and another one already shipped to
Hong Kong, but still in storage) and were quarantined. The
root cause of the reported product quality complaints was
clearly identified through analysis of the data generated
and collected as of 31 March 2021. According to the data,
the crimping process used for batches at the CMO fill and
finish site requires optimization to ensure the container
integrity during storage and shipment with dry ice. Under
the ultra-cold conditions created by storing and shipping
on dry ice, the stopper loses flexibility and, if not optimally
crimped, allows the ingress of ambient gas into the vial.
During thawing the flexibility of the stopper is regained
and the stopper reseals the vial. This can result in
increased pressure in the vial and presence of elevated
CO2 levels. Due to the identified root cause the MAH could
exclude any influence on batches that are on the market
anywhere outside of Hong Kong and Macau. The CMO in
question has not manufactured any batch that was
released for any market other than Hong Kong and Macau.
Vaccinations in Hong Kong and Macau were resumed with
a vaccine batch from a different CMO on 3 April 2021;
discussions to address the issue and resume supplies with
the previous CMO are ongoing, no batches from this CMO
are currently distributed.
On 5 February 2021 Health Canada requested to issue a Canada Health Product 8
joint Pfizer-Health Canada Health Product Risk Risk Februar
Communication to communicate revisions to Product Communicatio y 2021
Monograph (addition of 6-dose vial information and text on n to inform
anaphylaxis). Final HPRC was approved on 8 February about the
2021. revisions to
Product

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 Issue Country Action Taken Date

Monograph
(addition of 6-
dose vial
information
and text on
anaphylaxis).
On 15 January 2021, following fatal events involving Norway Norwegian 15
elderly patients vaccinated with BNT162b2 in Norway, the Agency January
Norwegian Agency updated their guidance for vaccination, updated their 2021
advising that caution and case-by-case judgement should guidance for
be used when vaccinating frail, elderly subjects. vaccination,
advising that
caution and
case-by-case
judgement
should be used
when
vaccinating
frail, elderly
subjects.
Significant Changes to the Reference Safety Information

The Reference Safety Information (RSI) for this ACO is the BNT162b2 CDS (Company Data Sheet)
Version 3.0, dated 20 April 2021, in effect at the end of the reporting period.

The previous CDS version 2.0 (dated 2 March 2021) and CDS version 1.0 (dated 12 February 2021)
were also in effect during the reporting period. The safety related changes made in CDSs is as follows:

CDS version 3.0 (dated 20 April 2021)

Section Revision Type Revision

Number

4.8 Addition A summary of the safety profile in the adolescents 12 through 15

years of age was added in Section 4.8 Undesirable effects, based
on the planned data analysis from the ongoing multi-country
clinical trial, C4591001, on adolescent study participants 12
through 15 years of age.

CDS version 2.0 (dated 2 March 2021)

4.8 Addition Diarrhoea, Pain in extremity (arm) and Vomiting were added as
adverse reactions from post-authorisation experience in Section
4.8 Undesirable effects

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The MAH also reported that after the DLP of this ACO, the CDS has been further updated (CDS ver.
4.0 dated 19 May 2021) with the following:

- a warning on stress-related responses associated with the process of vaccination was added in
section 4.4 Special warnings and precautions for use

- data from studies in section 4.8 Undesirable effects was updated to add available data in 12 to
15-year-old subjects and in stable HIV-infected subjects

- Decreased appetite, Lethargy, Hyperhidrosis, Night sweating and Asthenia were added as
Adverse Drug Reactions in section 4.8 Undesirable effects.

Respectively on 5 May 2021, on 10 May 2021 and on 28 May 2021, BNT162b2 was authorized for use
in individuals 12 years of age and older in Canada, in US and in Japan.

Variation 0030 (EMEA/H/C/005735/II/0030) was also submitted to EMA on 30 April 2021 to seek
expansion of the indication to subjects 12 to 15 years of age; on 28 May 2021, EMA CHMP
recommended granting the extension of indication for use in children aged 12-15 years and the
European Commission adopted a decision accordingly on 31 May 2021.

PRAC comment:

The SmPC is in line with the core data sheet (CDS).

Furthermore, the CHMP adopted an Opinion on the 16th September 2021 to add asthenia, lethargy,
decreased appetite, hyperhidrosis, and night sweats as side effects to the product information. In
addition, following the PRAC meeting in July, myocarditis and pericarditis were added to sections 4.4.
and 4.8 of the SmPC, and the package leaflet was updated accordingly.

Patient exposure

Clinical studies

Cumulatively up to 21 April 2021, the MAH estimated that 49,315 subjects have participated in the
Pfizer-managed studies of the COVID-19 vaccine clinical development program: 195 subjects received
BNT162b1 (modRNA which encodes a secreted trimerized SARS-CoV-2 receptor-binding domain);
41,368 subjects received BNT162b2 (modRNA which encodes a membrane-anchored SARS-CoV-2 full-
length spike) of which, 20,291 subjects, who had received Placebo, were offered BNT162b2 post-
unblinding and 758 subjects received BNT162b2 and the Blinded boost; 329 received BNT162S017,
6,370 subjects received blinded-therapy; and 1,053 subjects received placebo.

Additionally, 1,691 subjects have participated in 2 studies managed by BioNTech (BNT162-01 and
BNT162-04) and in 2 studies (BNT162-03 and BNT162-06) managed by Shanghai Fosun
Pharmaceutical in China.

PRAC comment:

The MAH was requested to explain what “BNT162S017” is, compared to BNT162b1 and BNT162b2.
(Request for Supplementary Information)

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Post-marketing experience worldwide

This estimation is based on the proportion of doses administered out of those shipped upon review of
data currently available for the EU countries and the US.

The MAH estimated that approximately 415,922,715 doses of BNT162b2 were shipped worldwide from
the receipt of the first temporary authorisation for emergency supply on 1 December 2020 through 29
April 2021, corresponding to 332,738,172 estimated administered doses.

The estimated cumulative number of shipped and administered doses of BNT162b2 by region based on
data provided in the shipment tracker (Order Book), from the receipt of the first temporary
authorisation for emergency supply on 1 December 2020 through 29 April 2021, are summarized in
Table 1 below.

Table 1. Cumulative Estimated Shipped/Administered Doses of BNT162b2 by Region

Worldwide
Region/Country/Other % of Doses Total Number of Total Number of
Shipped Doses Administered Doses
Europe 37.1% 154,251,240 123,400,992
European Uniona (27) 28.9% 120,356,925 96,285,540
Commonwealth of 0.0% 170,820 136,656
Independent Statesd
North Americae 41.8% 173,708,925 138,967,140
Central and South Americaf 5.1% 21,330,270 17,064,216
Asia 15.3% 63,627,720 50,902,176
Oceania 0.6% 2,377,440 1,901,952
Africah 0.2% 627,120 501,696
Total 100.0% 415,922,715 332,738,172
a. In this Region BNT162b2 was conditionally approved;
b. Includes Georgia, Moldova and Ukraine; in these countries BNT162b2 was shipped for COVAX;
c. In this Region BNT162b2 received authorization for emergency supply;
d. Includes Chile, Colombia, Costa Rica, Ecuador, Mexico, Panama, Peru and Uruguay where BNT162b2
received authorisation for emergency supply (some doses in Colombia and Peru were also shipped for COVAX),
Brazil where BNT162b2 was conditionally approved, and Bolivia and El Salvador where BNT162b2 was
shipped for COVAX;
e. Includes Cape Verde, Rwanda and Tunisia where BNT162b2 was shipped for COVAX and South
Africa where BNT162b2 received authorization for emergency supply.

Post-marketing exposure data in the EU

The MAH estimated that approximately 121,880,460 doses of BNT162b2 were shipped in the EU-EEA
countries from the receipt of the first conditional marketing authorisation approval on 21 December
2020 through 29 April 2021, corresponding to 97,504,368 estimated administered doses.

Table 2 provide the cumulative estimated number of persons who received 1 dose or 2 doses of
BNT162b2, in total, and by age group where available, in the EU-EEA countries.

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Table 2. Cumulative Administered 1&2 doses of BNT162b2 by Age Group in EU-EEA Countriesa
Countries 18-24 years 25-49 years 50-59 years 60-69 years 70-79 years ≥80 years Age Unknown All
Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2 Dose 1 Dose 2
Austria 32601 18144 239207 130993 219059 90021 318379 75014 326639 140700 335807 293603 4546 2246 1476238 750721
Belgium 52593 35800 293119 213871 244493 116179 509734 90760 521985 95815 379603 200561 2596 2161 2004123 755147
Bulgaria 6159 2994 91073 53735 62270 40928 68639 39715 45433 21092 13544 6110 230 114 287348 164688
Croatia 4569 1560 66321 29122 57981 20840 104365 27281 95611 32417 54000 28683 82 34 382929 139937
Cyprus 67 132 24777 1459 17825 1449 7243 5255 112 877 19812 7812 58343 47244 128179 64228
Czech Rep 24298 14744 300516 182307 186681 102898 411983 75205 462712 285166 233366 213979 1024 415 1620580 874714
Denmark 12172 11349 100433 95272 70155 64869 215219 79996 489102 148799 234027 216113 807 0 1121915 616398
Estonia 3900 1995 35929 15436 29141 9623 39210 10497 51796 18286 38854 24687 96 25 198926 80549
Finland 20009 5211 164266 52763 163750 27400 211291 16390 432259 13109 249309 50709 0 0 1240884 165582
France 10678144 5870393 10678144 5870393
Germany 16302110 6165751 16302110 6165751
Greece 8657 5508 178846 131191 123573 76311 174906 40155 478077 215987 463446 402532 3193 77 1430698 871761
Hungary 68071 19492 532097 164815 234138 84751 323113 159588 287650 208967 197264 170584 4142 928 1646475 809125
Iceland 1510 515 12660 4461 8658 1911 12582 4204 8571 8268 12357 12290 131 63 56469 31712
Ireland 14443 9893 121182 83267 73386 35093 48177 20871 297164 119213 163486 151163 2070 610 719908 420110
Italy 152389 107855 1179042 1023120 914562 659910 1258996 558357 1603504 535098 3295757 2773399 515532 2289 8919782 5660028
Latvia 1701 831 12069 2349 7009 1394 8473 1285 3894 1714 1595 776 15986 13069 50727 21418
Liechtenstein 4617 2152 4617 2152
Lithuania 17322 6725 86710 42364 72027 36875 109972 60902 89537 66043 52024 37840 752 292 428344 251041
Luxembourg 999 647 8506 5009 23442 2410 28819 1773 12309 11142 18133 17509 5221 4796 97429 43286
Malta 3715 2544 34966 18553 16833 9036 17636 10225 35820 32940 21394 19093 500 1 130864 92392
Netherlands 2867626 1059516 2867626 1059516
Norway 666707 77265 666707 77265
Poland 85825 60529 987763 418915 926701 235199 1332294 267273 1748066 896698 899037 738724 5781 3406 5985467 2620744
Portugal 19908 10838 248888 132357 143630 61761 248335 49080 400468 76875 557181 498668 365 232 1618775 829811
Romania 2626409 1655770 2626409 1655770
Slovakia 610591 451720 610591 451720
Slovenia 1710 1419 21019 18350 16002 11063 69804 30038 85139 70616 61059 56730 227 132 254960 188348
Spain 74690 66594 780878 720572 437097 401459 411832 270351 3037645 697953 2640774 2434770 1744 1209 7384660 4592908
Sweden 22699 12657 154168 96111 158728 61720 498361 63157 526616 125817 418347 323265 0 8 1778919 682735
Total 630007 397976 5674435 3636392 4207141 2153100 6429363 1957372 11040109 3823592 10360176 8679600 34379572 15361918 72720803 36009950
a. Source is https://covid19-vaccine-report.ecdc.europa.eu/ (point 6, cumulative period as of week 17, 02 May 2021).

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PRAC comment:

Up to 29 April 2021, it is estimated that over 332 Mio doses of BNT162b2 were administered
worldwide.

During the reporting period of this renewal, it is estimated that over 97 Mio doses of Comirnaty were
administered in the EU and EEA countries.

Data in Summary Tabulations

Cumulatively, there have been 882 clinical trial cases (1072 SAEs) reported.

Cumulatively 1 up to 29 April 2021, there have been 109,692 post-marketing cases (414,594 unique
PTs) reported. During the reporting interval, there have been 108,980 post-marketing cases (412,318
unique PTs) reported.

Significant Findings from Clinical Trials and Non-Interventional Studies

Completed Clinical Trials

No clinical trials were completed up to 21 April 2021.

Ongoing 2 Clinical Trials

There were 10 ongoing clinical trials up to 21 April 2021 (sponsored by BioNTech SE), out of which 2
studies (BNT162-03 and BNT162-04) for study vaccines BNT162b1 and BNT162b3.

Six studies were conducted by Pfizer: C4591001, C4591005, C4591007, C4591015, C4591017,
C4591020.

Four studies were conducted by BioNTech, including 2 studies in China managed by Shanghai Fosun
Pharmaceutical Development (BNT162-03 and BNT162-06).

Clinically important emerging efficacy and/or safety findings were identified for Study
C4591001/BNT162-02 3 and C4591005 and are summarized below.

• Study C4591001/BNT162-02

Title: A Phase 1/2/3, Placebo-Controlled, Randomized, Observer-Blind, Dose-Finding Study to Evaluate

the Safety, Tolerability, Immunogenicity, and Efficacy of SARS-COV-2 RNA Vaccine Candidates Against
COVID-19 in Healthy Individuals
Countries: Argentina, Brazil, Germany, South Africa, Turkey, US

This study is a Specific Obligation in the context of BNT162b2’s conditional marketing authorisation
and it is being conducted in order to confirm the efficacy and safety of the vaccine; the MAH should
submit the final Clinical Study Report, including a 2-year follow up of the studied population.

Study C4591001/BNT162-02 is an ongoing, randomized, placebo-controlled, observer-blind, dose-

finding Phase 1/2/3 registration study evaluating the safety, tolerability, immunogenicity, and efficacy
of SARS-CoV-2 RNA vaccine candidates against COVID-19 in healthy individuals.
Study C4591001/BNT162-02 was started as a Phase 1/2 study in adults in the US and was then
amended to expand the study to a global Phase 2/3 study to accrue sufficient COVID-19 cases to
conduct an efficacy assessment. The protocol was initiated in adults 18 years of age and older and
subsequently amended to include adolescents as young as 12 years of age. The study has

1 Collected since 01 December 2021, the date of the first temporary authorisation for emergency supply under regulation

174 in the UK.

2 Includes ongoing studies as well as studies in which patient enrolment and follow-up have been completed, but the

analysis and CSR are in-progress.

3 Pfizer-conducted clinical trial C4591001/BNT162-02 has an interim study report that is available upon request.

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enrolled approximately 46,000 participants, including 2,260 young adolescents 12 to 15 years of
age. Data from the Phase 1 part of the study was the basis for selection of the vaccine candidate and
dose level for Phase 2/3. The Phase 2/3 part of the study evaluated the safety, immunogenicity, and
efficacy of the selected vaccine candidate, BNT162b2, and is intended to support licensure globally.

The available clinical evidence for BNT162b2 includes a tolerable safety profile and high VE against
COVID-19 in individuals ≥12 years of age.

The potential risks are based on the observed safety profile to date, which shows mostly mild to
moderate reactogenicity, an acceptable incidence of severe or serious events, and no clinically
concerning safety observations. The vaccine appears to be safe and well tolerated across the safety
population and within demographic subgroups based on age, sex, race/ethnicity, country, and baseline
SARS-CoV-2 status. The preponderance of severe cases of COVID-19, as defined by the FDA Guidance
for Industry (June 2020) 4, in the placebo group relative to the BNT162b2 group (9 of 10) suggests no
evidence of vaccine-associated enhanced disease.

Vaccine efficacy was ≥95% for participants without prior evidence of SARS-CoV-2 infection and >94%
for those irrespective of prior infections. Observed VE was >93% when data were stratified by age,
sex, race/ethnicity, and country with the exception of the “all others” race group (89.3% VE) and
Brazil (87.7% VE).

Severe cases evaluated for efficacy were confined predominantly to the placebo group; only 1 severe
case was reported in the BNT162b2 group in the final analysis. The efficacy data suggest high
efficacy against COVID-19 in a broad population of individuals.

• Study C4591005

Title: A Phase 1/2, Placebo-Controlled, Randomized, and Observer-Blind Study to Evaluate the Safety,
Tolerability, and Immunogenicity of a SARS-CoV-2 RNA Vaccine Candidate Against Covid-19 In Healthy
Japanese Adults
Country: Japan

Study C4591005 is a Phase 1/2, randomized, placebo-controlled, and observer-blind study in healthy
Japanese adults. The study will evaluate the safety, tolerability, and immunogenicity of the SARS-CoV-
2 mRNA vaccine candidate (BNT162b2) against COVID-19 administered as two 30-µg doses, 21 days
apart, in Japanese adults 20 to 85 years of age.

Clinical laboratory tests were performed for the first 24 participants (12 participants 20 to 64 years of
age and 12 participants 65 to 85 years of age) (clinical laboratory subset). Local reactions (redness,
swelling, and pain at the injection site), systemic events (fever, vomiting, diarrhoea, headache,
fatigue, chills, new or worsened muscle pain, and new or worsened joint pain), and use of antipyretic
medication were collected by all participants in an e-diary from Day 1 through Day 7 after each
administration of study intervention. AEs were collected from the time the participant provided
informed consent through 1 month after Dose 2. SAEs will be collected from the signing of the ICD to
approximately 12 months after Dose 2.

In this study, 160 Japanese participants (including 130 participants 20 to 64 years of age [younger age
group] and 30 participants 65 to 85 years of age [older age group]) were randomized in an
approximate 3:1 ratio of BNT162b2 to placebo. Interim data show BNT162b2 was well tolerated, with
local reactions and systemic events mostly mild or moderate in severity, and no immediate AEs within
30 minutes reported. An acceptable safety profile was observed in both younger and older Japanese
adults with no SAEs reported through 1 month after Dose 2. Immune responses elicited
by BNT162b2 were robust 1 month after Dose 2, consistent with data from the global program. These

4 Development and Licensure of Vaccines to Prevent COVID-19 Guidance for Industry June 2020.

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encouraging results led to the marketing authorization of BNT162b2 in Japan. This study has since
been converted to a post-marketing study.

PRAC comment:

This small study does not add to the current knowledge on the safety profile of Comirnaty.

Non-Interventional Studies

There were 3 ongoing non-interventional studies (C4591008, C4591012 and C4591006) up to 21 April
2021, which are presented below:

Study No. Study Title and Country

C4591008 Study Title: HERO Together: A post-Emergency Use Authorization observational cohort
Voluntary PASS study to evaluate the safety of the Pfizer-BioNTech COVID-19 vaccine in US healthcare
workers.
Country: United States

Primary study objectives:

• Estimate the real-world incidence of safety events of interest and other clinically
significant events among US healthcare workers vaccinated with the Pfizer-
BioNTech COVID-19 vaccine following Emergency Use Authorization.
Secondary objectives:
• Evaluate whether the vaccine recipients experience increased risk of safety events
of interest and other clinically significant events post vaccination.
• Estimate the incidence rates of safety events of interest and other clinically
significant events among sub cohorts of interest such as individuals who are
pregnant, individuals who are immunocompromised, and stratified by age.
C4591012 Study Title: Post-Emergency Use Authorization Active Safety Surveillance Study among
Committed PASS Individuals in the Veteran’s Affairs Health System Receiving Pfizer-BioNTech Coronavirus
(post- Disease 2019 (COVID-19) Vaccine
authorisation Country: United States
commitment)
Primary study objectives:
• To assess whether individuals in the VHA system experience increased risk of
safety events of interest following receipt of the Pfizer-BioNTech COVID-19
vaccine.
• To assess whether sub-cohorts of interest (i.e., immunocompromised, elderly,
individuals with specific comorbidities, individuals receiving only one dose of the
Pfizer-BioNTech COVID-19 vaccine, and individuals with prior SARS-CoV-2
infection) in the VHA system experience increased risk of safety events of interest
following receipt of the Pfizer-BioNTech COVID-19 vaccine.
Secondary study objective:
• To characterize utilization patterns of the Pfizer-BioNTech COVID-19 vaccine
among individuals within the VHA, including estimating the proportion of
individuals receiving vaccine, 2-dose vaccine completion rate, and distribution of
time gaps between the first and second dose, demographics and health histories
of recipients, overall and among the sub-cohorts of interest.
C4591006 Study Title: General Investigation of Comirnaty Intramuscular Injection (Follow-up study
for Subjects [Healthcare Professionals] Who are Vaccinated at an Early post- Approval
Stage)
Country: Japan

Study objective: The healthcare professionals who are vaccinated with this product early
after the marketing approval of this product (participants in the Investigation of Health
Status of Recipients Vaccinated First conducted by the Science Research Group of the
Ministry of Health, Labour and Welfare) will be followed for 11 months from the day
following 28 days after the final vaccination of this product (end date of observation
period in Investigation of Health Status of Recipients Vaccinated First) to 12 months after
the final vaccination of this product, information on serious adverse events and COVID-19

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 Study No. Study Title and Country

observed during the follow-up period will be collected, and the long-term safety of this
product will be assessed (to be conducted as 11-month follow-up investigation after
completion of Investigation of Health Status of Recipients Vaccinated First).

According to the MAH, there was no new safety information reported regarding these ongoing non-
interventional studies.

PRAC comment:

Within the first interim report of the PASS study C4591012, which is listed in the RMP of Comirnaty,
(procedure EMEA/H/C/005735/MEA/010), only demographic and clinical characteristics of the two
cohorts (Pfizer-BioNTech COVID-19 vaccine recipients and seasonal influenza vaccines recipients) were
provided. No safety information was provided in the first interim report of study C4591012. Studies
C4591008 and C4591006 are not part of the EU RMP.

Medication Errors

During the reporting interval, there were no serious clinical trial cases contained in the Global safety
database that reported medication errors.

From post-authorisation sources, 4,591 cases potentially indicative of medication errors were retrieved
from the global safety database worldwide up to 29 April 2021. Upon review, 447 cases were
determined to be non-contributory and are not included in the discussion for the following reasons:

• Off-label use or misuse rather than medication error was reported in 95 cases;

• Questions about the scheduling of the 2 doses of BNT162b2 and/or information that the second
dose may be administered (but it was not administered yet at the time of reporting) or was
scheduled outside the prescribed dosing window were reported in 169 cases;

• No error or intercepted/potential error with BNT162b2 were identified in 183 cases, including
55 cases where the callers asked for information other than the scheduling of the 2 doses of
BNT162b2.

Among the 4,144 relevant medication error cases, the following scenarios, were described:

• Medication errors associated with harm [i.e., resulting in adverse reaction(s)] were reported in
154 cases (3.7% of relevant medication error cases);

• Medication errors without harm [i.e. not resulting in adverse reaction(s)] were reported in
3,814 cases (92.0% of relevant medication error cases), of which 2,043 cases involved co-
reported AEs;

• Potential medication errors were reported in 172 cases (4.1% of relevant medication error
cases).

• Intercepted medication errors were reported in 4 cases (0.1% of relevant medication error
cases).

The analysis of the relevant cases indicative of medication error did not lead to any change in the RSI
with regard to the instructions for preparation, administration or storage of BNT162b2.

PRAC comment:

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No new safety signal was identified from the cases reporting medication errors.

Medication errors are also analysed in the MSSRs for Comirnaty. From the MSSR assessments covering
the period from 21 December 2020 to 29 April 2021, no safety issues were identified that required
mitigation activity.

The MAH stated that further analysis of cases indicative of medication errors will be provided in the
PSUR with DLP of 18 June 2021. This is accepted.

Non-clinical Data

No new non-clinical safety findings were identified in the period from 21 December 2020 to 21 April
2021.

Literature

Nonclinical (Published)

According to the MAH, a search of the Medline and Embase databases did not identify non-clinical
studies that presented important new safety findings for Comirnaty up to 21 April 2021.

Clinical (Published)

From a search of the Medline and Embase databases up to 21 April 2021, the MAH identified 4 clinical
trials that presented important new safety/efficacy findings for Comirnaty when administered in at risk
patients (i.e., patients on haemodialysis) or special population, including elderly and pregnant/lactating
women. The abstracts are presented in table 3 below.

Table 3. Clinical Literature Articles that Presented New Safety Information in the Reporting
Interval

No. Citation/Abstract
At Risk Patients
1. Grupper A, Sharon N, Finn T, et al. Humoral Response to the Pfizer BNT162b2 Vaccine in
Patients Undergoing Maintenance Hemodialysis. Clin J Am Soc Nephrol. 2021. doi:
10.2215/CJN.03500321.
Background and objectives: Coronavirus disease 2019 (COVID-19) is associated with higher
morbidity and mortality in patients on maintenance hemodialysis. Patients on dialysis tend to have a
reduced immune response to infection or vaccination. We aimed to assess, for the first time to the
best of our knowledge, the humoral response following vaccination with the BNT162b2 vaccine in
patients on maintenance hemodialysis and the factors associated with it.
Design, setting, participants, & measurements: The study included 56 patients on maintenance
hemodialysis (dialysis group) and a control group composed of 95 health care workers. All
participants had received two doses of the BNT162b2 (Pfizer-BioNTech) vaccine. The serology testing
was done using Quant II IgG anti-Spike severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) assay by Abbott a median of 30 days after receipt of the second dose of the vaccine.
Results: All subjects in the control group developed an antibody response compared with 96% (54
of 56) positive responders in the dialysis group. The IgG levels in the dialysis group (median, 2900;
interquartile range, 1128–5651) were significantly lower than in the control group (median, 7401;
interquartile range, 3687–15,471). A Mann–Whitney U test indicated that this difference was
statistically significant (U=1238; P<0.001). There was a significant inverse correlation of age and
IgG levels in both groups. The odds of being in the lower quartile were significantly higher for older
individuals (odds ratio, 1.11 per year of age; 95% confidence interval, 1.08 to 1.20; P=0.004) and
for the dialysis group compared with the control group (odds ratio, 2.7; 95% confidence interval,
1.13 to 7.51; P=0.05). Within the dialysis group, older age and lower lymphocyte count were
associated with antibody response in the lower quartile (odds ratio, 1.22 per 1-year older; 95%

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Table 3. Clinical Literature Articles that Presented New Safety Information in the Reporting
Interval

No. Citation/Abstract
confidence interval, 1.13 to 1.68; P=0.03 and odds ratio, 0.83 per 10-e3/µl-higher lymphocyte
count; 95% confidence interval, 0.58 to 0.97; P=0.05).
Conclusions: Although most patients on maintenance hemodialysis developed a substantial humoral
response following the BNT162b2 vaccine, it was significantly lower than controls. Age was an
important factor in the humoral response, regardless of chronic medical conditions.
Special Patient Population(s)
2. Abu Jabal K, Ben-Amram H, Beiruti K, et al. Impact of age, ethnicity, sex and prior
infection status on immunogenicity following a single dose of the BNT162b2 mRNA COVID-
19 vaccine: Real-world evidence from healthcare workers, Israel, December 2020 to
January 2021. Euro Surveill. 2021; 26(6):2100096. doi: 10.2807/1560-
7917.ES.2021.26.6.2100096
The BNT162b2 mRNA COVID-19 vaccine showed high efficacy in clinical trials but observational data
from populations not included in trials are needed. We describe immunogenicity 21 days post-dose 1
among 514 Israeli healthcare workers by age, ethnicity, sex and prior COVID-19 infection.
Immunogenicity was similar by ethnicity and sex but decreased with age. Those with prior infection
had antibody titres one magnitude order higher than naïve individuals regardless of the presence of
detectable IgG antibodies pre-vaccination.
3. Rottenstreich A, Zarbiv G, Oiknine-Djian E, et al. Efficient maternofetal transplacental
transfer of anti- SARS-CoV-2 spike antibodies after antenatal SARS-CoV-2 BNT162b2
mRNA vaccination. Clin Infect Dis. 2021: ciab266. doi: 10.1093/cid/ciab266. (Accepted
manuscript).
Maternal and cord blood sera were collected from 20 parturients who received the BNT162b2
vaccine. All women and infants were positive for anti S- and anti-RBD-specific IgG. Cord blood
antibody concentrations were correlated to maternal levels and to time since vaccination. Antenatal
SARS-CoV-2 vaccination may provide maternal and neonatal protection.
4. Kelly JC, Carter EB, Raghuraman N, et al. Anti-SARS-CoV-2 antibodies induced in breast
milk after Pfizer-BioNTech/BNT162b2 vaccination: SARS-CoV-2 antibodies in breast milk
after vaccination. Am J Obstet Gynecol. 2021: S0002-9378(21)00211-8. doi:
10.1016/j.ajog.2021.03.031.
Objective: In December 2020, 2 lipid nanoparticle-formulated, nucleoside-modified messenger
RNA–based vaccines received emergency use authorization by the US Food and Drug Administration,
after their trials demonstrated 94% to 95% efficacy in preventing coronavirus disease 2019 (COVID-
19). Although no lactating people were included in the vaccine trials, national organizations support
vaccination of this population, suggesting potential infant protection by passive transfer of maternal
antibodies. The authors sought to characterize breast milk levels of anti–severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) antibodies in lactating people undergoing COVID-19
vaccination.
Study Design: Participants were prospectively recruited during phase IA rollout of the COVID-19
vaccine at a tertiary care center, after institutional review board approval. Inclusion criteria included
lactation and planned vaccination with the Pfizer-BioNTech BNT162b2 vaccine. After obtaining
informed consent, participants provided frozen breast milk samples at the following time points of
vaccination: before, within the first 24 hours, and the following week. Samples were assessed for
SARS-CoV-2 RNA by quantitative real-time polymerase chain reaction and antispike immunoglobulin
(Ig) G and IgA by an enzyme-linked immunosorbent assay.
Results: A total of 5 subjects and 29 human milk samples were included in the analysis. All
prevaccine milk samples tested negative for SARS-CoV-2 RNA, as defined by the cycle threshold
value of >40 for the N1 target. Antispike IgG and IgA levels were significantly elevated relative to
the prevaccine baseline at all time points. Antispike protein IgG remained sustained at a significant
elevation beginning at 20 days after the first dose compared with the prevaccine baseline (P=.0061),
through the final milk sample (day 30–39 P=.0095, >40 days P=.0040. Levels of antispike protein
IgA were significantly elevated from baseline, starting 2 weeks after the first dose (P=.0286)
through to the final sample (day 20–29 P=.0121, day 30–39 P=.0095, >40 days P=.0040);
however, individual level data suggest a possible gradual decline in antispike IgA in human milk over
time after the second dose.

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 Table 3. Clinical Literature Articles that Presented New Safety Information in the Reporting
Interval

No. Citation/Abstract
Conclusion. The Authors characterized longitudinal breast milk levels of antispike IgG/A following
Pfizer-BioNTech BNT162b2 vaccination, demonstrating sustained elevation of IgG/IgA levels. This
response is similar to previous studies on maternal vaccination, which have shown high levels of
breast milk IgA/G production for up to 6 months after vaccination for influenza and pertussis. A
concurrent decrease in infant respiratory illness rates suggest that maternal vaccination confers
protection against infection in breastfed infants. Thus, the Pfizer-BioNTech/BNT162b2 vaccination
may also confer protection against COVID-19 to breastfed infants as well. Our study is limited by a
small number of participants, but we report data that suggest a potential immune benefit to infants
of lactating people up to 80 days after COVID-19 vaccination. Further studies are needed to
characterize the length of antibody production in breast milk and the effect on infant infection rates
after maternal COVID-19 vaccination.

PRAC comment:

It is agreed with the authors that further investigation regarding vaccination with BNT162b2 in
subjects at higher risk of COVID-19 (e.g., patients on hemodialysis) or special populations, including
elderly and pregnant/lactating women, is needed. From the literature provided by the MAH, no new
safety issues were identified. No changes to the product information are considered warranted at this
moment.

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Overview of Signals: New, Ongoing, or Closed

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PRAC comment:

Regarding the ongoing signals ‘Myocarditis and Pericarditis’ and ‘Dizziness’:

After the DLP of the ACO, section 4.4 of the SmPC has been updated with a warning for myocarditis
and pericarditis (procedure IAIN/0050). Dizziness was included as part of ‘stress-related responses
associated with the process of vaccination’ in section 4.4 of the SmPC. Myocarditis and Pericarditis
were also added as ADRs in section 4.8 of the SmPC.

With regards to the closed signals for which signal closed is accepted:

Anaphylaxis: included as ADR in section 4.8 of the SmPC and added as important identified risk in the
RMP. Signal closed is accepted.

Hypersensitivity reactions (other than anaphylaxis): included as ADR in section 4.8 of the SmPC
(procedure Type II/0016/G).
Signal closed is accepted.

Pain in extremity: included as ADR in section 4.8 of the SmPC (procedure Type II/0016/G). Signal
closed is accepted.

Vomiting: included as ADR in section 4.8 of the SmPC (procedure Type II/0016/G). Signal closed is
accepted.

Diarrhoea: included as ADR in section 4.8 of the SmPC (procedure Type II/0016/G). Signal closed is
accepted.

Tachycardia: as part of a warning about stress-related responses with the process of vaccination added
to section 4.4. of the SmPC. Signal closed is accepted.

Vaccine stress-related responses: a warning about stress-related responses with the process of
vaccination added to section 4.4. of the SmPC. Signal closed is accepted.

Facial nerve palsy: included as ADR in section 4.8 of the SmPC. Signal closed is accepted.

Insomnia: included as ADR in section 4.8 of the SmPC. Signal closed is accepted.

Injection site pruritus: included as ADR in section 4.8 of the SmPC. Signal closed is accepted.

Overdose: based on review of post-authorisation medication errors of full vial dosing and co-reported
adverse event in the 2nd MSSR, no significant new safety information was identified and no updates to
the Overdose section of labelling was warranted. Signal closed is accepted.

Eye pain & Eye swelling: review of the cases reporting eye pain and/or eye swelling in the 2nd MSSR
did not suggest a causal association with the Comirnaty vaccine. No update of the included ADRs in the
Comirnaty SmPC was considered needed regarding eye pain and eye swelling. Closure of the signal
concerning “Eye pain” and “Eye swelling” is accepted.

Hearing loss and Tinnitus: In the 3rd MSSR AR (covering 1 February until 28 February 2021), based on
a cumulative review of the cases reporting hearing loss and/or tinnitus it was concluded that a causal
association with Comirnaty exposure was not suggested and the signal was closed.

Seizure: under close monitoring as part of Neurological AESIs in the MSSRs. At the moment no new
safety signal of seizure identified. Signal closed is accepted.

Reaction associated with dermal fillers: after the DLP of the ACO, Facial swelling (in vaccine recipients
with a history of injection of dermatological fillers) has been added to section 4.8 of the SmPC
(EMEA/H/C/005735/II/0038/G). Signal closed is accepted.

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Delayed skin reactions: based on a review by the MAH of literature and cases reporting delayed skin
reactions, a causal association was not supported. Signal closed is accepted.

Delayed syncope: following US-FDA request, delayed syncope and loss of consciousness were
evaluated by the MAH. It was concluded that there is insufficient evidence to support a causal
relationship to the vaccine. Signal closed is accepted.

Extensive swelling of vaccinated limb: after the DLP of the ACO, Extensive swelling of the vaccinated
limb has been added to section 4.8 of the SmPC (EMEA/H/C/005735/II/0038/G). Signal closed is
accepted.

The closed signals for which however further evaluation is ongoing or requested in MSSR/PSUR
and therefore cannot be considered closed are the following:

Paraesthesia: as part of a warning about stress-related responses with the process of vaccination
added to section 4.4. of the SmPC. This signal is closed, however, for the 8th MSSR (covering 1 July-31
July 2021) the MAH has been requested to provide an analysis of hypoaesthesia and paraesthesia and
to discuss whether paraesthesia and hypoaesthesia are sufficiently covered in the product information
in the context of stress-related reactions or these should be included in the product information as
separate ADRs.

As an outcome of the review provided by the MAH in the 9th MSSR, PRAC did not agree that
hypoesthesia/paraesthesia is sufficiently covered in the product information by the currently included
text regarding stress-related reactions and requested the MAH to add hypoesthesia and paraesthesia
to the product information (SmPC section 4.8 and PIL section 4) and to propose a frequency, via an
appropriate variation procedure.

Asthenia, Lethargy, Decreased appetite, Hyperhidrosis, Night sweats: the CHMP adopted an Opinion on
the 16th September 2021 to add as side effects to the product information of Comirnaty.

Deaths including elderly or frail individuals: no new safety information was identified based on review
of the fatal cases (EMEA/H/C/005735/LEG/019). Death/fatal cases are reviewed in the MSSRs as a
Special Situation.

Immune thrombocytopenia: a re-review of this signal is provided in the PSUR submitted in August
2021.

Thromboembolic events, including those associated with thrombocytopenia: at the moment, there is
insufficient evidence to support a causal association. However, TTS (Thrombosis with
Thrombocytopenia Syndrome) is an ongoing signal of the MSSR for Comirnaty. In addition,
thromboembolic events are reviewed in the MSSRs as AESIs.

Herpes zoster, including ophthalmic herpes zoster: it should be noted that following assessment of the
7th MSSR, the MAH was requested to provide an analysis of herpes zoster and discuss possible
mechanisms that could underpin herpes zoster reactivation following vaccination, in the PSUR
submitted in August 2021.

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Risk Evaluation

Summary of Safety Concerns

Safety Concerns at the beginning of the reporting period

Important Identified Risk Anaphylaxisa
Important Potential Risk Vaccine-Associated Enhanced Disease (VAED), Including
Vaccine-Associated Enhanced Respiratory Disease (VAERD)a,b
Missing Information Use in Pregnancy and While Breast Feedinga,b
Use in Immunocompromised Patientsa
Use in Frail Patients With Co-Morbidities (e.g. COPD,
Diabetes, Chronic Neurological Disease, Cardiovascular
disorders)a
Use in Patients With Autoimmune or Inflammatory Disordersa
Interaction With Other Vaccinesa
Long-Term Safety Dataa
Use in Paediatric Individuals <16 Years of Ageb
Vaccine Effectivenessb
a. As per EU RMP ver. 1.0 (dated 21 December 2020).
b. As per the EUA PVP ver. 0.2 (dated 05 December 2021).

During the reporting period, the EU RMP has been updated as follows:

• EU RMP version 1.0 (dated 21 December 2021, when the initial marketing authorization was
granted) was updated during the reporting period (EU RMP version 1.1, dated 17 March 2021
and approved on 15 April 2021), to revise the post-authorization vaccine effectiveness study
C4591014 included in the RMP (Category 3) as a commitment and to add 2 vaccine
effectiveness epidemiology studies (WI235284 and WI255886) not sponsored by Pfizer.

• After DLP of this ACO, on 4 May 2021 and on 14 May 2021, EU RMP version 2.0 (dated 29 April
2021) and version 2.1 (dated 14 May 2021) were submitted.

EU RMP version 2.0 was submitted on 30 April 2021 with Variation 0030 to seek for extension
of the indication to individuals aged 12-15 years of age; on 28 May 2021, EMA CHMP
recommended granting the extension of indication for use in children aged 12-15 years and the
European Commission adopted a decision accordingly on 31 May 2021.

EU RMP version 2.1 has been submitted in the context of Variation 0036.

No changes to the list of the safety concerns were implemented in the above stated EU RMPs during
and after the reporting period of this ACO.

PRAC comment:

Based on the data submitted with the renewal application, no changes are warranted for the RMP.

At the end of the interval period, the missing information “Use in pediatric individuals <16 years of
age” was re-worded to “Use in paediatric individuals <12 years of age”, which is only applicable for the
EUA US PVP.

Furthermore, the CHMP adopted an Opinion on the 16th September 2021 for the
EMEA/H/C/005735/II/0036 variation in which the RMP version 2.2 was approved.

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3.4. Pharmacovigilance inspections

During the renewal period, the following inspection of MAH’s pharmacovigilance system was
conducted:

Inspecting Site Inspection Inspection Type of Impact of

Authority Inspected Start Date End Date Inspection findings on
benefit/risk
balance of
BNT162b2

Swissmedic Pfizer 8 March 2021 9 March 2021 Routine None of the

Switzerland Pharmacovigilance findings
Office Inspection impacts the
(Virtual) B/R of
BNT162b2

PRAC comment:

The MAH was requested to provide the findings of the inspection performed by Swissmedic. (Request
for Supplementary Information)

4. Risk management plan

The MAH has confirmed the current approved RMP remains unchanged and applicable.

Since the granting of the marketing authorisation, the following changes have been implemented in
the RMP:

• Revision of the Pharmacovigilance Plan, including updates on milestones, objectives, study

rationale and design;

• Revision of the post-authorization vaccine effectiveness study C4591014 and addition of 2

new vaccine effectiveness epidemiology studies;

• Update of the indication to include individuals aged 12-15 years, with supporting
epidemiology and exposure data;

• Inclusion of myocarditis and pericarditis as important identified risks, with supporting data
from clinical trials and safety databases and update of the information on planned/ongoing
post-authorization safety studies with inclusion of 2 new studies, and the circulation of a
DHPC;

• Inclusion of a new formulation and update on potential medication errors.

5. Changes to the Product Information

No changes to the Product Information (PI) are introduced with this renewal procedure.

Additional monitoring

Pursuant to Article 23(1) of Regulation No (EU) 726/2004, Comirnaty (COVID-19 mRNA vaccine

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(nucleoside-modified)) is included in the additional monitoring list as it contains a new active
substance which, on 1 January 2011, was not contained in any medicinal product authorised in the
EU and it is approved under a conditional marketing authorisation.

The summary of product characteristics and the package leaflet therefore includes a statement that
this medicinal product is subject to additional monitoring and that this will allow quick identification of
new safety information. The statement is preceded by an inverted equilateral black triangle

6. Request for Supplementary Information - RfSI

The MAH should provide the following supplementary information in response to Day 60 RfSI:

6.1. Other concerns

Clinical aspects

1. The MAH is requested to provide the findings of the inspection performed on 8-9 March 2021
by Swissmedic.

2. The MAH is requested to explain what “BNT162S017” is compared to BNT162b1 and

BNT162b2.

7. Assessment of the MAH responses to the RfSI

7.1. Other concerns

Clinical aspects

Question 1

The MAH is requested to provide the findings of the inspection performed on 8-9 March 2021
by Swissmedic.

Summary of the MAH’s response

The findings of the inspection performed on 8-9 March 2021 by Swissmedic can be found in the audit
report herewith submitted as attachment to the cover letter. The audit report is a redacted copy of the
final Pfizer response (redacted inspector names and Pfizer names for privacy), also you will notice
there are track changes in the report as Swissmedic had asked for updated responses to be tracked in
the final response as accepted by Swissmedic. Additionally, please note that this audit report contains
information that is considered confidential by Pfizer..

Assessment of the MAH’s response

As requested, the MAH provided the findings of the inspection performed by Swissmedic on 8-9 March
2021. It is acknowledged that the content of the audit report is confidential and therefore is not

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presented in this assessment report. In the context of the MSSR assessment, several comments have
been made regarding the handling and presentation of data. The inspection from Swissmedic did not
raise additional issues relevant for the EU.

Conclusion

Issue is solved.

Question 2

The MAH is requested to explain what “BNT162S017” is compared to BNT162b1 and

BNT162b2.

Summary of the MAH’s response

The code BNT162S017 reported on page 12 of the Addendum to the Clinical Overview submitted in the
renewal application results from a typo and should be read as BNT162b2s01.

The figure 7 at the end of the code refers to the footnote 7 where it is stated that BNT162S01 is also
named BNT162SA. In the same footnote (footnote 7, Page 12) BNT162SA should read as
BNT162b2SA.

Both these codes (BNT162b2s01 and BNT162b2SA, in the submitted ACO erroneously reported as
BNT162S01 and BNT162SA) refer to the same clinical candidate, a new construct based on BNT162b2
and modified to address the B.1.351 lineage, first identified in South Africa. This clinical vaccine
candidate has been introduced in study C4591001 / BNT162-02 as part of the global program to
address emerging variants.

Assessment of the MAH’s response

The code “BNT162S017” was a typo and should be BNT162b2s01, also named BNT162b2SA , which is
explained as a new construct based on BNT162b2 and modified to address the B.1.351 lineage, first
identified in South Africa. This is noted.

Conclusion

Issue is solved.

8. Overall conclusions and benefit-risk balance

8.1. Specific Obligations (SOBs)

Compliance of SOB data submitted

During the period covered by this annual renewal, data on the Quality Specific Obligations (SOBs) have
been submitted. Interim reports and monthly updates have been provided as requested.

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Regarding the Quality SOB 003: In order to confirm the consistency of the finished product
manufacturing process, the MAH should provide additional validation data, on the 20th May 2021,
following the assessment of additional validation data (provided in variation
EMEA/H/C/005735/II/0023/G), the CHMP was of the opinion that the obligation had been fulfilled, and
therefore recommended its deletion from the Annex II.

For the Quality SOB 001, SOB 002, SOB 004 and SOB 005 the due date was July 2021. On 27 July and
2 August 2021 respectively, the MAH submitted two variations (EMEA/H/C/005735/II/0054/G and
EMEA/H/C/005735/II/0056/G) to provide the additional data requested to fulfil these SOBs. These
variations are currently under assessment by CHMP and Requests for Further Information have been
adopted on 14 October 2021.

During the period covered by this annual renewal interim data on the clinical SOB 006 have been
submitted that overall are compliant in terms of adherence to deadlines and in terms of acceptability of
data submitted. The available clinical evidence includes a tolerable safety profile and high vaccine
efficacy against COVID-19 in individuals ≥12 years of age.

Updated list of specific obligations (SOBs)

In the framework of a conditional marketing authorisation and pursuant to Article 14-a of Regulation
(EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following measures:

Number Description Due date

SOB 001 In order to complete the characterisation of the active substance July 2021
and finished product, the MAH should provide additional data.
SOB 002 In order to ensure consistent product quality, the MAH should July 2021
provide additional information to enhance the control strategy,
including the active substance and finished product specifications.
SOB 004 In order to confirm the purity profile and ensure comprehensive July 2021
quality control and batch-to-batch consistency throughout the
lifecycle of the finished product, the MAH should provide additional
information about the synthetic process and control strategy for
the excipient ALC-0315.
SOB 005 In order to confirm the purity profile and ensure comprehensive July 2021
quality control and batch-to-batch consistency throughout the
lifecycle of the finished product, the MAH should provide additional
information about the synthetic process and control strategy for
the excipient ALC-0159.
SOB 006 In order to confirm the efficacy and safety of Comirnaty, the MAH Dec 2023
should submit the final Clinical Study Report for the randomized,
placebo-controlled, observer-blind study C4591001.

8.2. Benefit-risk Balance

During the period covered by this annual renewal, new data have emerged. However, these data do
not have an impact on the established benefit-risk balance of Comirnaty in the approved indication.

The data collected as part of the specific obligations for Comirnaty during the period covered by this
annual renewal support its positive benefit-risk balance in the approved indication.

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Favourable effects

The favourable effects were demonstrated in the initial marketing authorisation for persons 16 years of
age and older and updated in a type II variation to also include adolescents 12-15 years of age. No
additional efficacy data have been submitted during this renewal procedure. The most important
favourable effects are briefly summarised below.

The overall vaccine efficacy against symptomatic laboratory confirmed COVID-19 from 7 days after
dose 2 was 95.0% (95% CI 90.0, 97.9) in subjects ≥16 years of age without prior evidence of SARS
CoV2 infection and 94.6% (95% CI 89.6, 97.6) in all subjects regardless of prior evidence of SARS
CoV-2 infection (primary endpoint). This outcome met the pre-specified success criteria.

The efficacy of the vaccine (BNT162b2, 2 doses of 30 µg, separated by 21 days) to prevent COVID-19
in the adolescents aged 12- 15 years either without or with and without evidence of prior SARS-CoV-2
infection, occurring at least 7 days after the second dose, was 100.0% (CI95% 75.3, 100).

In addition, Comirnaty was shown to elicit non-inferior immune responses in subjects 12-15 years of
age without previous Covid-19 compared to subjects 16-25 years in terms of geometric mean titres of
neutralising antibodies one-month post dose 2.

Uncertainties and limitations about favourable effects

The uncertainties and limitations of favourable effects are similar to those at the time of the initial
assessment and were updated in variation EMEA/H/C/005735/II/0030 (12-15-year-old subjects). The
principal uncertainties remain on duration of protection and efficacy in risk groups, e.g. pregnant
women and immunocompromised subjects. Since the initial approval, uncertainty regarding the
vaccine efficacy against upcoming virus variants of concern has arisen with variants of concern (VOC)
emergence.

Unfavourable effects

The safety of Comirnaty was evaluated in participants 16 years of age and older in 2 clinical studies
(BNT162-01 and C4591001) that included 21,744 participants that have received at least one dose of
Comirnaty in the initial approval application. Overall, the safety profile of Comirnaty is considered
acceptable. The product information has been updated since approval as new data has emerged. All
data have been assessed in other procedures such as monthly safety updates, signal assessments and
variations.

Uncertainties and limitations about unfavourable effects

The uncertainties and limitations of unfavourable effects have been discussed in other procedures. The
principal uncertainties are related to long-term effects, and effects in specific risk groups.

Benefit-risk assessment and discussion

The benefits of Comirnaty in terms of protection against COVID-19 clearly outweigh the identified
risks, and no new information has emerged during this renewal period that has changed the balance.
The clinical SOBs are currently ongoing, according to plan. The quality related SOBs are also
considered either fulfilled or ongoing according to plan.

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Importance of favourable and unfavourable effects

Not Applicable.

Balance of benefits and risks

Based on the cumulative evidence in terms of favourable and unfavourable effects, the benefit-risk
balance of Comirnaty remains positive.

9. Recommendations
Based on the review of the available information on the status of the fulfilment of Specific Obligations,
the marketing authorisation holder has complied with the specific obligations and the benefit-risk
balance for Comirnaty in its approved indication (please refer to the Summary of Product
Characteristics) continues to be favourable, and therefore the renewal of the conditional marketing
authorisation is recommended, subject to the conditions and obligations as detailed in this assessment
report.

Amendments to the marketing authorisation

The renewal requires no amendments to the terms of the marketing authorisation.

Conditions of the marketing authorisation

The marketing authorisation is subject to the following conditions:

Conditions or restrictions with regard to the safe and effective use of the
medicinal product

Risk management plan (RMP)

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and
interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and
any agreed subsequent updates of the RMP.

An updated RMP should be submitted:

• At the request of the European Medicines Agency;

• Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result
of an important (pharmacovigilance or risk minimisation) milestone being reached.

Specific obligations to complete post-authorisation measures for the

conditional marketing authorisation

This being a conditional marketing authorisation and pursuant to Article 14-a of Regulation (EC) No
726/2004, the MAH shall complete, within the stated timeframe, the following measures:

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 Description Due date

In order to complete the characterisation of the active substance and finished July 2021
product, the MAH should provide additional data.
In order to ensure consistent product quality, the MAH should provide additional July 2021
information to enhance the control strategy, including the active substance and
finished product specifications.
In order to confirm the purity profile and ensure comprehensive quality control and July 2021
batch-to-batch consistency throughout the lifecycle of the finished product, the
MAH should provide additional information about the synthetic process and control
strategy for the excipient ALC-0315.
In order to confirm the purity profile and ensure comprehensive quality control and July 2021
batch-to-batch consistency throughout the lifecycle of the finished product, the
MAH should provide additional information about the synthetic process and control
strategy for the excipient ALC-0159.
In order to confirm the efficacy and safety of Comirnaty, the MAH should submit Dec 2023
the final Clinical Study Report for the randomized, placebo-controlled, observer-
blind study C4591001.

PSUR cycle

The requirements for submission of periodic safety update reports for this medicinal product are set
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC and any subsequent updates published on the European medicines web-portal.

10. EPAR changes

The table in the “Steps after” module of the EPAR will be updated as follows:

Scope

Renewal of conditional marketing authorisation

Summary

The CHMP, having reviewed the available information on the status of the fulfilment of Specific
Obligations and having confirmed the positive benefit risk balance, is of the opinion that the quality,
safety and efficacy of this medicinal product continue to be adequately and sufficiently demonstrated
and therefore recommends the renewal of the conditional marketing authorisation for Comirnaty,
subject to the Specific Obligations and Conditions as laid down in Annex II to the opinion.

Please refer to Scientific Discussion ‘Comirnaty/H/C/005735/R/0046’

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