SUU, Alm.del - 2014-15 (2. samling) - Endeligt svar på spørgsmål 44: Spm. om ministeren i forlængelse af samrådet den 5/5-15 om bivirkninger ved HPV-vaccinen vil oplyse, hvornår den omtalte undersøgelse af alvorlige bivirkninger, der skal finde sted i regi af Sundhedsstyrelsen, forventes afsluttet, til sundheds- og ældreministeren

Sundheds- og Ældreudvalget 2014-15 (2. samling)
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Report for EMA and rapporteurs regarding HPV

04/09/2015

Report from the Danish Health and Medicines Authority for consideration

by EMA and rapporteurs in relation to the assessment of the safety profile

of HPV-vaccines

Background ........................................................................................................................................................ 2

Overview of ADR reports received in Denmark ................................................................................................ 4

Evaluation of reported serious ADR cases for HPV-vaccination in Denmark (DLP 19-03-2015) ....................... 5

Methods ........................................................................................................................................................ 5

Results ........................................................................................................................................................... 6

Discussion ...................................................................................................................................................... 7

Recommendations for assessments .............................................................................................................. 8

Information from Uppsala Monitoring Centre regarding cases in Vigibase ...................................................... 9

Information from Japanese Ministry of Health, Labour and Welfare ............................................................. 10

Further information to be obtained from registries in Denmark .................................................................... 11

Summary and conclusions. .............................................................................................................................. 11

References ....................................................................................................................................................... 13

Appendix 1: Legend to forms of symptoms registered ................................................................................... 15

Appendix 2: Information from Uppsala Monitoring Centre regarding cases in VigiBase

.............................. 18

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SUU, Alm.del - 2014-15 (2. samling) - Endeligt svar på spørgsmål 44: Spm. om ministeren i forlængelse af samrådet den 5/5-15 om bivirkninger ved HPV-vaccinen vil oplyse, hvornår den omtalte undersøgelse af alvorlige bivirkninger, der skal finde sted i regi af Sundhedsstyrelsen, forventes afsluttet, til sundheds- og ældreministeren

Report for EMA and rapporteurs regarding HPV

04/09/2015

Background

Vaccination against human papillomavirus (HPV) has been included in the Danish childhood vaccination

program since 2009. The inclusion was based on a thorough national health technology assessment (HTA)

The quadrivalent HPV-vaccine, Gardasil®, is the vaccine used in the Danish program.

Free vaccination is offered to girls aged 12 years through general practitioners. In addition to this, a

temporary catch-up program has been established offering free vaccination to adolescent and young

women up to 27 years. The catch-up program offer will run until end of 2015.

Around 0.5 million subjects have been vaccinated in Denmark (which is around 20 % of the entire female

population). The vaccine coverage in the target population has been 90 % but has decreased during the

past year to 80 %, with a trend towards further decline.

During the first years after introduction of the HPV vaccine the outcome of the routine safety surveillance

was in accordance with the expected, as post-marketing experience overall was similar to experiences

gained in clinical trials. However, from 2013 an onwards, the Danish Health and Medicines Authority has

received a number of reports regarding suspected serious adverse reactions after vaccination with

Gardasil®. Some of the cases first received (7 cases up to 10

of September 2013) had been diagnosed with

postural orthostatic tachycardia syndrome (POTS), and a number of additional serious cases (24 from 1

January to 9

of September 2013) was without diagnoses but included symptoms with resemblance of

cases of POTS such as long-lasting dizziness, headache, syncope and fatigue.

POTS is characterised by an abnormally large increase in heart rate when changing from a lying down to a

standing up position, without any orthostatic hypotension. In POTS, this excessive heart rate increase may

be accompanied by a range of symptoms which may include lightheadedness, visual blurring, palpitations,

weakness (especially of the legs), as well as fatigue, shortness of breath, chest pain, concentration

difficulties, and headaches. Before diagnosing POTS other differential diagnoses such as conditions that

cause tachycardia should be excluded

. The prevalence especially in children and teens is not known. Also

there is no consensus on the diagnostic criteria for pediatric POTS, but it has been suggested that there

should be evidence of chronic orthostatic intolerance for > 3 months, excessive postural tachycardia,

absence of significant orthostatic hypotension, and absence of a reversible cause

. By mid 2013 only a

single case report was published on POTS associated with HPV-vaccination

Denmark raised the signal to the EMA Pharmacovigilance Risk Assessment Committee (PRAC) in September

2013, and based on the data and number of cases at that point in time the PRAC concluded that the issue

should be evaluated in the yearly periodic safety update reports (PSURs) for Gardasil®.

During the same period a signal regarding complex regional pain syndrome (CRPS) was also raised. For CRPS

most common symptoms are severe pain, swelling and changes in the skin temperature and colour of the

arms or legs, but may also include amongst other symptoms headache, general fatigue, coldness of the

legs, limb pain and weakness. The cases of CRPS were mostly reported for Cervarix® and most case reports

originated from Japan. Following a review of all available data on CRPS PRAC concluded in 2014, that the

available evidence did not support a causal association and that the issue should be reviewed through the

PSURs.

In the latest PSUR assessment for December 2014 it was concluded that for both POTS and CRPS a causal

relationship could not be ruled out at the present time.

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The majority of the Danish POTS cases is reported from a Copenhagen-based hospital with a center

specialized in examining and diagnosing conditions with orthostatic intolerance, often with manifest

syncope. The specialized center in Copenhagen has published several case series with detailed data on their

patients evaluated for POTS in relation to HPV-vaccination

5,6,7

. In a case-series including 53 patients, they

describe a common pattern of symptoms in the patients with headache, orthostatic intolerance and fatigue

as the most common combination of symptoms. The average age of the patients is 23 years and they note

that a high percentage of the patients has a high or moderate activity level (e.g. physical, social) prior to

vaccination

. The authors hypothesize that POTS and orthostatic intolerance is only part of the clinical

manifestations, and report that within a group of patients referred to their clinic for suspected side effects

to HPV vaccination 51% fulfilled the criteria for POTS whereas almost 90% of patients fulfilled criteria for

chronic fatigue syndrome

. They suggest that a common underlying mechanism could be dysautonomia

caused by an autoimmune reaction to vaccination

A case-series of 6 patients presenting with new-onset POTS after HPV-vaccination has also been published

from the US recently

Other syndromes than POTS in particular with focus on pain-symptoms have been reported in publications

from 2014. Two cases of fibromyalgia-like illness was described in a publication

, a larger case-series of 45

young women presenting with widespread pain

and a series of 44 girls presenting with headache, fatigue

and limb pain, in some cases fulfilling criteria for POTS or CRPS, related to HPV-vaccination

. A signal from

the WHO database was presented in April 2015 regarding gastrointestinal motility disorders in 21 patients

after HPV-vaccination. In the signal evaluation from WHO, a common link to POTS and CRPS is proposed

A recent paper from 2015

has emphasized that the various syndromes described in cases after HPV-

vaccination are difficult to diagnose, and that they have overlapping clinical features.

The various publications in recent years are raising potential signals of concern regarding reactions after

HPV-vaccination. Based on the signals of POTS and CRPS as well as the description of case reports of other

syndromes like fibromyalgia and chronic fatigue it is found that very similar patterns of symptoms after

HPV-vaccination are described despite the differences in diagnoses. It is plausible, that similar types of

cases would receive different diagnoses depending on the national clinical setting, and that a safety signal

could be present but would potentially be diluted due to different diagnoses in different countries.

Several publications suggest that dysautonomia is the common underlying mechanism for the symptoms

presented

e.g. 6,10,12

, and some recent publications suggest that dysautonomia caused by small fiber

neuropathy is the mechanism behind the various presented clinical symptoms

8,13

.The mechanism by which

HPV-vaccination should lead to small fiber neuropathy is not clear, but some link between the aluminum

adjuvant damage to dorsal root ganglion combined with individual susceptibility is hypothesized

The design of the studies such as theoretical reviews or case series without non-vaccinated control groups

only allows for generation of hypotheses of possible mechanisms but provides no firm knowledge of the

causal association between vaccination and reported reactions. Since many of the symptoms are seen in

the background target population it is a significant challenge to distinguish causal from temporal

association.

Studies designed to elucidate whether excess risk of various diseases is seen in the vaccinated population

have also been published recently. Studies using US health insurance databases have not found any safety

signals for autoimmune disorders

or for excess adverse event in the period after vaccination

. A French

based case-control study found no evidence of an overall increase in autoimmune disorders in young

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females in the period after vaccination

. A large Scandinavian cohort study was published in 2013. The

study included almost 1 million girls and assessed 53 different outcomes for autoimmune, neurological and

venous thromboembolic events during a 180 days period after vaccination. The study found no evidence

supporting an association between exposure to quadrivalent HPV-vaccine and any of the outcomes

Another Scandinavian study from 2014 has focused specifically on multiple sclerosis and other

demyelinating diseases. This study included almost 4 million females from 10-44 years and did not find

evidence of association between HPV-vaccination and any of the diseases

. The risk of chronic fatigue

syndromes in relation to the bivalent HPV vaccine was investigated using database records and reported

adverse events in the UK. The study found no increased risk of chronic fatigue after vaccination compared

to expected background incidences

. The data from these safety studies including a large number of

women and with no evidence of increased risk of diseases are reassuring. However, a limitation in the

studies is that the use of registers to identify outcome measures is highly dependent on diagnoses. The

syndromes suspected as reactions to HPV-vaccination are often difficult to diagnose and has overlap in

symptoms between diagnoses. Also many cases reports symptoms without a diagnose. Such cases would

not be identified in the currently published register studies.

Since 2013 the number of reported cases of POTS and other symptoms seen after HPV-vaccination has

increased dramatically in Denmark. The media attention has been intense since 2013 and the issue has

raised considerable public concern, which is also reflected in the decrease in vaccination coverage.

Based on the evolving uncertainty and public concern, and based on the number and severity of reported

cases as well as the increasing amount of published scientific literature in the area, the Danish Health and

Medicines Authority has initiated a further review of the ADR reports received in Denmark to take stock of

the safety of HPV vaccines.

In the present report an overview of the serious adverse drug reaction reports for HPV-vaccination

accumulated in the Danish Pharmacovigilance database is provided, together with the outcome of a

comparative analysis between Danish and worldwide data performed by the WHO. Furthermore, a short

summary of the Japanese experiences is included.

Overview of ADR reports received in Denmark

Overview of all reports received by the Danish Health and Medicines Authority shows that the number of

reports have increased over the past years but also correlated to the number of doses distributed for the

vaccine.

HPV

vaccine

Number

reports

– of

which

serious

Number

of doses

sold

2009

2010

2011

2012

2013

2014

Q1 2015

Total

288

511

224

77*

1305

177

363

347,690

151,476

163,374

349,730

488,224

114,457

20,817

1,635,768

*The number of reports received in 2015 including both Q1-Q2 is 385

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Overview of all reports also showed that the age groups for which ADR reports have been received is well

correlated with the number of persons vaccinated in various age groups.

Number vaccinated compared to number of ADR reports

350.000

700

600

500

400

300

200

100

< 12 yr

12-15 yr 16-18 yr 19-24 yr 25-29 yr >= 30 yr

Number of persons vaccinated

300.000

250.000

200.000

150.000

100.000

50.000

Number of reports

Number vaccinated

Number of reports

Detailed review of the reports categorized as serious revealed a number of characteristics.

The overall data corresponds to what would be expected.

Evaluation of reported serious ADR cases for HPV-vaccination in Denmark (DLP 19-03-2015)

Methods

The case review included all spontaneous adverse reaction (ADR) reports received by the Danish Health and

Medicines Authority up to March 19, 2015 that were classified as serious according to internationally

agreed criteria.

The dataset consisted of 363 serious ADR reports received in the period. An experienced clinician reviewed

the information including narratives and reported preferred terms (PTs) in all individual cases.

The information in each case was described as symptoms rather than only individual PTs, since different

PTs in some cases could be different descriptions of the same symptom (e.g. burning sensation,

hyperesthesia and sensory disturbance all named as the symptom paresthesia). The PTs included in each

symptom are provided in appendix 1.

Based on a pilot review of the most recently received reports 5 main symptom categories were identified

based on the reviewers impression of the symptoms relatedness within each category, as well as frequency

and severity of occurrence. Eight additional categories were added, that included PTs frequently reported,

in order not to miss registration of symptoms that might prove relevant, when the whole material was

analyzed.

The 5 main categories were: severe fatigue, neurologic symptoms, circulatory symptoms, pain and

headache and the 8 additional categories: autonomic imbalance, abdominal discomfort, urinary tract

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symptoms, allergy, infections, menstrual disorder, thermal dysregulation and malaise. Details of definition

of the categories and symptoms is provided in appendix 1.

No attempt was made to evaluate any causal or time wise relation between the symptoms reported and

the HPV vaccination, as information of time of symptom onset and duration was too often missing or not

very accurate.

Results

Most frequently reported symptoms in the serious reports were (ranked order of symptoms occurring in

more than 100 cases) were: Headache, Pain, Dizziness, Malaise, Fatigue, Paresthesia and Cognitive

disorder.

The review identified 40 verified diagnoses of POTS.

Around 45% of the serious reports were received from non-health care professionals (consumers or

lawyers) and among the serious consumer reports about half of them have been medically confirmed.

The table below shows the results of the categorization. In the table 5/5 refers to cases with a minimum of

1 symptom in each of the 5 main categories, 4/5 to patients with a minimum of 1 symptom in 4 of the 5

main categories etc. Many cases have more than one symptom in each main category.

Category

Malaise

No.

Abdominal discomfort

No.

Thermal dysregulation.

No.

5/5

4/5

4/5+5/5

Discussion

This review reveals a significant increase in Denmark in post-marketing reporting of suspected serious ADRs

to the HPV vaccine Gardasil® from 2013 an onwards, following a 4 year period (2009-2012) without

remarkable findings and no particular reason for concern. The significant increase in reporting coincides

with intensive media and public attention and is likely to be at least partly stimulated reporting.

The overall age distribution of reports in general corresponds to the age groups vaccinated. The age is in

many cases higher than the general target population for vaccination (12 years), but corresponds to the

large group of young women also vaccinated in Denmark though the national catch-up program.

A high percentage of the case reports were submitted by non-HCPs, but many of these lay reports were

medically confirmed afterwards. Many of the case reports were very detailed and of good quality, whereas

others lacked important information, e.g. information on time to onset. Based on the reports it is not

possible to document a causal relation between the reported ADRs and HPV vaccination.

Review of the 363 serious adverse reaction reports received by the Danish Health and Medicines Authority

shows that a considerable number of the cases report a combination of symptoms. Most of the symptoms

was observed individually in clinical trials and are listed according to the product information, however the

combination, the seriousness and duration seen in the cases is not at all in accordance with the listed safety

profile for Gardasil®.

Approximately one third of those individuals described in the serious ADR reports, exhibit a symptom

complex characterized by a combination of severe fatigue, neurological and circulatory symptoms, pain and

headache and often accompanied by malaise, abdominal discomfort, thermal dysregulation and possibly

proneness to infection. Seventeen percent of the patients reported to be socially handicapped by their

condition.

Most of the cases do not have a diagnosis. Based on the review it appears that the symptoms could fit into

a number of different diagnoses.

The complex of symptoms observed does have similarity to the condition described in the literature as

Chronic Fatigue Syndrome (CFS), Myalgic Encephalomyelitis (ME) and Systemic Exercise Intolerance Disease

(SEID). For simplicity, the term CFS is used below.

The clinical description of CFS vary. Different agencies and scientific bodies have produced different

guidelines to define the condition although with overlap of symptoms between descriptions. The most

widely used criteria for CFS are probably the US Center for Disease Control (CDC) criteria published in 1994.

The CDC criteria specify, that the following criteria must be met:

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Clinically evaluated, unexplained, persistent or relapsing chronic fatigue, that has not been lifelong, but has

been present for at least 6 months, is not the result of ongoing exertion and is not substantially alleviated

by rest, and results in substantial reduction in previous levels of occupational, social or personal activities.

In addition 4 or more of the following symptoms: self reported impairment in short term memory or

concentration severe enough to cause reduction in previous levels of activity, muscle pain, multi-joint pain,

headaches of a new type, pattern or severity, unrefreshing sleep, post-exertional malaise for more than 24

hours, sore throat, tender cervical or axillary lymph nodes.

The Canadian criteria from 2003 require two or more neurological/cognitive manifestations and one or

more symptoms from at least two of the categories autonomic, neuroendocrine and immune

manifestations, in addition to fatigue and post exertional malaise or fatigue, chronic pain and sleep

dysfunction. The duration must be a minimum of 6 months.

The 2007 criteria from National Institute for Health and Clinical Excellence (NICE) in England require fatigue,

that is new, persistent or recurrent, not explained by other conditions and has resulted in substantial

reduction in activity level characterized by post exertional malaise and/or fatigue. In addition one or more

of the following symptoms: difficulty with sleeping, muscle and joint pain at multiple sites, headaches,

painful not enlarged lymph nodes, sore throat, cognitive dysfunction, worsening of symptoms by physical

or mental exertion, general malaise, dizziness or nausea and palpitations without identifiable heart

problems. These criteria require symptoms to have been present for only 3 months in children and 4

months in adults.

The Institute of Medicine-IOM-in 2015 proposes the term SEID with 5 main symptoms, characterizing CFS:

reduction or impairment to carry out normal daily acitivites accompanied by profound fatigue, post

exertional malaise (after physical, cognitive or emotional efforts), unrefreshing sleep, cognitive impairment

and orthostatic intolerance. Pain and abnormal immune function may also be present.

The varying quality and completeness of the reports as well as the differences regarding the diagnostic

criteria and nomenclature for this condition does not however allow for identifying the syndrome observed

as CFS/EM/SEID with certainty. There are also cases in the material that rather resemble Fibromyalgia or

Regional Pain Syndrome. For the time being one might consider using the expression Chronic Fatigue

Syndrome Like Illness or Chronic Fatigue Like Syndrome.

The occurrence of symptoms, and their worsening in relation to physical, mental and emotional exercise is

described in some cases, but not in others and in many not commented on.

A subjective observation from reviewing the reports is that in some cases the succession of events is quite

suggestive of a CFS like syndrome with relation to the vaccination, whereas there are others where it

appears extremely unlikely. One might speculate that the syndrome observed could be caused by a number

of different events like infections, physical and emotional trauma and possibly vaccinations.

A final clarification of whether this symptom complex is related to HPV vaccine will require further scientific

research.

Recommendations for assessments

Based on the review we recommend not only to focus any review of reported adverse reactions for HPV-

vaccines on diagnoses individually, but to also consider whether a pattern is observed based on symptoms

and/or whether different diagnoses reported could represent the same underlying symptom pattern.

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Information from Uppsala Monitoring Centre regarding cases in Vigibase

The Danish Health and Medicines Agency (DHMA) requested a consultation with the WHO Collaborating

Centre for International Drug Monitoring – Uppsala Monitoring Centre (UMC) for scientific advice regarding

a signal for Postural Orthostatic Tachycardia Syndrome (POTS) and HPV vaccine which was identified in

Denmark in 2013.

The UMC has provided a review with the aim to describe the adverse event profile for HPV vaccine using

worldwide VigiBase data, specifically related to the safety concern of POTS and related symptomology,

which have been reported with unexpectedly high proportion of serious adverse event reports from

Denmark.

The description of the reports of POTS and the related syndromes of CRPS, CFS, PVFS, fibromyalgia reveal a

large overlap between the different syndromes observed in the comparison of the top co-reported PTs (in

other words, symptomatology): fatigue is reported in greater than 50% of subjects who co-report POTS (65

%), CFS (51 %), PVFS (63 %), and fibromyalgia (52 %). Headache is also reported in greater than 50 % of

subjects who co-report POTS (71 %), CFS (50 %), and PVFS (52 %). Dizziness is also consistently highly

reported amongst cases of POTS (61 %), CFS (36 %), and PVFS (44 %). While it is acknowledged that these

symptoms can be non-specific and are commonly occuring events, it is noted that the reports of POTS, CFS

and PVFS from which these events arose have been largely classified as serious reports (POTS 80 %, CFS 78

%, PVFS 89 %) implying the need for hospitalisation and/or resulting in disability or interruption of normal

function.

Geographic differences, specifically within Europe, are noted in the reporting of POTS and other

syndromes. A fairly consistent finding is that the majority of reports of POTS and other syndromes arise

from the US (POTS 52 %, CFS 51 %, ME/PVFS 40 %). In contrast, DK represents 38 % of reports of POTS and

the UK represents only 4.8 %; however, the UK represents 26 % of the reports of CFS and DK represents

only 6.4 %. Furthermore, the UK represents 39 % of reports of PVFS and DK represents only 4.8 %. Such

differences could be speculated to represent coding variation between Denmark and other European

countries (for example, UK): the same constellation of symptoms have been coded to different diagnositic

PTs.

The total number of reports of POTS, CRPS, CFS and fibromyalgia have been increasing since 2012 with a

marked increase between 2012 and 2013.

Comparison of the most commonly reported PTs and HLTs between the WHO database and the DK

database show a consistency in the top reported adverse events. A comparison of HPV vaccines to all other

vaccines in females, at both the PT and HLT term levels, showed a consistency between HPV reports in the

different age groups and a difference to all other vaccines.

VigiPoint analysis has provided a comparison of HPV reports from Denmark to all other HPV reports and

showed that Danish HPV reports more commonly are classified as serious than all other HPV reports;

however, it is also noted that they are of a higher quality with more complete information. There were a

number of PTs which appear more commonly in Danish reports; however, many of these were of a

diagnostic nature (such as POTS, autonomic nervous system imbalance, orthostatic intolerance). There was

no difference in the reports from Denmark and those from the rest of the world in those PT which describe

symptomatology (such as headache, dizziness, activities of daily living impaired).

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VigiPoint analysis also compared the characteristics of HPV reports to all other vaccine reports included in

Vigibase which have been reported for the subset of females ages 9-25 years of age. The results show that

a greater proportion of HPV reports are serious and describe events which are consistent with

symptomatology included in the clinical case working definition for myalgic encephalitis / chronic fatigue

syndrome (ME/CFS) as described by the Canadian ME/CFS guidelines in the Journal of Chronic Fatigue

Syndrome in 2003. This finding is potentially significant because, although ME/CFS is more common in the

adolescent female population, it is being reported more commonly with HPV vaccine in comparison to

other vaccines in this same population.

In summary, the UMC review of VigiBase data suggests that there is an increasing trend in the number of

HPV reports containing the PTs of POTS and related syndromes. Furthermore, there is the suggestion that a

similar constellation of symptoms may have been labelled with different diagnostic labels depending on the

country of origin. Also, the HPV case reports from Denmark are distinguished from those from other

countries primarily by the fact that there is an increased amount of clinical information provided in the

reports and that certain, specific diagnostic PTs are more commonly used; however, there is no difference

between Danish HPV reports and all other HPV reports in the reporting of clinical relevant PTs describing

symptomatology experienced by young women after HPV vaccination.

Finally, the data suggest that there is an over-representation of serious case reports which describe a

constellation of symptomatology and subsequent medical evaluation potentially consistent with a chronic

fatigue – like syndrome which may be specific to HPV vaccines.

The full report from UMC can be found in Appendix 2.

Information from Japanese Ministry of Health, Labour and Welfare

Much of the initial concerns regarding HPV-vaccination came from CRPS cases as well as publications

originating in Japan. The Japanese authorities suspended the active recommendation for HPV-vaccination

in the public immunization program in 2013.

The Danish Health and Medicines Authority met with the Japanese Ministry of Health, Labour and Welfare

in May 2015 in order to gain further knowledge of the current situation in Japan.

The bivalent as well as the quadrivalent HPV-vaccine are approved and have been used in Japan. The

bivalent vaccine Cervarix® is the most used and the number of adverse reactions reported for the vaccines

are proportional to the usage.

Since the suspension of the vaccine recommendation, the vaccine coverage has fallen dramatically to below

5% although the vaccines are still available and reimbursed.

The Japanese authorities are currently conducting a large investigation of all adverse event reports received

in their pharmacovigilance database. Although the initial concerns have focused on pain and the diagnose

CRPS, the adverse event reports in the Japanese database were characterized by a wider variation of

symptoms, often difficult to standardize. Often reported symptoms were pain, movement disorders,

orthostatic intolerance, dizziness, menstrual abnormalities and fatigue. Symptoms were reported to

fluctuate and in some patients lasting for a long time. This pattern reflects much of the same symptoms as

are also reported in the Danish cases.

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As in Denmark no firm conclusions could be drawn regarding the association between vaccination and

symptoms based on the Japanese experiences, and further knowledge and conduction of studies in the

area were considered a key way forward by the Japanese authorities.

Further information to be obtained from registries in Denmark

Information in ADR reports is based on the data submitted actively by the reporting physician or consumer.

In order to obtain more detailed information on the individual ADR cases, work is currently ongoing to

collect information from the Danish registries for hospital admissions, diagnoses and GP visits.

Data from the registries can potentially reveal additional information regarding diagnoses, risk factors for

reactions or alternative explanations for the symptoms described in the ADR reports.

Summary and conclusions.

This report provides an overview of post-marketing safety experiences with the HPV vaccines, in terms of a

description of data retrieved form the Danish, the Japanese and the WHO databases. Furthermore the most

recent literature publications are quoted.

The main observations and interpretations are the following:

The introduction of the HPV vaccines in the publicly funded vaccination program did not give rise to safety

concerns during the first 4 years.

From 2013 and onwards an increase in ADR reports have been noted in Denmark (exclusively in relation to

use of Gardasil®, the most prominent feature being POTS) and Japan (primarily in relation to use of

Cervarix®, the most prominent feature being CRPS).

The evolving safety concern has had impact on the vaccination coverage, which is declining.

Review of the 363 serious reports submitted to the Danish Pharmacovigilance Database for HPV-vaccines

shows that a large proportion of the reports (34-43%) describe a symptom complex of headache, pain,

fatigue, circulatory symptoms and neurological symptoms. In most cases the patients are left undiagnosed.

In some cases the patients fulfill criteria for POTS. Several patients are severely physically and socially

incapacitated for months / years.

The disease diagnose encompassing most of the symptoms could be a CFS-like condition. Classification is

hampered though by lack of international consensus with regard to diagnostic criteria for CFS (and other

syndromes).

The review highlights the necessity to evaluate (combinations of) symptoms rather than only performing

separate evaluation of individual diagnoses.

Controlled trials or post-marketing epidemiology studies have not found evidence of any new or

unexpected safety issues for the HPV-vaccines. However, the duration of proactive safety follow-up in the

clinical trials might not have been adequate to detect the onset of symptoms. It should also be noted that

post-marketing studies often rely on disease registries, and that many patients are left undiagnosed, and

therefore will not appear in the registries.

Evaluation of data from WHO shows that although the number of cases for POTS is very high in Denmark,

compared to the rest of the world, the symptom patterns seen in the Danish dataset is similar to reports

submitted from many other countries.

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A potential explanation for the huge geographic variation in the observed reporting pattern could be that

similar combinations of symptoms could lead to different diagnoses depending on the country, culture or

clinical setting.

Several case series have been published in recent years, and various hypotheses have been presented to

explain the underlying pathophysiological mechanism, e.g. that symptoms are compatible with autonomic

dysfunction, associated with vaccination due to provoked autoimmune phenomena. It is hypothesized that

the dysautonomia is caused by small fiber neuropathy, but the mechanism is not clear.

The data provided in spontaneous reports cannot be used to provide evidence for causal relationship

between symptoms and vaccination. It is therefore highly important to consider the possibilities for further

studies to evaluate any causal relationship with the vaccination.

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References

[only available in Danish]: SST 2007 – Reduktion af risikoen for livmoderhalskræft ved vaccination mod

HPV-

http://sundhedsstyrelsen.dk/publ/Publ2007/MTV/HPV/HPV_vaccination.pdf

Freeman R, et al. Consensus statement on the definition of orthostatic hypotension, neutrally mediated

syncope and the postural tachycardia syndrome. Clin Auton Res 2011; 21:69-72.

Jarjour IT. Postural tachycardia syndrome in children and adolescents. Semin Pediatr Neurol 2013; 20:18-

26.

Blitshteyn S. Postural tachycardia syndrome after vaccination with Gardasil. Eur J Neurol 2010; 17: e52.

Brinth L, Theibel AC, Pors K, Mehlsen J (2015) Suspected side effects to the quadrivalent human papilloma

vaccine. Dan Med J 62(4): A5064.

Brinth LS, Pors K, Theibel AC, Mehlsen J (2015) Orthostatic intolerance and postural tachycardia syndrome

as suspected adverse effects of vaccination against human papilloma virus. Vaccine 33(22): 2602-2605.

Brinth et al. Is Chronic Fatigue Syndrome/Myalgic Encephalomyelitis a Relevant Diagnosis in Patients with

Suspected Side Effects to Human Papilloma Virus Vaccine? Brinth L et al. Int J Vaccines Vaccin 2015, 1(1):

00003

Blitshteyn S (2014) Postural tachycardia syndrome following human papillomavirus vaccination. Eur J

Neurol 21(1): 135-139

Martinez-Lavin M (2014) Fibromyalgia-like illness in 2 girls after human papillomavirus vaccination. J Clin

Rheumatol 20(7): 392-393.

Kinoshita T, Abe RT, Hineno A, Tsunekawa K, Nakane S, et al. (2014) Peripheral sympathetic nerve

dysfunction in adolescent Japanese girls following immunization with the human papillomavirus vaccine.

Intern Med 53(19): 2185-2200.

Nishioka K (2014) Clinical features and preliminary diagnostic criteria of human papillomavirus

vaccination associated with neuroimmunopathic syndrome (HANS). International Journal of Rheumatic

Diseases 17(Suppl 2): 6-29.

HPV vaccine – Gastrointestinal motility disorders, Signal April 2015 p.20-25, Uppsala monitoring Centre,

WHO collaborating Centre for international drug monitoring.

Martinez-Lavin M (2015) Hypothesis: Human papilloma virus vaccination syndrome – small fiber

neuropathy and dysautonomia could be its underlying pathogenesis. Clin Rheumatol [Epub ahead of print]

Chao C et. al., Surveillance of autoimmune conditions following routine use of quadrivalent human

papillomavirus vaccine. J Intern Med. 2012 Feb;271(2):193-203

Klein NP et. Al., Safety of quadrivalent human papillomavirus vaccine administered routinely to females.

Arch Pediatr Adolesc Med. 2012 Dec;166(12):1140-8.

Grimaldi-Bensouda L. Autoimmune disorders and quadrivalent human papillomavirus vaccination of

young female subjects, J Intern Med. 2014 Apr;275(4):398-408

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Arnheim-Dahlstrom L, Pasternak B, Svanstrom H, Sparen P, Hviid A (2013) Autoimmune, neurological, and

venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human

papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ 347: f5906.

Scheller NM, Svanstrom H, Pasternak B, Arnheim-Dahlstrom L, Sundstrom K, et al. (2015) Quadrivalent

HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous

system. JAMA 313(1): 54-61.

Donegan K, Beau-Lejdstrom R, King B, Seabroke S, Thomson A, et al. (2013) Bivalent human

papillomavirus vaccine and the risk of fatigue syndromes in girls in the UK. Vaccine 31(43): 4961-4967.

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Appendix 1: Legend to forms of symptoms registered

PTs leading to registration are that of the main heading and those others listed below under the heading.

All PTs reported more than 10 times for the period covered are included as well as some others considered

important.

Symptoms and PTs included in the 5 main categories:

1. Severe fatigue

Fatigue: asthenia, fatigue extreme, fatigue (when described as severe in narrative), lethargy

Muscular weakness: muscle fatigue, physical disability, wheelchair user

Considerable impact on daily life: School or work attendance <30% for min. 3 months, activity of daily living

impaired, disability

2. Neurological symptoms

Paraestesia: sensory disturbance, hypoaestesia, hyperaestesia, burning sensation, dysaestesia, sensory loss,

hypersensitivity, neurological disorder

Paralysis: paresis, hemiplegia, hemiparesis, facial nerve palsy

Convulsions: epilepsy, grand mal epilepsy, petit mal epilepsy, seizure, convulsion, febrile convulsion,

cataplexia (when not combined with narcolepsy)

Involuntary movements: muscle spasms, muscle stiffness, muscle twitching, tremor, myoclonia, involuntary

muscle contraction, tremor, tics, dyskinesia, clumsiness, gait disturbance, balance disorder, movement

disorder, speech disorder, dyslalia, aphasia, eylid twitching, ataxia, dystonia, dystasia , coordination

abnormal , eye movement disorder, joint lock

Visual impairment: vision blurred, visual acuity reduced, diplopia, visual field defect, photophobia, visual

field defect, eye pain, ocular discomfort, papillary oedema, transient blindness, sudden blindness, eyelid

oedema, eye inflammation. (eylid oedema and eye inflammation are included under visual impairment as

they in the reports are often accompanied by complaints of difficult vision, which could be an independent

symptom or secondary to the oedema/inflammation. No case, however, has been categorized as having

neurologic symptoms on the bases of these symptoms alone).

Hearing impaired: hyperacusis, hypacusis, tinnitus,ear pain, ear discomfort, deafness

Cognitive disorder: disturbance in attention, memory impairment, confusional state, amnesia

Mood changes: anxiety, mood swings, depression, depressed mood, feels abnormal, restlessness, stress.

(Mood changes have been characterized as neurologic symptoms as they in the narratives are often

describes as “unexplained” without relation to other symptoms, but of course they could also be secondary

in character. No case, however, has been classified as having neurologic symptoms on the basis of mood

changes alone).

Sleep disorder: insomnia, hypersomnia, somnolence, poor quality sleep

Circulatory symptoms

Palpitations

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Dyspnoea: difficulty breathing, fast breathing

Presyncope: orthostatic hypotension, hypotension, blood pressure decreased

Tacycardia: increased heart rate

Dizziness: vertigo

Syncope: loss of consciousness, fall

POTS: registered when fulfilling official, published POTs criteria

Orthostatic intolerance: registered when symptoms occur in upright position and are relieved when lying

down

Pain

Pain: myalgia, arthralgia, pain in extremity, musculosceletal pain, back pain, neck pain, pain in jaw,

allodynia, neuralgia, chest pain, chest discomfort, bone pain, orpharyngeal pain.

(does not include hedache, migraine, arthritis, pain at injection site, abdominal pain, bladder pain, dysuria).

Headache

Headache: head discomfort

Migraine: migraine with aura

Symptoms and PTs included in the 8 additional categories:

1. Autonomic imbalance:

registered when Compass-51 is judged positive

2. Abdominal discomfort:

abdominal pain (upper, lower), abdominal distension, constipation,

diarrhoea, change of bowel habits, gasto-intestinal irritation, gasto- intestinal migraine

3. Urinary tract symptoms:

dysuria, pollakisuria, urinary incontinence, urinary retention, bladder

disorder, bladder pain, blood in urine present. (excluded cystitis)

4. Allergy

Allergy after vaccination:

new or worsened symptoms after vaccination of: asthma, urticaria, eczema,

allergic rhinitis, rash, erythema, pruritus, erythema nodosum, angio-oedema

Anaphylaxis:

anaphylactic shock

5. Infections

Infection:

cough, pneumonia, lymphadenopathy, cystitis, sinusitis, oral mucosa blisters, otitis, influenza

like illness

Recurrent infection

Fever:

pyrexia

6. Menstrual disorder:

dysmenorrhea, metrorhagia, menorrhagia, menstruation irregular

7. Thermal dysregulation;

feeling cold, cold sweat, peripheral coldness, body temperature decreased,

body temperature fluctuation,, sweating

8. Malaise:

nausea, vomiting

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Specific diagnosis:

when a specific diagnosis is listed (f.x. MS) the various symptoms already explained by

the specific diagnosis have not been listed.

Others:

here are other concomitant diagnoses listed, that do not explain the symptoms observed and

listed

Explanation for categories:

no/5 indicates the number of categories with at least one symptom reported within the category, for the 5

categories: severe fatigue, neurologic symptoms, circulatory symptoms, pain and headache.

no/8 indicates the number of categories with at least one symptom reported within the category for the

remaining 8 categories: autonomic dysbalance, abdominal discomfort, urinary tract symptoms, allergy,

infections, menstrual disorder, thermal dysregulation and malaise.

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Appendix 2: Information from Uppsala Monitoring Centre regarding cases in VigiBase

The Danish Health and Medicines Agency (DHMA) requested a consultation with the WHO Collaborating

Centre for International Drug Monitoring – Uppsala Monitoring Centre (UMC) for scientific advice regarding

a signal for Postural Orthostatic Tachycardia Syndrome (POTS) and HPV vaccine which was identified in

Denmark in 2013.

According to the invitation letter,

“Since POTS is a rare and difficult diagnosis to give, we are particularly interested in identification of cases

in the WHO database that could be related to the same type of reactions as seen in the POTS cases based

on symptoms of autonomic dysfunction rather than only on a specific diagnosis. We will be grateful to have

the expert advice and collaboration of WHO on this issue.”

The aim of this review therefore was to describe the adverse event profile for HPV vaccine using worldwide

VigiBase data, specifically as it relates to the safety concern of POTS and related symptomalogy which have

been reported from the unexpectedly high proportion of serious adverse event reports from Denmark.

The data included in Vigibase has been presented in a number of ways in this report: 1) a description of the

total number of reports of POTS and related clinical syndromes which have been received into the

database, 2) a presentation of the most commonly reported PTs and HLTs from HPV reports classified as

serious reports from both the VigiBase and the Danish database, and 3) comparative analyses of Danish

HPV reports to all other HPV reports and of all HPV reports to all other vaccine reports and using vigiPoint

methodology.

Please note that VigiBase can contain duplicate reports. It should be noted also that VigiBase includes both

serious and nonserious reports. Also please note that not all reports come in to UMC/WHO VigiBase with a

seriousness designation, and therefore, the analysis in part 2 (focus on serious reports) will have excluded

some potential serious cases. Australia is the country of most importance, as they routinely use HPV

vaccine in the vaccination program, but their reports do not include seriousness. Finally, it is noted that

MedDRA coding terminology has been used throughout this document.

1. Description of all (serious, nonserious, seriousness not reported) HPV case reports

included in VigiBase which include the MedDRA reported Preferred Terms (PT) of

postural orthostatic tachycardia syndrome (POTS) and other similar syndromes

POTS

On a data retrieval performed on 03 August 2015, VigiBase included a total of 147 reports for POTS and

HPV vaccines contained in VigiBase. For comparison, there were a total of 257 reports for POTS for all

drugs. In other words, 57% of all reports of POTS have been reported with HPV vaccine.

One-hundred seventeen (80%) of the reports were considered serious.

The following table displays the top co-reported PTs in all POTS reports received for HPV vaccines.

Table 1. Top 10 co-reported PTs in POTS reports received for HPV vaccines.

MedDRA PT / PT group

Number of reports

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Headache

Fatigue

Syncope

Dizziness

Pain

Nausea

Palpitations

Abdominal pain

Autonomic nervous system imbalance

Orthostatic intolerance

104

(71%)

(65%)

(63%)

(61%)

(48%)

(42%)

(35%)

(31%)

(28%)

Please note: The following applies to the above table and all other similar tables in this report.

The headache PT group includes the all PTs including the terms headache and migraine.

The dizziness PT group includes the PTs of dizziness and dizziness postural.

The abdominal pain PT group includes the PTs of abdominal pain, abdominal pain upper and abdominal pain lower.

The syncope PT group includes the PTs of syncope and presyncope.

There is a concern that the constellation of symptoms observed in subjects with POTS has been potentially

coded to different “diagnosis-type” PTs given the relative unfamiliarity of the diagnosis of POTS outside of

the cardiology/neurology practice, the presence of other syndromes with similar and overlapping

symptoms, and also potential geographical coding differences. Therefore, a number of other PTs were

reviewed in VigiBase: complex regional pain syndrome (CRPS), chronic fatigue syndrome (CFS), myalgic

encephalomyelitis (ME/PVFS), and fibromyalgia (FM).

Complex Regional Pain Syndrome

On a data retrieval performed on 03 August 2015, VigiBase included a total of 94 reports for CRPS and HPV

vaccines contained in Vigibase. For comparison, there are a total of 677 reports for CRPS for all drugs. In

other words, 14% of all reports of CRPS have been reported with HPV vaccine.

Sixty-five (69%) of the reports were considered serious. Twenty-six of the reports were considered non-

serious. Three reports had no seriousness reported.

The following table displays the top co-reported PTs in all CRPS reports received for HPV vaccines.

Table 2. Top 10 co-reported PTs in CRPS reports received for HPV vaccines.

MedDRA PT / PT group

Pain

Pain in extremity

Headache

Arthralgia

Gait disturbance

Hypoaesthesia

Muscular weakness

Nausea

Abdominal pain

Number of reports

41 (44%)

32 (34%)

28 (30%)

26 (28%)

25 (27%)

22 (23%)

16 (17%)

15 (16%)

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Dizziness

Chronic fatigue syndrome

15 (16%)

On a data retrieval performed on 03 August 2015, VigiBase included a total of 94 reports for chronic fatigue

syndrome (CFS) and HPV vaccines contained in VigiBase. For comparison, there were a total of 809 reports

for CFS for all drugs. In other words, 12% of all reports of CFS have been reported with HPV vaccine.

Six (6.4%) of these reports also reported the PT of POTS; 3 of these reports were from the USA and 3 were

from the UK.

Seventy-three (78%) of the reports were considered serious. Sixteen of the reports were considered non-

serious. Five reports had no seriousness reported.

The following table displays the top co-reported PTs in all CFS reports received for HPV vaccines.

Table 3. Top 10 co-reported PTs in CFS reports received for HPV vaccines.

MedDRA PT / PT group

Fatigue

Headache

Dizziness

Arthralgia

Nausea

Activities of daily living impaired

Post-viral fatigue syndrome

Malaise

Pain

Abdominal pain

Number of reports

48 (51%)

47 (50%)

34 (36%)

33 (35%)

30 (32%)

27 (29%)

25 (27%)

24 (26%)

23 (24%)

Myalgic encephalomyelitis (MedDRA PT = post viral fatigue syndrome)

On a data retrieval performed on 03 August 2015, VigiBase included a total of 62 reports for myalgic

encephalitis / post viral fatigue syndrome (ME/PVFS) and HPV vaccines contained in VigiBase. For

comparison, there are a total of 396 reports for ME/PVFS for all drugs. In other words, 16% of all reports

of ME/PVFS have been reported with HPV vaccine.

Five (8.0%) of these reports also reported the PT of POTS; 3 of these reports were from the UK, 1 from

Denmark and 1 from the UK.

Fifty-five (89%) of the reports were considered serious. Five of the reports were considered non-serious.

Two reports had no seriousness reported.

The following table displays the top co-reported PTs in all ME/PVFS reports received for HPV vaccines.

Table 4. Top 10 co-reported PTs in ME/PVFS reports received for HPV vaccines.

MedDRA PT / PT group

Number of reports

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Fatigue

Headache

Dizziness

Chronic fatigue syndrome

Malaise

Nausea

Asthenia

Arthralgia

Abdominal pain

Syncope

Fibromyalgia

(63%)

(52%)

(44%)

(40%)

(34%)

(32%)

(31%)

(27%)

(26%)

(24%)

On a data retrieval on performed 03 August 2015, VigiBase included a total of 87 reports for fibromyalgia

(FM) and HPV vaccines contained in VigiBase. For comparison, there are a total of 6297 reports for FM for

all drugs. In other words, 1.4% of all reports of FM have been reported with HPV vaccine.

Three (3.4%) of these reports also reported the PT of POTS; all three of these reports came from Denmark.

Sixty-four (74%) of the reports were considered serious. Twenty-two of the reports were considered non-

serious. One report had no seriousness reported.

The following table displays the top co-reported PTs in all FM reports received for HPV vaccines.

Table 6. Top 10 co-reported PTs in FM reports received for HPV vaccines.

MedDRA PT / PT group

Number of reports

Pain

51 (59%)

Fatigue

45 (52%)

Arthralgia

36 (41%)

Headache

34 (39%)

Dizziness

25 (29%)

Abdominal pain

25 (29%)

Insomnia

24 (29%)

Activities of daily living impaired

22 (25%)

Nausea

21 (24%)

Myalgia

20 (23%)

Geographic distribution of reports of POTS and related syndromes

The following table displays the countries from which all reports of POTS and each of the related

syndromes have originated. The data reveal that the largest proportion of reports for all of the syndromes

come from the US. However, the second largest proportion of reports for each syndrome varies between

several different countries: 38% of POTS reports come from Denmark, 26% of CRPS reports come from

Japan, 26% of CFS reports and 39% of ME/PVFS come from UK . These data suggest that different

diagnostic labels could be being used in different countries to describe a similar constellation of symptoms.

Table 6. Geographic distribution of reports of POTS and related syndromes

Country

POTS

CRPS

CFS

ME/PVFS

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United States

Denmark

United

Kingdom

Ireland

Norway

Sweden

Germany

France

Italy

Spain

Slovenia

Malta

Japan

Australia

Total reports

76 (52%)

56 (38%)

7 (4.8%)

50 (53%)

2 (2.1%)

7 (7.4%)

1 (1.1%)

48 (51%)

6 (6.4%)

25 (26%)

3 (3.2%)

1 (1.1%)

2 (2.1%)

1 (1.1%)

25 (40%)

3 (4.8%)

24 (39%)

3 (4.8%)

4 (6.4%)

1 (1.6%)

61 (70%)

11 (12.6%)

1 (1.1%)

1 (0.7%)

3 (2.0%)

3 (3.2%)

1 (1.1%)

2 (2.1%)

1 (1.1%)

2 (2.3%)

4 (2.7%)

25 (26.6%)

3 (3.2%)

5 (5.3%)

2 (3.2%)

7 (8.0%)

1 (1.1%)

147

Temporal distribution of reports

The following figure displays of the total number of reports in VigiBase (x-axis) for each of the clinical

syndromes plotted over time (y-axis). As can been seen, the total number of reports of POTS, CRPS, CFS

and fibromyalgia have been increasing since 2012 with a marked increase between 2012 and 2013.

Furthermore, the number of POTS cases as of August 2015 are nearly equivalent to the total number of

cases reported in the whole of 2014. 2010 stands out in the data with an increased number of cases

compared to both 2009 and 2011; the reason for this is likely due to the receipt by the UMC of a large

backlog of cases from the US FDA. This pattern is observed for all vaccines included in the database.

Figure 1. Temporal distribution of total number of reports of POTS and related syndromes (x- axis) over

time, represented by year (y-axis)

2009

2010

2011

2012

2013

2014

2015

POTS

CRPS

CFS

Fibromyalgia

PVFS

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2. Presentation of the most commonly reported PTs and HLTs from HPV reports from

serious reports from both the Vigibase and the Danish database

The tables below are the product of a search request of the UMC by the Danish Health and Medicines

Agency.

Top 20 events (PT) from serious reports on HPV vaccines in WHO VigiBase (as of 02.06.2015) versus the

Danish database of adverse reactions (as of 27.05.2015):

HPV vaccines

VigiBase

Number of

reports

2308

1582

1365

1348

1247

1201

851

824

820

780

762

758

756

732

730

706

687

671

644

584

MedDRA PT

Headache

Dizziness

Nausea

Syncope

Pyrexia

Fatigue

Vomiting

Arthralgia

Malaise

Asthenia

Pain

Pain in extremity

Seizure

Hypoaesthesia

Paraesthesia

Dyspnoea

Loss of consciousness

Abdominal pain

Muscular weakness

Myalgia

MedDRA PT

HEADACHE

FATIGUE

DIZZINESS

NAUSEA

ARTHRALGIA

DISTURBANCE IN ATTENTION

SYNCOPE

ABDOMINAL PAIN

MYALGIA

PALPITATIONS

SENSORY DISTURBANCE

MUSCULAR WEAKNESS

DYSPNOEA

PARAESTHESIA

MEMORY IMPAIRMENT

AUTONOMIC NERVOUS

SYSTEM IMBALANCE

VISUAL IMPAIRMENT

MUSCLE SPASMS

PAIN IN EXTREMITY

HYPOAESTHESIA

Number of

reports

229

217

212

149

127

109

107

Top 20 events (PT) from serious reports on females age 12-17 years in VigiBase for HPV vaccines versus

other vaccines (as of 09.06.2015):

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HPV Vaccines, WHO, Females 12-17 years

Number MedDRA PT

of reports

1540

1066

998

894

831

780

559

551

531

526

504

503

460

449

438

433

429

411

409

336

Headache

Dizziness

Syncope

Nausea

Pyrexia

Fatigue

Malaise

Vomiting

Arthralgia

Asthenia

Loss of consciousness

Seizure

Pain in extremity

Abdominal pain

Hypoaesthesia

Pain

Dyspnoea

Paraesthesia

Muscular weakness

Myalgia

All other vaccines, WHO, Females 12-17 years

Number

of reports

269

219

143

139

125

120

104

MedDRA PT

Headache

Pyrexia

Nausea

Dizziness

Vomiting

Syncope

Asthenia

Paraesthesia

Dyspnoea

Fatigue

Pain

Seizure

Muscular weakness

Pain in extremity

Loss of consciousness

Hypoaesthesia

Arthralgia

Myalgia

Guillain-Barre syndrome

Malaise

Top 20 events (PT) from serious reports on females age 18-44 years in WHO VigiBase for HPV vaccines

versus other vaccines (as of 09.06.2015):

HPV Vaccines, WHO, Females 18-44 years

Number MedDRA PT

of reports

459

355

309

289

259

246

214

212

211

202

196

191

Headache

Dizziness

Nausea

Fatigue

Pyrexia

Paraesthesia

Arthralgia

Hypoaesthesia

Syncope

Pain

Pain in extremity

Dyspnoea

All other vaccines, WHO, Females 18-44 years

Number

of reports

743

460

350

317

303

272

265

242

231

229

226

223

MedDRA PT

Pyrexia

Headache

Pain

Injection site pain

Nausea

Injection site erythema

Myalgia

Arthralgia

Paraesthesia

Dizziness

Vomiting

Dyspnoea

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188

178

177

161

158

142

138

112

Vomiting

Myalgia

Malaise

Muscular weakness

Asthenia

Seizure

Abdominal pain

Exposure during pregnancy

220

217

215

213

208

202

187

179

Chills

Pain in extremity

Asthenia

Cellulitis

Malaise

Fatigue

Injection site swelling

Erythema

Top 20 events (HLT) from serious reports on females age 9-18 years in the Danish database of adverse

reactions for HPV vaccines versus other vaccines (as of 02.07.2015):

HPV vaccines, DK, Females 9-18 years

Number

of reports

148

141

121

All other vaccines, DK, Females 9-18 years

Number

of reports

Sensory abnormalities NEC

General signs and symptoms NEC

Disturbances in consciousness NEC

Lymphatic system disorders NEC

Mental impairment (excl dementia and

memory loss)

Purpura and related conditions

Pain and discomfort NEC

Muscle weakness conditions

Gastrointestinal and abdominal pains

(excl oral and throat)

Autonomic nervous system disorders

Feelings and sensations NEC

Musculoskeletal and connective tissue

pain and discomfort

Paraesthesias and dysaesthesias

Seizures and seizure disorders NEC

MedDRA HLT

Asthenic conditions

Headaches NEC

Neurological signs and symptoms

NEC

Nausea and vomiting symptoms

Disturbances in consciousness NEC

Mental impairment (excl dementia

and memory loss)

Gastrointestinal and abdominal pains

(excl oral and throat)

Joint related signs and symptoms

Pain and discomfort NEC

Cardiac signs and symptoms NEC

Paraesthesias and dysaesthesias

Visual disorders NEC

Musculoskeletal and connective

tissue pain and discomfort

Breathing abnormalities

Muscle related signs and symptoms

NEC

Muscle weakness conditions

Muscle pains

Sensory abnormalities NEC

Memory loss (excl dementia)

Rate and rhythm disorders NEC

MedDRA HLT

Febrile disorders

Nausea and vomiting symptoms

Headaches NEC

Asthenic conditions

Neurological signs and symptoms NEC

Visual disorders NEC

Top 20 events (HLT) from serious reports on females age 19-41 years in the Danish database of adverse

reactions for HPV vaccines versus other vaccines (as of 02.07.2015):

HPV vaccines, DK, Females 19-41 years

All other vaccines, DK, Females 19-41 years

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Number

of reports

116

109

108

MedDRA HLT

Neurological signs and symptoms

NEC

Asthenic conditions

Headaches NEC

Nausea and vomiting symptoms

Paraesthesias and dysaesthesias

Musculoskeletal and connective

tissue pain and discomfort

Sensory abnormalities NEC

Joint related signs and symptoms

Mental impairment (excl dementia

and memory loss)

Visual disorders NEC

Muscle weakness conditions

Muscle pains

Memory loss (excl dementia)

Muscle related signs and symptoms

NEC

Gastrointestinal and abdominal pains

(excl oral and throat)

Cardiac signs and symptoms NEC

Disturbances in consciousness NEC

Breathing abnormalities

Pain and discomfort NEC

Apocrine and eccrine gland disorders

Number

of reports

MedDRA HLT

Febrile disorders

General signs and symptoms NEC

Asthenic conditions

Injection site reactions

Headaches NEC

Musculoskeletal and connective tissue

pain and discomfort

Paraesthesias and dysaesthesias

Neurological signs and symptoms NEC

Urticarias

Gastrointestinal and abdominal pains

(excl oral and throat)

Exposures associated with pregnancy,

delivery and lactation

Anaphylactic responses

Sensory abnormalities NEC

Disturbances in consciousness NEC

Muscle weakness conditions

Mental impairment (excl dementia and

memory loss)

Nausea and vomiting symptoms

Allergic conditions NEC

Coordination and balance disturbances

Joint related signs and symptoms

3. Comparative analyses of HPV reports to all other vaccine reports and of Danish HPV

reports to all other HPV reports using vigiPoint methodology

vigiPoint is a methodology by which two subsets (or more) of case reports from VigiBase can be compared

on case report characteristics. vigiPoint has here been used to compare of the characteristics for case

safety reports describing adverse events with HPV vaccines in females aged 9-25 years. The first

comparison was made between the subset of Danish HPV reports to all other HPV reports (worldwide) to

investigate if there are differences in the case report characteristics which could explain the Danish

”signal”. The second comparison was made between all HPV reports and all other vaccine reports in

females aged 9-25 to investigate if this constellation of symptomatology is specific for HPV vaccines and

thus may not be simply explained by the background incidence of this diagnosis in the adolescent, female

population.

The analytical framework is called vigiPoint is an analytical framework which relies on the logarithm of

shrunk OE ratios to highlight and rank characteristic reporting patterns

. It should be noted that the data

used in this investigation includes data received into VigiBase up until 1

of January 2015. This data lock

point is different from the VigiBase review of POTS and related PTs as provided earlier in this report.

Furthermore, the date precedes the media attention generated by the announcement of the Referral

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04/09/2015

procedure by the EMA in mid July 2015. The entire data set has not been reproduced in this report; only

those results with statistical significance are reported. There is mention of clinically relevant results which

did not reach the statistical significance threshold (log OR 005 > 0.50) which was determined outside of

this current clinical question.

Please observe that this data is as of yet unpublished. It has been accepted as a poster presentation at the

annual meeting of the International Society of Pharmacovigilance in Prague, Czech Republic in October of

2015.

Comparison of all HPV reports from Denmark to all other HPV vaccine reports in females, aged 9-25

This analysis has compared 549 reports for HPV vaccine from Denmark with 45,327 HPV reports (all other

HPV reports from the rest of the world) which were received from females between the ages of 9-25 years

of age.

Key features which were highlighted when HPV reports from Denmark were compared to HPV reports from

the rest of the world were: a significantly greater proportion of the reports were considered “good

reports” (determined the amount of clinically relevant information in an ICSR of the report

), were

classified as “serious”, and were received from either a physician, consumer or a lawyer. The SOC over –

represented in Danish reports were “Skin and subcutaneous disorders” and “Cardiac disorders”. PTs

significantly reported more commonly in Danish reports were the following: autonomic nervous system

imbalance, orthostatic intolerance, eczema, sensory disturbance, disturbance in attention, POTS, memory

impairment, palpitations, cognitive disorder, fatigue, infection, visual impairment, influenza-like illness,

muscle spasms, and arthralgia.

A significantly greater proportion of HPV reports from the rest of the world included terms from the SOCs

of General disorders and administration site conditions; Injury, poisoning and procedural complications,

and Investigations. The PTs significantly reported more commonly in HPV reports from the rest of the

world were exposure during pregnancy, vaccination site pain, and injection site pain.

Clinically relevant PTs for which there was no significant difference between Danish reports and reports

from the rest of the world were: headache, malaise, myalgia, asthenia, dizziness, dizziness postural,

orthostatic hypotension, presyncope, syncope, hyperhidrosis, heart rate increased, tachycardia, muscular

weakness, abdominal pain, tremor, hypersomnia, quality of life decreased and activities of daily living

impaired. Nor was there a significant difference between Danish reports and reports from the rest of the

world for the following diagnosis PTs: chronic fatigue syndrome, post viral fatigue syndrome, fibromyalgia,

or CRPS.

Report characteristic

Number

of HPV

Reports

Number

of other

vaccine

reports

9642

Log

005

Log

095

% of

total

HPV

reports

90%

% of

total

other

vaccine

reports

21%

Good Report

Dermatitis atopic

Lawyer

495

4.67

3.40

3.15

4.50

2.85

2.56

4.84

3.87

3.65

p. 27/41

Report for EMA and rapporteurs regarding HPV

04/09/2015

Autonomic nervous system

imbalance

Orthostatic intolerance

Eczema

Sensory disturbance

Disturbance in attention

Postural orthostatic tachycardia

syndrome

Memory impairment

Palpitations

Consumer/Non Health Professional

Skin and subcutaneous tissue

disorders

Cognitive disorder

Physician

Fatigue

Infection

Visual impairment

Cardiac disorders

Influenza like illness

Muscle spasms

Arthralgia

SeriousOrFatal

100

244

438

199

136

211

140

229

1086

8045

11759

2271

410

982

352

403

1543

8777

2.87

2.83

2.73

2.61

2.51

2.35

2.32

2.11

1.87

1.81

1.80

1.70

1.68

1.62

1.60

1.51

1.47

1.20

2.23

2.18

2.07

1.97

1.88

1.58

1.60

1.39

1.48

1.57

0.82

1.52

1.28

0.61

0.86

1.02

0.69

0.67

0.64

0.93

3.41

3.38

3.27

3.15

3.03

2.98

2.91

2.70

2.21

2.04

2.55

1.87

2.05

2.40

2.23

2.09

2.17

2.12

1.67

1.45

18%

44%

80%

16%

36%

18%

55%

19%

General disorders and

administration site conditions

NonSerious

Injury, poisoning and procedural

complications

220

350

24717

36550

4438

0.83

1.23

1.26

1.09

1.43

2.08

0.59

1.04

0.60

40%

64%

55%

81%

10%

p. 28/41

Report for EMA and rapporteurs regarding HPV

04/09/2015

Investigations

Exposure during pregnancy

Vaccination site pain

Injection site pain

Pharmacist

Other Health Professional

Other

Bad Report

Not Conv/Unspecified

8108

1502

1354

6163

1038

6129

2207

35685

23825

1.47

1.76

2.13

2.31

2.71

3.52

3.76

4.96

6.45

2.10

3.54

4.34

3.32

4.92

4.49

5.97

5.48

8.23

0.94

0.60

0.80

1.54

1.38

2.76

2.42

4.51

5.29

10%

18%

14%

29%

10%

79%

53%

Comparison of all HPV reports to all other vaccine reports in females, aged 9-25

This analysis has compared 45,876 reports for HPV vaccine with 79,678 reports for all other vaccines which

were received from females between the ages of 9-25 years of age. The most frequent vaccines contained

in the reports for “other vaccines” were hepatitis B vaccines (12,662 reports), meningococcal vaccines

(11,587 reports), influenza vaccines (6,941 reports), varicella zoster vaccines (5690 reports), and MMR

vaccines (5,465 reports).

A significantly increased proportion of HPV reports were classified as

serious

compared to other vaccine

reports.

Seriousness

Number

of HPV

Reports

Number

of other

vaccine

reports

7410

Log

005

Log

095

% of total

HPV

reports

% of

total

other

vaccine

reports

11.1%

SeriousOrFatal

8976

0.90

0.86

0.93

19.6%

NonSerious

36900

59316

-0.95

-0.97

-0.93

80.4%

88.9%

p. 29/41

Report for EMA and rapporteurs regarding HPV

04/09/2015

The

countries

reporting a significantly increased proportion of HPV reports compared to other vaccine

reports were Malaysia, Italy, Japan, Denmark, and Australia. The countries reporting a significantly

decreased proportion of HPV reports were Canada, the UK, Sweden, and France.

Country

Number

of HPV

Reports

Number Log

of other OR

vaccine

reports

135

1229

141

210

1930

3.56

2.04

1.31

0.74

0.72

Log

OR 005

Log

095

% of total % of

HPV

total

reports

other

vaccine

reports

12.9%

10.1%

2.0%

1.2%

5.3%

0.2%

1.8%

0.2%

0.3%

2.9%

Malaysia

Italy

Japan

Denmark

Australia

5927

4622

918

549

2420

3.52

1.99

1.21

0.62

0.65

3.61

2.09

1.41

0.86

0.78

New Zealand

France

Sweden

United Kingdom

Canada

449

620

585

1048

1660

2792

3236

8096

6034

-0.83

-1.17

-1.41

-2.14

-3.32

-0.96

-1.29

-1.52

-2.24

-3.49

-0.71

-1.06

-1.29

-2.05

-3.16

1.0%

1.4%

1.3%

2.3%

0.1%

2.5%

4.2%

4.8%

12.1%

9.0%

We are currently investigating the explanation for the geographical differences. It is noted that Japan and

Denmark, those countries reporting a high incidence of serious adverse events, are over-represented in the

HPV reports. However, there are number of countries which have incorporated HPV into their national

vaccination programmes which are under-represented in the HPV reports (the UK, Canada, and Sweden).

The differences may be related to the status of the HPV vaccine in the routine childhood vaccination

programs, the vaccination coverage or vaccine uptake, and/or potentially administrative issues (for

example, there can be a delay in the transfer of adverse event reports from national reporting centers to

UMC, and these delays may vary by country ).

The

MedDRA System Organ Classes (SOC)

most over-represented in HPV reports were the Reproductive

system and breast disorders SOC, the Investigations SOC, and Surgical and medical procedures. The SOC

most under-represented in the HPV reports were Immune system disorders, Infections and infestations,

p. 30/41

Report for EMA and rapporteurs regarding HPV

04/09/2015

and Skin and subcutaneous disorders. Both the Nervous system disorders and Psychiatric disorders SOC

were also over-represented in the HPV reports.

MedDRA SOC

Number Number Log

of HPV

of other OR

Reports vaccine

reports

1433

8145

1164

795

4459

440

291

5025

396

312

3484

1.53

1.28

1.16

0.90

0.84

0.82

Log

005

Log

095

% of

total

HPV

reports

3.1%

17.8%

2.5%

1.7%

9.7%

1.0%

% of

total

other

vaccine

reports

0.4%

7.5%

0.6%

0.5%

5.2%

0.1%

Reproductive system and

breast disorders

Investigations

Surgical and medical

procedures

Social circumstances

Injury, poisoning and

procedural complications

Neoplasms benign,

malignant and unspecified

(incl cysts and polyps)

Nervous system disorders

Psychiatric disorders

1.45

1.24

1.07

0.80

0.79

0.69

1.62

1.32

1.25

1.01

0.90

0.94

20963

2382

22921

2151

0.67

0.57

0.64

0.50

0.69

0.64

45.7%

5.2%

34.4%

3.2%

Skin and subcutaneous

tissue disorders

Infections and infestations

Immune system disorders

8289

2434

898

18476

6252

3032

-0.76

-0.77

-0.94

-0.80

-0.84

-1.04

-0.72

-0.71

-0.84

18.1%

5.3%

2.0%

27.7%

9.4%

4.5%

The

MedDRA High Level Terms (HLT)

most over-represented in HPV reports were imaging procedures,

vaccination site reactions and exposures associated with pregnancy, delivery and lactation. The HLT most

under-represented in HPV reports were application and instillation site reactions, infections NEC, and

allergic conditions NEC.

There were a number of HLT over-represented in the HPV reports into which many of symptoms of interest

are located, suggesting that these symptoms are potentially specific for HPV vaccines. Additionally, there

are a number of HLT describing diagnostic procedures which implies serious events without a clear

diagnosis of clinical grounds. These HLT of interest are bolded in the table below.

p. 31/41

Report for EMA and rapporteurs regarding HPV

04/09/2015

MedDRA HLT

Number

of HPV

Reports

Number

of other

vaccine

reports

552

564

655

Log OR

Log

005

Log

095

% of

total

HPV

reports

5.0%

4.9%

3.5%

% of

total

other

vaccine

reports

0.8%

1.0%

Imaging procedures NEC

Vaccination site reactions

Exposures associated with

pregnancy, delivery and

lactation

Neurologic diagnostic

procedures

Disturbances in

consciousness NEC

Reproductive hormone

analyses

Muscle weakness

conditions

Investigations NEC

Disability issues

Seizures and seizure

disorders NEC

Menstruation and uterine

bleeding NEC

Non-site specific injuries

NEC

Central nervous system

imaging procedures

Reproductive organ and

breast histopathology

procedures

Blood counts NEC

Site specific injuries NEC

2277

2237

1612

1.73

1.70

1.21

1.66

1.63

1.12

1.80

1.77

1.29

1116

7268

830

1260

1810

709

2086

494

1120

640

376

354

4936

206

525

1068

233

1327

574

222

1.17

1.12

1.11

1.08

0.95

0.92

0.91

0.90

0.85

1.08

1.00

0.99

0.87

0.81

0.84

0.79

0.80

0.74

0.72

1.27

1.17

1.21

1.17

1.03

0.99

1.03

0.99

0.96

0.97

2.4%

15.8%

1.8%

2.7%

3.9%

1.5%

4.5%

1.1%

2.4%

1.4%

0.8%

0.5%

7.4%

0.3%

0.8%

1.6%

0.3%

2.0%

0.1%

0.9%

0.3%

0.0%

774

524

351

150

0.82

0.81

0.71

0.69

0.93

1.7%

1.1%

0.5%

0.2%

p. 32/41

Report for EMA and rapporteurs regarding HPV

04/09/2015

ECG investigations

Protein analyses NEC

Autoimmunity analyses

Bacteria identification and

serology (excl mycobacteria)

Neurological signs and

symptoms NEC

Physical examination

procedures and organ

system status

Virus identification and

serology

Gastrointestinal and

abdominal imaging

procedures

Vascular tests NEC (incl

blood pressure)

Therapeutic and

nontherapeutic responses

578

575

523

615

7315

1430

201

204

184

302

6769

1051

0.80

0.79

0.75

0.69

0.68

0.67

0.63

0.58

0.65

0.60

0.91

0.90

0.87

0.80

0.73

0.78

1.3%

1.1%

1.3%

15.9%

3.1%

0.3%

0.5%

10.1%

1.6%

765

332

446

0.68

0.57

0.54

0.79

0.81

1.7%

0.7%

0.1%

603

1834

305

1468

0.67

0.66

0.56

0.58

0.78

0.74

1.3%

4.0%

0.5%

2.2%

Erythemas

Pruritus NEC

Dermal and epidermal

conditions NEC

Febrile disorders

Bacterial infections NEC

Rashes, eruptions and

exanthems NEC

Oedema NEC

Non-site specific vascular

disorders NEC

Allergic conditions NEC

Infections NEC

1493

1856

763

4388

214

2413

917

389

208

3590

4438

2065

9904

884

6370

3029

826

2241

1842

-0.61

-0.64

-0.67

-0.81

-0.92

-1.07

-1.27

-1.40

-0.70

-0.71

-0.74

-0.72

-0.82

-0.88

-1.02

-1.25

-1.40

-1.54

-0.53

-0.56

-0.53

-0.61

-0.53

-0.74

-0.82

-0.91

-1.14

-1.26

3.3%

4.0%

1.7%

9.6%

0.5%

5.3%

2.0%

0.1%

0.8%

0.5%

5.4%

6.7%

3.1%

14.8%

1.3%

9.5%

4.5%

1.2%

3.4%

2.8%

p. 33/41

Report for EMA and rapporteurs regarding HPV

04/09/2015

Application and instillation

site reactions

123

1930

-1.65

-1.80

-1.50

0.3%

2.9%

Given the above results, a decision was taken to explore the impact of lowering the threshold of statistical

significance to log OR 005 > 0.25. When this adjustment is made, a number of additional, and more

specific, HLT become highlighted as key features; many of these highlighted features contain PTs describing

symptoms which are of clinical interest. These HLT of interest are bolded in the table below.

MedDRA HLT

Number Number Log

of HPV

of other OR

Reports vaccine

reports

458

613

490

2139

221

383

262

1995

Log

005

Log

095

% of

total

HPV

reports

1.0%

1.3%

1.1%

4.7%

% of

total

other

vaccine

reports

0.3%

0.6%

0.4%

3.0%

Haematological analyses NEC

White blood cell analyses

Urinalysis NEC

Gastrointestinal and

abdominal pains (excl oral and

throat)

Migraine headaches

Cardiac function diagnostic

procedures

Menstruation with decreased

bleeding

Red blood cell analyses

Gait disturbances

Visual disorders NEC

Skin neoplasms benign

Alopecias

Muscle related signs and

symptoms NEC

Therapeutic procedures NEC

Asthenic conditions

Microbiology and serology tests

NEC

0.59 0.46

0.57 0.46

0.57 0.45

0.52

0.45

0.71

0.69

0.60

486

282

250

347

698

1067

218

347

760

363

5626

389

261

133

506

904

153

610

180

6197

214

0.57

0.45

0.57 0.43

0.55 0.42

0.52

0.41

0.51 0.41

0.54 0.39

0.52 0.38

0.48

0.37

0.50 0.37

0.41

0.36

0.49 0.36

0.69

0.71

0.68

0.63

0.60

0.67

0.64

0.58

0.63

0.46

0.61

1.1%

0.6%

0.5%

0.8%

1.5%

2.3%

0.5%

0.8%

1.7%

0.8%

12.3%

0.8%

0.4%

0.1%

0.0%

0.2%

0.8%

1.4%

0.0%

0.2%

0.9%

0.3%

9.3%

0.3%

p. 34/41

Report for EMA and rapporteurs regarding HPV

04/09/2015

Sensory abnormalities NEC

Carbohydrate tolerance

analyses (incl diabetes)

Skin injuries NEC

Ocular nerve and muscle

disorders

Memory loss (excl dementia)

Musculoskeletal and

connective tissue pain and

discomfort

Inflammations

Metabolism tests NEC

Thyroid analyses

Cervix disorders NEC

Respiratory tract and thoracic

imaging procedures

Platelet analyses

Mental impairment (excl

dementia and memory loss)

Musculoskeletal and

connective tissue signs and

symptoms NEC

Tremor (excl congenital)

Site specific vascular disorders

NEC

Mineral and electrolyte

analyses

Pituitary analyses anterior

Papilloma viral infections

Induced abortions

485

354

369

474

336

2871

324

180

199

318

168

3058

0.47

0.35

0.48 0.35

0.48 0.34

0.46 0.34

0.47

0.34

0.40

0.33

0.59

0.61

0.60

0.58

0.60

0.46

1.1%

0.8%

1.0%

0.7%

6.3%

0.5%

0.3%

0.5%

0.3%

4.6%

319

292

214

179

302

258

318

749

151

129

159

109

179

681

0.47 0.33

0.46 0.32

0.46 0.31

0.42 0.28

0.43 0.28

0.42

0.28

0.39

0.28

0.60

0.59

0.60

0.55

0.56

0.55

0.49

0.7%

0.6%

0.5%

0.4%

0.7%

0.6%

0.7%

1.6%

0.2%

0.1%

0.0%

0.2%

0.3%

1.0%

944

1773

241

200

153

164

911

1899

103

0.38 0.28

0.35 0.27

0.40 0.26

0.41 0.26

0.41 0.25

0.40 0.25

0.47

0.43

0.54

0.55

0.56

0.54

2.1%

3.9%

0.5%

0.4%

0.3%

0.4%

1.4%

2.8%

0.2%

0.1%

0.0%

The

MedDRA preferred terms (PT)

most over-represented in HPV reports were vaccination site pain, loss of

consciousness, exposure during pregnancy, presyncope, syncope, and muscular weakness. Also

p. 35/41

Report for EMA and rapporteurs regarding HPV

04/09/2015

significantly over-represented in the HPV reports were the PTs of activities of daily living impaired,

computerised tomography normal, and magnetic resonance imaging normal.

The PTs most under-represented in HPV reports were application site reaction, injection site reaction,

injection site inflammation, injection site hypersensitivity, and injection site oedema. Also significantly

under-represented were maculopapular rash, rash and face oedema.

MedDRA PT

Number Number Log

of HPV

of other OR

Reports vaccine

reports

1354

2146

1504

974

4673

1260

1039

6176

911

502

470

514

501

531

438

1645

652

266

879

580

310

3003

525

386

4457

343

127

137

165

1148

324

Log

005

Log

095

% of total % of

HPV

total

reports

other

vaccine

reports

3.0%

4.7%

3.3%

2.1%

10.2%

2.7%

2.3%

13.5%

2.0%

1.1%

1.0%

1.1%

1.2%

1.0%

3.6%

1.4%

0.4%

1.3%

0.9%

0.5%

4.5%

0.8%

0.6%

6.7%

0.5%

0.1%

0.2%

0.1%

1.7%

0.5%

Vaccination site pain

Loss of consciousness

Exposure during pregnancy

Presyncope

Syncope

Muscular weakness

Fall

Injection site pain

Immediate post-injection

reaction

Vaccine positive

rechallenge

Vaccination site reaction

Computerised tomogram

normal

Laboratory test normal

Activities of daily living

impaired

Nuclear magnetic

resonance imaging normal

Convulsion

Lethargy

1.51 1.42

1.32 1.25

1.21 1.13

1.10 1.00

1.10 1.04

1.08 0.99

1.06 0.96

1.01 0.96

0.99 0.88

0.93 0.81

0.86 0.73

0.83 0.71

0.80 0.68

0.79 0.67

0.78 0.66

0.77 0.69

0.71 0.60

1.59

1.39

1.29

1.20

1.15

1.17

1.15

1.05

1.09

1.05

0.98

0.95

0.92

0.91

0.85

0.82

p. 36/41

Report for EMA and rapporteurs regarding HPV

04/09/2015

Head injury

Blood test

Smear cervix abnormal

Vaccination site swelling

Laboratory test

Full blood count normal

Electroencephalogram

normal

No reaction on previous

exposure to drug

Injection site swelling

435

431

277

389

415

449

309

321

2719

130

106

131

167

2413

0.71 0.58

0.70 0.57

0.68 0.54

0.67 0.54

0.66 0.54

0.66 0.52

0.65 0.51

0.61 0.55

0.83

0.82

0.81

0.80

0.79

0.78

0.68

0.9%

0.6%

0.8%

0.9%

1.0%

0.7%

5.9%

0.2%

0.0%

0.2%

0.3%

0.1%

3.6%

Chills

Pyrexia

Cellulitis

Infection

Oedema

Face oedema

Injection site warmth

Rash

Rash maculo-papular

Pruritus

626

4242

130

344

1788

110

1333

1745

9794

661

635

766

702

1363

4892

787

3906

-0.74

0.63

-0.75

0.70

-0.88

0.72

-0.89

0.72

-0.91

0.75

-0.96

0.79

-0.94

0.81

-0.89

0.81

-0.98

0.82

-0.94

0.85

-0.51

-0.64

-0.56

-0.57

-0.60

-0.64

-0.68

-0.74

-0.67

-0.76

1.4%

9.2%

0.2%

0.3%

0.2%

0.7%

3.9%

0.2%

2.9%

2.6%

14.7%

1.0%

1.1%

2.0%

7.3%

1.2%

5.9%

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Drug ineffective

Skin reaction

Vasodilatation

Injection site abscess

Hypersensitivity

Injection site oedema

Injection site

hypersensitivity

Injection site inflammation

Injection site reaction

Application site reaction

339

106

400

679

789

793

935

2127

1325

1196

1607

3221

1733

-1.15

0.98

-1.16

0.99

-1.29

1.11

-1.41

1.24

-1.43

1.30

-1.52

1.36

-1.66

1.49

-1.65

1.49

-1.82

1.69

-1.94

1.77

-0.81

-0.83

-0.94

-1.07

-1.17

-1.20

-1.32

-1.34

-1.56

-1.61

0.0%

0.1%

0.0%

0.7%

0.2%

0.0%

0.2%

0.9%

0.1%

1.0%

1.2%

1.4%

3.2%

2.0%

1.8%

2.4%

4.8%

2.6%

There were no statistically significant differences noted between the groups of reports for any specific

diagnoses. Postural orthostatic tachycardia syndrome had been reported 82 times for HPV vaccine and 1

time for other vaccines (0.2% vs 0.0%), complex regional pain syndrome: 69 times for HPV vaccine and 16

times for other vaccines (0.2% vs 0.0%). autonomic nervous system imbalance: 76 times for HPV vaccine

and 16 times for other vaccines (0.2% vs 0.0%), chronic fatigue syndrome: 65 for HPV vaccine and 30 times

for other vaccines (0.1% vs 0.0%), fibromyalgia: 62 times for HPV vaccine and 39 times for other vaccines

(0.1% vs 0.1%), post viral fatigue syndrome: 47 times and 53 times for other vaccines (0.1% and 0.1%) and

finally autonomic nervous system imbalance: 76 times for HPV vaccine and 16 times for other vaccines

(0.2% vs 0.0%).

4. Conclusions

This report has been prepared to describe the adverse event profile for HPV vaccine using worldwide

VigiBase data, specifically as it relates to the safety concern of POTS and related symptomalogy which have

been reported from the unexpectedly high proportion of serious adverse event reports from Denmark.

The description of the reports of POTS and the related syndromes of CRPS, CFS, PVFS, fibromyalgia reveal a

number of potentially important findings. First, there is a large overlap between the different syndromes

observed in the comparison of the top co-reported PTs (in other words, symptomatology): fatigue is

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Report for EMA and rapporteurs regarding HPV

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reported in greater than 50% of subjects who co-report POTS (65%), CFS (51%), PVFS (63%), and

fibromyalgia (52%). Headache is also reported in greater than 50% of subjects who co-report POTS (71%),

CFS (50%), and PVFS (52%). Dizziness is an important PT which is also consistently highly reported amongst

cases of POTS (61%), CFS (36%), and PVFS (44%). While it is acknowledged that these symptoms can be

non-specific and are commonly occuring events, it is noted that the reports of POTS, CFS and PVFS from

which these events arose have been largely classified as serious reports (POTS 80%, CFS 78%, PVFS 89%)

implying the need for hospitalisation and/or resulting in disability or interruption of normal function.

Second, there are geographic differences, specifically within Europe, noted in the reporting of POTS and

other syndromes. A fairly consistent finding is that the majority of reports of POTS and other syndromes

arise from the US (POTS 52%, CFS 51%, ME/PVFS 40%). In contrast, DK represents 38% of reports of POTS

and the UK represents only 4.8%; however, the UK represents 26% of the reports of CFS and DK represents

only 6.4%. Furthermore, the UK represents 39% of reports of PVFS and DK represents only 4.8%. Such

differences could be speculated to represent coding variation between Denmark and other European

countries (for example, UK): the same constellation of symptoms have been coded to different diagnositic

PTs. Finally, the graphical display of reports over time demonstrate that the total number of reports of

POTS, CRPS, CFS and fibromyalgia have been increasing since 2012 with a marked increase between 2012

and 2013. A review of the introduction of HPV into the routine vaccination programmes throughout the

world, specifically in Europe, would be of interest to explore this finding further. Furthermore, the total

number of POTS cases for half of the year of 2015 is equivalent to the total number of cases for the whole

of 2014.

The presentation of the most commonly reported PTs and HLTs has also allowed a number of observations.

First, the comparison between the WHO database and the DK database show a consistency in the top

reported adverse events: for example, headache and dizziness are both within the top 3 reported terms

and there is a 60% similarity in the listing of the top 10 events between the databases. A comparison of

HPV vaccines to all other vaccines in females, at both the PT and HLT term levels, showed a consistency

between HPV reports in the different age groups (neurological and asthenia symptoms: headache,

dizziness, syncope) and a difference to all other vaccines (febrile and general signs and symptoms: fever,

nausea, headache).

The first vigiPoint analysis has provided a comparison of HPV reports from Denmark to all other HPV

reports included in VigiBase. Danish HPV reports more commonly are classified as serious than all other

HPV reports; however, it is also noted that they are of a higher quality with more complete information.

There were a number of PTs which appear more commonly in Danish reports; however, many of these

were of a diagnostic nature (such as POTS, autonomic nervous system imbalance, orthostatic intolerance).

There was no difference in the reports from Denmark and those from the rest of the world in those PT

which describe symptomatology (such as headache, dizziness, activities of daily living impaired).

The second vigiPoint analysis have allowed for a comparison of the characteristics of HPV reports to all

other vaccine reports included in Vigibase which have been reported for the subset of females ages 9-25

years of age. The results show that a greater proportion of HPV reports are serious and describe events

which are consistent with symptomatology included in the clinical case working definition for myalgic

encephalitis / chronic fatigue syndrome (ME/CFS) as described by the Canadian ME/CFS guidelines in the

Journal of Chronic Fatigue Syndrome in 2003. This finding is potentially significant because, although

ME/CFS is more common the adolescent female population, it is being reported more commonly with HPV

vaccine in comparison to other vaccines in this same population.

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According to the diagnostic protocol for ME/CFS, a patient will meet the criteria for fatigue, post-exertional

malaise, sleep dysfunction, and pain. Furthermore, the patient will have two or more neurological /

cognitive manifestations and one or more symptoms from two of the categories of autonomic,

neuroendocrine and immune manifestations. Finally, the illness should have a distinct onset and have

persisted for at least 3 months in a pediatric subject.

The corresponding highlighted HLT when HPV reports were compared with all other vaccine reports in

females 9-25 years of age were:

Fatigue: Asthenia conditions (12.3% in HPV reports compared to 9.3% in all other vaccine reports)

Post-exertional malaise: Disability issues (1.5% compared to 0.3%), Muscle weakness conditions (2.7%

compared to 0.8%) and Gait disturbances (1.5% compared to 0.8%)

Pain: Gastrointestinal and abdominal pains (4.7% compared to 3.0%), Migraine headaches (1.1% compared

to 0.4%), and Musculoskeletal and connective tissue pain and discomfort (6.3% compared to 4.6%).

Neurological / Cognitive manifestations: Neurological signs and symptoms NEC (15.9% compared to 10.1%),

Visual disorders NEC (2.3% compared to 1.4%), Sensory abnormalities NEC (1.1% compared to 0.5%);

Mental impairment (excluding dementia and memory loss) (0.7% compared to 0.3%), and Tremor

(excluding congenital) (2.1% compared to 1.4%).

Furthermore, there is evidence from the reports that the HPV patients reporting these symptoms have

undergone extensive medical evaluation, as there are a number of relevant HLT which suggest abnormality

of cardiac, nervous system dysfunction; all of which were significantly over-represented in the HPV reports

compared to all other vaccine reports in the same age group: Neurological diagnostic procedures (2.4%

compared to 0.5%), Central nervous system imaging procedures (1.4% compared to 0.3%), ECG

investigations (1.3% compared to 0.3%), Gastrointestinal and abdominal imaging procedures (0.7%

compared to 0.1%), Vascular tests (1.3% compared to 0.5%).

In summary, this review of VigiBase data suggests that there is an increasing trend in the number of HPV

reports of containing the PTs of POTS and related syndromes. Furthermore, there is the suggestion that a