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Rapporteurs Day 150 Joint Response Assessment

Report

Clinical Assessment of the responses to the CHMP List of Questions

Gardasil 9

International non-proprietary name:


Human Papillomavirus Type 6 L1 protein
Human Papillomavirus Type 11 L1 protein
Human Papillomavirus Type 16 L1 protein
Human Papillomavirus Type 18 L1 protein
Human Papillomavirus Type 31 L1 protein
Human Papillomavirus Type 33 L1 protein
Human Papillomavirus Type 45 L1 protein
Human Papillomavirus Type 52 L1 protein
Human Papillomavirus Type 58 L1 protein

Procedure no. EMEA/H/C/3852

Applicant: Sanofi Pasteur MSD SNC


Rapporteur: Kristina Dunder (SE)

Co-Rapporteur: Jan Mueller- Berghaus (DE)

Start of the procedure: 2014-03-26

Date of this report: 2014-11-25

Deadline for comments: 2014-12-08


LIST OF ABBREVIATIONS
9vHPV vaccine Nine-valent Human Papillomavirus vaccine
AE Adverse experience
AIN Anal intraepithelial neoplasia
AIS Adenocarcinoma in situ
ANSS All (HPV Type-specific) Nave Subjects with Serology
ASC-H Atypical squamous cells cannot rule out HSIL
ASC-US Atypical squamous cells of undetermined significance
CI Confidence interval
CIN Cervical intraepithelial neoplasia
cLIA Competitive Luminex Immunoassay
CRF Case report form
DSMB Data and Safety Monitoring Board
EGLs External genital lesions
ELISA Enzyme-linked immunosorbent assay
FAS Full Analysis Set
GMR Geometric mean ratio
GMTs Geometric Mean Titres
HN-TS HPV-Nave Type-Specific
HPV Human Papillomavirus
HR High-risk
HSIL High-Grade Squamous Intraepithelial Lesion
LR Low-risk
MSM Men who have sex with men
Pap Papanicolaou
PBNA Pseudovirion-based neutralization assay
PPE Per Protocol Efficacy
PPI Per Protocol Immunogenicity
qHPV vaccine Quadrivalent Human Papillomavirus vaccine
RR Risk reduction
SAEs Serious Adverse Experiences
SCC Squamous cell carcinoma
VaIN Vaginal Intraepithelial Neoplasia
VE Vaccine efficacy
VIN Vulvar Intraepithelial Neoplasia
VLP Virus-Like Particle
Clinical Safety

Question 61.

Overall, 9.7% of subjects who received 9vHPV reported severe systemic events within 15 days of any
vaccination. The Applicant is requested to review of the severe systemic events as these were
reported by a significant number of subjects (1,290); a table with event totals by SOC will suffice.

Summary of the Applicants Response

Tables with counts and percentage of Subjects With Systemic Adverse Events By Maximum Intensity
reported Days 1 to 15 following any vaccination and Subjects With Vaccine-Related Systemic Adverse
Events By Maximum Intensity reported Days 1 to 15 following any vaccination, in subjects who
received 9vHPV vaccine are provided in Appendix Q61A and Appendix Q61B of this response,
respectively.

The following comments can be made regarding the Subjects With Systemic Adverse Events and
Vaccine-related Systemic Events by Maximum Intensity in subjects who received 9vHPV vaccine:

Among subjects who received 9vHPV vaccine, approximately 9.7% and 3.3% reported severe
systemic adverse events and severe vaccine-related adverse events, respectively.

For all system organ classes (SOC), most of the events were mild to moderate in intensity.

Most of the reported systemic and vaccine-related systemic events were of mild or moderate
intensity.

Overall, the reported severe systemic events were diverse and affected multiple system organ
classes (SOCs).

The most frequently reported (0.2%) vaccine-related events of severe intensity were
headache (1.5%), pyrexia (0.5%), nausea (0.3%), vomiting (0.2%), fatigue (0.2%), and
dizziness (0.2%).

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In summary, reports of severe-intensity systemic adverse events were diverse and affected
multiple SOCs. With the exception of headache, vaccine-related adverse events of severe
intensity were uncommon (<1%). Overall, systemic adverse events of severe intensity
following administration of 9vHPV vaccine do not appear to raise a safety
concern.Assessment of the Applicants Response

The Applicant has presented a listing of subjects reporting systemic adverse events, both overall and
vaccine-related, in tabular format organised by SOC/AE. The most commonly reported severe events
assessed as vaccine-related are headaches (204 subjects), pyrexia (66 subjects), nausea (40
subjects), and dizziness (27 subjects), all of which are included in the SPC.

There were a number of severe AE also assessed as vaccine-related which may be significant based
upon their reporting rate relative to those events included in the SOC: abdominal pain in 15 subjects;
abdominal pain upper in 19 subjects. However, as noted by the Applicant, there were less than 1% of
the total of these events assessed as vaccine-related overall and thus these terms are not included in
the SPC. These events are further discussed in Q62 below, and it is concluded that there is no clear
evidence to support the need for inclusion of abdominal pain into the SPC at the present time.

It appears that the overall reporting of vaccine-related systemic AEs reported to have a severe
intensity are consistent with the overall expected adverse event profile.

Conclusion: Issue resolved.

Question 62.

Abdominal pain / upper abdominal pain were reported by 2-3% of subjects receiving 9vHPV within 15
days of any vaccination. Similar rates of vaccine-related abdominal events were reported by females
and males in the 9-15 year age group. A four-fold increase in the use of drugs for function abdominal
disorders was noted between the 3 days prior and the 15 days after vaccination. The Applicant is
requested to discuss the potential association between 9vHPV vaccination and abdominal pain and to
discuss the need for the inclusion of this term into the SPC.

Summary of the Applicants Response

A detailed review of the adverse experiences of abdominal pain and upper abdominal pain does not
suggest a direct association between 9vHPV vaccination and these events. Based on the findings
presented in the response, considering (1) incidence of abdominal pain/upper abdominal pain and (2)
use of drug for functional gastrointestinal disorders, the Applicant concludes that there is no need to
combine and include the 2 terms in the SmPC.

Incidence of Abdominal Pain/Upper Abdominal Pain

As shown in Table 2.7.4: 17 of the original marketing application, across all subjects who received
9vHPV vaccine, the incidences of abdominal pain and upper abdominal pain within 15 days
following any vaccination were 2.2% and 2.9%, respectively. The incidences of vaccine-
related reports of abdominal pain and upper abdominal pain reported within 15 days
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following any vaccination were 0.7% and 0.9%, respectively. A majority of the reported
events in subjects who received 9vHPV vaccine were of mild or moderate severity.

In all subjects who received the 9vHPV vaccine, the incidences of abdominal pain and upper abdominal
pain reported within 15 days of Vaccination 1, Vaccination 2, and Vaccination 3, respectively were also
assessed. The incidence of abdominal pain and upper abdominal pain were highest following
Vaccination 1 (abdominal pain = 1.3% and upper abdominal pain = 1.7%). The incidences
for both of these events following Vaccinations 2 and 3 were less than following Vaccination
1 (0.6% and 0.5%, respectively). Based on this data, the frequency of abdominal pain/upper
abdominal pain does not appear to increase across vaccination visits.

In the V503-001 study, similar trends in the overall and by vaccination visit incidences of abdominal
pain/upper abdominal pain were observed in 9vHPV vaccine and qHPV groups.

Use of Drugs for Functional Gastrointestinal Disorders

In the original marketing application, Appendix 2.7.4: 10 presents counts and percentages of subjects
with prior medications within 3 days prior to any vaccination with 9vHPV vaccine and Appendix 2.7.4:
15 presents counts and percentages of subjects with concomitant medications Days 1 to 15 following
any vaccination with 9vHPV vaccine. Drugs for Functional Gastrointestinal Disorders were used
by approximately 0.6% of the subjects 3 days prior to any vaccination and by
approximately 2.4% of the subjects within 15 days following any vaccination. The most
commonly used medications in this category were: butylscopolamine bromide, domperidone,
metoclopramide, metoclopramide hydrochloride, simethicone, and trimebutine.

A detailed review of drugs for functional gastrointestinal disorders 3 days prior to and the 15 days
following vaccination with V503 does not suggest that the increased use of these medications is
specifically related to increased incidence of abdominal pain/upper abdominal pain for the following
reasons.

1) Use of Drugs for Functional Gastrointestinal Disorders does not appear directly correlated with
occurrence of events of abdominal pain

As noted, the incidence of abdominal pain is higher after Vaccination 1 than after Vaccination 2 or
Vaccination 3. However, as summarized in Table 9, use of drugs for functional gastrointestinal
disorders remain approximately the same before and after each vaccination visit across the
3-vaccination series.

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Table 9
Percentage of Subjects (Overall and by Vaccination Visit) with Systemic Adverse Events of
Abdominal Pain and Upper Abdominal Pain and Specific Concomitant Medications (Drugs
for Functional Gastrointestinal Disorders) Prior and Following Any Vaccination Visit.
Vaccination Vaccination Vaccination Any

Visit 1 Visit 2 Visit 3 Vaccination
Visit#
Abdominal pain Days 1 to 15 following 1.3% 0.6% 0.5% 2.2%
vaccination visit
Upper abdominal pain Days 1 to 15 1.7% 0.8% 0.6% 2.9%
following vaccination visit
Drugs for functional gastrointestinal 0.3% 0.3% 0.4% 0.6%
disorders 3 days prior to vaccination
Drugs for functional gastrointestinal 1.2% 0.9% 1.0% 2.4%
disorders Days 1 to 15 following vaccination
Data source: Appendix Q62A - Subjects With Specific Concomitant Medications (Incidence >0%
in One or More Vaccination Groups) Subjects Who Received 9vHPV Vaccine (Protocols 001, 002,
005, 006, 007, and 009) (Days 1 to 15 Following Vaccination 1) (attached)

Data source: Appendix Q62B - Subjects With Specific Concomitant Medications (Incidence >0%
in One or More Vaccination Groups) Subjects Who Received 9vHPV Vaccine (Protocols 001, 002,
005, 006, 007, and 009) (Days 1 to 15 Following Vaccination 2) (attached)

Data source: Appendix Q62C - Subjects With Specific Concomitant Medications (Incidence >0%
in One or More Vaccination Groups) Subjects Who Received 9vHPV Vaccine (Protocols 001, 002,
005, 006, 007, and 009) (Days 1 to 15 Following Vaccination 3) (attached)

#
Appendix 2.7.4: 15 of the original marketing application

Additionally, the specific reason a medication was taken is available for approximately 50% of the
prior/concomitant medication records. A review of the reasons the most common Drugs for Functional
Gastrointestinal Disorders were taken shows that these medications were not used exclusively to treat
abdominal pain/upper abdominal pain. Other commonly treated conditions were migraine and
nausea. Therefore, use of drugs for functional gastrointestinal disorders may not be strictly correlated
with incidence of such disorders.

2) The increase in the number of subjects using Drugs for Functional Gastrointestinal Disorders post-
vaccination may be due to a longer data collection timeframe post-vaccination vs. pre-vaccination.

The time frame for collecting post-vaccination medications (Days 1 to 15 following any vaccination) is
5 times greater than that for collecting pre-vaccination medications (3 days prior to any vaccination).
Because of the longer collection time frame, it is expected that a greater number of occurrences may

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be collected for the post vaccination medications than for the pre-vaccination medications. The
increase from 0.6 % to 2.4% for Drugs for Functional Gastrointestinal Disorders is consistent with the
longer collection timeframe. In support of this interpretation, this increase does not appear specific to
drugs for functional gastrointestinal disorders. Other medications typically given for acute disorders
were reported by a higher proportion of subjects in the Days 1 to 15 post-vaccination period than in
the 3 days pre-vaccination period. As shown in the table below, proportions (post-vaccination vs. pre-
vaccination) ranged from approximately 2 to 6 fold, which is generally consistent with the longer
reporting post-vaccination time frame.

Therefore, for the reasons outlined above, the increased use of Drugs for Functional Gastrointestinal
Disorders 15 days following any vaccination cannot be specifically attributed to the treatment of
abdominal pain/upper abdominal pain.

Need for Inclusion of Abdominal pain/Upper abdominal pain in the SPC

As shown in Table 2.7.4: 17 of the original marketing application, across all subjects who received
9vHPV vaccine, the incidences of vaccine-related abdominal pain and upper abdominal pain reported
within 15 days following any vaccination were 0.7% and 0.9%, respectively. Since the frequencies of
these 2 distinct MedDRA terms (abdominal pain and upper abdominal pain) are both below 1%, and
because the use of Drugs for Functional Gastrointestinal Disorders does not appear directly correlated
with the occurrence of events of abdominal pain, the Applicant is of the opinion that there is no
compelling safety rationale to deviate from standard methodology and combine 2 distinct MedDRA
terms in the SmPC. Since both abdominal pain and upper abdominal pain are considered to be
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separate terms, and since their respective incidences are less than 1%, they would not appear in
Section 4.8 of the SmPC.

Assessment of the Applicants Response

The Applicant has reviewed the data on abdominal pain/upper abdominal pain and on the use of drugs
for functional abdominal disorders and concludes that no inclusion into the SPC is required. Regarding
the AEs: While rates of these events were between 2-3% within 15 days after vaccination, those
events assessed as vaccine-related were less than 1% for each term. Furthermore, incidence rates
decreased with successive doses of vaccine. Regarding the medications: the use of these drugs was
constant over successive vaccinations (both pre- and post-vaccination) while rates of abdominal
pain/upper abdominal pain decreased. Furthermore, there is data to suggest that these agents were
used for other reasons than abdominal pain, such as migraines and headaches.

Conclusion

The conclusions of the Applicant can be endorsed. There is no clear evidence to support the need for
inclusion of abdominal pain into the SPC at the present time. Issue resolved.

Question 63.

There were a number of adverse events with isolated or few occurrences but which were
predominantly considered to be vaccine-related and could share an underlying pathophysiological
mechanism. Moreover, many of these events could be linked to potential neurological / autoimmune
safety concerns. These events were: facial paresis (1 event, vaccine-related), neuralgia (2 events, 1
vaccine-related), sensory disturbance (1 event, vaccine-related), VIIth nerve paralysis (3 events, 2
vaccine-related), vagus nerve disorder (1 event, vaccine-related), sleep disorder (6 events, 1 vaccine-
related), hyperhidrosis (21 events, 15 vaccine-related). The Applicant is requested to provide case
narratives for the vaccine-related cases and to discuss the need for inclusion of any safety concerns
related to these events into the RMP as important potential risks.

Summary of the Applicants Response

A detailed review suggests that these events generally do not raise neurological or autoimmune safety
concern.

The vaccine-related neurological events and some key information are summarized in the table below.

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Case narratives

Facial Paresis

male from Germany with a medical history of respiratory tract infection


received his first, second, and third dose of 9vHPV vaccine on 02-Aug-2010, 07-Oct-2010, and 08-
Feb-2011, respectively. He also received a dose of Repevax on 16-Sep-2010. On 13-Aug-2010 (12
days post-dose 1), the subject experienced facial paresis of moderate intensity. The subject received
no treatment for his facial paresis. On 30-Aug-2010, the subject recovered from his facial paresis.
The subject did not report any events of facial paresis following subsequent vaccination visits. The
reporting investigator felt the facial paresis was related to 9vHPV vaccine.

Assessors comment: It is agreed that there is confounding given that 2 vaccinations were
administered prior to the event. Negative rechallenge. It is reassuring that there was no recurrence
with subsequent doses.

Neuralgia

white female from Denmark with no medical history received her first, second,
and third dose of 9vHPV vaccine on 01-Oct-2009, 27-Nov-2009, and 20-Apr-2009, respectively. On
02-Oct-2009 (2 days post-dose 2), the subject experienced neuralgia of mild intensity in her left arm.
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On the same day, the subject also experienced a headache. The subject received no treatment for her
neuralgia. On 05-Oct-2009, the subject recovered from neuralgia. The subject did not report any
events of neuralgia following subsequent vaccination visits. The reporting investigator felt the
neuralgia was related to 9vHPV vaccine.

Assessors comment: Negative rechallenge. It is reassuring that there was no recurrence with the
third dose of 9vHPV.

Sensory Disturbance

white female from the United States with a medical history of seasonal
allergy, depression, gynaecological chlamydia infection, vulvovaginal candidiasis, and dysmenorrhea
received her first and second dose of 9vHPV vaccine on 03-Mar-2009 and 21-Apr-2009, respectively.
On 03-Mar-2009 (1 day post-dose 1) the subject experienced sensory disturbance of mild intensity in
her left foot which lasted approximately 4 minutes. On 23-Apr-2009 (3 days post-dose 2), the subject
experienced a second episode of sensory disturbance of mild intensity in her left foot that lasted for 10
seconds. The subject received no treatment for either episode of sensory disturbance. The subject did
not receive her third dose of study vaccine due to the subjects personal decision, however, she
continued in the follow-up phase of the study. The reporting investigator felt that both episodes of
sensory disturbance were related to 9vHPV vaccine.

Assessors comment: This case could be described as a positive rechallenge. There is a recurrence of
symptoms after a subsequent dose. The location of the AE occurs at a site distant from the site of
injection. The symptoms are, however, quite unspecific and of very short duration.

VIIth Nerve Paralysis

black female from Denmark with no medical history received her first,
second, and third dose of 9vHPVvaccine on 19-May-2009, 12-Aug-2009, and 03-Nov-2009,
respectively. On 12-Aug-2009 (1 day post-dose 2), the subject experienced VIIth nerve paralysis of
severe intensity. The subject received no treatment for her VIIth nerve paralysis. On 14-Aug-2009,
the subject recovered. The subject did not report any events of VIIth nerve paralysis following
subsequent vaccination visits. The reporting investigator felt that the VIIth nerve paralysis was related
to 9vHPV vaccine. The investigator indicated that the causality assessment was based solely on
temporal association.

Assessors comment: Negative rechallenge. It is reassuring that there was no recurrence with the
third dose of 9vHPV.

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multiracial (black, white) male from Colombia with no medical history
received his first, second, and third dose of 9vHPV vaccine on 05-Dec-2009, 06-Feb-2010, and 17-
Jun-2010, respectively. On 20-Jun-2010 (4 days post-dose 3), the subject experienced VIIth nerve
paralysis of mild intensity. The subject was treated with dexamethasone and methlylprednisolone. On
12-Jul-2010, the subject recovered. The reporting investigator felt that the VIIth nerve paralysis was
related to 9vHPV vaccine.

Assessors comment: This event of nerve paralysis occurred after the last dose of vaccination, so no
rechallenge information is available. It is noted that she required therapy with steroids.

Vagus Nerve Disorder

white female from Finland with a medical history of lactose intolerance


received her first dose of study vaccine (9vHPV vaccine administered concomitantly with Repevax )
on 28-May-2010. She received her second and third dose of 9vHPV vaccine on 27-Jul-2010 and 05-
Nov-2010, respectively. On 28-May-2010 (1 day post-dose 1), the subject experienced vagus nerve
disorder of mild intensity. The subject received no treatment for her vagus nerve disorder. On 30-
May-2010, the subject recovered from vagus nerve disorder. The subject did not report any events of
vagus nerve disorder following subsequent vaccination visits. The reporting investigator felt that the
vagus nerve disorder was related to 9vHPV vaccine.

Assessors comment: Negative rechallenge. It is reassuring that there was no recurrence with
subsequent doses.

Sleep Disorder

white female from Denmark with a medical history of Aspergers disorder


received her first, second, and third dose of 9vHPV vaccine on 29-Apr-2009, 19-Jun-2009, and 26-
Oct-2009, respectively. On 08-May-2009 (10 days post-dose 1), the subject experienced sleep
disorder of mild intensity that lasted 23 hours. The subject received no treatment for her sleep
disorder. The subject did not report any events of sleep disorder following subsequent vaccination
visits. The reporting investigator felt that the sleep disorder was related to 9vHPV vaccine.

Assessors comment: Negative rechallenge. It is reassuring that there was no recurrence with
subsequent doses.

The events of vaccine-related hyperhidrosis are summarized in the table below.


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Case narratives

white female from the United States with a medical history of seasonal
allergy and sinus disorder received her first, second, and third dose of 9vHPV vaccine on 18-Oct-
2007, 08-Jan-2008, and 25-Apr-2008, respectively. On 08-Jan-2008 (1 day post-dose 2), the subject
experienced hyperhidrosis of moderate intensity that lasted 20 minutes. The subject received no
treatment for her hyperhidrosis. The subject did not report any events of hyperhidrosis following
subsequent vaccination visits. The reporting investigator felt that the hyperhidrosis was related to
9vHPV vaccine.

Assessors comment: Negative rechallenge. It is reassuring that there was no recurrence with the
third dose of 9vHPV.

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white female from the United States with a history of vulvovaginal
candidiasis, gingival bleeding, and non-cardiac chest pain received her first and second dose of
9vHPV vaccine on 06-Nov-2008 and 07-Jan-2009, respectively. On 07-Jan-2009 (1 day post-dose
2), the subject experienced hyperhidrosis of severe intensity that last 8 hours. On the same day, the
subject also experienced pain, nausea, pyrexia, asthenia, dizziness, and fatigue. The subject received
no treatment for her hyperhidrosis. The subject did not receive her third dose of study vaccine due to
adverse experiences reported on 07-Jan-2009, however, she continued in the follow-up phase of the
study. The reporting investigator felt that the hyperhidrosis was related to 9vHPV vaccine.

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Assessors comment: Of concern in this case is the constellation of accompanying symptoms and lack
of clear infectious etiology as well as the fact that the case declined further vaccination.

multi-racial female from Mexico with no medical history received her first,
second, and third dose of 9vHPV vaccine on 24-Oct-2008, 19-Dec-2008, and 27-Mar-2009,
respectively. On 27-Mar-2009 (1 day post-dose 3), the subject experienced hyperhidrosis of moderate
intensity. On the same day, the subject also experienced chills, headache, and eye pain. The subject
received no treatment for her hyperhidrosis. On 28-Mar-2009, the subject recovered from
hyperhidrosis. The reporting investigator felt that the hyperhidrosis was related to 9vHPV vaccine.

Assessors comment: The concomitant presence of chills could indicate an infectious process. This
event of hyperhidrosis occurred after the last dose of vaccination, so no rechallenge information is
available.

white female from Canada with a medical history of joint injury, headache,
and urinary tract infection received her first, second, and third dose of 9vHPV vaccine on 29-May-
2009, 30-Jul-2009, and 25-Nov-2009, respectively. On 06-Jun-2009 (9 days post-dose 1), the subject
experienced hyperhidrosis of mild intensity. On the same day, the subject also experienced chills. The
subject received no treatment for her hyperhidrosis. On 08-Jun-2009, the subject recovered from
hyperhidrosis. The subject did not report any events of hyperhidrosis following subsequent vaccination
visits. The reporting investigator felt that the hyperhidrosis was related to 9vHPV vaccine.

Assessors comment: The concomitant presence of chills could indicate an infectious process.
Negative rechallenge. It is reassuring that there was no recurrence with subsequent doses.

female from Brazil with a medical history of polycystic ovaries,


dysmenorrhea, ectropion of cervix, vaginal discharge, headache, and dyspareunia received her first,
second, and third dose of 9vHPV vaccine on 03-Jun-2009, 04-Aug-2009, and 20-Nov-2009,
respectively. On 22-Nov-2009 (3 days post-dose 3) the subject experienced hyperhidrosis of
moderate intensity that lasted approximately 8 hours. On 21-Nov-2009 (2 days post-dose 3), prior to
the event of hyperhidrosis, the subject experienced pyrexia, dizziness, headache, myalgia, and
asthenia. The event of pyrexia was classified as a serious adverse experience. The subject received no
treatment for her hyperhidrosis. The reporting investigator felt that the hyperhidrosis was related to
9vHPV vaccine.

Assessors comment: Although not concomitantly reported, the subject also experienced pyrexia
which could indicate an infectious process.

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white female from Canada with a medical history of urinary tract infection,
back pain, psoriasis, acne, and anxiety received her first, second, and third dose of study medication
on 03-Jun-2009, 03-Aug-2009, and 17-Nov-2009, respectively. On 19-Nov-2009 (3 days post-dose 3)
the subject experienced hyperhidrosis of moderate intensity. On the same day, the subject also
experienced erythema (of the face) and headache. Additionally, on 18-Nov-2009 (2 days post-dose
3), prior to the event of hyperhidrosis, the subject experienced dizziness, hypoaesthesia, nausea, and
diarrhea. The subject received no treatment for her hyperhidrosis. On 20-Nov-2009, the subject
recovered from hyperhidrosis. The reporting investigator felt that the hyperhidrosis was related to
9vHPV vaccine.

Assessors comment: Of potential concern in this case is the constellation of accompanying symptoms
and lack of clear infectious etiology.

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white female from Canada with a medical history of allergy to animal,
wisdom teeth removal, seasonal allergy, dizziness, nasopharyngitis, and urinary tract infection
received her first, second, and third dose of 9vHPV vaccine on 28-Jul-2009, 17-Sep-2009, and 14-Jan-
2010, respectively. On 17-Sep-2009 (1 day post-dose 2), the subject experienced hyperhidrosis of
mild intensity. The subject received no treatment for her hyperhidrosis. On 22-Sep-2009, the subject
recovered from hyperhidrosis. The subject did not report any events of hyperhidrosis following
subsequent vaccination visits. The reporting investigator felt that the hyperhidrosis was related to
9vHPV vaccine.
Assessors comment: Negative rechallenge. It is reassuring that there was no recurrence with
subsequent doses of 9vHPV.

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white female from Germany with a medical history of seasonal allergy,
asthma, neurodermatitis, and nasopharyngitis received her first, second and third dose of 9vHPV
vaccine on 23-Sep-2009, 04-Nov-2009, and 29-May-2010, respectively. On 04-Nov-2009 (the day of
vaccination for dose 2), the subject experienced hyperhidrosis of mild intensity. On the same day, the
subject experienced dizziness. On 05-Nov-2009 (2 days post-dose 2), the subject experienced
influenza and dysmenorrhoea. On 06-Nov-2009 (3 days post-dose 2) experienced back pain. The
subject received no treatment for her hyperhidrosis. On 05-Nov-2009, the subject recovered from
hyperhidrosis. The subject did not report any events of hyperhidrosis following subsequent vaccination
visits. The reporting investigator felt that the hyperhidrosis was related to 9vHPV vaccine.

Assessors comment: It is documented that the subject experienced influenza in temporal relationship
to hyperhidrosis.

white female from New Zealand with a medical history of headache,


seasonal allergy, acne, drug hypersensitivity, and tonsillectomy received her first, second, and third
dose of 9vHPV vaccine on 13-Aug-2009, 29-Sep-2009, and 23-Feb-2010, respectively. On 14-Aug-
2009 (2 days post-dose 1), the subject experienced hyperhidrosis of moderate intensity. On the same
day, the subject also experienced pyrexia. The subject treated her hyperhidrosis and fever with
acetaminophen. On 18-Aug-2009, the subject recovered from hyperhidrosis. On 22-Aug-2009 (10
days post-dose 2), the subject experienced a second episode of hyperhidrosis of moderate intensity.
On the same day, the subject experienced a second episode of pyrexia. She again treated her
hyperhidrosis and pyrexia with acetaminophen. On 23-Aug-2009, the subject recovered from
hyperhidrosis. The subject did not report any events of hyperhidrosis following subsequent vaccination
visits. The reporting investigator felt that both episodes of hyperhidrosis were related to 9vHPV
vaccine.

Assessors comment: Positive rechallenge. This subject experienced both pyrexia and hyperhidrosis
after the first and second doses. While pyrexia could be indicative of an infectious process, there are
no localizing signs of infection and it recurred after the second dose of vaccine. There was no
evidence of recurrence after the third dose.

white female from Denmark with no medical history received her first,
second, and third dose of 9vHPV vaccine on 10-Sep-2009, 09-Nov-2009, and 02-Mar-2010,
respectively. On 07-Mar-2010 (7 days post-dose 3), the subject experienced hyperhidrosis of
moderate intensity that lasted for 23 hours. On the same day, the subject also experienced nausea,
discomfort, diarrhoea, abdominal pain, dizziness, and headache. On 10-Mar-2010, the subject

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experienced nasal congestion. The subject was treated with acetaminophen and xylometazoline
hydrochloride. The reporting investigator felt that the hyperhidrosis was related to 9vHPV vaccine.

Assessors comment: This event of hyperhidrosis occurred after the last dose of vaccination, so no
rechallenge information is available. There were concomitant symptoms but nonspecific for fever.

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r white female from Denmark with a medical history of dysmenorrhea received
her first, second, and third dose of 9vHPV vaccine on 13-Oct-2009, 16-Dec-2009, and 13-Apr-2010,
respectively. On 17-Dec-2009 (2-days post-dose 2), the subject experienced hyperhidrosis of mild
intensity. On the same day the subject also experienced fatigue, pain (general), feeling cold,
oropharyngeal pain, and pyrexia. On 19-Dec-2009, the subject experienced a second episode of both
oropharyngeal pain and pyrexia. The subject was treated with acetaminophen, tipronin, and ibuprofen.
On 19-Dec-2009, the subject recovered from hyperhidrosis. The subject did not report any events of
hyperhidrosis following subsequent vaccination visits. The reporting investigator felt that the
hyperhidrosis was related to 9vHPV vaccine.

Assessors comment: Negative rechallenge. It is reassuring that there was no recurrence with
subsequent doses of 9vHPV.

multiracial female from Colombia with a medical history of caesarian


section, nasal obstruction, and appendectomy, received her first, second, and third dose of 9vHPV
vaccine on 28-Apr-2009, 03-Jul-2009, and 03-Oct-2009, respectively. On 28-Apr-2009 (1 day post-
dose 1), the subject experienced hyperhidrosis of moderate intensity that lasted for 3 hours. The
subject received no treatment for her hyperhidrosis. The subject did not report any events of
hyperhidrosis following subsequent vaccination visits. The reporting investigator felt that the
hyperhidrosis was related to 9vHPV vaccine.

Assessors comment: Negative rechallenge. It is reassuring that there was no recurrence with
subsequent doses of 9vHPV.

white female from Norway with a medical history of vaginal discharge and
infection (of unknown type) received her first, second, and third dose of 9vHPV vaccine on 21-Oct-
2009, 08-Dec-2009, and 19-Apr-2010, respectively. On 19-Apr-2010 (1 day post-dose 3), the subject
experienced hyperhidrosis of mild intensity that lasted 8 hours. On the same day the subject also
experienced nasal obstruction. The subject received no treatment for her hyperhidrosis. The reporting
investigator felt that the hyperhidrosis was related to 9vHPV vaccine.

Assessors comment. This event of hyperhidrosis occurred after the last dose of vaccination, so no
rechallenge information is available. There were concomitant symptoms but nonspecific for fever.

white female from Belgium with a medical history of gastritis and drug
hypersensitivity received her first, second, and third dose of 9vHPV vaccine on 17-Feb-2010, 07-
Apr-2010, and 02-Aug-2010, respectively. On 07-Apr-2010 (1 day post-dose 2), the subject
experienced hyperhidrosis of mild intensity that lasted 10 hours. The subject received no treatment for
her hyperhidrosis. On 07-Apr-2010, the subject recovered from hyperhidrosis. The subject did not

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report any events of hyperhidrosis following subsequent vaccination visits. The reporting investigator
felt that the hyperhidrosis was related to 9vHPV vaccine.

Assessors comment: Negative rechallenge. It is reassuring that there was no recurrence with
subsequent doses of 9vHPV.

white female from Belgium with no medical history received her first,
second, and third dose of 9vHPV vaccine on 21-Nov-2009, 17-Jan-2010, and 06-Jun-2010,
respectively. On 08-Jun-2010 (3 days post-dose 3), the subject experienced hyperhidrosis of
moderate intensity that last 23 hours. The subject received no treatment for her hyperhidrosis. On 08-
Jun-2010, the subject recovered from hyperhidrosis. The reporting investigator felt that the
hyperhidrosis was related to 9vHPV vaccine.

Assessors comment. This event of hyperhidrosis occurred after the last dose of vaccination, so no
rechallenge information is available.

white male from the United States with a medical history of hernia repair
and osteochondrosis received his first dose of study vaccine (9vHPV vaccine administered
concomitantly with Adacel and Menactra ) on 04-Feb-2010. He received his second and third dose
of 9vHPV vaccine on 12-May-2010 and 13-Jul-2010, respectively. On 04-Feb-2010 (1 day post-dose
1), the subject experienced hyperhidrosis of mild intensity that lasted for 15 minutes. Subsequently,
on 06-Feb-2010, the subject experienced pain in extremity. Later, on 10-Feb-2010, the subject
experienced vomiting and abdominal pain. The subject received no treatment for her hyperhidrosis.
On 04-Feb-2010, the subject recovered from hyperhidrosis. The subject did not report any events of
hyperhidrosis following subsequent vaccination visits. The reporting investigator felt that the
hyperhidrosis was related to 9vHPV vaccine.

Assessors comment: The subject reported concomitant symptoms although none specific for
infection, such as fever or pyrexia. Negative rechallenge. It is reassuring that there was no
recurrence of symptoms with subsequent doses of vaccine.

The following comments can be made regarding the events:

Neurological events

Events are generally of brief duration and mild to moderate intensity.

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Subjects generally received no treatment.

Subjects generally did not discontinue study vaccination.

Events fully resolved and did not reoccur after a subsequent vaccination.

Two of the neurological events are confounded by concomitant administration of 9vHPV


vaccine with either Repevax or Menactra and Adacel; of note, post-marketing experience
with Menactra and Repevax includes neurological events.

There is no pattern in terms of age and gender of subjects reporting neurological events

Events of hyperhidrosis

Events are generally of brief duration and mild to moderate intensity.

Subjects generally received no treatment.

Subjects generally did not discontinue study vaccination.

Events fully resolved and did not reoccur after a subsequent vaccination.

A number of events of hyperhidrosis occurred together with other symptoms (fever, chills, flu-
like symptoms) that may be suggestive of acute infection, a condition which can be associated
with hyperhidrosis.

Most subjects reporting hyperhidrosis are young women 16 to 26 years of age. This trend is
consistent with previous findings that the highest prevalence rates of hyperhidrosis are among
those aged 18 years and older [1].

Conclusions

Because of the above considerations, and particularly the generally brief duration, mild to moderate
intensity, and absence of reoccurrence with subsequent vaccination, these events do not suggest a
safety risk and are not evocative of a neurological or autoimmune concern. Thus, inclusion of any
safety concern related to these events into the RMP as important potential risks is not warranted.

Reference

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[1] Strutton DR, Kowalski JW, Glaser DA, and Stang PE. US prevalence of hyperhidrosis and impact on
individuals with axillary hyperhidrosis: results of a national survey. J Am Acad Dermatol 51:241-248,
2004

Assessment of the Applicants Response

The Applicant has provided case narratives for the cases reporting potential adverse events of concern
which occurred at low incidence but were assessed as vaccine-related.

Regarding the various neurological events, 5 of 7 cases did not experience recurrence of symptoms
with subsequent doses of vaccine, which is reassuring. One of the 7 cases experienced the adverse
event (VIIth nerve paralysis) after the 3 rd vaccination, and therefore no rechallenge data is available.
The last case ( ) experienced sensory disturbance of very short duration (4 minutes and 10
seconds, respectively) after the 1st and 2nd doses and therefore refused to accept the final dose. It is
acknowledged that the majority of cases do not exhibit a pattern of positive re-challenge, and the
assessment of these cases is, overall, reassuring.

Regarding hyperhidrosis, of the 16 cases reviewed, only 1 documented the presence of a concomitant
infection influenza) and 4 subjects demonstrated concomitant symptoms which were
similar between cases (dizziness, headache, gastrointestinal symptoms, hypoaesthesia). Eight of the
16 cases had no recurrence of their symptoms with subsequent doses and 6 experienced symptoms
after the 3rd dose and thus have no re-challenge information.

At the current time, there is not enough data to suggest the need for inclusion of any of the individual
events discussed in this response into the SPC.

Conclusion: Issue resolved.

Question 64.

There is a case describing pulmonary vasculitis and a positive ANA in female 2 months
after her second dose of 9vHPV. The histology report notes that lupus pneumonia is a likely diagnostic
consideration. Additionally, there is one event of butterfly rash noted in the table presenting all
systemic events occurring within 15 days of any vaccination. The Applicant is requested to discuss the
potential association between 9vHPV vaccination and SLE and to discuss the need for inclusion of SLE
into the RMP as an important potential risk and for further investigation of this concern in the post
authorisation period.

Summary of the Applicants Response

Narratives regarding the butterfly rash case ( ) and the pulmonary vasculitis case ( )
mentioned in the Agency question:

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This event was reported in an Multi-racial female subject ( ) from
Mexico with no medical history enrolled in the V503-005 study. This subject received her first, second
and third doses of 9vHPV vaccine on 25-May-2010, 22-Jul-2010, and 22-Nov-2010, respectively. She
also received Adacel and Menactra on 23-Jun-2010. The subject reported rash at malar region that
began on 25-May-2010 (date of first dose of 9vHPV vaccine). The reported rash at malar region
encoded to butterfly rash. The rash lasted 1 day, was mild in intensity, and considered related to
vaccine. The only other adverse events reported by this subject were injection site pain and no other
medical conditions were reported during the entire study. Therefore, there is no evidence to suggest
that the reported rash was associated with any other conditions.

), a white girl from Spain developed pulmonary vasculitis and


anemia diagnosed approximately 2 months after receiving the second dose of 9vHPV vaccine on 23
June 2011. She had received a first dose of 9vHPV vaccine on 19 April 2011. The subject was healthy,
with no relevant medical family history. She had menarche in December 2010, with cycles every 15-
20 days, lasting approximately 5 days, with profuse bleeding and no dysmenorrhoea. She had been
hospitalised in March 2011 for abdominal pain due to ovarian cyst. On 1 September 2011, the subject
presented tiredness for approximately four months, with dyspnoea for 2 months, tachycardia on slight
exertion, appetite decrease with weight loss of 5 kg since the symptoms started, and frequent
headache treated with analgesics. She had an episode of fever (max. 39.5C), nausea and headache,
which spontaneously resolved within 24 hours. Lab tests showed anaemia. Chest X-ray showed
baseline multifocal illness with poorly defined nodular images in both inferior lobes, indicating
oedema or haemorrhage, with probable interstitial thickening. The subject was hospitalized on 08
September 2011. Physical exam was normal except a slight pallor of skin and mucous membranes.
Lab investigations on admission showed Haemoglobin 8.4 g/dl, Hematocrit 27.3%, MCV 85.2 fl,
Leukocytes 4,130/mm3 (59% neutrophils, 30% lymphocytes, 5.3% monocytes), Platelets
355,000/mm3. ESR: 40 mm 1st hour. Iron metabolism test: iron 31 mcg/dL, transferrin saturation
index 13%, ferritin normal. LDH was 421 IU/l and the other biochemical parameters were within the
normal range. Urine analysis test showed hematuria and proteinuria and the remainder was normal.
Complement testing (C2, C3, C4, CH50) was within normal range. Antinuclear Antibodies (ANA) were
positive at 1/1280 as well as anti-DNA antibodies; Anti-neutrophils cytoplasmic antibodies (ANCA),
anti-proteinase 3, antimyeloperoxidase, antireticulin, and anti glomerular basement membrane
antibodies testing were negative. ENA, anti-Ro antibodies, anti-La antibodies, anti-RNP antibodies, anti
SCL-70 antibodies and anti-SM antibodies were pending at discharge. Anti-transglutaminase and
antiendomysial antibodies were negative. Viral serology were negative (HBV, HCV, HIV, herpes
simplex virus, CMV, Adenovirus and Parvovirus B19). Chest CT scan showed extensive diffuse bilateral
opacities predominantly in the inferior lobes, and small parenchymatous consolidations in both lung
bases, also in middle lobe. Lung function tests showed lung disorder of restrictive nature consistent
with the suspected diagnosis of vasculitis or haemosiderosis. Fibrobronchoscopy showed that bronchial
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trees contained erythematous mucosa and traces of blood. Result of histology from transbronchial
biopsy in the right inferior lobe showed extensive areas of alveolar bleeding, both old and recent,
combined with small areas of inflammation of the interalveolar septum (focal capillaritis). These
morphological findings are consistent with the variant of alveolar haemorrhage and capillaritis found in
Wegeners disease, microscopic polyangiitis and other diseases associated with capillaritis, such as
acute lupus pneumonia, rheumatoid arthritis, polymyositis and connective tissue disease. Given that
there were elevated ANA, the spectrum of diagnostic options is restricted to other diseases associated
with capillaritis, such as lupus pneumonia, and other processes, such as Wegeners disease and
microscopic polyangiitis, are ruled out. The subject received oral ferrous sulphate, cyclophosphamide
(750 mg intra-venous, once every month, planned for 6 courses) and oral prednisone (40 mg/day).
During hospitalisation, her condition gradually improved. The subject was discharged on 5 October
2011. Haemogram prior to discharge was Haemoglobin 10.1 g/dL with Hematocrit 32.6%. Diagnoses
at discharge were diffuse alveolar haemorrhage due to focal pulmonary capillaritis, with elevated
antinuclear antibodies and positive anti-DNA antibodies, secondary haemosiderosis, iron deficiency,
dysfunctional uterine haemorrhage and multifactorial anaemia. This was suggesting of a possible
connective tissue disorder although not fulfilling any category yet. Final diagnosis was isolated
pulmonary capillaritis with positive ANA and multifactorial anemia. Anaemia was mainly related to
profuse menstrual bleeding cycles before the current disease but was mainly exacerbated by diffuse
alveolar haemorrhage secondary to main diagnosis. It was considered to be resolved on 5 December
2011 as the last Haemoglobin (1 December 2011) was 13.8 g/dL. The latest information received on
March 2012 was that the subject was asymptomatic since 21 December 2011, considered as the date
of resolution of the SAE pulmonary vasculitis. Thoracic CT-scan showed resolution of previous lesions.
ANA: 1/1280 with anti-DNA antibody: 25 (Normal: 0-10) on 12 September 2011 and ANA: 1/320 with
anti-DNA antibody: 13 on 03 February 2012. The subject had received 5 cures of cyclophosphamide
and the last is planned. Prednisone was stopped on 23 February 2012.

The subject was withdrawn from the study due to adverse event, because the drug used to treat
pulmonary capillaritis was immunosuppressive. According to the investigator, the diagnosis of diffuse
alveolar haemorrhage secondary to focal pulmonary capillaritis, together with the high level of
antinuclear antibodies suggested an underlying connective tissue disease. Anemia was mainly related
to profuse menstrual bleeding cycles before the current disease but was exacerbated by diffuse
alveolar haemorrhage secondary to main diagnosis. The investigator assessed the relationship of both
SAEs to vaccine as not related.

As described in the narrative, the butterfly rash did not appear to be associated with a chronic
systemic autoimmune condition.

Regarding the condition of pulmonary vasculitis with ANA, a condition of acute lupus
pneumonia was initially suggested among other possible diagnoses. The sponsor of the study
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(Sanofi Pasteur MSD) re-contacted the investigators (Drs. Frederico Martinon Torres and
Lorenzo Redondo) on 22-Sep-2014 (approximately 3 years after the resolution of the event)
to obtain an update of the clinical evolution since the closing of the clinical study. The
investigators indicated that (1) The subject is currently in good health; (2) She reported no
major medical problem since the resolution of the SAE of pulmonary vasculitis; it was noted
that she had a magnetic resonance imaging (MRI) of the brain (performed on 15-May-2014)
because of persistent headache: the MRI was normal and the headache resolved
spontaneously afterwards; (3) No new conditions have occurred that would be in favor of a
diagnosis of lupus; (4) The diagnosis remains unchanged (pulmonary vasculitis with positive
ANA) and the subject does not fulfill the criteria for lupus according to the physician in charge
of her follow-up; and (5) Results of testing which were pending at the time the CSR narrative
was written are now available: Extractable Nuclear Antibodies (ENA), including anti-Ro
antibodies, anti-La antibodies, anti-RNP antibodies, anti SCL-70 antibodies and anti-Sm
antibodies were all negative. In summary, the episode of vasculitis promptly resolved and has
not reoccurred to date. The subjects complete recovery argues against the diagnosis of lupus.

In addition, the Applicant would like to inform the Agency that, during review of this case by the
US Food and Drug Administration (USFDA) in the scope of the US marketing authorization
of the 9vHPV vaccine, the USFDA asked whether ANA testing could be performed on pre-
vaccination serum from this subject. A retained pre-vaccination serum sample is available for this
subject in the US central laboratory performing the anti-HPV testing for the study. The informed
consent signed by the parents allows using the sample for further testing within the scope of the study.
Consequently, logistics measures are currently being set up to ship serum sample to the principal
investigator of the investigating centre, who will further investigate this serious adverse event by
testing pre-vaccination ANA. Further information will be provided to the Agency when available.

Following the question from the Agency, the Applicant is providing a summary of the systemic lupus
erythematosus (SLE) cases in the 9vHPV vaccine program and a discussion of the potential association
between 9vHPV vaccination and SLE. All diagnosed SLE cases in the 9vHPV vaccine occurred in
Protocol V503-001.

Summary of SLE Cases in V503-001

In the V503-001 study, there have been 2 reports of systemic lupus erythematosus (SLE) in the
9vHPV vaccine group (N=7,071) and 1 case reported in the qHPV vaccine group (N=7,078). The
incidence of systemic lupus erythematosus per 100,000 person-years of follow-up during the study
period was 7.0 and 3.5 in the 9vHPV and qHPV vaccine groups, respectively, as shown in Table 25.
These rates had wide overlapping confidence intervals, suggesting no statistically significant difference.
The numeric difference in incidence rates and wide confidence intervals is reflective of the small
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number of cases in both treatment groups. As described in further detail below, both these rates are
within the range of background rates reported in the literature for females in this age group.
Therefore, the numeric difference in incidence rates is likely due to random variation. This information
does not suggest there is need for inclusion of SLE into the RMP as an important potential risk, nor for
specific investigation of SLE in the post-authorization period.

A brief summary of the 3 reported cases of lupus is provided in Table 26. The SLE case narratives
from the V503-001 CSR are provided at the end of this response. As a point of comparison, in the
V501 clinical program, there were 4 reported cases of SLE: 1 occurred in the qHPV vaccine group
(N=10,706) and 3 occurred in the placebo group (N=9,412) (GARDASIL Product Insert).

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A summary of recent literature on SLE epidemiology, detailing age-specific incidence rates in young
females is provided in the table below. The incidence of SLE rises in females through the teen years
and peaks in the twenties and thirties (Somers et al, 2014; Yeh et al, 2013; Shim et al, 2014). Data
from the United States suggest that Black females may have a higher incidence rate of SLE than White
females (Somers et al, 2014; Yeh et al, 2013). Sparse data are available for Latin America; a recent
study from Brazil reported rates generally at the higher end of the literature range. All 3 cases
reported in V503-001 were in their mid- to late-twenties and the rates observed in this trial for the
9vHPV and qHPV treatment groups (7.0 and 3.5 per 100,000 person-years, respectively) are in the
lower end of the range of background incidence rates of SLE reported in the literature for women in
their late teens and twenties. This information does not suggest there is need for inclusion of SLE into
the RMP as an important potential risk, nor for specific investigation of SLE in the post-authorization
period.

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References:

Alonso M.D., Llorca J., Martinez-Vazquez F., Miranda-Filloy J.A., Diaz De Teran T., Dierssen T.,
Vazquez-Rodriguez T.R., Gomez-Acebo I., Blanco R., Gonzalez-Gay M.A. Systemic lupus
erythematosus in Northwestern Spain: A 20-year epidemiologic study. Medicine 2011;90:5;350-358.

Arnheim-Dahlstrm L., Pasternak B., Svanstrm H., Sparn P., Hviid A. Autoimmune, neurological,
and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent
human papillomavirus vaccine in Denmark and Sweden: Cohort study. BMJ (Online) 2013 347:7930.

Chao C., Klein N.P., Velicer C.M., Sy L.S., Slezak J.M., Takhar H., Ackerson B., Cheetham T.C., Hansen
J., Deosaransingh K., Emery M., Liaw K.-L., Jacobsen S.J. Surveillance of autoimmune conditions
following routine use of quadrivalent human papillomavirus vaccine. J Internal Medicine
2012 271:2(193-203).

Klein N.P., Ray P., Carpenter D., Hansen J., Lewis E., Fireman B., Black S., Galindo C., Schmidt J.,
Baxter R. Rates of autoimmune diseases in Kaiser Permanente for use in vaccine adverse event safety
studies. Vaccine 2010 28:4(1062-1068).

Lerang K., Gilboe I., Garen T., Thelle D.S., Gran J.T. High incidence and prevalence of systemic lupus
erythematosus in Norway. Lupus 2012 21:12(1362-1369).

Lim S.S., Bayakly A.R., Helmick C.G., Gordon C., Easley K.A., Drenkard C. The incidence and
prevalence of systemic lupus erythematosus, 2002-2004: The Georgia lupus registry. Arthritis and
Rheumatology 2014 66:2(357-368).

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Shim J.-S., Sung Y.-K., Joo Y.B., Lee H.-S., Bae S.-C. Prevalence and incidence of systemic lupus
erythematosus in South Korea. Rheumatology International 2014 34:7(909-917).

Somers E.C., Marder W., Cagnoli P., Lewis E.E., DeGuire P., Gordon C., Helmick C.G., Wang L., Wing
J.J., Dhar J.P., Leisen J., Shaltis D., McCune W.J. Population-based incidence and prevalence of
systemic lupus erythematosus: The Michigan lupus epidemiology and surveillance program. Arthritis
and Rheumatology 2014 66:2(369-378).

Pereira Vilar M.J., Sato E.I. Estimating the incidence of systemic lupus erythematosus in a tropical
region (Natal, Brazil). Lupus 2002 11:8(528-532).

Yeh K.-W., Yu C.-H., Chan P.-C., Horng J.-T., Huang J.-L. Burden of systemic lupus erythematosus in
Taiwan: A population-based survey. Rheumatology International 2013 33:7(1805-1811).

Assessment of the Applicants Response

The Applicant has provided the requested case narratives containing the reported events of butterfly
rash and pulmonary vasculitis, as well as a review of cases of SLE which occurred in the clinical safety
database. The case of butterfly rash was without concomitant symptoms and resolved within 1 day.
The case of pulmonary vasculitis with positive ANA was subject to followup; there have been no new
symptoms as well as negative results for multiple laboratories. A review of the 3 cases of SLE do not
exhibit symptoms in close temporal relationship to vaccination, and the observed incidence is not over
the expected background incidence rate in this population of young women. It is agreed that there is
no clear evidence to support the need for inclusion of SLE into the SPC at the present time.

However, concern remains regarding the case of given the onset of an autoimmune
process, a vasculitis, in temporal relationship with the receipt of the second dose of vaccine. As
mentioned by the Applicant in the response above, the US FDA has requested ANA testing on a pre-
vaccination sample from this subject. The results are awaited.

The isolated case of pulmonary vasculitis could possibly be related to the vaccination. Although further
ANA analysis may add some diagnostic information it cannot help the assessment of potential
causality and risk and subsequently can not impact on the regulatory measures to be taken.
Occurrence of vasculatis or related conditions within a plausible time window after vaccination should
therefore be monitored within the PSURs but presently no other regulatory action is considered
warranted.Conclusion: Issue resolved.

Question 65.

There is one case describing a who was diagnosed with dysautonomia after presentation
with signs of both syncope and tachycardia of unspecified cause after receiving 2 doses of 9vHPV.
This case is concerning for the syndrome of postural orthostatic tachycardia syndrome (POTS) which is
ongoing safety concern for the both the quadrivalent and bivalent HPV vaccines currently in use. The

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Applicant is requested to discuss whether or not this case meets the diagnostic criteria for POTS and
to discuss if there are any additional cases within the clinical safety database which could be
suggestive of POTS.

Summary of the Applicants Response

This response provides a summary of the case of dysautonomia noted by the reviewer, a review of all
cases of postural orthostatic tachycardia syndrome (POTS), and a review of subjects with specific
symptoms of POTS that might be suggestive of POTS. The findings do not suggest an association
between the 9vHPV vaccine and POTS.

a. Review of the case of dysautonomia diagnosed in a subject

An incident condition of dysautonomia was reported for subject in the V503-006 study. The
narrative is provided below for reference. The subject presented a single episode of syncope 13 d ays
after receiving her 2nd dose of 9vHPV vaccine. The investigator indicated that the SAE was rapidly
resolved. The subject remained in the study, received her 3 rd dose of 9vHPV vaccine, and no other
symptom was subsequently reported in the database for this subject which suggests that this was an
acute event, not a recurrent or chronic condition. Following a tilt table test result of neurocardiogenic
syncope, a cardiologist made the diagnosis of dysautonomia. In the absence of numerical findings
from the tilt test it is not known whether or not this case would meet the diagnostic criteria for
postural orthostatic tachycardia syndrome (POTS). The absence of recurrent episodes is not
suggestive of POTS.

white female from Columbia with dysmenorrhoea, anaemia, atopic


dermatitis, citrus allergy, menstrual cycle irregularity and urticaria and a medical history of acute
rhinosinusitis diagnosed on 08-NOV-2010 received two doses of 9vHPV vaccine (1 st dose 02-SEP-
2010, 2nd dose 22-NOV-2010). The patient was previously vaccinated with Gardasil vaccine in
2007/2008. On 05-DEC-2010 (13 days post-dose 2), at 11:00 a.m, the subject had an episode of
syncope for about 30 minutes after having presented with global headache of moderate
intensity. She was hospitalized. There was no previous neurologic medical history.
Hemoleukogram was normal. Brain trans-axial tomography and electroencephalogram (EEG) were
normal, cerebrospinal fluid (CSF) from lumbar puncture was normal (no leukocytosis, no
polymorphonucleocytes (PMN), normal glucose, normal protein, presence of leukocytes). Lab
testing: hemogram, Blood Urea Nitrogen (BUN), creatinine, ionogram all normal. There was no
evidence of infection. The initial diagnosis was epilepsy and epileptic symptoms. The subject was
treated with sodic fenitoine, midazolam, ranitidine, alizapride, dipyrone, omeprazole, ketoprofen
and ondansetron. On 07-DEC-2010, the subject recovered from syncope and was discharged from
the hospital. The discharge diagnosis was epileptic syndrome symptomatic with focalization and

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simple partial attacks, syncope and collapse. A control EEG was planned and new metabolic
testing was expected. Fasting glucose on 14-JAN-2011 was normal. The subject was seen by a
neurologist on 18-JAN-2011; the neurologist concluded syncope and collapse with tachycardia of
non-specified cause. On 03-FEB-2011, tilt-test showed positive for neurocardiogenic syncope
mixed and positive for syncope mix cardiogenic. Following the Tilt test, the cardiologist provided a
diagnosis of dysautonomia. The subject received her third dose of 9vHPV vaccine on 09-
FEB-2011. The reporting investigator felt that syncope was not related to 9vHPV vaccine.

b. Search for cases within the clinical safety database which could be
suggestive of POTS

The MAH has performed the following queries of the integrated clinical safety database to identify any
other potential additional cases of POTS among subjects who received the 9vHPV vaccine. The
approach outlined below is based on recent feedback from the PRAC in March, 2014 and from the
Danish Health Authority regarding identification of possible POTS cases in the GARDASIL post-
marketing database. Therefore, the outline below is the same as that used to search the MAH post-
marketing database for GARDASIL. The following queries were run on the integrated safety data set
of subjects who received the 9vHPV vaccine:

1. Search for preferred term of postural orthostatic tachycardia syndrome.


2. Search for preferred terms orthostatic hypotension or dizziness postural.
3. Search for a combination of less specific symptoms (by the preferred term) as stated
below:

Query #1: Search for preferred term of POTS

Result: Three cases were identified:

Case #1 One case of POTS was identified in a female subject ( ) in Protocol


V503-002 approximately 24 days post-dose 1. The basis of the diagnosis has not been reported:
information is limited since the event was reported as new medical history (the investigator did
not consider it a serious adverse event). The subject received all 3 doses of 9vHPV vaccine and
completed the base study at Month 12. Follow-up during the study included collection of new medical
conditions at each study visit. There were no additional symptoms reported in the study database that
suggested that this condition was recurrent or chronic. The absence of recurrent episodes is not
suggestive of POTS. A narrative is provided below.

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Protocol V503-002
White female from Chile with no prior medical history received her first
dose of 9vHPV vaccine on 12-Mar-2010. The subject reported no adverse events within 15 days
following the first dose of vaccine. At the next visit (11-Jun-2010), the subject reported new
medical conditions of syncope and postural orthostatic tachycardia syndrome (POTS); both
with onset dates of 05-Apr-2010. The subject went on to receive her second and third dose of
9vHPV vaccine on 11-Jun-2010 and 08-Oct-2010, respectively. No new medical conditions and
no symptoms related to POTS were reported as adverse events following the second and third
vaccinations. The subject completed the study at Month 12.

Case #2 One case of POTS was identified in a female subject ( ) randomized to


9vHPV vaccine in Protocol V503-001 approximately 1389 days post-dose 3. The diagnosis appears
based on a rigorous evaluation. Detailed information about this case is available below.

Protocol V503-001

White female from Denmark ( ) with a medical history of migraines


at Day 1 received her first, second and third dose of 9vHPV vaccine on 06-Jul-2009, 02-Sep-2009 and
12-Jan-2010, respectively, in the V503-001 study. The subject had her last study visit on 10-Oct-
2013. On 01-Nov-2013 (1389 days post-dose 3), the subject was diagnosed with postural
orthostatic tachycardia syndrome (POTS). On 04-Oct-2013, the general practitioner referred the
subject to the syncope unit of the Frederiksberg Hospital for symptoms of syncope, dizziness,
nausea, headache, tired, low muscle strength and low sensitivity in left side arm and leg
(based on physical examination by a hospital physician). The investigator noted in the report
that this referral took place after a media campaign about possible side effects of HPV vaccination. On
01-Nov-2013, a head-up tilt test was performed as part of the diagnostic work-up for autonomic
dysfunction. The subject was diagnosed with non-progressive POTS disease on the basis of her clinical
symptoms, an abnormal tilt test (heart rate increased from 52/min to 83/min despite treatment with
60 mg propranolol b.i.d), normal heart rate variability (showing normal function of the
parasympathetic nervous system), and a positive COMPASS-31 score (standardized questionnaire on
autonomic dysfunction developed by the Mayo Clinic). Having already completed the study, the
subject did not report this adverse event to the investigator at this time. The syncope unit of the
Frederiksberg Hospital reported this condition to the Danish Health Authority in November 2013. The
Danish Health Authority subsequently reported this event to site. The site reported the event of POTS
in the V503-001 clinical database in November, 2013. The onset date of the POTS was reported as 01-
Nov-2013. Upon further follow-up, it was learned that the subject had a history of severe
dizziness and was hospitalized for investigation from 13 to 16-Aug-2013. The patient was
recommended to take 2-3L of water daily and ibuprofen as needed. On 09-Dec-2013, the subject
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reported rotatory dizziness, near fainting attacks, and migraines, and the subject was taking
propranolol hydrochloride and rizatriptan benzoate for migraines. The general practitioner was
contacted by the sub-investigator on 20-Feb-2014. At that time, there was no new additional
information. The subject cancelled her visit with her family doctor that was scheduled for 9-May-
2014. No additional information is expected. The study investigator felt that the event of POTS
was related to study therapy. The rationale for assigning a possible relation between vaccination
and POTS included that a possible relation between HPV vaccination and POTS has been mentioned in
scientific publications. The investigator specifically cited the following two publications: Blitshteyn S.
Eur J Neurol 21:135-9, 2014; Wang XL Proteomics Clin Appl 6:615-25, 2012.

Case #3 The Danish Health Authority reported directly to the SPONSOR a case of POTS in a subject
in the V503-006 study. The reporting occurred after the end of the V503-006 study, and no allocation
number was reported. After additional follow up, it has been recently determined that the information
reported may be related to subject female who was randomized to 9vHPV
vaccine in the V503-006 study. Additional information has been requested.

Protocol V503-006

White female from Denmark with a history of sporadic hypotension received


her first, second, and third dose of 9vHPV vaccine on 26-Aug-2010, 05-Nov-2010, and 21-Mar-
2011, respectively. This subject had received 3 doses of GARDASIL in 2007, which was required
for participation in the study. Following each vaccination of 9vHPV vaccine within the study, injection
site reactions were reported. In addition, after the second vaccination, the subject reported
adverse events of headache and vomiting of severe intensity which lasted 1 day and were
considered not related to vaccine. New medical history of flu was reported at the Month 6 visit.
The subject completed the study at Month 7 on 27-Apr-2011. On 21-Oct-2013, the Sponsor received
a report from the Danish Health and Medicines Authority indicating a subject who participated in the
V503-006 study had experienced postural orthostatic tachycardia syndrome. According to the
report, the reporting health professional (not a study investigator) saw the subject for a tilt test in
2012 and diagnosed POTS. Per the report, the adverse events improved (no timing provided) and the
subject is recovering from POTS after medical treatment and rehabilitation. According to the report,
the reporting health professional considered the events were related to the 9vHPV vaccine. Since
learning recently the identification of the patient as a subject in the V503-006 study, the Sponsor is
working with the site to update the clinical database and the CIOMS report to include all related
information.

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Query #2: Search for the term orthostatic intolerance or dizziness postural

Result:
Orthostatic intolerance There were no reports of orthostatic intolerance in subjects who
received the 9vHPV vaccine.

Dizziness postural In the second query for dizziness postural there were 2 cases identified in
subjects who received the 9vHPV vaccine. Both cases ( ) occurred in the
V503-001 study, were reports of new medical conditions, occurred outside the 15-day follow up
period for adverse event reporting, and were not considered serious. Both cases were single
reports of postural dizziness. These were acute, one-time events and, therefore are not
suggestive of POTS. The narratives for the 2 cases are provided in Section d. below.

Protocol V503-001
Asian female from Canada with a medical history of chronic sinusitis,
productive cough, collapse of lung, foot fracture, syncope, depression, dysmenorrhea,
menstruation irregular, menorrhagia, and convulsion received her first, second, and third dose of
9vHPV vaccine on 14-May-2009, 09-Jul-2009, and 14-Oct-2009, respectively. The subject
reported the following adverse events following the first vaccination: headache, fatigue, flushing,
nasal congestion, and pelvic pain. No other adverse events were reported following the second
and third doses of vaccine. At the Month 12 visit (22-Apr-2010), the subject reported new
medical conditions of cough, muscle twitching, muscle spasms, dizziness postural, vision
blurred, myalgia, and anxiety. At the following Month 18 visit (09-Dec-2010), the subject
reported that she was diagnosed with essential tremor. According to a comment from the clinical
site entered in the clinical database, the essential tremor syndrome was diagnosed based on
twitching and body jerks. The subject had MRI and EEG, and all clear. She is under a neurologist.
She was told it can be hereditary and her Dad did have the same thing in his 20's. There were
no other events of dizziness postural reported for this subject. The subject continued in the study
until her final visit at Month 48.

Protocol V503-001
Multi-racial female from Canada with a medical history of urinary tract
infection, menorrhagia, lentigo, and back pain received her first, second, and third dose of 9vHPV
vaccine on 20-May-2009, 06-Aug-209, and 28-Jan-2010. The subject reported no adverse events
suggestive of POTS following any vaccination. After Day 1, the subject reported new medical
conditions of hiccups, menstruation irregular, menorrhagia, vulvovaginal pain, cough, respiratory
tract congestion, back pain, spinal x-ray, gastrointestinal sounds abnormal. At the Month 18 visit
(30-Nov-2010), the subject reported new medical condition of dizziness postural. A comment
entered by the clinical site in the clinical database indicates Lightheaded when standing from
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sitting position. It happens several times a wk. (2- 5 times) for about 4 mos. now. Had not seen a
Doctor. Was advised to see one. BP - 112/69 Pulse - 66/min. The subject continued in the study
and reported no other events of dizziness postural. The subject completed the study at Month 48.

Query #3: Search for a combination of less specific symptoms

The following methodology was used:

Step 1: The following groups of preferred terms were specified as representing symptoms of
POTS to be used in the queries:

Group Preferred Term


Group A palpitations OR tremor OR heart rate increased OR tachycardia OR
tachyarrhythmia
Group B dizziness OR dizziness exertional OR dizziness postural
Group C syncope OR presyncope OR loss of consciousness
Group D orthostatic intolerance OR orthostatic heart rate response increased
Group E paraesthesia OR sensory disturbance
Group F hyperhidrosis
Group G memory impairment OR disturbance in attention OR confusional state
OR cognitive disorder
Group H autonomic nervous system imbalance OR urinary retention OR
constipation OR diarrhoea

Step 2: Run the following six queries using the logic displayed below:

Query Query Logic


Query 1 Group A AND Group B AND Group C AND Group D AND Group E AND
Group F AND Group G AND Group H
Query 2 Group A AND Group B AND Group D AND Group F
Query 3 Group A AND Group B AND Group D AND Group E
Query 4 Group C AND Group E AND Group F
Query 5 Group C AND Group D AND Group E AND Group F
Query 6 Group C AND Group D AND Group E AND Group H

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Result: No case was identified.

c. Discussion

Following are the MAH conclusions regarding the case of dysautonomia noted by the Agency and
the three cases reported as POTS in the clinical database:

One case ( ) was reported under the term POTS; however, the basis for the
diagnosis has not been reported, and the condition does not appear to be recurrent or
chronic which does not support the diagnosis of POTS

For the second case ( ), a diagnosis of dysautonomia was made based on tilt
table test results; however, it is not known whether or not the results of the test met
POTS criteria; moreover, the condition does not appear to be recurrent or chronic which is
not in favor of a diagnosis of POTS.

For the third case, the diagnosis of POTS was made based on rigorous criteria; however,
this event occurred approximately 3.8 years post-dose 3, after the subject had completed
her last visit in the study; the subject was followed for safety in the study during that time
and no safety events potentially associated with POTS were reported in the database.
Moreover, there are potential confounders in this reporting: (1) the investigator noted that
this event was reported by the subject following a local media campaign on potential
adverse effect of HPV vaccination; and (2) the AE reporting was prompted by the local
Health Authorities based on reporting from non-study physicians, a procedure that
deviates from the procedures of safety collection described in the protocol.

The fourth case was reported by local Health Authorities with a statement that the subject
participated in Protocol V503-006. The case was reported to the MAH on 21-Oct-2013,
more than 2 years after the completion of the V503-006 study and after the media
campaign mentioned in the third case. Recently, the site confirmed the identity of the
subject as in the V503-006 study. Additional information has been requested.

In addition, a query of the safety database for subjects who had received 9vHPV and reported any
event of orthostatic intolerance or dizziness postural yielded 0 and 2 cases, respectively. The 2
events of dizziness postural appear to be chronic in nature and not reoccurring, and therefore not
suggestive of POTS.

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Finally, a more detailed query of the safety database for presence of 3 or more symptoms typically
associated with POTS did not yield any results.

Overall, this analysis does not suggest a safety risk of 9vHPV vaccination with respect to POTS.

Assessment of the Applicants Response

At the time of the initial evaluation of the application for licensure, there was 1 case ( )
identified as a potential case of POTS (coded PT: dysautonomia). The Applicant was requested to
review the clinical safety database for additional cases potentially suggestive of POTS. The Applicant
has identified 5 additional potential cases:

Three cases coded with the PT of POTS ( , and ). POTS is currently being
reviewed in the PSUR for 4-valent Gardasil as a potential safety signal identified in the post-marketing
period.

In case (Chile), POTS was reported to have occurred 24 days post first vaccination together
with syncope. The basis for the diagnosis of POTS is uncertain, and no recurrence of symptoms was
reported when the subject received dose two and three.

In case (Denmark), the subject was enrolled in Protocol 001 and followed for 54 months.
The diagnosis of POTS was made 1389 days post dose 3 and approximately 3 weeks after her last
study visit in Protocol-001. It is noted that the patient was hospitalised for severe dizziness in August
which was 2 months prior to her last study visit. The study investigator assessed the event as related
to study therapy. The case appears well characterised by the reporting clinician. The period from
vaccination to onset of symptoms is, however, very long. While this does not preclude a causal
relation, it is considered to markedly reduce the probability of a causal relation. The reporting of this
case was apparently stimulated by media attention around safety of HPV vaccination. In case
(Denmark), the subject was enrolled in Protocol -006 and followed for 7 months. She had received 3
prior doses of 4 valent Gardasil 3-4 years earlier. The Applicant received information approximately
2.5 years after the final study visit that the subject had experienced POTS. At the current time, there
is no additional information on the date of onset of symptoms or date of diagnosis. Since learning
recently (October 2013) about the subject, the Applicant is working to update the clinical database
regarding this patient.

Two cases coded with the PT of dizziness postural. One of the cases ( has been under the
care of a neurologist and been diagnosed with hereditary tremor, the other ( had been
encouraged to seek the care of a physician.

At this time, the findings presented do not support a possible causal relation between 9vHPV vaccine
and POTS. While the background incidence may be uncertain spontaneous cases are expected. The
diagnosis is in one of the cases not clear, and no symptoms were reported after she had received the
second or third doses. The two well characterized cases both have a long time to onset, and are
complicated by media attention and stimulated late reporting.

At present, continued monitoring within the PSURs is warranted.

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Conclusion: Issue resolved with continued monitoring in PSURs.

Question 66.

Of concern is the fact that both of the above cases had preferred terms identified in the case
narratives which were not included in the line listing of SAEs (Appendix 2.7.4: 41). Case
contains only the term pulmonary vasculitis and anaemia in the line listing, but the narrative notes
also the term positive ANA. Case contains only the term syncope in the line listing, but the
narrative contains also the terms tachycardia of non-specified cause and dysautonomia. The
Applicant is requested to explain why these additional terms were not included in the line listing.

Summary of the Applicants Response

Data entry and table listings related to these cases are accurate and consistent with the data entry
instructions provided to site personnel and the data analysis and reporting plans. Specifically, Data
Entry Guidelines for Adverse Event reporting, including reporting of serious adverse events (SAE), in
the 9vHPV clinical program stated the following:

An adverse event term is a clinical diagnosis or condition, not a list of symptoms caused by a clinical
condition (e.g. enter flu and not fever, chills, achy) unless there is no specific diagnosis made.

This approach is consistent with the adverse events reporting guidelines generally used by Merck. As
stated in Mercks electronic Case Report Form (eCRF) Entry Guidelines Template, If both a specific
diagnosis and its characteristic signs and symptoms are reported, select a term for the diagnosis and
not for the signs and symptoms associated with the diagnosis.

This approach is also consistent with guidelines from the EMA (Note for Guidance on Clinical Safety
Data Management: Definitions and Standard for Expedited Reporting [CPMP/ICH/377/95]) which state
that In addition to a description of the reported signs and symptoms, whenever possible, attempts
should be made to establish a specific diagnosis for the reaction.

In summary, for reporting of adverse events (including serious events), the investigator determines
what condition is reported as an AE/SAE and what are symptoms of the SAE. Related symptoms or
conditions are typically reported under one SAE so that all pertinent information is captured together
and also to reduce redundancies in reporting. In addition, all the related information is extensively
described in full narratives for each and every SAE.

Assessment of the Applicants Response

The Applicant has reviewed the guidelines for reporting of adverse events from both the company as
well as the EMA. However, in case syncope and tachycardia would preferably be regarded as
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signs while dysautonomia would preferably be regarded as a diagnosis and therefore should have
been preferentially reported over the other two terms. This does not, however, substantially influence
the clinical assessment of this case.

Conclusion: Issue resolved.

Question 67.

There were 2 subjects in the clinical safety database who have received a diagnosis of leukemia, case
(acute lymphoblastic leukemia) and case (acute promyelocytic leukemia). It is
understood that these are different types of leukemias in different age groups; however the Applicant
is requested to review the events of leukemia in the clinical trial programs for both quadrivalent and
9v HPV, to discuss if there is a potential biological mechanism between leukemia and HPV vaccination,
and to discuss the need for post-marketing surveillance for leukemia.

Summary of the Applicants Response

This response is comprised of 4 parts: (1) A review of the events of leukemia in the 9vHPV vaccine
clinical program; (2) A review of the events of leukemia following qHPV vaccination; (3) A discussion
of potential mechanism between leukemia and HPV vaccination; and (4) A discussion about the need
for post-marketing surveillance for leukemia. Narratives for the events of leukemia are provided at the
end of the response. Based on available evidence, the MAH concludes that a link between
9vHPV vaccination and leukemia is unlikely and no post-marketing surveillance is required.

The question from the Agency refers to 2 events of leukemia that were reported in the Initial
Application. Additional leukemia events that were reported after the Initial Application in additional
follow-up periods of the V503-001 and V503-002 studies are also summarized in this response. These
events are reported in the V503-001 End-of-Study Report and the V503-002-10 Statistical Report.

1. Events of leukemia in the 9vHPV vaccine clinical program

A total of 5 events of leukemia were reported in the 9vHPV vaccine program, including the 2
events identified in the question from the Agency, and 3 additional events that are not
reported in the original marketing application. These 3 additional events are reported in the
V503-001-03 End of Study Report or the V503-002-10 Statistical Report.

A listing and brief summary of the 5 reported leukemia cases is provided in Table 10. Case narratives
follow. Three events were reported in the V503-001 and 2 events were reported in the V503-002
study. No leukemia cases were reported in the V503-005, -006, -007, and -009 studies. These 5

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cases appear as sporadic cases since no apparent patterns relating to type of leukemia, age
at onset leukemia, race, or vaccination group are discernible.

Table 10

Listing of Cases of Acute Leukemia


(V503 P001 and P002 Studies)

Vaccine Allocation Age at Time of Age at


group Number Country Race Diagnosis Enrollment Onset Diagnosis
Protocol V503-001
9vHPV Colombia Multi- Acute 1285 days
racial promyelocytic post-dose 3
leukemia
9vHPV Colombia Multi- Acute 27 days
racial lymphoblastic post-dose 3
leukemia
qHPV Canada White Acute 1279 days
lymphocytic post-dose 3
leukemia
Protocol V503-002
9vHPV Colombia Multi- Acute 482 days
racial leukemia post-dose 3
9vHPV United White Acute myeloid 705 days
States leukemia post-dose 3

Narratives of the leukemia events reported in the 9vHPV vaccine clinical program

Protocol V503-001

multi-racial female from Colombia with a medical history of


tonsillitis at Day 1 received her first, second and third dose of 9vHPV vaccine on 17-Apr-2009,
27-Jun-2009 and 20-Oct-2009, respectively, in the V503-001 study. Starting on 26-Apr-2013
(1285 days post-dose 3), the subject presented with progressive gingivorrhagia and
headache. She was hospitalized on 02-May-2013. Blood cell examination was suggestive of
leukemia. Bone marrow biopsy showed acute promyelocytic leukemia. Evolution under
treatment (AIDA-PHETEMA scheme started on 04-May-2013) was not favorable. Subject
presented multiple hemorrhages, tumor lysis syndrome, pneumonia, and hydric overload. She

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died on 15-May-2013 of multiple organ failure and sepsis. Medical records were not made
available to the investigator. The investigator felt that the acute promyelocytic
leukemia was not related to the 9vHPV vaccine.

White female from Canada enrolled in the study with a history of


eczema, oral herpes, environmental allergies, and bladder infection. She received her first,
second, and third dose of qHPV vaccine on 05-Jun-2009, 19-Aug-2009, and 04-Dec-2009. In
2013, while at the Month 48 visit (29-Jul-2013), the subject reported a new medical condition
of acute lymphocytic leukemia. Per comments entered in the database, the acute
lymphoblastic leukemia was diagnosed on 04-Jun-2013 (1279 days post-dose 3). The
subject started chemotherapy on 05-Jun-2013 (Dana Farber Protocol) Q7 days approximately
two years. Doxorubicin Q3 weeks (start date not available) and Vincristine Q2 weeks (start
date unknown). Both were ongoing at the time of the Month 48 visit. The subject had no
additional study visits and completed the study. The subject is eligible to participate in the
extension study to receive 3 doses of 9vHPV vaccine which has just recently begun enrolling in
July, 2014.

Multi-racial female from Colombia with a history of cold sore


and flu received three doses of 9vHPV vaccine (1st dose 22-JUL-2009, 2nd dose 01-SEP-2009,
3rd dose 22-DEC-2009). The subjects father informed the site that she had been diagnosed
with leukemia. According to the subjects mother, the subject experienced increasing myalgia
and polyarthralgia in early December 2009 (approximately 90 days post-dose 2). She
visited the emergency room, was treated with dypirone, but had no relief. She was
hospitalized on 11-JAN-2010 with a diagnosis of myeloproliferative syndrome. Myelogram on
17-JAN-2010 (27 days post-dose 3) came back with a result of acute lymphoblastic leukemia
(ALL). There was no metastasis to the central nervous system (CNS). Chemotherapy
(Doxorubicin, Vincristine, Prednisone) was started on 18-JAN-2010. The subject was
hospitalized for 28 days and was discharged on 10-FEB-2010 with a diagnosis of common type
acute B cell lymphoblastic leukemia. Hemograms in March 2010 and April 2010 were normal
with no blasts. Myelogram and lumbar puncture on 10-APR-2011 were normal. White blood
cell and platelet counts were normal, without blasts. The subject continued receiving
ambulatory chemotherapy and had gone back to school. As of 01-JUL-2010 she was
asymptomatic and in very good condition. Lumbar puncture was performed in Oct-2010. CSF
analysis was performed with cytometry, confirming leukemic infiltration. The subject was
hospitalized from 22-OCT-2010 to 05-NOV- 2010, due to meningeal infiltrationby ALL. This
event was considered a CNS relapse. On 22-OCT-2010 the subject had intermittent mild
headache of increasing intensity (especially with neck or trunk movements), together with
vomiting for 24 hours. Intrathecal chemo therapy was initiated. Analysis was performed 48
hours after initiation of therapy which showed no leukemic cells in the CSF. She was
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discharged and was to continue with radiotherapy (1.8 Gray, daily, starting 12-NOV-2010) and
chemotherapy. Chemotherapy was discontinued on 11-JAN-2011. Myelogram and lumbar
puncture on 10-APR-2011 came back normal. The subject was seen for study visit 7 on 19-
APR-2011. Myelogram on 03-MAY-2011 was normal as well. On 14-SEP-2011 she was stable
and undergoing chemotherapy. Her medical condition had not changed. Information was
received from the subject's mother, and as of 06-DEC-2011 the subject was hospitalized for
worsening of ALL. Chemotherapy for ALL relapse was started on 02-NOV-2011. She had
anemia and thrombocytopenia and was to receive a blood transfusion. She was discharged
from the hospital on 04-NOV-2011. She was hospitalized again on 11-NOV-2011 for
neutropenic colitis. The subject had a relapse of ALL and chemotherapy was started on 02-
DEC-2011. She had anemia and thrombocytopenia and was to receive a blood transfusion.
She received chemotherapy on 06-DEC-2011 and was discharged on 14-DEC-2011. As of 03-
JAN-2012, she was stable and receiving chemotherapy until a bone marrow transplant could
be performed. On 20-JAN-2012, she was hospitalized to receive chemotherapy. On 17-FEB-
2012, she was stable, discharged at home, waiting for a bone marrow transplant. On 09-MAR-
2012, a new relapse at the CNS was reported. On 03-APR-2012, she was hospitalized in stable
condition. On 04-MAY-2012, she was hospitalized with flu symptoms. A new relapse was
diagnosed on 22-MAY-2012. The family reported that the subject died on 28-MAY-2012. No
autopsy was performed. The reporting investigator felt that acute lymphoblastic leukemia and
meningeal infiltration by acute lymphoblastic leukemia were not related to 9vHPV vaccine.

Protocol V503-002

White female from United States with a medical history of eye


infections and otitis media received her first, second, and third dose of 9vHPV vaccine on 01-
Jan-2010, 29-Mar-2010 and 11-Jun-2010, respectively in the V503-002 study. In 2013, while
at the Month 36 visit (01-Apr-2013), the subject reported having been diagnosed with a new
medical condition of acute myeloid leukemia in May 2012 (approximately 705 days post-
dose 3). The subject completed the first extension study (V503-002-10) and has not entered
into the second extension study (V503-002-20). No additional information is known about the
condition or treatment of acute myeloid leukemia.

multi-racial female from Colombia with no prior medical history


received her first, second and third dose of 9vHPV vaccine on 30-Nov-2009, 29-Jan-2010 and
11-Jun-2010, respectively, in the V503-002 study. On 05-Oct-2011 (482 days post-dose 3),
the subject was diagnosed with acute leukemia. The subject was hospitalized twice for IV
chemotherapy. The second round of chemotherapy was initiated on 15-Dec-2011. Starting on
19-Dec-2011 (557 days post-dose 3), subject presented with fever, cervical lymph node
enlargement, sore throat, arthralgia, and myalgia. Blood culture was positive (bacteria type
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has not been reported). The subject died of sepsis on 22-Dec-2011. The investigator felt that
the sepsis was not related to the 9vHPV vaccine.

2. Events of leukemia in the quadrivalent HPV (qHPV) vaccine program

2.1 qHPV vaccine clinical program

In the qHPV vaccine clinical program, 1 case of leukemia was identified:


1 case of acute lymphocytic leukemia reported in the V501-019 study in the placebo group in
an Asian woman, at first vaccination.

2.2 Post-marketing reports with qHPV vaccination

Methods To identify postmarketing reports of leukemia for the qHPV vaccine, an aggregate
analysis tool was used to identify medically confirmed AE reports received from the marketed
environment temporally associated with qHPV vaccine as suspect therapy that involved events of
leukemia cumulative through 05-Aug-2014. The relevant leukemia terms that were in the Company
safety data base are as follows: Acute leukaemia, Acute lymphocytic leukaemia, Acute myeloid
leukaemia, Acute promyelocytic leukaemia, B-cell type acute leukaemia, Chronic myeloid leukaemia,
Leukaemia. The 19 cases that met these criteria are presented in Fel! Hittar inte referensklla.
which can be found at the end of this response.

Summary of the findings In summary, there are 19 reports from 01-Jun-2006 to August 5, 2014.
By country of report, 9 are from the United States, 5 are from France and one each from Colombia,
Germany, Netherlands, New Zealand and Portugal. Age at onset was reported in 18 cases; 11
occurred in persons under 19 years of age and 7 in persons above 19 years of age. The most common
reported AE was acute lymphocytic leukemia and acute myeloid leukemia with 6 reports each,
leukemia alone with 4 reports, and one report each of B-cell type acute leukemia, chronic myeloid
leukemia and acute promyelocytic leukemia. Time to onset was available for 18 cases; 14 cases
occurred less than 180 days after vaccination and 4 occurred more than 180 days after exposure to
the last dose. By dose, 3 occurred after the first dose, 7 after the second dose and 5 after the third
dose (for 4 cases, this information was unknown). In conclusion, based on postmarketing reports with
qHPV, there is no evidence of an association between vaccine exposure and the outcomes described.
The reporting rate after approximately 165 million doses administered is one report for every 9 million
doses administered up to 31 May 2014.

3. Discussion of a potential mechanism between leukemia and HPV vaccination


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Leukemia is thought to result from mutations in the DNA. A number of genetic and environmental risk
factors have been identified including carcinogenic substances (e.g., benzene, toluene, formaldehyde,
some petrochemicals, alkylating chemotherapy agents), artificial ionizing radiation, viruses (e.g.,
human T-lymphotropic virus), chromosomal abnormalities (e.g., Down syndrome, Fanconi anemia),
genetic predisposition (e.g., twin studies, family history). Other risk factors are suspected such as
infections, exposure to pesticides, low frequency magnetic fields, hair dyes.

Based on a review of available information, the following comments can be made regarding the
question of a potential link between 9vHPV vaccination and leukemia events:

The 9vHPV vaccine is based on recombinant proteins (HPV L1 virus-like particles [or VLP])
adsorbed on an aluminum adjuvant (amorphous aluminum hydroxyphosphate sulfate [or
AAHS], an adjuvant that is used in a number of widely used licensed vaccines such as
HBvaxPRO and GARDASIL) and other excipients (sodium chloride, L-histidine, polysorbate
80, sodium borate), as well as trace amounts of yeast proteins. None of these vaccine
components are known or suspected as carcinogenic substances. The vaccine does not contain
live HPV.

Based on extensive experience with qHPV vaccine (including clinical studies and post-
marketing surveillance), leukemia has not been identified as a safety risk. As noted, (1) in
clinical studies, no cases of leukemia were identified in subjects who received qHPV vaccine;
and (2) no evidence of association between qHPV vaccination and leukemia events was found
based on post-marketing reports. Since 9vHPV vaccine is made based on the same
manufacturing process as qHPV vaccine, it is reasonable to extend these conclusions to the
9vHPV vaccine

Vaccination in general is not known to increase the risk of leukemia. A study conducted in
2003 and 2004 concluded that there was no evidence of a role of vaccination in the etiology of
childhood leukemia [1].

For these reasons, vaccination with 9vHPV vaccine is unlikely to be a risk factor for leukemia.

4. Discussion of the need for post-marketing surveillance for leukemia

The leukemia cases reported in the 9vHPV vaccine clinical program appear as sporadic cases. Based
on current scientific knowledge, no mechanism linking HPV vaccination with leukemia is known or
suspected.
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Events of leukemia following 9vHPV vaccination will continue to be monitored as follows:

Two long term follow-up studies are ongoing to assess 9vHPV vaccine long term
immunogenicity, safety and effectiveness, including V503-021 (a passive surveillance study of
subjects from Nordic countries who were enrolled in Protocol V503-001), and V503-002-20, an
extension of Protocol V503-002. Health outcomes including cancers will be collected in
Protocol V503-021. Incident conditions of immunosuppressive disorders will be collected in
Protocol V503-002-20 (per protocol, leukemia is solicited). Therefore, incident cases of
leukemia, should they occur, will continue to be documented in these 2 studies.

Events of leukemia following 9vHPV vaccine administration will be documented and reported
based on post-marketing pharmacovigilance (similar to what is currently done for the qHPV
vaccine).

Based on the above considerations, additional post-marketing surveillance for leukemias is not
warranted. Reports of leukemia would all be considered serious and will be closely monitored as part
of routine pharmacovigilance practices.

Reference

[1] Mallol-Mesnard N, Menegaux F, Auvrignon A et al. Vaccination and the risk of childhood leukemia:
the ESCALE study (SFCE). Int J Epidemiol 36:110-116, 2007

Assessment of the Applicants Response

At the time of the initial evaluation of the application for licensure, there were 2 reports cases of
leukemia. In this response, it is reported that there were 3 additional cases that were not reported in
the original marketing application. Therefore, there have been a total of 5 cases (4 with 9vHPV and 1
with qHPV) in a clinical safety database with 13,360 exposed to 9vHPV.

Three cases occurred in protocol -001 which enrolled a total of approximately 13,380 subjects, 7106
of which received 9vHPV and 7109 of which received qHPV. The follow-up time was planned for 54
months. Two cases occurred in the 9vHPV group, one diagnosed day 1285 after dose 3 and another
day 90 after dose 2. One case occurred in the qHPV group, diagnosed day 1279 after dose 3. Ages of
these cases were and

Two cases occurred in protocol-002 which enrolled a total of 2966 subjects, all of which received
9vHPV and were followed for 36 months. Both cases occurred in females, one diagnosed day 705 post
dose 3 and the other day 482 post dose 3. Ages of these cases were and years.

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Taken together, the number of observed cases in the study populations could be greater than would
be expected.

We have a total of 3 cases of leukemia in subjects younger than the age of 19 years who received
9vHPV (0 cases in the qHPV group within this age range). The denominator of these study
populations is at most roughly 10,000 subjects, and likely less, as only a fraction of the total
population from study -001 was below the age of 20.

It is acknowledged that the time to onset in 4/5 cases is prolonged (482-1285 days); leukemia may
have a prolonged latent phase prior to clinical manifestation of symptoms.

It is agreed that data from the post-marketing experience with qHPV do not show evidence of a signal
with leukemia. However, the potential for a prolonged latency prior to presentation coupled with the
underreporting inherent in passive surveillance systems, this might not be unexpected.

Regarding the biological plausibility, current hypotheses in the etiology of childhood leukemia suggest
a role for immune development and response to infection. Although a specific infectious agent has yet
to be implicated, there have been multiple reports that generally show that infant vaccinations may
reduce the risk of subsequent childhood leukaemia. However, these studies have been
limited to vaccinations received by infants and young children in routine immunisation
programs. There appears to be no report involving older children /adolescents and human
papilloma virus vaccination.

The Applicant is requested to present and discuss the observed versus expected numbers of
leukemia, taking into account the different geographical regions included i n the trial, in
subjects aged less than 20 years in the clinical trial program. Relevant age- and region-
specific estimates of crude background incidence for the source populations in the clinical
trial program should be provided. The Applicant should also discuss the need for inclusion of
this potential safety concern into the RMP given that the proposal in the response to this
question to follow up leukemia in both the long-term follow-up studies and post-marketing
safety database.

Conclusion : Issue not resolved.

Question 68.

Approximately 51.9% of subjects reported at least one new medical condition. The most commonly
reported new medical conditions were vaginal infections (14.7%), nasopharyngitis (6.1%), and
influenza (5.4%). However, the Applicant has discussed only those new medical conditions which
occurred with an incidence of > 1%. The conditions of greatest concern which are likely to be
detected as new medical history probably will have an incidence of < 1% given that they occur more
rarely at baseline (for example, multiple sclerosis, narcolepsy). Furthermore, we are particularly
interested in the age group 9-15 years as this population is the main target for vaccination programs.
The Applicant is requested to supply this information.

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Summary of the Applicants Response

Analyses of new medical history conditions (incidence >0%) are presented in each CSR. Additionally,
Subject New Medical History Conditions with an incidence of >0% in the two studies that were
controlled with qHPV vaccine, V503-001 and V503-009/GDS01C, are provided in the study CSRs. As
requested by the Agency, integrated reports from all studies in the 9vHPV vaccine program of new
medical conditions for subjects who received 9vHPV vaccine with incidence >0% for subjects 16 to 26
years old and subjects 9 to 15 years old are provided as attachments to this response.

Appendix Q68A displays Subject New Medical History Conditions (Incidence >0% in One or
More Vaccination Groups) Subjects 9 to 15 Years of Age at Enrollment Who Received 9vHPV
Vaccine (Protocols 002, 005, 006, 007, and 009/GDS01C) (Post Day 1).

Appendix Q68B displays Subject New Medical History Conditions (Incidence >0% in One or
More Vaccination Groups) Females Subjects 16 to 26 Years of Age at Enrollment Who Received
9vHPV Vaccine (Protocols 001, 002, and 006) (Post Day 1).

The following comments can be made regarding Subject New Medical History Conditions with an
incidence of < 1%:

Overall, the reported conditions were diverse and affected multiple system organ classes.

Across all studies, in subjects who received 9vHPV vaccine, a majority of the New Medical
History Conditions reported were very rare with incidence rates of <0.1%.

Based on data collected in the 2 qHPV vaccine-controlled studies (presented in V503-001 and
V503-009/GDS01C CSRs), the conditions reported and their incidences were similar in the
9vHPV and qHPV vaccine groups, respectively.

In addition to the overall analyses of new medical history conditions provided in each CSR, the
Applicant prospectively analyzed certain rare incident conditions that were considered of potential
interest. Specifically, incident conditions considered potentially indicative of autoimmune disorders
(based on a pre-established list of terms) were analyzed in each CSR (refer to the table below for the
specific CSR sections). The vast majority of these events were reported in Protocol V503-001. As
stated in the V503-001 CSR:

The most frequent conditions were arthralgia, thyroid conditions and celiac disease
The other conditions were rare (frequency <0.1%), no specific pattern or cluster of events was
identified, and the distribution of events was generally comparable between the 9vHPV vaccine
and qHPV vaccine groups
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Findings in the other studies (including all studies that enrolled girls and boys 9 to 15 years of age)
were generally consistent with those in V503-001.

Conclusions

Based on the analyses provided in the original marketing Application and the additional tables
attached to this response, no pattern of rare events was identified that may represent a safety
concern.

Assessment of the Applicants Response

The Applicant was requested to provide data regarding all new medical conditions reported by subjects
enrolled in the clinical trial program. This data was provided in 2 tables included as Appendices 68A
and B.

In subjects between the ages of 9-15 at enrolment who received 9vHPV, 1,031 of 3,498 (29.5%)
reported at least one new medical condition. Of interest is the 1 case of POTS and 1 of autonomic
nervous system imbalance ; also of potential interest are 3 with tachycardia, 21 with pain in
extremity, 1 with orthostatic hypotension, 2 with vertigo and 12 with dizziness.

In subjects between the ages of 16-26 at enrolment who received 9vHPV, 5,411 of 8,053 (67.2%)
reported at least one new medical condition. Of interest is 1 case of Complex regional pain
Syndrome and 4 cases of autonomic nervous system imbalance; also of potential interest are 10 with
tachycardia, 36 with vertigo, 2 with vertigo positional, 41 with pain in extremity, 69 with dizziness, 3
with dizziness postural, 11 with hypoaesthesia, 6 with presyncope, 20 with syncope, and 2 with
orthostatic hypotension.

The review does not reveal any concerns regarding the majority of autoimmune diseases which have
been subject to close monitoring, such as rheumatoid arthritis, multiple sclerosis, etc whose
incidences peak in the ages represented in the study population.

In this study all AEs were reported during the first 15 days following each vaccination, SAEs were
reported during 6 months following each vaccination (i.e one year after the first vaccination for those
who received the full vaccination schedule). At all other time points in the study medical events were
reported as new medical history. This is an unconventional and suboptimal study procedure. This
was also noted in the GCP Inspection report (INTEGRATED INSPECTION REPORT INS/GCP/2014/009):

The reporting procedure for AEs in this trial was complicated by the fact that as per protocol
there was only specific, short, AE reporting periods in connection to each vaccination. In
between, any new symptoms were only to be reported as new medical events The
information available about new medical events was however limited, as only symptoms were
collected and no further medical assessments were made and no outcome was recorded. The
reporting of SAEs was also not required during the full course of the trial.
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As the AE reporting procedure as seen at the inspection sites was in line with the approved
protocol, the inspectors did not comment on it in the inspection reports. It was discussed with
assessors during the course of the inspections, as in the inspectors opinion it is not an optimal
method of collecting safety data, especially not systemic side effects that could appear long
after the vaccinations were given. As previously mentioned, the general advice from the sponsor
to sites regarding performance of physical examinations could also potentially have limited the
reporting of new medical events.

The safety reporting procedure is a systemic issue related to study design and as such not an
inspection finding. However, the inspectors want to bring it to the attention of the assessors.

While it is considered that the required safety data eventually has been made available for
assessment, this feature of the study protocol brings some degree of uncertainty into safety
assessment. The Applicant should discuss the impact of this unconventional and suboptimal method of
reporting adverse events and provide reassurance on the overall completeness and accuracy of safety
data provided in the application.

Conclusion: Issue not resolved.

Question 69.

The proportion of subjects who received 9vHPV with systemic immunosuppressives and with
medications with anti-inflammatory/anti-pyretic properties who reported adverse events was greater
than the proportion of subjects who received 9vHPV alone. This pattern was observed for both the 9-
15 year and 16-26 year age group. Rates of at least one adverse event were as high as 99.5% and
vaccine-related events as high as 96.6%. Given that one might expect a decreased proportion of
adverse events related to the immunogenicity of the vaccine with concomitant use of these types of
medications, the Applicant is requested to discuss/explain the increased adverse event reporting in
subjects using systemic immunosuppressives and medications with anti-inflammatory properties. With
regards to anti-inflammatory medications, it should be clarified whether this medication was
administered prophylactically or therapeutically. The Applicant should also discuss how it intends to
further follow up this potential safety concern in the post-marketing period.

Summary of the Applicants Response

Adverse events occurring Days 1 to 15 following any vaccination were assessed in subjects who
received immunosuppressives Days 1 to 15 following any vaccination and in subjects who received
antipyretics/anti-inflammatories Days 1 to 15 following any vaccination. Based on the analyses
presented in this response, systemic adverse events (AEs) are more frequent in subjects who received
immunosuppressives (mostly corticosteroids) or anti-inflammatories/antipyretics because these

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subjects are taking these medications to treat these events (in other words, AE analyses focusing on
subjects who take these medications select for subjects who have AEs that are treated with these
medications).

Subjects who received 9vHPV vaccine with systemic immunosuppressives:

Use of immunosuppressives or other therapies known to interfere with immune response


excluded subjects from enrollment into studies of the 9vHPV vaccine. In addition, subjects
who were currently receiving steroid therapies or had received such therapy within 2 weeks of
enrollment or had received 2 or more courses of high dose systemic corticosteroids (orally or
parenterally) lasting at least 1 week in duration in the year prior to enrollment were excluded from
entering into the studies. During the study, unless medically necessary, subjects and investigators
were advised to avoid use of immunosuppressives and corticosteroids from 3 days prior to Day 1
through the Month 7 visit. Nonetheless, some subjects did still receive such medications
during this time period.

An assessment of adverse events in subjects who received immunosuppressives is provided in Section


2.7.4.5.2.1.1 of the Original marketing Application. A list of immunosuppressives considered for these
analyses is provided in Appendix 2.7.4: 191 of the Original Marketing Application. Immunosuppressive
therapies were determined based on therapeutic class; all therapies within a therapeutic class were
included. Primarily, the types of immunosuppressive taken were corticosteroids (in most cases taken
at doses that were not immunosuppressive).

Subjects who received immunosuppressives Days 1 to 15 following any vaccination represented only a
small fraction (<3%) of the overall study population:

Young women: 2.7% (213/8027)


Girls and boys: : 2.1% (110/5280)

A comparison of systemic AEs between subjects who received immunosuppressives, Days 1 to 15


following any vaccination (Appendix 2.7.4: 196 and Appendix 2.7.4: 199) and the overall study
population (Appendix 2.7.4: 47 and Appendix 2.7.4: 66) was conducted with the following conclusions:
Systemic AEs frequencies were higher in subjects who received immunosuppressives
compared with the overall study population:
o Young women 16 to 26 years of age: 90.1% vs. 56.2%;
o Girls and boys 9 to 15 years of age: 86.4% vs. 49.8%
The greatest increases (2 fold or greater) in subjects with immunosuppressives vs. overall
population were observed in the following system organ classes (SOC):
o Young women: infections: 36.6% vs. 15.8%; musculoskeletal disorders: 14.1% vs.
7.7%; respiratory disorders: 15.5% vs. 7.7%; skin disorders: 19.7% vs. 3.5%

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o Girls and boys: infections: 47.3% vs. 15.5%; injuries: 11.8% vs. 2.9%;
musculoskeletal disorders: 11.8% vs. 4.7%; respiratory disorders: 29.1% vs. 8.4%;
skin disorders: 11.8% vs. 2.7%

Interpretation of the results In both age groups, infections contributed the most to AEs in subjects
with immunosuppressives. However, the overall AE frequency increase compared to the overall
population cannot be explained by infections only and also involves other SOCs. As noted, the vast
majority of systemic immunosuppressives taken by these subjects are corticosteroids. Corticosteroids
are often used (for their anti-inflammatory properties) in the treatment of the groups of AEs identified
above (i.e., infections, injuries, musculoskeletal, respiratory, and skin disorders). Therefore, the
most straightforward explanation for the increased frequency of these events in the
subgroup receiving immunosuppression is that these subjects are taking corticosteroids to
treat these events. In support of this interpretation, the reasons given by the study
subjects for immunosuppressive use (and provided by the study sites on the concomitant
medication form) included infections, allergies, and skin conditions. Immunosuppressives
were generally received after study vaccinations,consistent with the protocol requirement
that subjects were not to receive immunosuppressives for the 3 days prior to any study
vaccination. Of note, given the relatively small number of subjects who received
immunosuppressives in these studies, results among this subgroup should be interpreted with caution.
Overall, the Applicant considers that the increase in systemic AEs in subjects who received
immunosuppressives Days 1 to 15 following any vaccination is not indicative of a safety concern and
does not warrant specific follow-up in the post-licensure period.

Subjects who received 9vHPV vaccine with medications with anti-inflammatory/antipyretic


properties:

Although there were no protocol-defined restrictions related to use of anti-inflammatory and anti-
pyretic medications, analyses were done for the subset of subjects taking such medications since
these types of medications may mask certain adverse experiences such as pain (e.g., headache,
myalgia, or injection-site pain) or elevated temperatures.

An assessment of adverse events in subjects who received anti-inflammatory and anti-pyretic


medications is provided in Section 2.7.4.5.2.1.2 of the Original marketing Application. A list of
medications with anti-inflammatory/antipyretic properties considered for these analyses is provided in
Appendix 2.7.4: 201 of the Original Marketing Application. These medications were determined based
on therapeutic class; all therapies within a therapeutic class were included.

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Subjects who received anti-inflammatory/antipyretic medications Days 1 to 15 following any
vaccination represented approximately 30% of the overall study population:

Young women: 36.1% (2899/8027)


Girls and boys: : 18.5% (977/5280)

Following this question from the Agency, a comparison of systemic AEs between subjects who received
medications with anti-inflammatory/antipyretic properties Days 1 to 15 following any vaccination
(Appendix 2.7.4: 203 and Appendix 2.7.4: 206) and the overall study population (Appendix 2.7.4: 47
and Appendix 2.7.4: 66) was conducted with the following conclusions:
Systemic AEs frequencies were higher in subjects who received anti-inflammatory/antipyretic
medications compared with the overall study population:
o Young women 16 to 26 years of age: 91.1% vs. 56.2%;
o Girls and boys 9 to 15 years of age: 90.1% vs. 49.8%
The greatest increases (2 fold or greater) in subjects with anti-inflammatory/antipyretic
medications vs. overall population were observed in the following system organ classes (SOC):
o Young women: infections: 29.6% vs. 15.8%; musculoskeletal disorders: 15.0% vs.
7.7%; nervous system disorders: 61.5% vs. 30.3%; respiratory disorders: 13.5% vs.
7.7%
o Girls and boys: gastrointestinal disorders: 24.8% vs. 13.0%; general disorders:
31.0% vs. 17.0%; infections: 32.9% vs. 15.5%; injuries: 6.4% vs. 2.9%;
musculoskeletal disorders: 10.7% vs. 4.7%; nervous system disorders: 49.0% vs.
22.8%; respiratory disorders: 18.7% vs. 8.4%

Interpretation of the results In young women, nervous system disorders and infections contributed
the most to AEs in subjects with anti-inflammatories/antipyretics. Among nervous system disorders,
the frequency of the AE of headache is 56.6% in subjects with anti-inflammatories/antipyretics
(compared to 26.7% in the overall study population). Thus, the overall AE frequency increase
compared to the overall population is largely explained by the increase in frequency of the AE of
headache.

In girls and boys, nervous system disorders, infections, and general disorders contributed the most to
AEs in subjects with anti-inflammatories/antipyretics. Among nervous system disorders, the frequency
of the AE of headache is 46.2% in subjects with anti-inflammatories/antipyretics (compared to 20.6%
in the overall study population). Among general disorders, the frequency of the AE of pyrexia is
24.2% in subjects with anti-inflammatories/antipyretics (compared to 12.4% in the overall study
population). Thus, the overall AE frequency increase compared to the overall population is
predominantly explained by the increase in frequency of the AEs of headache and pyrexia.

Anti-inflammatories/antipyretics are often used in the treatment of the groups of AEs identified above
(i.e., infections, injuries, pyrexia, headache, gastrointestinal, musculoskeletal, and respiratory
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disorders). These AEs are not evocative of an increase in adverse reaction to anti-
inflammatories/antipyretics. In particular, there is no increase in frequency of dyspepsia or more
severe gastrointestinal disorders such as gastrointestinal bleeding, alteration in renal function, or
other liver disorders that might be indicative of side effects related to anti-inflammatory and
antipyretic medications rather than study vaccine. Therefore, the most straightforward
explanation is that these events are more frequent in subjects who received anti-
inflammatories/antipyretics because these subjects are taking these medications to treat
these events. This interpretation is further supported by the reason indicated for use of anti-
inflammatories/antipyretics by study subjects. More than half of subjects taking anti-
inflammatories/antipyretics indicated the reason for taking such medications as headache. In addition
to headache as the most common reason for taking anti-inflammatories/antipyretics, other common
reasons for use included common cold, cold-like symptoms, fever, flu, upper respiratory tract
infections, and dysmenorrhea and menstrual cramps. There was no recommendation in the study
protocols to administer anti-inflammatories/antipyretics prior to any study vaccination because this
could confound safety results. Thus, it is likely that anti-inflammatories/antipyretics
administered because of post-vaccination AEs were received after study vaccinations.
Overall, the Applicant considers that the increase in systemic AEs in subjects who received anti-
inflammatories/antipyretics Days 1 to 15 following any vaccination is not indicative of a safety concern
and does not warrant specific follow-up in the post-licensure period.

Assessment of the Applicants Response

The Applicant has reviewed the data on both immunosuppressive use as well as anti-
inflammatory/anti-pyretic use in the clinical trial program.

Regarding immunosuppressive therapy, the Applicant notes that use of immunosuppressive drugs was
prohibited for 3 days prior to receipt of vaccination. It is also reported that the most common uses for
these agents (primarily corticosteroids) were for infections, allergies and skin. The Applicant explains
that it is likely that AEs reported for these agents are related to the underlying conditions which they
are intended to treat, and that reports are most commonly post vaccination given that the use of
immunosuppressives were not permitted prior to vaccination.

Regarding anti-inflammatory/anti-pyretic therapy, the Applicant notes that the use of these products
was primarily secondary to the treatment of the common adverse events reported after vaccination
(headaches and pyrexia).

The Applicant therefore does not consider the increase in systemic AEs observed for subjects receiving
either immunosuppressive or anti-inflammatory/anti-pyretic therapy after vaccination to be a safety
concern.

The conclusions of the Applicant are endorsed.

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Conclusion: Issue resolved.

Question 70.

There was a higher proportion of spontaneous abortions in subjects with an estimated date of
conception within 30 days of vaccination with 9vHPV (27.8%) compared to subjects with an estimated
date of conception not within 30 days (10.9%). The Applicant should discuss the significance of this
observation and if comparable results were noted in the qHPV clinical trial program.

Summary of the Applicants Response

This response includes the following: 1) a review of the available clinical information for each
pregnancy with estimated date of conception (EDCn) within 30 days before or after any vaccination
with an outcome of spontaneous abortion (SAB) in the 9vHPV clinical program, 2) an analysis of SAB
rates in the 9vHPV vaccine and qHPV vaccine clinical programs and 3) an assessment of the estimated
rates of SAB in the 9vHPV vaccine program relative to published rates in the general population.

Based on the information summarized in this response document, the Applicant concludes that:
a) in the 9vHPV vaccine program, pregnancies with EDCn within 30 days of any vaccination were
identified based on sensitive human chorionic gonadotropin (hCG) testing,
b) the SAB rates observed in the 9vHPV vaccine clinical program among pregnancies with EDCn
within 30 days of any vaccination with 9vHPV vaccine are consistent with rates expected for
pregnancies detected by sensitive hCG testing,
c) the SAB rates observed in the 9vHPV vaccine clinical program among pregnancies with EDCn
not within 30 days of any vaccination are consistent with reported SAB rates for clinically
recognized pregnancies (i.e., subject suspects she is pregnant based on late menstrual period
or symptoms of early pregnancy),
d) the SAB rates observed in the 9vHPV vaccine clinical program among pregnancies with EDCn
within 30 days of any vaccination with 9vHPV vaccine are consistent with rates in the placebo
group in the qHPV vaccine clinical program and
e) the extensive clinical and post-marketing experience with the qHPV vaccine (including a post-
licensure pregnancy registry) showed no association between qHPV vaccine administration and
adverse pregnancy outcomes. The Applicant acknowledges there are 5 new HPV types in V503,
as such, there will be inadvertent exposures and therefore a pregnancy registry similar to that
for GARDASIL is proposed in the V503 Risk Management Plan.

Analysis of Individual SAB Cases in the 9vHPV Vaccine Program Investigation of Potential
Biologic Explanations for SAB Outcomes

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The available clinical data for each of the SAB reported in the 9vHPV vaccine and qHPV vaccine groups
where the EDCn occurred within 30 days before or after vaccination are briefly summarized in Table
11. Table 11 provides a line listing of the last menstrual period (LMP) reported by the subject, the
prior vaccination date and dose, date of termination, gestational age at termination determined by the
site, and other related information for each case. The intent is to assess how pregnancies were
identified, whether biologic explanations of SAB outcomes can be identified, and if there are
confounders. Based on Table 11, the following observations can be made:

Pregnancy detection
All of the pregnancies (except one: ) were identified based on human chorionic gonadotropin
(hCG) testing. Only 3 subjects had ultrasound examination ( , , , all three
in the qHPV vaccine group). In the general population, studies have shown that the proportions of
pregnancies that result in spontaneous abortions depend on the manner in which pregnancy is
detected. Studies of healthy women that evaluated pregnancy using sensitive hCG testing suggest
that in early pregnancy, spontaneous abortion rates are up to approximately 33% [1-4]. This rate
applies for the analyses presented here since pregnancies with outcome of SAB were detected based
on hCG testing.

Potential biologic explanations for SAB outcomes


a. Most events occurred after vaccination 1 which suggests no relation between SAB and magnitude of
antibody response to vaccination.
b. Most subjects did not report an adverse experience (AE) following the vaccination temporally
associated with the fetal loss. Subjects who experienced AEs had mostly injection-site AEs. There
were few systemic AEs (see Table 11) and no pattern was identified. This suggests no relationship
between AEs occurring post-vaccination and SAB events.
c. Seven (7) of the 24 subjects had a history of spontaneous abortion prior to receiving any
vaccinations and of these subjects, 3 also experienced a subsequent SAB during the course of the
study. Of the 7 subjects, 4 received 9vHPV vaccine and 3 received qHPV vaccine and of the 3
subjects who had subsequent spontaneous abortions, 2 were in the 9vHPV vaccine cohort and 1 in
the qHPV vaccine cohort. Therefore, there was no notable difference in history of spontaneous
abortions between vaccine groups.

Summary
This evaluation of clinical characteristics of the pregnancies with an EDCn within 30 days of
vaccination and with an outcome of SAB did not identify a clustering of SAB events relative to 9vHPV
vaccination, associated systemic AEs, or trends suggesting a risk with subsequent doses. These clinical
findings are consistent with developmental and reproductive preclinical toxicology studies that showed
that administration of the 9vHPV vaccine did not negatively impact pregnancy outcomes, including no

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evidence of vaccine effect on embryonic/fetal viability, fetal weights, and morphology, and no
evidence of post-natal developmental toxicity.

Confounders
Several confounders can be identified, which is not unexpected given this study was not specifically
designed to assess pregnancy outcomes. These confounders are detailed here because they can affect
the interpretation of analyses of SAB outcomes:

a. Approximately 75% of the subjects considered in Table 11 were from countries in Latin
America (shown in the rows shaded in gray in the table) where the reported outcome of
pregnancy may not accurately reflect the true circumstances for the termination of
pregnancies (because elective abortions are generally not legal in Latin America). For instance,
reports suggest that women in Latin America frequently use misoprostol to self-induce
abortion [5-6]. It should be noted that in the V503-001 study, subjects randomized in Latin
American countries represents only approximately 33% of all subjects randomized. Therefore,
in the case of subjects who experienced a SAB where the EDCn was within 30 days of
vaccination, a disproportionate number of cases were reported in subjects in Latin American
countries, which could be a major confounder in analyses of SAB. Most of the subjects from
Latin American sites are in the 9vHPV vaccine group (9vHPV vaccine: 12 subjects, qHPV
vaccine: 6 subjects). Other than a higher number of the cases being reported from subjects in
Latin American countries, there does not seem to be any other distinguishing characteristics
between vaccine groups.

b. The Estimated Date of Conception (EDCn) was determined by the following formula: EDCn =
Date of Last Menstrual Period (LMP) + 14 days. The date of the last menstrual period (LMP) is
reported by the subject based on the subjects recall only after pregnancy is detected.
Therefore, it is understood that this method has limited accuracy and precision. For example,
two (2) subjects in the 9vHPV vaccine subgroup ( , ) could not recall the
exact date of the LMP, only the month and year. For the purposes of calculating the EDCn, an
LMP date of the 15th of the month is assigned. Two other subjects in the 9vHPV group (
), provided unreliable LMP dates according to the study site. All subjects in
the qHPV vaccine subgroup recalled a LMP date, month, and year.

Summary:
Pregnancies were identified using hCG testing.
No biological mechanism associated with SAB outcome was identified.

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Confounders (subjects from Latin American sites, imprecision of LMP dates) were
recognized and they should be taken into consideration when assessing SAB rates in this
subset of subjects.

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Table 11
Summary of Spontaneous Abortions Cases Occurring Within 30 Days of Any Vaccination in the V503-001 Study
Subje Site Countr Vaccin Vaccinatio LMP Date Pregnanc Date of Gestational Pregnanc Subsequ AEs
ct y e n Date y Terminati Age y History ent occurrin
Group (Dose) Confirme on Provided at at Day 1 occurren g with
Prior to d (How) Termination ce of SAB this
SAB vaccinati
on
9vHPV Vaccine Dose 1
14-Nov-
United 18-Oct- Yes (hCG 26-Dec-
9vHPV 2008 (dose 9 weeks 1 birth No None
States 2008 test) 2008
1)
30-Sep-
7-Oct- Yes (hCG 2-Dec-
Canada 9vHPV 2008 (dose 8 weeks 0 No None
2008 test) 2008
1)
Injection
17-Oct-
23-Oct- Yes (hCG 27-Dec- site pain,
Mexico 9vHPV 2008 (dose 9 weeks 1 birth No
2008 test) 2008 bruises
1)
on legs
17-Oct-
11-Oct- Yes (hCG 14-Jan-
Mexico 9vHPV 2008 (dose 10 weeks 0 No No
2008 test) 2008
1)
17-Nov-
17-Nov- Yes (hCG 29-Jan-
Thailand 9vHPV 2008 (dose Unknown 1 birth No No
2008 test) 2009
1)
Korea, 30-Mar- 16-Mar- Yes (hCG 30-Jun-
9vHPV Unknown 0 No No
Republic 2009 (dose 2009 test) 2009

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Subje Site Countr Vaccin Vaccinatio LMP Date Pregnanc Date of Gestational Pregnanc Subsequ AEs
ct y e n Date y Terminati Age y History ent occurrin
Group (Dose) Confirme on Provided at at Day 1 occurren g with
Prior to d (How) Termination ce of SAB this
SAB vaccinati
on
of 1)

25-Apr-
2009
13-Apr-
Colombi (comment Yes (hCG 1-Jun-
9vHPV 2009 (dose 5 weeks 1 birth No No
a from site test) 2009
1)
LMP not
reliable)
19-May-
2009
11-May-
Colombi (comment Yes (hCG 1-Sep-
9vHPV 2009 (dose 6 weeks 1 SAB No No
a from site test) 2009
1)
LMP not
reliable)
22-Aug- Yes (1 in Headache
Denmar UNK-Aug- Yes (hCG UNK-Oct- 1 birth, 1
9vHPV 2009 (dose Unknown May , fatigue,
k 2009 test) 2009 SAB
1) 2010) diarrhea
9vHPV Vaccine Dose 2
Dyspepsi
11-Feb-
27-Jan- Yes (hCG 2-Apr- a,
Peru 9vHPV 2009 (dose Unknown 1 birth No
2009 test) 2009 injection
2)
site

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Subje Site Countr Vaccin Vaccinatio LMP Date Pregnanc Date of Gestational Pregnanc Subsequ AEs
ct y e n Date y Terminati Age y History ent occurrin
Group (Dose) Confirme on Provided at at Day 1 occurren g with
Prior to d (How) Termination ce of SAB this
SAB vaccinati
on
redness,
pain,
numbnes
s,
headache
,
diarrhea,
constipati
on
03-Feb-
Colombi 2-Feb- Yes (hCG 9-Mar-
9vHPV 2010 (dose 6 weeks 1 SAB No No
a 2010 test) 2010
2)
16-Jul-2009 20-Jul- Yes (hCG 22-Aug-
Mexico 9vHPV 3 weeks 0 No No
(dose 2) 2009 test) 2009
25-Nov- Injection
Colombi 7-Dec- 29-Jan-
9vHPV 2009 (dose No Unknown 1 birth No site pain,
a 2009 2010
2) headache
Injection
03-Dec-
17-Dec- Yes (hCG 31-Dec- Yes (1 in site
Mexico 9vHPV 2009 (dose 4 weeks 1 SAB
2009 test) 2009 Mar 2011) redness,
2)
injection

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Subje Site Countr Vaccin Vaccinatio LMP Date Pregnanc Date of Gestational Pregnanc Subsequ AEs
ct y e n Date y Terminati Age y History ent occurrin
Group (Dose) Confirme on Provided at at Day 1 occurren g with
Prior to d (How) Termination ce of SAB this
SAB vaccinati
on
site pain

9vHPV Vaccine Dose 3


24-Sep-
Colombi 4-Oct- Yes (hCG 6-Nov-
9vHPV 2009 (dose Unknown 0 No No
a 2009 test) 2009
3)
Injection
site
07-Nov- swelling,
Colombi 11-Oct- Yes (hCG 12-Nov-
9vHPV 2009 (dose 3 weeks 1 birth No redness,
a 2009 test) 2009
3) pain,
abdomina
l cramps
Injection
14-Jan-
Colombi UNK-Jan- Yes (hCG 9-Apr- site pain,
9vHPV 2010 (dose 9 weeks 0 No
a 2010 test) 2010 swelling,
3)
redness
qHPV Vaccine Dose 1
Injection
07-Mar-
20-Mar- Yes (hCG 1-Jun- site
Chile qHPV 2009 (dose 10 weeks 0 No
2009 test) 2009 redness,
1)
injection

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Subje Site Countr Vaccin Vaccinatio LMP Date Pregnanc Date of Gestational Pregnanc Subsequ AEs
ct y e n Date y Terminati Age y History ent occurrin
Group (Dose) Confirme on Provided at at Day 1 occurren g with
Prior to d (How) Termination ce of SAB this
SAB vaccinati
on
site pain
Injection
22-May- site
Colombi 10-May- Yes (hCG 19-Jun-
qHPV 2009 (dose 5 weeks 0 No swelling,
a 2009 test) 2009
1) pain,
bone pain
qHPV Vaccine Dose 2
3: 1
20-Aug- birth, 1
17-Jul- Yes (hCG
Brazil qHPV 2009 (dose 6-Oct-2009 9 weeks SAB, 1 No No
2009 test)
2) elective
abortion
27-Aug- Injection
Colombi 20-Aug- Yes (hCG
qHPV 2009 (dose 7-Oct-2009 6 weeks 1 birth No site pain,
a 2009 test)
2) headache
qHPV Vaccine Dose 3
17-Sep- 2: 1
Colombi 4-Sep- Yes (hCG 3-Nov-
qHPV 2009 (dose 6 weeks birth, 1 No No
a 2009 test) 2009
3) SAB
Korea, 15-Dec- 30-Nov- Yes (hCG 29-Jan- Yes (1 in Injection
qHPV 4 weeks 1 SAB
Republic 2009 (dose 2009 test) 2010 July 2010) site pain,

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Subje Site Countr Vaccin Vaccinatio LMP Date Pregnanc Date of Gestational Pregnanc Subsequ AEs
ct y e n Date y Terminati Age y History ent occurrin
Group (Dose) Confirme on Provided at at Day 1 occurren g with
Prior to d (How) Termination ce of SAB this
SAB vaccinati
on
of 3) headache
28-Oct-
Colombi 24-Oct- Yes (hCG 15-Dec-
qHPV 2009 (dose 6 weeks 1 birth No fever
a 2009 test) 2009
3)

SAB: spontaneous abortion; hCG: human chorionic gonadotropin


Cases in subjects from Latin American sites are shaded in gray.

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Analysis of SAB Rates in Pregnancies with EDCn within 30 Days Before and After Vaccination
in the 9vHPV Vaccine Program and the qHPV Vaccine Program

Summary of SAB in the 9vHPV vaccine program


SAB rates were calculated as the proportions of spontaneous abortions among pregnancies with a
natural outcome (pregnancies that had as an outcome a live birth or non-elective pregnancy loss [i.e.,
spontaneous abortion or late fetal death]). Results are shown in Table 12 and Table 13. These tables
show the counts of pregnancies with natural outcomes; the counts of such pregnancies that resulted in
SAB; and the counts of SAB as percent of pregnancies with natural outcomes. Table 12 provides SAB
rates for all study sites. Table 13 provides SAB rates for non-Latin American sites.
Table 12

Summary of Spontaneous Abortions Overall Study Population


9vHPV Vaccine qHPV Vaccine
Time of EDC Relative to Time of EDC Relative to
All All
Any Vaccination Any Vaccination
pregnancies pregnancies
30 days >30 days 30 days >30 days
Count (%) Count (%) Count (%) Count (%) Count (%) Count (%)
Live births,
spontaneous
1,022 (100) 62 (100) 960 (100) 988 (100) 55 (100) 933 (100)
abortions, late
fetal deaths
Spontaneous
122 (11.9) 17 (27.4) 105 (10.9) 143 (14.5) 7 (12.7) 136 (14.6)
abortions
Fel! Hittar inte Fel! Hittar inte
Table Appendix Appendix Appendix
Data source referensklla. referensklla.
2.7.4:41 2.7.4:241 2.7.4:242 2.7.4:233

Shown at the end of this response document.


Percent is calculated relative to the count of live births, spontaneous abortions, and late fetal deaths.
EDC = Estimated date of conception.
Table 13

Summary of Spontaneous Abortions Non-Latin American Sites


9vHPV Vaccine qHPV Vaccine
Time of EDC Relative to Any Time of EDC Relative to
All All
Vaccination Any Vaccination
pregnancies pregnancies
30 days >30 days 30 days >30 days
Count
Count (%) Count (%) Count (%) Count (%) Count (%)
(%)
Live births,
spontaneous
618 (100) 27 (100) 591 (100) 601 (100) 31 (100) 570 (100)
abortions, late
fetal deaths
Spontaneous
59 (9.5) 5 (18.5) 54 (9.1) 71 (11.8) 1 (3.2) 70 (12.3)
abortions
Fel! Hittar inte Fel! Hittar inte
Table Appendix Appendix Appendix
Data source referensklla. referensklla.
2.7.4:41 2.7.4:243 2.7.4:244 2.7.4:235

Shown at the end of this response document.


Percent is calculated relative to the count of live births, spontaneous abortions, and late fetal deaths.
EDC = Estimated date of conception.

Conclusions based on results shown in Table 12 and Table 13


The observed rates of SAB in the 9vHPV vaccine group for pregnancies with EDCn within 30 days of
vaccination are within the ranges reported in the general population when sensitive methods to
detect early pregnancies are utilized (i.e., approximately 33% [1-4]). This remains true regardless
of analyzing all sites or non-Latin American sites.
The observed SAB rates in the 9vHPV and qHPV vaccine groups for pregnancies with EDCn not
within 30 days of vaccination are within the ranges reported in the general population among
clinically recognized pregnancies (i.e., subject suspects she is pregnant based on late menstrual
period or symptoms or early pregnancy) (i.e., approximately 15% [7]). This remains true
regardless of analyzing all sites or non-Latin American sites.
Study protocols required the use of hCG screening to detect pregnancies during the vaccination
period. Therefore, the difference in rates between pregnancies with EDCn within 30 days of any
vaccination vs. pregnancies not within 30 days of any vaccination may be due to the use of
sensitive hCG screening during the vaccination period.
The observed rates in the qHPV vaccine group are for pregnancies with EDCn within 30 days of
vaccination are unexpectedly low, likely by chance. In support of this interpretation, a similar

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analysis in the qHPV vaccine clinical program also showed a difference between cohorts that was
likely due to chance (see next paragraph).

Summary of SAB in the qHPV vaccine program


In the qHPV vaccine program, the rates of SAB were consistent with published studies in healthy
women and generally comparable between the 2 groups (qHPV vaccine and placebo) (Table 14 and
Table 15). However, in pregnancies from all study sites with EDCn within 30 days of a vaccination visit,
SAB rates were lower in the qHPV vaccine group than in the placebo group (qHPV vaccine: 20.9%;
placebo: 28.3%). Likewise, in pregnancies from non-Latin American sites, with EDCn within 30 days of
a vaccination visit, SAB rates were lower in the qHPV vaccine group than in the placebo group (qHPV
vaccine: 11.1%; placebo: 21.2%). In analyses considering non-Latin American sites, the observed SAB
rates in the placebo group was consistent with published rates in healthy women, whereas the
observed rates in the qHPV vaccine group were unexpectedly low. These differences are unlikely due to
a vaccine effect and likely reflect a chance observation given the small number of events.

Table 14
Summary of Spontaneous Abortions Gardasil Clinical Program
Overall Study Population

qHPV Vaccine Placebo


Time of EDC Relative to Time of EDC Relative to
All All
Any Vaccination Any Vaccination
pregnancies pregnancies
30 days >30 days 30 days >30 days
Count (%) Count (%) Count (%) Count (%) Count (%) Count (%)
Live births,
spontaneous
700 (100) 91 (100) 604 (100) 694 (100) 92 (100) 599 (100)
abortions, late fetal
deaths
Spontaneous
220 (31.4) 19 (20.9) 198 (32.8) 211 (30.4) 26 (28.3) 183 (30.6)
abortions
Table Appendix Appendix Table Appendix Appendix
Data source
2.7.4:31 2.7.4:186 2.7.4:187 2.7.4:31 2.7.4:186 2.7.4:187

From the GARDASIL Initial Application.


Percent is calculated relative to the count of live births, spontaneous abortions, and late fetal deaths.
EDC = Estimated date of conception.

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Table 15
Summary of Spontaneous Abortions Gardasil Clinical Program
Non-Latin American Sites

qHPV Vaccine Placebo


Time of EDC Relative to Any Time of EDC Relative to
All All
Vaccination Any Vaccination
pregnancies pregnancies
30 days >30 days 30 days >30 days
Count
Count (%) Count (%) Count (%) Count (%) Count (%)
(%)
Live births,
spontaneous
281 (100) 36 (100) 242 (100) 263 (100) 33 (100) 228 (100)
abortions, late fetal
deaths
Spontaneous
77 (27.4) 4 (11.1) 72 (29.8) 66 (25.1) 7 (21.2) 58 (25.4)
abortions
Appendix Appendix Appendix Appendix Appendix Appendix
Data source
2.7.4:180 2.7.4:189 2.7.4:190 2.7.4:180 2.7.4:189 2.7.4:190

From the GARDASIL Initial Application.


Percent is calculated relative to the count of live births, spontaneous abortions, and late fetal deaths.
EDC = Estimated date of conception.

Conclusions based on results shown in Table 14 and Table 15


SAB rates in both vaccine groups are within the ranges reported in the general population when
sensitive methods to detect early pregnancies are utilized. This remains true regardless of analyzing
all sites or non-Latin American sites.
The observed rates of SAB in the placebo group of the qHPV vaccine program are numerically
consistent with observed rates of SAB in the 9vHPV vaccine group in the 9vHPV vaccine program
The observed rates in the qHPV vaccine group in the qHPV vaccine program are unexpectedly low,
likely by chance.

This suggests similarities between observations in the qHPV vaccine and 9vHPV vaccine programs. In
particular, SAB rates in the 9vHPV group in the 9vHPV program and the placebo group in the qHPV
vaccine program are consistent with expected rates.

There are several limitations to these analyses:

Because study protocols required the use of an effective contraception method during the
vaccination period and pregnancy testing prior to any vaccination, only ~1% of subjects
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became pregnant within 30 days of a vaccination. SAB rates among pregnancies inadvertently
exposed to qHPV vaccine are somewhat lower than expected both in the 9vHPV vaccine
program and the qHPV vaccine program, and this appears to be due to random variation
observed among the small numbers of subjects who became pregnant during the vaccination
period of the study.

While comparisons between 2 different vaccine programs should be generally interpreted with
caution, these data may be informative because of similarities between the 2 programs. These
include similar study populations (same age range, same general geographic areas, same
eligibility criteria) and similar criteria for evaluation of pregnancy outcomes, including similar
proportions of pregnancies with EDCn within 30 days of any vaccination (~12% in the qHPV
vaccine program: ~8% in the 9vHPV vaccine program) as shown in the Table 16.

Caution should be exercised in interpreting all above analyses which are conducted post-hoc in
a study that is not designed to assess the impact of the 9vHPV vaccine on pregnancy outcomes.
The rates were calculated based on small number of events as the numerator; and the
denominators were formed out of post-randomization outcomes (i.e., not randomized groups).
Rates from such numbers are not suitable for making definitive conclusions about vaccination
group differences.

Table 16
Numbers of Subjects with Pregnancies reported in the Initial Filings
in the V503 & V501Clinical Programs

V503 Clinical Program V501 Clinical Program

Number of subjects with


2321 1901
pregnancies
Number of subjects with
pregnancies with EDCn 30 180 (7.8%) 226 (11.8%)
days of vaccination
V503 WMA: Appendix 2.7.4:
233, Appendix 2.7.4: 241 and V501 WMA: Table 2.7.4:31,
Data Sources
Tables 37, 38, 39, 40 in this Appendix 2.7.4:186
response

Overall Conclusions
As summarized in the 9vHPV vaccine initial Application, and in this document, findings from the 9vHPV
vaccine program show no evidence that administration of 9vHPV vaccine is associated with adverse
pregnancy outcomes (spontaneous fetal loss, congenital anomalies) as follows:

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1. In all analyses, the SAB rates among pregnancies occurring in the 9vHPV vaccine group were
within ranges observed in published studies in healthy women, as well as within ranges previously
observed in the placebo cohort of the GARDASIL clinical development program.

2. An evaluation of clinical characteristics of the pregnancies with an EDCn within 30 days of


vaccination and with an outcome of SAB did not identify a clustering of SAB events relative to
9vHPV vaccination, associated systemic AEs, or trends suggesting a risk with subsequent doses.

3. Extensive clinical and post-marketing experience with the qHPV vaccine (including a post-licensure
pregnancy registry) showed no association between qHPV vaccine administration and adverse
pregnancy outcomes; these findings are relevant since the 9vHPV vaccine is based on the same
manufacturing process as the qHPV vaccine and the 2 vaccines contain similar components.

a. SAB rates will be further addressed in the V503 pregnancy registry should the 9vHPV
vaccine be licensed (as included in the V503 Risk Management Plan). This pregnancy
registry is intended to be conducted using a similar approach as that for the pregnancy
registry of qHPV vaccine.

4. Administration of the 9vHPV vaccine did not negatively impact pregnancy outcomes in
developmental and reproductive preclinical toxicology studies, including no evidence of vaccine
effect on embryonic/fetal viability, fetal weights, and morphology, and no evidence of post-natal
developmental toxicity.

5. At this point of time, based on all data available, the safety conclusions for 9vHPV vaccine have
not changed from those presented in the original marketing application; pregnancy outcomes with
respect to SAB are consistent with expected published SAB rates and they are within ranges
previously observed in the placebo group of the qHPV vaccine clinical development program.

Assessment of the Applicants Response

The Applicant has thoroughly discussed the data regarding spontaneous abortions in the clinical tria l
program. Specifically, the Applicant has revealed that SAB rates observed with EDCn within 30 days
of any vaccination with 9vHPV vaccine are consistent with rates expected for pregnancies detected by
sensitive hCG testing, that the SAB rates observed with EDCn not within 30 days of any vaccination
are consistent with reported SAB rates for clinically recognized pregnancies and that the SAB rates
observed with EDCn within 30 days of any vaccination with 9vHPV vaccine are consistent with rates in
the placebo group in the qHPV vaccine clinical program. Furthermore, it is agreed that there has been
no safety signal for SAB in the post-marketing period for quadrivalent Gardasil.

Conclusion: Issue resolved.

Question 71.

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In 10 subjects with severe injection-site adverse events in clinical trial P002 (i.e.: pain, erythema,
swelling, movement impairment and pruritus) sequelae are reported in the adverse-event-listings (1)
submitted in the dossier. Narratives of kind and severity of the sequelae should be discussed.

Summary of the Applicants Response

In Appendix 16.2.7.1 of the V503-002 Clinical Study Report the applicant correctly identified 9 (not 10)
subjects who reported a total of 16 injection-site adverse events of severe intensity with outcomes of
sequelae and summarized the findings.

The applicant determined 15 of the 16 reported events to be related to data entry reporting errors
made by the study sights. The errors have been corrected by site staff. Adverse event outcomes were
updated from Recovered/resolved with sequelae to Recovered/Resolved.

The applicant provided an updated table that summarizes the key information for all of the injection-
site adverse events of severe intensity including the Preferred Term, Intensity/Maximum size, Onset
Date, Stop Date, and Dose Number/Vaccine Given. All 16 reported events have a confirmed Onset
Date and Stop Date and are of short duration.

For 1 of the 16 reported AEs the outcome could not be investigated because of closure of the study
site. However the applicant provided the narrative of the subject including the recorded AEs. This
narrative did not provide evidence of sequelae of sever injection site pain or any other recorded AE.
The subject recovered from the sever injection site pain one day following the onset. The subject
completed the study at month 12 visit at which no additional AEs or new medical history events were
recorded.

Assessment of the Applicants Response

Overall, according to the applicant there is no evidence for subjects who experienced injection-site AEs
with sequelae.

Conclusion: The issue is solved.

Question 72.

Arthralgia/arthritis was one of the more common adverse events potentially indicative of an
autoimmune disorder. There were a number of subjects in 2 clinical trials (7 subjects in P005 and 6
subjects in P007) in whom the outcomes were not reported. Were they lost to follow up? Did they
resolve? If the subjects were not lost to follow up the outcomes should subsequently be reported.

Summary of the Applicants Response

The applicant identified 5 missing outcomes of arthralgia in the Listing of Subjects with Adverse
Events and/or New Medical History Potentially Indicative of an Autoimmune Disorder (During the Entire
Study Period - All Vaccinated Subjects) in protocols V503-005 and V503-07. This is the correct
number.

According to the applicant a table programming error that is limited to protocols 005 and 007 was the
reason for the missing outcomes. A description of the error was provided by the company.

Reporting of outcome is determined by the presence or absence of a stop date or duration (for events
lasting less than 24 hours only) of the New Medical History. If a stop date or duration is present, the
outcome is derived as Recovered/Resolved. If no stop date or duration is present, the outcome is
derived as Not Recovered/Not Resolved. For 9 of the 10 subjects, a stop date was correctly reported

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and for one subject the duration. Because a stop date or duration was reported, the outcome should
have been derived as Recovered/Resolved but due to the programming error, it did not and appeared
blank in the listing. The outcomes of the 10 subjects were updated and a table with a listing that
included the outcomes was provided.

Assessment of the Applicants Response

The programming error was detected by the company. The error was limited to the protocols of study
005 and 007. All missing outcomes were provided.

Conclusion: Issue is solved.

Question 73

It is unclear whether the women listed with serious adverse events among subjects who were
breastfeeding were actually vaccinated at the time they were breastfeeding or at the beginning of the
pregnancy as most of the serious adverse events are pregnancy related. This should be clarified by the
sponsor.

Summary of the Applicants Response

Overall, there were 12 subjects who were breastfeeding during the vaccination period (Day 1 to Month
7) and experienced a SAE. Ten (10) of the subjects experienced the SAEs during pregnancy before
they were breastfeeding. These subjects received one or two doses of vaccine, became pregnant and
then experienced a SAE related to pregnancy. The subjects then went on to complete their vaccination
series while they were breastfeeding, and no further SAEs were experienced by these subjects while
they were breastfeeding. Only two subjects ( and ) were enrolled in the study while
breastfeeding and subsequently experienced a SAE during the vaccination period after having received
9vHPV vaccine. Narratives of the two women are provided for these two subjects below. Only the
second subject ( ) experienced the SAE (cholelithiasis) while still breastfeeding and after
having received vaccine.

Multi-Racial female from Colombia entered into the study while breastfeeding.
She had begun breastfeeding on 14-AUG-2008. She received her first dose of 9vHPV vaccine on 09-
MAY-2009 and her second dose on 18-JUN-2009. The subject reported having ended breastfeeding in
AUG-2009. On 05-NOV-2009 (141 days post-dose 2) the subject was admitted to the hospital to treat
an incomplete spontaneous abortion. According to the chart, the subject had experienced bleeding and
pain since 01-NOV-2009. Curettage was performed without complications. The spontaneous abortion
was considered not related to vaccine. The subject recovered and received her third dose of 9vHPV
vaccine on 24-DEC-2009.

Multi-racial female from Colombia entered into the study while


breastfeeding. She had begun breastfeeding on 30-Nov-2008. This subject received one dose of qHPV
vaccine on 25-MAR-2009. The subject had a recent medical history of cholelithiasis which included a
previous episode of severe abdominal pain in January 2009, necessitating a 2-hour stay in the
emergency room. Abdominal ultrasound confirmed the diagnosis of cholelithiasis. Treatment consisted
of Buscapina. A second episode occurred between 22-FEB-2009 and 10-MAR-2009, and she was
treated at home with Buscapina. On 31-MAR-2009 (7 days post-dose 1), the subject experienced
severe acute abdominal pain, fever, and diarrhea and was hospitalized. She underwent a
cholecystectomy that same day

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Assessment of the Applicants Response

The applicant sufficiently clarified the time point of vaccination for breastfeeding women.

Conclusion: Issue is solved. The provided data have no influence on the R/B assessment of
Gardasil 9.

Question 74

There were a number of adverse events of special interest which occurred in the clinical trial program
to which the MAH should commit to continued surveillance in the post-marketing period through
specific review in the PSUR: acute disseminated encephalomyelitis, pancreatitis, and thyroid disorders.
The continued surveillance should be discussed with the PRAC.

Summary of the Applicants Response

The MAH is committed to continued surveillance in the post-marketing phase through specific review in
the PSUR including those conditions listed above (to be re-evaluated after 3 years of PSURs). The
continued surveillance will be discussed with the PRAC.

Conclusion: Issue is solved.

Question 75

Outcomes of pregnancies and children, not already born at cut-off date in studies P001, P002 and P006
should be provided.

Summary of the Applicants Response

The Applicant summarizes the pregnancy outcomes that were not known by the cut-off dates for
studies P001, P002, and P006 in this response and in the relevant reports included in module 5.3.5.1.

Protocol V503-001

The V503-001 CSR (included in the Original Marketing Application) provides outcomes of pregnancies
up to the visit cut-off date of 10-Apr-2013. The V503-001 End of Study Clinical report (included in
module 5.3.5.1.) provides end-of-study efficacy, immunogenicity, and safety analyses which include
data collected from the initiation of the study through 10-Mar-2014. This report provides is an updated
summary of pregnancy outcomes which is also included in Table 43 (below) for reference, showing
pregnancy outcomes from the start of the study through 10-Mar-2104.

As shown in Table 43, the outcomes of a few pregnancies are still unknown (generally because the
pregnancies were still ongoing at the cut-off date). The outcomes of these pregnancies will be
summarized in a future safety report.

The V503-001 study continues in a study extension (Protocol V503-001-04) to offer 9vHPV vaccine to
the qHPV recipients and to assess immune memory, and, therefore, it is anticipated that new
pregnancies and pregnancy outcomes will continue to be collected and reported for the duration of the
current extension and summarized in a safety report.

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Table 43: Current pregnancy outcome P001

Pregnancy outcome at initial MAA P001

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Assessors comment: Around 100 pregnancies more in both vaccination groups were reported
compared to the initial data base. Some pregnancies are still ongoing, which will be reported at a later
time point. The proportion of normal/abnormal outcome and fetal loss did not alter.

Protocol V503-002

The V503-002 CSR (included in the Original Marketing Application) provides outcomes of pregnancies
through the Month 12 study visit (end of the base study). Protocol V503-002 enrolled a cohort of
adolescents (boys and girls), 9 to 15 years of age, and a cohort of young women, 16 to 26 years of
age. The study continued as an extension (Protocol V503-002-10) through Month 36. Only the
adolescent cohort was followed in the extension; the young women terminated the study at the Month
12 visit. The last visit in Protocol V503-002-10 occurred on 02-May-2013 and the results are provided
in the V503-002-10 Statistical Report (included in module 5.3.5.1).

The pregnancy outcomes in the young women cohort are presented in the V503-002 CSR. The new
pregnancies and pregnancies outcomes continued to be collected in the girls cohort during the V503-
002-10 study extension Table 44 (below) provides an updated summary of pregnancy outcomes for
that cohort from the start of the study through Month 36.

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As shown in Table 44, the outcomes of a few pregnancies are still unknown (generally because the
pregnancies were still ongoing at the cut-off date). The outcomes of these pregnancies will be
summarized in a future safety report.

A second extension of the V503-002 study is ongoing (Protocol V503-002-20) to assess long term
safety, immunogenicity and effectiveness. It is anticipated that new pregnancies and pregnancy
outcomes will continue to be collected and reported for the duration of the current extension (up to
Month 126).

Table 44: Current pregnancy outcome P002

Pregnancy outcome initial MAA P002

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Assessors comment:

The number of reported pregnancies increased from 4 at the initial submission up to 22 subjects aged
9 to 15 years today, but still some pregnancies are ongoing. Most of the fetal loss pregnancies were
initiated by elective abortion (4 out of 6). The number of reported pregnancies is too low to interpret
an effect of vaccination with Gardasil 9.

Protocol V503-006

At the time of the original application, the V503-006 study was complete; however, pregnancy
outcomes for 3 of the 4 subjects who reported pregnancies during that study were not known. The
single pregnancy outcome reported in the Original Application (in the V503-006 CSR) was an elective
abortion. Table 45 (below) provides the outcomes of the 3 additional subjects. All 3 subjects had
vaginal live births and reported normal infant outcomes.

Assessment of the Applicants Response

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Overall not many new data regarding pregnancy outcomes of three trials were provided in the
response document and some pregnancies are still ongoing, where the outcome will be provided at a
later time point. In Study P001 most of the pregnancy outcomes are unknown 77% Gardasil 9 group
and 81.2 % in the Gardasil 9 group. The high fetal loss rate in P002 in the young women aged 9 to 15
years mostly induced by elective abortion was already reported in the literature. All data regarding
pregnancy outcome were reported and the future pregnancy outcomes will be reported in safety
reports.

Conclusion: Issue resolved

Question 76

The CSR P001 stated a numerical discrepancy between 7 induced abortions and 10 elective abortions
also in Table 12-38. What is the correct number?

Summary of the Applicants Response

Thank you for bringing this apparent discrepancy to our attention. The Applicant agrees that there is a
numerical difference in the number of induced abortions specified in the narrative summary in Section
12.2.4.4 of the V503-001 CSR (which mentions 7 events) as compared to the number of elective
abortions specified in Section 12.2.6.1.1.1 and Table 12-38 of the V503-001 CSR (which both mention
10 events). In both of these sections of the CSR, all these events relate to subjects enrolled in the
dose-ranging substudy. The correct number of reported elective abortions in the dose-ranging
substudy is 10.

The differences in the numbers of induced/elective abortions reported in these 2 sections involve the
following subjects: , , and ,

Following is a brief explanation of each case.

(High-dose 9vHPV vaccine group)

This subject received Dose 3 of high-dose 9vHPV vaccine on 24-Jun-2008 and reported a pregnancy at
an unscheduled visit on 18-Jul-2008. The date of her last menstrual period was 25-May-2008 which is
within the vaccination phase (Day 1 to Month 7). The subject reported a pregnancy outcome of fetal
loss (elective abortion) with a date of termination of 30-Jul-2008. This event is correctly captured in
the pregnancy outcomes table (Table 12-38). Per protocol, this event of fetal loss was also reported as
serious adverse experience (induced abortion) with an onset date of 29-Jul-2008 and outcome date of
30-Jul-2008 (in the follow-up phase) and this event correctly appears in Table 14.5-43 (listing of
subjects with serious adverse events of fetal loss). The text in Section 12.2.4.4 relative to the dose-
ranging substudy cohorts is focused on events that were reported during the dose-ranging
substudy. The serious adverse experience of induced abortion falls within the follow-up phase of the
study and out of the period of the dose-ranging substudy and, therefore, was not counted in the
narrative summary of serious adverse events of fetal loss reported Day 1 to Month 7 in Section
12.2.4.4.

(Mid-dose 9vHPV vaccine group)

This subject reported 2 pregnancies during the study, both within the vaccination phase (Day 1 to
Month 7). Both of the pregnancies had an outcome of fetal loss (elective abortion). Both of these fetal
losses were reported as serious adverse experiences (induced abortions) as shown in Table 14.5-43
(listing of subjects with serious adverse events of fetal loss). The summary text in Section 12.2.4.4

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specified the number of subjects with events of each type of fetal loss and should have included a note
indicating that this subject reported 2 events of elective abortion but did not.

(qHPV vaccine group)

This subject reported one pregnancy at an unscheduled visit on 10-Jan-2008. The pregnancy outcome
for this event was fetal loss (elective abortion). At the time the pregnancy was reported, the protocol
did not require a pregnancy outcome of elective abortions to be reported as a serious adverse event.
In Nov-2009 there was a change in the rules for reporting fetal loss outcome events. This change was
initiated voluntarily by the Sponsor. Under the new rules, all fetal loss pregnancy outcomes (ectopic
pregnancy, elective termination, spontaneous abortion, late fetal death) for pregnancies in subjects
with a Last Menstrual Period (LMP) prior to or equal to Day 180 following the final vaccination will be
reported as a Serious Adverse Experience (SAE). This new rules were to be applied retrospectively. In
Jan-2010, there was a change in primary investigator at this site. In May-2010, the new investigator
was requested to report the elective abortion as serious adverse event, however, the new investigator
was reluctant to change the determination made by the previous investigator and for this reason there
is no SAE record for this event.

Conclusion: Issue resolved

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