SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

Sundheds- og Ældreudvalget 2015-16
SUU Alm.del Bilag 68
Offentligt

11 November 2015

EMA/762033/2015

Pharmacovigilance Risk Assessment Committee (PRAC)

Cervarix: EMEA/H/A20/1421/C/0721/0071

Gardasil: EMEA/H/A20/1421/C/0703/0060

Silgard: EMEA/H/A20/1421/C/0732/0054

Gardasil 9: EMEA/H/A20/1421/C/3852/0001

Note

information of a commercially confidential nature deleted.

30 Churchill Place

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Assessment report as adopted by the PRAC and taken into account by the CHMP in its opinion with all

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Procedure numbers:

An agency of the European Union

Human papillomavirus (HPV) vaccines

Review under Article 20 of Regulation (EC) No 726/2004

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SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

Table of contents

Table of contents ......................................................................................... 2

1. Background information on the procedure .............................................. 3

2. Scientific discussion ................................................................................ 4

2.1. Introduction......................................................................................................... 4

2.2. Data on safety ................................................................................................... 12

2.2.1. Cervarix ......................................................................................................... 13

2.2.2. Gardasil/Silgard/Gardasil 9 ............................................................................... 15

2.2.3. Literature review ............................................................................................. 17

3. Expert consultation ............................................................................... 32

5. Overall discussion and conclusions........................................................ 37

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6. Grounds for the PRAC recommendation ................................................. 39

4. Pharmacovigilance activities ................................................................. 36

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2.2.4. Other data ...................................................................................................... 24

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SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

1. Background information on the procedure

Human papillomavirus (HPV) vaccines have been authorised in the European Union since 2006 for the

prevention of premalignant genital lesions (cervical, vulvar and vaginal), and cervical cancers caused

by HPV infection. Gardasil, Silgard and Gardasil 9 are additionally indicated for prevention of

premalignant anal lesions, and anal cancers and genital warts (condyloma

acuminata)

causally related

to specific HPV types. Following approval, these vaccines have been introduced in national

immunisation programs worldwide, including in most EU Member States.

The efficacy and safety of the HPV vaccines have been evaluated in large clinical studies and the

benefit of these vaccines in protecting against HPV related diseases is well established. Every year,

34,000 women in Europe are diagnosed with cervical cancer, and 13,000 of them die. The use of HPV

Since launch, more than 63 million subjects are estimated to have been vaccinated with Gardasil

subjects worldwide.

association between the use of the vaccines and two syndromes in particular, which are known as

Complex regional pain syndrome (CRPS) and Postural orthostatic tachycardia syndrome (POTS). The

Individual case reports and case series of CRPS and POTS suspected to be linked to a HPV vaccine

have been published in the literature from several geographically distinct locations. Literature reports

of CRPS come from Australia, Germany and Japan and reports of POTS originate from USA, Japan and

Denmark.

whether the currently available data supports a causal association with HPV vaccines.

The majority of POTS cases that have been reported come from one clinic in Denmark. Furthermore,

(EC) No 726/2004 resulting from pharmacovigilance data. The EC requested the Agency to give its

opinion on whether there is evidence of a causal association between HPV vaccines and CRPS and/or

POTS, and if available information may require updates to the advice to healthcare professionals and

patients, including changes to product information or other regulatory measures on the marketing

authorisations concerned.

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On 09 July 2015 the European Commission (EC) triggered a procedure under Article 20 of Regulation

asked the European Commission to initiate another in depth review.

vaccine, and concerns regarding the safety of these vaccines have been raised. Therefore, Denmark

there has been great media attention regarding potential adverse reactions associated with the HPV

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with the HPV vaccines is greater than would ordinarily be expected in the absence of vaccination and

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therefore important to undertake further review to determine whether the number of cases reported

recognised that these syndromes can occur in the general non-vaccinated population and it was

These syndromes have been known for a long time before the introduction of the HPV vaccines. It is

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relationship with HPV vaccines has not been concluded in these previous procedures.

reviewed repeatedly since 2013 by the PRAC within routine safety follow-up procedures, and a

majority of the reported cases do not have a well-defined diagnosis. These syndromes have been

Routine surveillance of suspected adverse reaction reports has raised questions on the potential

worldwide. Cumulative marketing exposure to Cervarix is estimated as being more than 19 million

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vaccines are expected to eventually prevent a large proportion of these cases.

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2. Scientific discussion

2.1. Introduction

HPV infection

HPV infection causes benign and malignant dysplastic disease in both men and women, localized

primarily in the anogenital area and aerodigestive tract. Persistent HPV infection significantly increases

the risk of cervical and other anogenital cancers, and oropharyngeal cancers. Overall, HPV is

responsible for approximately 5% of the global cancer disease burden.

Cervical Cancer and Precancerous Dysplasia.

Nearly 100% of cervical cancers are caused by HPV

infection. Cervical cancer is the second most common cancer in women worldwide, with approximately

34,000 new cervical cancer cases are diagnosed every year causing about 13,000 deaths per year.

every year in Europe.

The incidence of HPV-associated oropharyngeal cancer is also increasing and approximately 8,100 new

HPV-related oropharyngeal cancer cases are estimated to be diagnosed every year in Europe.

Benign HPV Disease.

Infection with HPV also causes benign lesions like

condyloma acuminata

(anogenital warts) located in the genital or perianal region and juvenile recurrent respiratory

papillomatosis (RRP) primarily located in the larynx. RRP is rare but can be life-threatening and is

lesions is often lengthy and painful, and RRP often has high recurrence rate. In Europe, the incidence

sensory, vasomotor, sudomotor, motor and dystrophic changes after injury to that limb. The events

surgery, but may also include injections, local infections, burns, frostbites, even pregnancy, as well as

stroke or myocardial infarction. However, the exact nature and combination of CRPS symptoms and

their severity are not related to the severity of precipitating trauma, and more than 10% of patients

may not even recall any precipitating event. CRPS can be divided into two types based on the absence

(CRPS-1, much more common) or presence (CRPS-2) of a lesion to a major nerve.

CRPS usually affects one limb, but in a small proportion of cases may later spread to additional limbs.

Pain is typically the predominant symptom of CRPS, often associated with limb dysfunction and

psychological distress.

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that precipitate CRPS are most commonly some sort of trauma, such as fractures, sprains, and

Complex regional pain syndrome (CRPS) is a debilitating, painful condition in a limb, associated with

Complex regional pain syndrome (CRPS)

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general population, and is generally found to be highest among 20-24 years old individuals.

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rate of anogenital warts is estimated to vary between 150 and 170 per 100,000 person-year in the

thought to occur by transmission of the virus from an infected mother to her child. Treatment of these

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about 16,000 new non-cervical HPV-related anogenital cancer cases are diagnosed in men and women

70% of vaginal cancers, and 30 to 40% of penile cancers are estimated to be caused by HPV infection;

several decades. In Europe, for example, approximately 90% of anal cancers, 15% of vulvar cancers,

concern, the incidence of anal cancer has been increasing in both men and women over the past

but taken together, they represent a significant human health and economic burden. Of particular

oropharyngeal cancers. Each of the HPV-related diseases is much less frequent than cervical cancer,

Non-Cervical HPV Disease.

Infection with HPV is also associated with anal, vulvar, vaginal, penile, and

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530,000 new cases diagnosed each year and 275,000 deaths annually. In the European Union, about

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The diagnosis of CRPS is based on clinical examination and is given when patients meet certain

diagnostic criteria (Harden et al, 2007

and 2010)

. There are no specific imaging or laboratory tests

for CRPS. An international consensus group has agreed on criteria for CRPS (the ‘Budapest’ criteria,

table 1). These criteria were developed by using approved and codified, empirically validated,

statistically derived revisions of the International Association for the Study of Pain (IASP) criteria for

CRPS.

The ‘Budapest’ criteria are summarised in the table 1 below.

Table 1. - The ‘Budapest’ criteria for CRPS

considered best practice in order to avoid secondary physical problems associated with disuse of the

possible conditions seen by practitioners from various professional backgrounds, patients commonly

Two population-based studies

3,4

of outcome in CRPS have been published. One suggested that 74% of

Another suggested that only 30% of CRPS patients considered themselves recovered, 16% still

suffered from severe progressive disease, and the remainder was stable an average of 5.8 years after

onset.

Harden et al, (2007), Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med;8(4):326-31.

Harden et al, (2010), Validation of proposed diagnostic criteria (the "Budapest Criteria") for Complex Regional Pain

Syndrome. Pain. Aug;150(2):268-74

Sandroni et al, (2003) Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a

population-based study. Pain;103(1-2):199-207.

de Mos et al, (2009) Outcome of the complex regional pain syndrome Clin J Pain; 25,590–597

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patients experienced resolution of the syndrome, with symptoms lasting a median of 7 months.

these patients are referred to pain specialists for adequate assessment and tailored treatment

experience a delay in diagnosis and the start of appropriate therapies. It is generally expected that

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Since the condition is infrequent, and the range of symptoms can mimic a large number of other

affected limb and the psychological consequences of living with undiagnosed chronic pain.

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immobilisation of the limb. There is no proven cure for CRPS. Prompt diagnosis and early treatment are

The onset of symptoms in the majority of cases occurs within one month of the trauma or

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A definition of recovery from CRPS has not yet been agreed. Limb signs (such as swelling, sweating

and colour changes) usually reduce with time, even where pain persists. However, such reduction of

limb signs is in itself not ‘recovery’. Where pain persists, the syndrome is best considered to be active.

Approximately 15% of sufferers will have unrelenting pain and physical impairment >5 years after

CRPS onset, although more patients will have a lesser degree of ongoing pain and dysfunction

impacting on their ability to work and function normally. For those in whom pain persists, psychological

symptoms (anxiety, depression), and loss of sleep are likely to develop, even if they are not prominent

at the outset.

Based on data by de Mos and colleagues (2007)

, the incidence rate of CRPS-1 in the background

population is reported to be 14.9 and 28.0 per 100,000 person-years in females 10-19 years old and

20-29 years old, respectively. Corresponding rates were lower in males, reported to be 1.8 and 6.2 per

100,000 person-years in males 10-19 years old and 20-29 years old, respectively.

Overall, given the complexity of the syndrome and likely differential practice in approaches to

between countries.

Postural orthostatic tachycardia syndrome (POTS)

hypotension. In POTS, this excessive heart rate increase is usually accompanied by a range of

weakness, ‘brain-fog’, peripheral coldness and purplish skin discolouration and blurred vision. Some

sufferers also experience fainting.

Although defined and diagnosed mainly by the tachycardia and orthostatic symptoms, POTS is often

associated with a wide range of other symptoms such as migraine-like headaches, chronic aches and

people will show different symptoms. This wide spectrum of symptoms probably reflects that the

syndrome has several distinct pathophysiological mechanisms.

If other causes are ruled out, POTS may be diagnosed if these chronic symptoms are also associated

see table 2).

The diagnostic criteria of POTS are based on the tilt-test or active standing test (also known as

Schellong test). Studies on subjects from the general population have suggested that having a positive

tilt-test in an adolescent patient – regardless of symptoms – is common (Singer et al, 2012

, Zhao et

de Mos et al, (2007) The incidence of complex regional pain syndrome: A population-based study, Pain; 129, 12-20.

Sheldon et al, (2015) 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural

tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 12(6): e41-63.

Singer et al, (2012). Postural tachycardia in children: what is normal? Journal of Pediatrics; 160:222-226.

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For those aged 12–19 years this increase should be least 40 beats per minute (Sheldon et al, 2015

;

minute or more within 10 minutes of standing (or with tilt table test), without a fall in blood pressure.

POTS to be diagnosed, patients need to experience a sustained increase in heart rate of 30 beats per

with an excessive increase in heart rate when changing from horizontal to a standing up position. For

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pattern of symptoms in POTS sufferers and, aside from the defining symptom of tachycardia, different

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significant overlap between POTS and Chronic fatigue syndrome (CFS). However, there is no set

of breath. In particular, fatigue is a very common feature and there is now recognised to be a

pains, gastrointestinal symptoms (nausea, bloating, abdominal pain), sleep disturbance and shortness

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symptoms of orthostatic intolerance. These symptoms may include palpitations, light headedness,

heart rate when changing from a lying down to a standing up position, without any orthostatic

Postural orthostatic tachycardia syndrome (POTS) is characterised by an abnormally large increase in

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diagnosis and management across countries and centres, reported background incidence may differ

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SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

al, 2015

). A diagnosis of POTS requires that other symptoms – such as light-headedness, dizziness, or

fatigue – are present as well. A definition of a syndrome that combines unspecific symptoms with a

diagnostic test that is frequently positive in the normal population underlines the difficulties of studying

such a syndrome and trying to establish reliable incidence estimates. This also underlines the necessity

to exclude other conditions before a diagnosis of POTS is made.

In many people diagnosed with POTS, the range of symptoms can have a detrimental impact on the

overall quality of life. Anxiety, depression, and other psychiatric disorders can also add to the

complexity of the syndrome.

Table 2. - Definition of cases for POTS (based on Raj SR, 2013

and Sheldon et al, 2015)

POTS can affect people of all ages, but the overwhelming majority of patients are women (80% to

85%) of child-bearing age (13–50 years). In adolescence, the majority of affected individuals report

symptoms beginning within a year or two of the beginning of puberty, with worsening symptoms until

the age of 16. About 80% of female patients report an exacerbation of symptoms around menstruation

sound familiar. Parents and adolescent patients with POTS often describe the long and difficult process

they experience from the moment they became ill, to decreased school attendance with dropped

identified in many adolescent POTS patients at presentation, including symptom onset during early

puberty, high achievers in school and athletics, joint hypermobility, and recent illness or injury. Many

adolescents with POTS have hyper-extensibility, and some are thought to have “benign joint

hypermobility syndrome”. It is not clear whether the elastic soft tissues actually predispose to the

development of POTS or if the lax tissues simply allow further increases in vasodilatation that make it

Zhao et al, (2015) A cross-sectional study on upright hear rate and BP changing characteristics: basic data for

establishing diagnosis of postural orthostatic tachycardia syndrome and orthostatic hypertension. BMJ Open; 5:e007356.

Raj SR, (2013) Postural tachycardia syndrome (POTS). Circulation. Jun 11;127(23):2336-42.

Kizilbash et al, (2014) Adolescent fatigue, POTS, and recovery: A guide for clinicians. Current Problems in Pediatric and

Adolescent Health Care. 44; 5, 108–133

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According to Kizilbash and colleagues (2014) there are several typical features retrospectively

find answers about their child's illness. In this process, they often receive different diagnoses.

extracurricular activities and poor academic performance, to visiting a variety of doctors in order to

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in adolescence. Whilst each patient has a unique set of symptoms, it is said that their stories often

A recent review by Kizilbash and colleagues (2014)

summarises what is currently known about POTS

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of POTS and diagnoses may be increasing.

each year. Although POTS is thought to be under-diagnosed, there is a gradually increasing awareness

(Raj SR, 2013). It is estimated that at least 150 girls and young women per million may develop POTS

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more likely for hyper-extensible individuals to report more venous pooling and dizziness when they get

POTS.

Patients frequently report that their symptoms began after acute stressors such as pregnancy, major

surgery, or a presumed viral illness, but in others cases, symptoms develop more insidiously (Raj SR,

2013). A large number of patients initially become symptomatic following a significant febrile illness,

often mononucleosis or influenza (Kizilbash et al, 2014).

The causes and pathophysiology of POTS are not well understood, and there is no single precipitating

factor. Although a decrease in return of blood to the heart generally underlies the symptoms of POTS,

the causes of this likely involve multiple abnormal or excessive physiological processes that differ

between sufferers. This is why POTS is classed as a syndrome, rather than a specific disease.

symptoms. About 50% of patients with post-viral POTS will have partial or complete recovery within

two to five years. Prognosis is generally better in younger people. Ninety per cent of patients will

patients experience deterioration in their daily life activity over time to such an extent that they are

respond to a combination of physical and pharmacotherapy (Grubb et al, 2006)

. Occasionally, some

dysfunction. Several studies have shown that POTS can also be diagnosed in those with CFS, ranging

from 13% (Lewis et al, 2013)

to 27% (Hoad et al, 2008)

. Some studies in the US suggest the

proportion of CFS patients with POTS is even higher. The level of overlap will likely depend on the

selection criteria within each study, and it is unclear how these estimates can be generalised. Donegan

and colleagues (2013)

provided an estimated background incidence rate of CFS among adolescent

diagnosed initially (or co-diagnosed) particularly in adolescents. With increasing recognition of POTS in

a subset of CFS patients, POTS may be a differential diagnosis in many who are under evaluation for

Grubb et al, (2006) The postural tachycardia syndrome: A concise guide to diagnosis and management. Journal

Cardiovascular Electrophysiology 17: 108-112

Lewis et al, (2013) Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural

orthostatic tachycardia syndrome. J.Int Med; 273, 5, 501–510

Hoad et al, (2008) Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue

syndrome. Q J Med. 101, 961-965.

Donegan et al, (2013) Bivalent human papillomavirus vaccine and the risk of fatigue syndromes in girls in the UK.

Vaccine; 31(43): 4961-7

Bakken et al, (2014) Two age peaks in the incidence of chronic fatigue syndrome/myalgic encephalomyelitis: A

population based registry study from Norway, BMC Medicine, 12:167

MacDonald et al, (2014) Postural tachycardia syndrome is associated with significant symptoms and functional

impairment predominantly affecting young women: a UK perspective. BMJ Open;4:e004127

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historically, many patients with POTS were given a diagnosis of CFS.

CFS. According to MacDonald and colleagues (2014)

, it is becoming increasingly clear that,

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(Lewis et al, 2013). As chronic fatigue is a common presenting feature in POTS, CFS may often be

with POTS form a subset of those with CFS with a specific group of particularly marked symptoms

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It is currently unclear whether POTS is a separate clinical entity distinct from CFS, or whether patients

estimate of 70 per 100,000 person-years in Norway.

girls of 30-70 per 100,000 person-years in the UK and Bakken and colleagues (2014)

provided an

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encephalomyelitis or ME) also show symptoms of orthostatic intolerance and signs of autonomic

Many patients diagnosed with Chronic fatigue syndrome (CFS, also known as myalgic

Overlap of POTS with Chronic fatigue syndrome (CFS)

unable to continue normal employment or educational activities.

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Many sufferers experience full recovery over time with or without treatment, but some have persistent

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Medicinal products involved in this review

HPV vaccines have been authorised in the European Union since 2006. Following approval, these

vaccines have been introduced in national immunisation programs worldwide, including in most EU

Member States.

Cervarix

Cervarix (Bivalent HPV vaccine (types 16, 18)) is a non-infectious recombinant vaccine prepared from

the highly purified virus-like particles (VLPs) of the major capsid L1 protein of oncogenic HPV types 16

and 18. This vaccine is adjuvanted with AS04 (composed of aluminium hydroxide and 3-O-desacyl-4’-

monophosphoryl lipid A (MPL)).

HPV 16 and HPV 18 are estimated to be responsible for approximately 70% of cervical cancers and 75-

intraepithelial neoplasia (CIN 2/3); 25% of low grade cervical intraepithelial neoplasia (CIN 1);

neoplasia and 80% of HPV related high-grade anal (AIN 2/3) intraepithelial neoplasia.

•

From 9 up to and including 14 years of age: 2 doses each of 0.5 ml. The second dose given

between 5 and 13 months after the first dose

; or 3 doses each of 0.5 ml at 0, 1, 6 months

From 15 years of age and above: 3 doses each of 0.5 ml at 0, 1, 6 months

†

•

Although the necessity for a booster dose has not been established, an anamnestic response has been

Neoplasia (CIN) grade 2 and 3 (CIN2/3) and cervical adenocarcinoma in situ (AIS) were used in the

month persistent infection. The primary analyses of efficacy were performed on the According to

Protocol cohort (ATP cohort: including women who received 3 vaccine doses and were DNA negative

and seronegative at month 0 and DNA negative at month 6 for the HPV type considered in the

analysis) This cohort included women with normal or low-grade cytology at baseline and excluded only

women with high-grade cytology (0.5% of the total population).

If the second vaccine dose is administered before the 5

month after the first dose, a third dose should always be

administered

If flexibility in the vaccination schedule is necessary, the second dose can be administered between 1 month and 2.5

months after the first dose and the third dose between 5 and 12 months after the first dose

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clinical trials as surrogate markers for cervical cancer. The secondary endpoints included 6- and 12-

endpoint was CIN2+ associated with HPV-16 and/or HPV-18 (HPV-16/18). Cervical Intraepithelial

infection, i.e. regardless of baseline cytology and HPV serological and DNA status. The primary efficacy

The phase III trial (study 008) enrolled women without pre-screening for the presence of HPV

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clinical trials that included a total of 19,778 women aged 15 to 25 years.

The efficacy of Cervarix was assessed in two controlled, double-blind, randomised Phase II and III

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Cervarix is for intramuscular injection in the deltoid region.

observed after the administration of a challenge dose.

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depends on the age of the subject:

can vary between countries depending on their official recommendations. The vaccination schedule

The age at which people receive the vaccine, e.g. in the context of a national vaccination programme,

(squamous-cell carcinoma and adenocarcinoma) caused by oncogenic HPV.

premalignant genital (cervical, vulvar and vaginal) lesions and cervical, vulvar and vaginal cancers

Cervarix is indicated in females from 9 years of age onwards for the prevention of persistent infection,

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approximately 70% of HPV related high-grade vulvar (VIN 2/3) and vaginal (VaIN 2/3) intraepithelial

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80% of anal cancers; 80% of adenocarcinoma in situ (AIS); 45-70% of high-grade cervical

SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

Vaccine efficacy against the primary endpoint CIN2+ at the end of study was 94.9% (95% CI 87.7;

98.4) against CIN2+ and 91.7% (95% CI 66.6;99.1) against CIN 3+ related to HPV 16/18. Vaccine

efficacy against virological endpoints (6-month and 12-month persistent infection) associated with

HPV-16/18 observed in the ATP cohort at the end of study was 94.3% (95% CI 92.0; 96.1) against 6-

month persistent infection and 92.9% (95% CI 89.4; 95.4) against 12-month persistent infection.

In a pooled analysis, 99.7% and 100% of females aged 9 years seroconverted to HPV types 16 and 18,

respectively after the third dose (at month 7) with GMTs at least 1.4-fold and 2.4-fold higher as

compared to females aged 10-14 years and 15 to 25 years, respectively.

In two clinical trials (HPV-012 & -013) performed in girls aged 10 to 14 years, all subjects

seroconverted to both HPV types 16 and 18 after the third dose (at month 7) with GMTs at least 2-fold

higher as compared to women aged 15 to 25 years.

In clinical trials (HPV-070 and HPV-048) performed in girls aged 9 to 14 years receiving a 2-dose

schedule (0, 6 months or 0, 12 months) and young women aged 15-25 years receiving Cervarix

according to the standard 0, 1, 6 months schedule, all subjects seroconverted to both HPV types 16

On the basis of these immunogenicity data, the efficacy of Cervarix is inferred from 9 to 14 years of

age.

September 2007. It is currently approved in 135 countries worldwide.

At the data lock point (15 June 2015) used for this analysis, a total of 57,094,396 doses have been

distributed worldwide, and the number of subjects exposed to at least one dose of Cervarix can be

estimated to be to 19 million.

Gardasil/Silgard

genital warts and 10% of low grade cervical intraepithelial neoplasia (CIN 1). CIN 3 and AIS have been

accepted as immediate precursors of invasive cervical cancer.

•

genital warts (condyloma

acuminata)

causally related to specific HPV types.

The efficacy of Gardasil was assessed in 16- through 26- year-old women in 4 placebo-controlled,

double-blind, randomized Phase II and III clinical studies including a total of 20,541 women, who were

enrolled and vaccinated without pre-screening for the presence of HPV infection. The primary analyses

of efficacy, with respect to vaccine HPV types (HPV 6, 11, 16, and 18), were conducted in the per-

protocol efficacy (PPE) population (i.e. all 3 vaccinations within 1 year of enrolment, no major protocol

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cancers and anal cancers causally related to certain oncogenic HPV types

•

premalignant genital lesions (cervical, vulvar and vaginal), premalignant anal lesions, cervical

Gardasil/Silgard are indicated for use from the age of 9 years of age for the prevention of:

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HPV types 16 and 18 are described above. HPV 6 and 11 are responsible for approximately 90% of

amorphous aluminium hydroxyphosphate sulphate.

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of the major capsid L1 protein of HPV types 6, 11, 16 and 18. The vaccine is adjuvanted with

recombinant quadrivalent vaccines (qHPV) prepared from the highly purified virus-like particles (VLPs)

Gardasil and Silgard are two different marketing authorisations for the same adjuvanted non-infectious

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Cervarix was first authorised in Australia in May 2007 and has been authorised in Europe since

years was non-inferior to the response after 3 doses in women aged 15 to 25 years.

and 18 one month after the second dose. The immune response after 2 doses in females aged 9 to 14

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deviations and naïve to the relevant HPV type(s) prior to dose 1 and through 1 month after dose 3

(Month 7)).

The primary efficacy endpoints included HPV 6-, 11-, 16-, or 18-related vulvar and vaginal lesions

(genital warts, VIN, VaIN) and CIN of any grade and cervical cancers (Protocol 013, FUTURE I), HPV

16- or 18-related CIN 2/3 and AIS and cervical cancers (Protocol 015, FUTURE II), HPV 6-, 11-, 16-, or

18-related persistent infection and disease (Protocol 007), and HPV 16-related persistent infection

(Protocol 005).

At end of study and in the combined protocol analysis, the efficacy of Gardasil against HPV 6-, 11-, 16-

, 18-related CIN 1 was 95.9 % (95% CI: 91.4, 98.4), the efficacy of Gardasil against HPV 6-, 11-, 16-,

18-related CIN (1, 2, 3) or AIS was 96.0% (95% CI: 92.3, 98.2), the efficacy of Gardasil against HPV

6-, 11-, 16-, 18-related VIN2/3 and VaIN 2/3 was 100% (95% CI: 67.2, 100) and 100% (95% CI:

was 99.0% (95% CI: 96.2, 99.9).

The quadrivalent human papillomavirus (qHPV) vaccine has been authorised in the EU for prevention of

cervical and various other cancers caused by HPV infection since 2006. Worldwide 190,897,611 doses

Gardasil 9

Gardasil 9 is an adjuvanted non-infectious recombinant 9-valent vaccine. It is prepared from the highly

purified virus-like particles (VLPs) of the major capsid L1 protein from the same four HPV types (6, 11,

16, 18) in qHPV vaccine Gardasil/Silgard and from 5 additional HPV types (31, 33, 45, 52, 58). It uses

the same amorphous aluminium hydroxyphosphate sulphate adjuvant as the qHPV vaccine.

high-grade cervical intraepithelial neoplasia (CIN 2/3), 85-90% of HPV related vulvar cancers, 90-95%

of HPV related high-grade vulvar intraepithelial neoplasia (VIN 2/3), 80-85% of HPV related vaginal

HPV related anal cancer, 85-90% of HPV related high-grade anal intraepithelial neoplasia (AIN2/3),

•

Efficacy and/or immunogenicity of Gardasil 9 were assessed in seven clinical studies. Clinical studies

evaluating the efficacy of Gardasil 9 against placebo were not acceptable because HPV vaccination is

recommended and implemented in many countries for protection against HPV infection and disease.

Assessment report

EMA/762033/2015

following HPV diseases:

Premalignant lesions and cancers affecting the cervix, vulva, vagina and anus caused by

vaccine HPV types

Genital warts (Condyloma

acuminata)

caused by specific HPV types.

Gardasil 9 is indicated for active immunisation of individuals from the age of 9 years of age against the

and 90% of genital warts.

cancers, 75-85% of HPV related high-grade vaginal intraepithelial neoplasia (VaIN 2/3), 90-95% of

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approximately: 90% of cervical cancers, more than 95% of adenocarcinoma in situ (AIS), 75-85% of

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Based on epidemiology studies, Gardasil 9 is anticipated to protect against the HPV types that cause

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individuals exposed (assuming 3 doses per individual).

of qHPV vaccine have been distributed until 31 May 2015, corresponding to more than 63 million

not yet been determined.

immune responses remain on a plateau level for at least 8 years. The exact duration of protection has

The protective effect has been statistically significant for up to 6 years following vaccination, and

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55.4, 100), respectively. The efficacy of Gardasil against HPV 6-, 11-, 16-, 18-related genital warts

Page 11/40

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Therefore, the pivotal clinical study (Protocol 001) evaluated the efficacy of Gardasil 9 using qHPV

vaccine as a comparator.

Efficacy against HPV Types 6, 11, 16, and 18 was primarily assessed using a bridging strategy that

demonstrated comparable immunogenicity. Immune responses, measured by GMT, for Gardasil 9 were

non-inferior to immune responses for Gardasil. In clinical studies 99.6% to 100% who received

Gardasil 9 became seropositive for antibodies against all 9 vaccine types by Month 7 across all groups

tested.

In the pivotal study the efficacy of Gardasil 9 against HPV Types 31, 33, 45, 52, and 58 was evaluated

compared to qHPV vaccine in women 16 through 26 years of age (N=14,204: 7,099 receiving Gardasil

9; 7,105 receiving qHPV vaccine). The primary efficacy analysis was performed in the per protocol

efficacy (PPE) population (individuals who received all 3 vaccinations within one year of enrolment, did

relevant HPV type(s) (Types 31, 33, 45, 52, and 58) prior to dose 1, and who remained PCR negative

preventing HPV 31-, 33-, 45-, 52-, and 58-related persistent infection (96.0 – 96.7%, CI 94.6 – 97.9)

and 58-related Pap test abnormalities, cervical and external genital procedures (92.9%, CI 90.2 –

95.1), and cervical definitive therapy procedures (90.2%, CI 75.0 – 96.8).

clinical trials corresponded to 15,800 subjects. As it is newly authorised, exposure outside of clinical

trials to date is expected to be very low compared to exposure to Gardasil.

2.2. Data on safety

order to evaluate the cases of CRPS and POTS reported with their product. This was in response to a

methods should be clearly described, and MAHs were asked to provide in depth reviews of all identified

common search strategies, which also used an algorithm to identify reports with combinations of signs

by the MAHs to determine if the established criteria (see above section 2.1) of CRPS and POTS were

fulfilled. A report was considered to either fully meet the diagnostic criteria, partially meet the

diagnostic criteria or not to meet the diagnostic criteria. The MAHs were also asked to provide analyses

of ‘Observed versus expected’ (O/E) number of reports. These analyses compared the number of

reported cases (observed) with the number that would be expected to have occurred naturally in the

target population, taking into account a wide range of scenarios regarding underreporting and also

including reports that did not fully meet the diagnostic criteria for the respective syndrome.

Assessment report

EMA/762033/2015

and symptoms common in CRPS or POTS. The clinical details of all reports were individually evaluated

to identify possible cases of undiagnosed CRPS and POTS, PRAC also requested the MAHs to use

requested by the PRAC to search for reports specifically containing the terms POTS and CRPS. In order

To identify potential cases of CRPS and POTS, the marketing authorisation holders (MAHs) were

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reports, and discuss whether they fulfil published or recognised diagnostic criteria.

list of questions agreed by the PRAC at its meeting on 9 July 2015. Review and case detection

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cumulative reviews of available data from clinical trials, post-marketing surveillance, and literature in

At the start of the referral the marketing authorisation holders (MAHs) were asked to provide

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Gardasil 9 was granted a marketing authorisation in the EU on 10 June 2015. The exposure within

immunological bridging.

As for Gardasil and Cervarix, protection in younger subjects, 9-15 years, was inferred through

and disease (97.4%, CI 85.0 – 99.9). Gardasil 9 also reduced the incidence of HPV 31-, 33-, 45-, 52-,

to the relevant HPV type(s) through one month postdose 3 (Month 7)). Gardasil 9 was efficacious in

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not have major deviations from the study protocol, were naïve (PCR negative and seronegative) to the

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Observed versus expected (O/E) analyses cannot determine causality, but they are useful in signal

validation and, in the absence of robust epidemiological data, in preliminary signal evaluation

. Given

uncertainties around the ‘observed’ number of cases, the levels of diagnostic certainty, the level of

vaccine exposure and the background incidence rates, sensitivity analyses are usually applied in

statistical analyses around assumed levels of under-reporting, numbers of ‘confirmed’ and ‘non-

confirmed’ cases (using several categories of diagnostic certainty as appropriate), numbers of

vaccinated individuals or vaccine doses administered and confidence intervals of incidence rates.

In addition to data provided by the MAHs, all other data available to the PRAC was considered in the

review, including data from the published literature, from Eudravigilance and data provided by other

parties (Member States and the public).

Clinical safety data (CRPS and POTS)

15 June 2015).

when searching for cases reported as ‘CRPS’ or ‘POTS’, or when searching for any cases that include

signs and symptoms of CRPS (according to Harden et al, 2010; table 1), or POTS (according to Raj SR,

Post marketing safety data for CRPS

Using the above-mentioned search strategy and case definitions, since launch (17 May 2007) until

15 June 2015, 49 reports containing the specific term of CRPS, and 13 reports containing a range of

CRPS symptoms (without the term CRPS) were identified. In identifying and evaluating the reports of

Of the reports containing the term of CRPS, 5 reports fulfilled the diagnostic criteria, 37 partially

sufficient details for it to be able to be classified. Out of the 49 spontaneous case reports identified

Guideline on good pharmacovigilance practices (GVP) Product – or Population - Specific Considerations I: Vaccines for

prophylaxis against infectious diseases;

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/12/WC500157839.pdf

Assessment report

EMA/762033/2015

diagnostic criteria.

reported. A total of 13 additional reports were identified, none of which fully or partially met the

The search also identified reports which reported signs and symptoms of CRPS but CRPS itself was not

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using the term CRPS, 40 originated from Japan, 8 from the UK and 1 from the Republic of Korea.

fulfilled the diagnostic criteria, 6 cases did not fulfil the diagnostic criteria and a further case lacked

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CRPS the ‘Budapest’ criteria for CRPS were employed.

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2013 and Sheldon et al, 2015; see table 2).

No serious or non-serious adverse event of CRPS or POTS were identified in clinical study data i.e.

42,047 vaccinees (21,268 in HPV group and 20,779 in comparator groups) was pooled (data lock point

another vaccine other than an HPV vaccine, i.e. Hepatitis B, Hepatitis A) which includes a total of

Safety data from 18 completed and unblinded studies with a comparator group (either placebo or

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2.2.1. Cervarix

SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

Table 3 - Post marketing data for Cervarix and CRPS

Based on term “CRPS”

Total

Met case definition criteria

Partially met criteria

Criteria not met

Other*

Based on symptom query

Reports lack sufficient detail for them to be classified

The O/E analysis for Cervarix covered a range of scenarios that included some or all of the cases

spontaneously reported with term CRPS regardless of whether they met the diagnostic criteria and

examined a risk period between 1 week and 2 years, reporting rates between 1-100%, and utilised

included a total of 49 cases.. The observed versus expected scenarios which were employed, also

be unlikely.

Post marketing safety data for POTS

Since launch (17 May 2007) until 15 June 2015, a total of 19 reports were identified that reported the

specific term ‘POTS’. In identifying and evaluating diagnosis of reports of POTS the Raj SR (2013) and

Sheldon and colleagues (2015) case definition was employed (table 2).

One of these cases also had a MedDRA PT ‘POTS’ and therefore was included in the above analysis. The

Table 4 - Post marketing data for Cervarix and POTS

remaining 6 reported cases were considered not to meet the diagnostic criteria.

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unrecognised cases. As a result of this additional search, 7 reports of potential POTS were identified.

reports that reported signs and symptoms of POTS to determine potential undiagnosed or

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further case lacked sufficient details for it to be able to be classified. A search was also conducted for

Out of these 19 cases, 5 fully met the diagnostic criteria, 13 partially met the diagnostic criteria and a

Based on term “POTS”

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media attention that is likely to have increased reporting rates and therefore low reporting rates would

Met case definition criteria

Partially met criteria

Criteria not met

Other*

Total

* Reports lack sufficient detail for them to be classified

de Mos et al, (2007) The incidence of complex regional pain syndrome: A population-based study, Pain; 129, 12-20.

Assessment report

EMA/762033/2015

only at low reporting rates and in individual countries, such as Japan, that have experienced significant

expected. The O/E analyses are generally reassuring with observed counts exceeding the expected

Based on symptom query

The O/E analysis has suggested that the number of observed CRPS cases is low compared to those

14.9-28 / 100,000 person years (estimated from literature

)

distribution data to estimate exposure.The background incidence rates which were used for CRPS are

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The O/E analysis for Cervarix covered a range of scenarios that included some or all of the cases

regardless of whether they met the diagnostic criteria and included a total of 19 cases. The O/E

scenarios which were employed, also examined a risk period between 1 week and 2 years, reporting

rates between 1-100%, and utilised distribution data to estimate exposure. The background incidences

that were used for POTS were 15, 35, 60 or 140 per 100,000 person years (estimated from literature

that 10-40% CFS patients have POTS and 20% POTS patients have CFS).

The analysis of O/E cases suggests that the number of observed POTS cases is low compared to those

expected. The analyses are generally reassuring with observed counts exceeding the expected only at

low reporting rates, with the exceptions of countries, such as Japan, that have experienced significant

media attention that is likely to have increased reporting rates. Even in these situations the observed

count only exceeded the expected if a risk period of 1 week was examined and was not true for longer

risk periods.

the Gardasil/Silgard group was reported 736 days after vaccination, and the placebo case does not

seem to fulfill the criteria for CRPS.

No cases suggestive of POTS were identified in clinical trials with Gardasil/Silgard, and two cases

suggestive of POTS were identified with Gardasil 9. One Gardasil 9 case did not fulfil the criteria for

POTS, and for the second case it is unclear how long had passed between vaccination and onset of

Overall, the incidences of CRPS and POTS observed in clinical studies were less than 1 case per 10,000

that include various combinations of symptoms of CRPS yielded 37 additional reports.

A total of 90 potential cases of CRPS were identified worldwide for Gardasil/Silgard based on reports

reported (n=37). In identifying and evaluating diagnosis of reports of CRPS the ‘Budapest’ criteria for

CRPS were employed (table 1).

Of these 53 cases where the term CRPS was reported, 7 cases were classified as having fully met the

CRPS criteria, 16 cases as having partially met the criteria and 30 cases as not meeting the criteria. Of

the 37 cases which reported a combination of various symptoms of CRPS, 0 cases were classified as

having fully met the diagnostic criteria, 6 cases as having partially met the diagnostic criteria and 31

cases are not meeting the diagnostic criteria.

Assessment report

EMA/762033/2015

where the term CRPS was reported (n=53) or where a combination of various symptoms of CRPS were

reports temporally associated with the administration of qHPV vaccine. A separate query for reports

The query of the company safety data base regarding CRPS yielded 53 unique medically confirmed

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Post marketing safety data for CRPS

person-years in each of the Gardasil 9, Gardasil/Silgard and placebo cohorts.

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symptoms (diagnosis was made 1389 days after administration of dose 3).

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case in the Gardasil 9 vaccine group had a likely onset of symptoms before vaccination. The report in

identified in the clinical trial data base (60,594 subjects with 197,983 person-years follow-up). The

A total of 3 reports suggestive of CRPS (1 in Gardasil 9, 1 in Gardasil/Silgard and 1 in placebo) were

Clinical safety data (CRPS and POTS)

Data for these vaccines are presented together.

Page 15/40

2.2.2. Gardasil/Silgard/Gardasil 9

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SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

Out of the 53 case reports identified using the term CRPS, 18 originated from Japan, 13 from the EU,

11 from the US and the remaining 11 from countries in the rest of the world. Out of the 37 cases which

reported a combination of various symptoms of CRPS, 1 originated from Japan, 24 from the EU, 11

from the US and the remaining report from the a country in the rest of the world.

Table 5 - Post marketing data for Gardasil/Silgard for CRPS

Based on term “CRPS”

Total

Met case definition criteria

Partially met criteria

Criteria not met

Based on symptom query

O/E scenarios which were employed, examined a risk period between 1 week and 2 years, reporting

It is noted that the MAH did not include a conservative analysis to include all cases of CRPS, including

expected in most scenarios of under-reporting, case definitions and risk periods. The observed count

exceeded the expected generally in scenarios that included partial criteria cases and at the lowest 1%

reporting level. Only in Denmark and Japan did the observed exceed the expected for higher reporting

levels (10-50% for Denmark (depending on risk period) and 10% for Japan). These higher reporting

rates are plausible given the high public awareness in those countries.

The query of the company safety data base for cases that include the term of POTS yielded a total of

15 June 2015. The query of the company safety data base for case reports that include various

combinations of symptoms of POTS (but without specific mention of POTS) yielded 30 additional case

reports. In identifying and evaluating diagnosis of reports of POTS the Raj 2013 and Sheldon 2015

POTS criteria, 10 cases as having partially met the criteria and 40 cases as not meeting the criteria. Of

the 30 cases which reported a combination of various symptoms of POTS, 0 cases were classified as

having fully met the diagnostic criteria, 3 cases as having partially met the diagnostic criteria and 27

cases are not meeting the diagnostic criteria

Out of the 83 case reports identified using the term POTS, 48 originated from the EU (41 from

Denmark, 7 from the rest of EU), 28 from the US, 4 from Japan and the remaining 3 from countries in

the rest of the world. Out of the 30 cases which reported a combination of various symptoms of POTS,

15 originated from the EU, 13 from the US and 2 from Japan.

Assessment report

EMA/762033/2015

Of these 83 cases where the term POTS was reported, 33 cases were classified as having fully met the

case definition was employed.

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83 reports of POTS reported following of Gardasil/Silgard received worldwide from first marketing to

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Post marketing safety data for POTS

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The results of the O/E analysis for Gardasil/Silgard showed that the observed counts were less than

number of expected cases would not have been as relevant in such analyses.

add value and would simply have included cases that are unlikely to be CRPS. Furthermore, the

those that do not meet the diagnostic criteria, however, it is considered that this approach would not

rates between 1-100%, and utilised distribution data to estimate exposure.

Page 16/40

A total of 29 cases that either fully or partially met the criteria were included in the O/E analyses. The

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SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

Table 6 - Post marketing data for Gardasil/Silgard for POTS

Based on PT

“POTS”

Total

Met case definition criteria

Partially met criteria

Criteria not met

Based on symptom query

O/E scenarios which were employed, examined a risk period between 1 week and 2 years, reporting

It is noted that the MAH did not include a conservative analysis to include all cases of POTS, including

than expected for certain reporting scenarios (low reporting rates or short risk period). Considering the

recent media attention in Denmark and active identification of cases it seems unlikely that any of the

lower reporting rate scenarios are applicable and the pattern of time to onset in these cases appears to

differ to that seen in cases from outside Denmark.

Literature review for CRPS

literature. This article reports cases from one centre but mechanisms for referral/presentation to the

centre are not described. Only two of the CRPS cases are described in some detail. Descriptive data

vaccine to the adverse event was overall in the study population 5.47±5.00 months, i.e. highly

used, i.e. if “±5.00” represents the standard deviation, range, or something else. Individual values for

onset from the CRPS cases as presented in the literature.

The literature references describing CRPS in relation to HPV vaccines are summarized in the table

below.

relevant specifically for the CRPS cases are limited. The average interval from the first dose of the

variable. It is, however, not clear from the methods description what measure of variability has been

time to onset are not presented. This means that it is not possible to compile a description of time to

Kinoshita et al, (2014) Peripheral sympathetic nerve dysfunction in adolescent Japanese girls following immunization

with the human papillomavirus vaccine. Intern Med; 53:2185-2200.

Assessment report

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A Japanese article (Kinoshita et al, 2014)

generates the majority of CRPS cases identified in the

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2.2.3. Literature review

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except for Denmark. The data showed that only in Denmark is the observed number of reports higher

cases was generally lower than expected under almost all assumptions for all regions and countries

The results of the O/E analyses for POTS with Gardasil/Silgard showed that the observed number of

number of expected cases would not have been as relevant in such analyses.

add value and would simply have included cases that are unlikely to be POTS. Furthermore, the

those that do not meet the diagnostic criteria, however, it is considered that this approach would not

Page 17/40

rates between 1-100%, and utilised distribution data to estimate exposure.

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A total of 46 cases that either fully or partially met the criteria were included in the O/E analyses. The

SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

Table 7 - Summary of key publications reporting cases of CRPS in relation to HPV vaccines.

Study type / reference

Population /

setting /

exposure

Case series

(Richards et al, 2012)

5 adolescents

from Australia and

UK. 4 exposed to

HPV vaccine (3

qHPV)

The 4 HPV exposed had time-to-

onset (TTO) of 0, 0, 0, and 4 days,

respectively. Symptom resolution

was seen within 5, 14, 60, and 201

days, respectively.

“Intramuscular immunisation is

of CRPS-1, rather than a particular

Key result / authors conclusion

Case report in congress abstract

(Haug et al, 2013)

1 individual

exposed to qHPV

Within 24 hours severe pain,

right deltoids in the course of the

Nervus cutaneous

brachialis

Case series / Kinoshita et al, 2014

15 adolescents

from Japan with

in total (7

CRPS. 40 patients

exposed to

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Abstract /Kinoshita et al. 2014

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Cervarix). 3 with

CRPS+POTS. 1

with POTS.

48 patients (from

same clinic as

above and largely

overlapping time

period). 18

fulfilling the

diagnostic criteria

for CRPS-1.

17 patients from

an unknown time

period.

Abstract /Kinoshita et al, 2014

Gardasil, 22 to

Letter to the editor /

2 adolescents

Richards et al, (2012) Complex regional pain syndrome following immunisation. Arch Dis Child;97(10):913-915.

Assessment report

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15 cases with CRPS. In 2 cases (out

of 3 with biopsy results) morphology

showed endoneurial oedema and

selective degeneration of

unmyelinated fibres.

Both patients fulfilled the

fibromyalgia criteria and were

lateralis.

small inflammatory focus in the

the right arm and hand. On MRI

swelling, numbness, and coldness of

Page 18/40

vaccine antigen.”

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sufficient to trigger the development

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Study type / reference

Population /

setting /

exposure

Key result / authors conclusion

Martinez-Lavin 2014

from Mexico.

considered fibromyalgia-like illness

after HPV immunization.

Paper presented at meeting /

Okuyama 2014

8 cases from

Japan (bivalent

type in 5 and

qHPV in 3)

Adolescents may experience

symptoms that are pathologically

difficult to explain, including pain in

the limbs after HPV vaccination.

Based on the temporal sequence

these are understood to be side

Few cases of POTS following vaccination with Cervarix have been published (Kinoshita et al, 2014) and

those cases were included in the MAH safety data base and discussed above.

Overall the majority of cases described in the literature review in association with the vaccine are from

one Danish Centre (Brinth et al, 2015). These are discussed in detail below and are also referenced in

section 2.2.4.1 below.

below.

Table 8 - Summary of key publications reporting cases of POTS in relation to HPV vaccines.

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The literature references describing POTS in relation to HPV vaccines are summarized in the table

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Study type / reference

Population /

setting / exposure

6 patients in the US

(qHPV). Unclear

referral /selection

mechanism.

15 adolescents from

Japan with CRPS. 40

patients in total (7

exposed to Gardasil,

22 to Cervarix). 3

Case series

(Blitshteyn et al, 2014)

Case series

(Kinoshita et al, 2014)

Martínez-Lavín, M. (2014 ) Fibromyalgia-like illness in 2 girls after human papillomavirus vaccination. Journal of Clinical

Rheumatology, 20;7,392–393.

Blitshteyn, S. (2014). Postural tachycardia syndrome following human papillomavirus vaccination. Eur J Neurol, 21(1):

135-139.

Assessment report

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Literature review for POTS

Key result / authors conclusion

Symptoms 6 days to 2 months

following HPV vaccination. 3 patients

also experiencing NCS. 3 patients with

small fibre neuropathy.

4 cases of POTS. 2 cases presented in

more detail, none of those strictly

fulfilling POTS criteria.

counselling and pharmacotherapy.

therapy of physical exercise,

other diagnoses and combination

Management consists of excluding

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effects from the vaccine.

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Study type / reference

Population /

setting / exposure

with CRPS+POTS. 1

with POTS. One

hospital department,

unclear referral

/selection

mechanism.

Key result / authors conclusion

Brief report / Ikeda, 2014

Apparently from the

same population

described in

Kinoshita et al 2014a

above

The author strongly opposes the

opinion of the specialist group of the

Japanese Ministry of Health, Labor and

organic lesions have been observed in

following cervical cancer vaccine.

2012

US (qHPV)

Case series / Brinth et al, 2015a

53 patients in

Denmark included

(out of 75 referred

for suspected side

effects to qHPV

vaccination), 38

diagnosed with

POTS.

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lis

Case series / Brinth et al, 2015b

35 women in

Denmark (exposed to

qHPV).

Case series Brinth et al, 2015c

39 women in

Tomljenovic et al, (2012) Death after Quadrivalent Human Papillomavirus (HPV) Vaccination: Causal or Coincidental?

Pharmaceut. Reg Affairs. 2012, S12:001

Brinth et al, 2015 (a) Suspected side effects to the quadrivalent human papilloma vaccine. Dan Med J.;62(4):A5064

Brinth et al, 2015 (b) Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of

vaccination against human papillomavirus: Vaccine; 10.1016

Brinth et al, (2015) (c) Is chronic fatigue syndrome/myalgic encephalomyelitis a relevant diagnosis in patients with

suspected side effects to human papilloma virus vaccine? International J. of Vaccines and Vaccination 06; 1(1):3.

Assessment report

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Case report / Tomljenovic et al,

2 adolescents in the

above.

Post-mortem brain tissue specimens

from two young women who suffered

from cerebral vasculitis type symptoms

following vaccination with qHPV.

A close chronological association to the

vaccination observed. POTS should

probably be looked upon as a symptom

secondary to another yet unidentified

condition rather than as a disease

entity of its own. Patients experienced

the same degree and pattern of

symptoms regardless of the POTS

diagnosis.

Findings from this study neither rule

out nor confirm a causal link between

symptoms and the HPV vaccine, but do

suggest that further research is

urgently warranted.

POTS diagnosed in 55-56% of

Kinoshita et al, 2014

Kinoshita et al, 2014b

the same patients

being reported in

Case series (abstract)/

Appears to be mainly

Page 20/40

patients with serious side-effects

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Welfare, provided the opinion that no

SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

Study type / reference

Population /

setting / exposure

Denmark (exposed to

qHPV) who had

responded to a

questionnaire about

symptoms and onset

after vaccination.

Key result / authors conclusion

individuals, while CFS/ME was

diagnosed in 87-90% The authors

cannot confirm or dismiss a causal link

between HPV vaccine and the disabling

symptoms. A consensus on

classification is needed.

The authors felt that this case clearly

fulfils the criteria for POTS/CFS. In

addition, the patient fulfilled the first 2

Autoimmune/autoinflammatory

Case report / Tomljenovic et al,

2014

1 girl in US (qHPV)

compatible with autonomic dysfunction as suspected side effects following vaccination with Gardasil.

The paper states that patients were interviewed with a special focus on symptoms and on the temporal

association between vaccination and symptom onset and that the narrative report was supplemented

by the short form of the International Physical Activity Questionnaire (IPAQ-SF) quantifying the

patient’s physical activity at the time of referral and just before vaccinations on a recall basis. Patients

were excluded if they could not account for the temporal association between vaccination and

within the first two months post-vaccination. In this paper, the mean age at symptom onset was 21.0

11.1 ± 12.5 days (range: 0-58 days) and symptoms were reported to appear after the first vaccination

in 21 patients (40%), after the second vaccination in 19 patients (36%), and after the third vaccination

in 13 patients (25%). The overall distribution of time-to-onset and the relation between time to onset

longer than 2 months or uncertain have been excluded from the study.

Based on the physical activity questionnaire, 67% had a high and 33% had a moderate activity level

before symptom onset. Five patients had a very high activity level and were competing on a national or

international level in their sport.

Twenty eight (53%) patients were diagnosed with POTS at tilt table test.

Tomljenovic et al, (2014) Postural Orthostatic Tachycardia With Chronic Fatigue After HPV Vaccination as Part of the

“Autoimmune/Auto-inflammatory Syndrome Induced by Adjuvants”. J Investig Med High Impact Case Rep.; 2(1):

2324709614527812.

Assessment report

EMA/762033/2015

and clinical presentation is, however, not fully interpretable since patients where time to onset is

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± 7.4 years (range: 12-39 years). The mean time between vaccination and onset of symptoms was

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Only 53 patients were included who reported onset of symptoms consistent with autonomic dysfunction

illness.

symptom onset, had possible triggering factors other than vaccination or had chronic pre-existing

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May 2011 to December 2014 for a head-up tilt test due to orthostatic intolerance and symptoms

This first paper refers to 75 patients referred to the Frederiksberg Hospital Syncope Unit from

62(4):A5064

Brinth et al, 2015 (a) Suspected side effects to the quadrivalent human papilloma vaccine. Dan Med J;

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Syndrome Induced by Adjuvant (ASIA).

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major criteria and 3 minor criteria for

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The authors conclude that POTS should probably be looked upon as a symptom secondary to another

yet unidentified condition rather than as a disease entity of its own. This is underscored by the fact

that patients experienced the same degree and pattern of symptoms regardless of the POTS diagnosis.

Brinth et al. 2015(b) Orthostatic intolerance and postural tachycardia syndrome as suspected adverse

effects of vaccination against human papillomavirus: Vaccine; 10.1016

This second paper described the frequency of symptoms in a group of patients consecutively referred

to the same syncope unit for the same reason as stated above. This paper describes only 35 patients.

There is no reference to how this specific subset of cases was selected for inclusion in the analysis.

This publication additionally included an analysis of blood tests, as well as use of a specific

The mean age at onset of symptoms was 22.0 years (range: 12–39). There was a mean delay between

symptoms and examination was 1.9 years (range: 0–5). Symptoms were reported to appear after the

Twenty-one of the referred patients (60%) fulfilled the criteria for a diagnosis of POTS.

11 patients all reported irregular periods. Median serum bilirubin level was 5 (ranging from below

The authors comment that the observed low levels of bilirubin may have affected the immune response

to vaccination, and that high levels of physical activity may increase both pro- and anti-inflammatory

cytokines as well as leukocyte subsets. They also suggest that irregular periods could contribute to

development of autoimmune conditions. Coupled with references to a study that suggested exercise

Vaccines and Vaccination 06; 1(1):3.

additional 15 referrals between December 2014 and April 2015. However, in this paper the authors

(CFS).

The authors included 39 of the 90 subjects who voluntarily responded to a questionnaire about

symptoms and onset following vaccination.

The study included 39 girls/women aged 22.9 ± 7.2years (mean±sd) (range 13-39) at time of

examination. Twenty of the patients (51%) fulfilled the criteria for a diagnosis of POTS. Thirty-four

(87%) and 35 (90%) of the patients fulfilled the Canadian and Institute of Medicine (IOM) criteria for

CFS/ME (myalgic encephalomyelitis), respectively. POTS was diagnosed in 56% and 55% of patients

who fulfilled the Canadian and the IOM CFS/ME criteria, respectively.

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EMA/762033/2015

investigated to what extent these patients fulfilled the diagnostic criteria for chronic fatigue syndrome

patients are presented, referred to the syncope unit from May 2011 to April 2015, assuming an

This third publication reports on the same case series as the previous two publications. A total of 90

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patients with suspected side effects to human papilloma virus vaccine? International Journal of

Brinth et al, 2015 (c), Is chronic fatigue syndrome/myalgic encephalomyelitis a relevant diagnosis in

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increase the susceptibility to HPV vaccine-induced reactions in this subset of vaccinees.

in immune responses to endurance exercise, the authors’ hypothesis is that all of these factors could

may enhance the immune response to vaccination and other data suggesting gender-based differences

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detection limit to 13 micromol) All other laboratory tests were within normal range.

international level in their sport. Twenty-four of the 35 patients used oral contraception. The remaining

stated in the first publication, half of those with a high activity level were competing at a national or

Before symptom onset 71% of the patients had a high and 29% had a moderate activity level. As

first vaccination in 24%, after the second vaccination in 51%, and after the third vaccination in 25%.

vaccination and onset of symptoms of 9.3 days (range: 0–30), and mean time between onset of

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questionnaire (COMPASS 31) to evaluate the severity of specified symptoms of autonomic dysfunction.

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Evaluation of the Brinth and colleagues (2015, a,b,c) case series

In these three papers from Brinth and colleagues (2015a, b, c), all patients were referred to the same

syncope unit for evaluation for an existing concern of HPV vaccine-induced illness. This reason for

referral in itself makes the case series unrepresentative of the general population who may present for

evaluation and diagnosis of such illnesses.

It is clear from the first paper that patients were excluded if they do not meet a pre-defined hypothesis

of vaccine-induced illness (symptoms prior to vaccination, onset greater than 2 months after

vaccination, unknown onset time or if other causes could be found). Patients were included in the third

paper based only on voluntary responses to a questionnaire.

The consistency in symptom profile across

presence of specific symptoms was solicited by the interviewer, although the presentation of results

suggests this was the case. If so, then it is perhaps not surprising that such a selected case series

of these symptoms would require some sort of objective clinical evaluation, yet there is no information

interviewed retrospectively in this way would yield these symptom characteristics. Furthermore, many

the case series is highlighted in the papers. However, it is

unclear whether or not the absence or

As the initial symptoms of POTS and autonomic dysfunction most likely have an insidious onset,

questionable, and inherent recall bias in the methods is likely.

Although the case series included only patients with self-reported symptom onset within 2 months of

vaccination, it is notable that the mean reported onset time after vaccination was very short at around

9 to 11 days (with day zero included in the range). The authors suggested that these symptoms could

be caused by an autoimmune response to the vaccine. However, a short onset would not necessarily

response and then for this to have an obvious clinical consequence. The lack of any consistent

support this, on the basis that it would take longer for the body to mount a specific auto-immune

Furthermore, there appears to be no correlation between the likely age-specific exposure to HPV

mean age of vaccinees in Denmark from May 2011 to April 2015 was most likely closer to 12 years,

between 15 and 19 years, 37% between 19 and 27 years, and 25% were 27 years or older). If HPV

series and a distribution of ages more closely aligned to the likely age-specific vaccine exposure could

be expected.

Finally, in this case series two thirds of patients had a high level of physical activity (one third had a

moderate level) prior to symptom onset, half of whom were competing at a national or international

level in their sport. Based on this, the authors suggested that exercise may be a risk factor for HPV

vaccine-induced illness. However, available medical literature on POTS suggests that high athletic (and

academic) achievement is a common pre-existing characteristic of POTS sufferers in general. The

authors’ suggestion that high levels of physical activity in females, whether or not coupled with low

Assessment report

EMA/762033/2015

vaccine was a cause of the reported symptoms, a lower mean age of symptom onset amongst the case

yet the mean age of the case series was 21 years (17% were aged between 12 and 15 years, 21%

vaccine in the Danish population and the age characteristics of these patients at symptom onset. The

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of a specific autoimmune response to the vaccine.

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relationship with the dose sequence also does not support the notion that this case series is suggestive

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examination was stated as 1.9 years (range: 0–5). The reliability and objectivity of such recall is

to achieve. This is particularly so given that the mean time between onset of symptoms and

objective recall of exact symptom onset (as well as the date/trigger for the symptoms) will be difficult

causes of the symptoms.

on how this was done or what other clinical assessment may have been undertaken to exclude other

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bilirubin levels and irregular periods, is a risk factor for vaccine-induced injury is not supported by the

data.

Taken together, it is considered that the case series is compatible with the natural background

characteristics and epidemiology of POTS (and chronic fatigue-like syndromes) in those eligible for

vaccination in Denmark (and other countries). This is further supported by the authors’ analysis in the

third paper.

There is evidence in the medical literature that up to 40% of patients diagnosed with POTS also meet

the diagnostic criteria for CFS, with some authors suggesting the overlap could be higher. The finding

by Brinth and colleagues (2015 c) that just over half of their case series fulfilling a CFS diagnosis also

meet the criteria for POTS is therefore consistent with the background epidemiology of POTS in the

absence of HPV vaccine exposure. The authors now suggest that CFS should be considered as a

dysfunction following HPV vaccine (whether or not they also meet the POTS criteria).In this paper, the

increased risk of CFS following bivalent HPV vaccine (Cervarix) but consider this to be of limited value,

and colleagues (2013) which used a self-controlled case series method, are presented in section

2.2.4.2 below. Such methodology only uses vaccinated cases, however, even if one assumes that CFS

is under-diagnosed in the UK, there is no good reason to suspects that this would apply differentially to

Overall, the case series reported by Brinth and colleagues (2015) is considered to represent a highly

selected sample of patients, apparently chosen to fit a pre-specified hypothesis of vaccine-induced

injury. The methods used to ascertain the trigger and time to onset of specified symptoms of

autonomic dysfunction may inherently bias patient recall. Whilst Brinth and colleagues (2015)

acknowledge that their cases series cannot prove a causal association with HPV vaccine, they do not

and prevalence of POTS and autonomic dysfunction amongst a population cohort with 90% vaccine

acknowledge or discuss the possibility that their case series simply reflects the expected characteristics

trigger. Finally, Brinth and colleagues (2015) now propose that their case series should be considered

as having CFS induced by HPV vaccine and that this requires further, robust study, but dismiss an

The PRAC reviewed reports submitted by Member States, additional data from the Eudravigilance, and

data submitted voluntarily by the public.

2.2.4.1. Overview of Danish report

The Danish Health and Medicines Authority (DHMA) submitted a report for consideration by PRAC as

part of the ongoing assessment, titled “Report from the Danish Health and Medicines Authority for

Assessment report

EMA/762033/2015

2.2.4. Other data

existing study that has already tested this hypothesis and found no association.

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suggesting that this is a commonly-reported characteristic in POTS patients, regardless of putative

development of HPV vaccine-induced illness, but do not reflect upon the available medical literature

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uptake. The authors speculate that high intensity physical exercise may be a risk factor for

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diagnosis.

cases referred by their General Practitioner for symptoms of chronic fatigue, but had not yet received a

vaccinated and non-vaccinated subjects. Furthermore, the UK study included a sensitivity analysis of

based on the assumption that CFS is under-diagnosed in the UK. The results of the study by Donegan

authors acknowledge the published study (Donegan et al, 2013)

which found no evidence of an

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diagnosis in patients who report chronic symptoms of orthostatic intolerance and autonomic

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

vaccines”

The Danish report includes a descriptive overview of serious suspected adverse drug reactions (ADR)

reports following HPV vaccine from Denmark, a summary of available literature, comparative analysis

of worldwide data provided to the Danish Health and Medicines Authority by the Uppsala monitoring

centre and a summary of the situation in Japan.

The case series analyses from Brinth and colleagues (2015) at a syncope centre based in Copenhagen,

were referred to in the Danish Health and Medicines Authority report. These publications are presented

and considered in detail in section 2.2.3 above.

The overview of all reports received by the Danish Health and Medicines Authority shows that the

the vaccine.

The Danish report includes a descriptive overview of all spontaneous serious suspected ADRs (n=363)

symptom categories were identified by the Danish Health and Medicines Authority based on the

severity of occurrence; severe fatigue, neurologic symptoms, circulatory symptoms, pain and

headache. Eight additional categories were added, that included frequently reported terms; autonomic

thermal dysregulation and malaise.

The Danish report did not evaluate any causal or temporal relation between the symptoms reported

and the HPV vaccine exposure, as information about time of symptom onset and duration was too

often missing or not accurate.

The most frequently reported symptoms in the serious reports were (ranked order of symptoms

occurring in more than 100 cases): headache, pain, dizziness, malaise, fatigue, paresthesia and

http://sundhedsstyrelsen.dk/~/media/0A404AD71555435BB311CD59CB63071A.ashx

Assessment report

EMA/762033/2015

imbalance, abdominal discomfort, urinary tract symptoms, allergy, infections, menstrual disorder,

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

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received up to 19 March 2015. Based on a review of the most recently received reports, 5 main

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distributed

Authority between 2009-Q1 2015, and corresponding number of doses of HPV vaccine

Table 9 - Total number of ADR reports received by the Danish Health and Medicines

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

SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

cognitive disorder. The Danish report states that the review identified 40 reports with 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.

Of the 363 reports, 77 (21%) had a well-defined, specific diagnosis of an adverse reaction. Of the

remaining reports, 44 % had symptoms in 4 or 5 of the 5 main categories. A total of 62 of 117 cases

(53 %) reporting fatigue were reportedly associated with a social handicap, i.e. reduced ability to

attend school or work or carry out daily activities. For 17 % of all patients considerable impact on daily

life was described. The most frequently occurring of the 8 additional categories were malaise,

abdominal discomfort, autonomic imbalance, infections and thermal dysregulation in that order.

from the specific case reports under evaluation in this review and discussed separately, this overall

reporting rate is similar to the overall suspected ADR reporting rate in the UK (~ 1 per 1,000 doses

doses distributed; or ~ 1.1 per 1,000 doses). The reporting rate of serious suspected ADRs in Denmark

administered), or the global suspected ADR reporting rate (~180,000 adverse events per 165 million

There was a notable increase in serious suspected ADRs in 2013 and, as acknowledged in the Danish

report, the characteristics of these reports in Denmark was likely to be influenced by the publicity in

As most of the reports do not have a specific diagnosis but an overlapping range of symptoms, the

Uppsala monitoring centre (see below), the Danish report argues that there is an increasing trend in

worldwide reports that could fit this category of undiagnosed but similar ‘chronic fatigue-like syndrome’

which may be specific to HPV vaccine.

The PRAC noted the descriptive analysis submitted by the Danish Health and Medicines Authority but

The majority of reports of POTS from Denmark have been reported by a Copenhagen-based syncope

fibromyalgia, and reports without a specific diagnosis but including symptoms that may potentially

relate to autonomic dysfunction.

As of 3 August 2015, Vigibase contained 147 reports with the MedDRA

term POTS associated with

HPV vaccines. Vigibase also included the following reports in association with HPV vaccines - 94 CRPS,

The Medical Dictionary for Regulatory Activities (MedDRA) is a rich and highly specific standardised medical terminology

developed by the International Conference on Harmonisation (ICH) to facilitate sharing of regulatory information

internationally for medical products used by humans. It is used for registration, documentation and safety monitoring of

medical products both before and after a product has been authorised for sale. Products covered by the scope of MedDRA

include pharmaceuticals, vaccines and drug-device combination products.

http://www.ich.org/products/meddra.html

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EMA/762033/2015

overview focused on POTS, CRPS, CFS, myalgic encephalitis (ME)/post viral fatigue syndrome (PVFS),

Vigibase is an international drug safety database sponsored by the World Health Organisation. This

provided an overview of worldwide suspected ADRs associated with HPV vaccines from Vigibase.

At the request of the Danish Health and Medicines Authority, the Uppsala Monitoring Centre has

Information provided to the Danish Health and Medicines Authority by the Uppsala Monitoring Centre

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discussed in section 2.2.3 above.

three publications to date (Brinth et al, 2015 a, b and c). These three publications are summarised and

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centre, and are therefore most likely the same case series described by Brinth and colleagues in their

concluded that it is not sufficient to inform the causality assessment in the context of the referral.

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report states that the ADR reports show similarity to CFS. Based on an analysis of data provided by the

Denmark.

is ~0.22/1,000 doses, also similar to the reporting rate in the UK (~0.24/1,000 doses).

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The overall reporting rate of all suspected ADRs in Denmark is ~0.8 per 1,000 doses distributed. Aside

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94 CFS, 62 ME/PVFS and 87 fibromyalgia. Most reports for each of these preferred terms (PTs)

originated in the US. Denmark and Japan reported the second highest number of POTS and CRPS,

respectively. The UK reported the second highest number of CFS, ME/PVFS.

Fibromyalgia, CFS and ME/PVFS have been reported relatively constantly since 2009 (with a slight

decrease in 2011/12), but reports of POTS and CRPS had notably increased since 2013. It is not stated

in the Uppsala monitoring centre report if these dates relate to symptom onset, diagnosis or report

receipt date, although the latter is most likely.

The Uppsala Monitoring Centre report highlights that there is consistency between the WHO database

and the Danish database in the top 20 reported events for HPV vaccines, with 60% similarity in the

listing of the top 10 events. It then states that the comparison of HPV vaccines to all other vaccines in

females, showed a difference to all other vaccines (febrile and general signs and symptoms: fever,

The first analysis compared 549 HPV vaccine reports from Denmark vs 45,327 worldwide HPV vaccine

all events, rather than only serious events. However, given that Denmark had received 1,228 reports

This analysis showed the terms POTS, orthostatic intolerance and autonomic nervous system

imbalance are reported disproportionately more in HPV reports from Denmark vs HPV reports in other

The second analysis compared 45,876 worldwide HPV vaccine reports against 79,678 worldwide

reports for all other vaccines combined and received for females between the age of 9 to 25 years.

It was found that disproportionately more HPV vaccine reports were coded as serious compared to

other vaccine reports. Malaysia, Italy, Japan, Denmark, and Australia report disproportionately more

and poisoning are received compared to other vaccines.

system imbalance: 76 times for HPV vaccine and 16 times for other vaccines (0.2% vs 0.0%), CFS: 65

vaccine and 39 times for other vaccines (0.1% vs 0.1%) and PVFS: 47 times and 53 times for other

vaccines (0.1% and 0.1%).

In its conclusions, the Uppsala monitoring centre report highlights an overlap in symptoms in reported

cases of POTS, CRPS, CFS, PVFS and fibromyalgia, notably fatigue, headache and dizziness. Whilst it

acknowledges that these symptoms are non-specific and are commonly occurring events, it notes that

the reports of POTS, CFS and PVFS from which these events arose have been largely classified as

A preferred term (PT) is a distinct descriptor (single medical concept) for a symptom, sign, disease, diagnosis,

therapeutic indication, investigation, surgical, or medical procedure, and medical, social, or family history characteristic.

http://www.meddra.org/sites/default/files/guidance/file/intguide_18_1_english.pdf

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for HPV vaccine and 30 times for other vaccines (0.1% vs 0.0%), fibromyalgia: 62 times for HPV

CRPS: 69 times for HPV vaccine and 16 times for other vaccines (0.2% vs 0.0%), autonomic nervous

POTS had been reported 82 times for HPV vaccine and 1 time for other vaccines (0.2% vs 0.0%),

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Nervous system disorders and Psychiatric disorders SOC, Social circumstances, Neoplasms and Injury

reports related to Reproductive system, the Investigations SOC, Surgical and medical procedures,

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In terms of reporting within MedDRA System Organ Class (SOC), disproportionately more HPV vaccine

disproportionately fewer HPV vaccine reports compared to other vaccines.

HPV vaccine reports compared to other vaccines, whilst Canada, the UK, Sweden, and France report

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arthralgia also show disproportionality.

cognitive disorder, fatigue, infection, visual impairment, influenza-like illness, muscle spasms, and

countries. Eczema, sensory disturbance, disturbance in attention, memory impairment, palpitations,

(322 serious) up to Q1 2015, it is unclear how the 549 reports were selected.

reports received for females between the age of 9 to 25 years. This analysis appears to have included

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nausea, and headache).

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serious reports (POTS 80%, CFS 78%, PVFS 89%) stating the need for hospitalisation and/or resulting

in disability or interruption of normal function.

It is further stated that the different levels of reporting of the different syndromes across countries

could be explained by the same syndrome being diagnosed/coded differently depending on different

national practices.

Evaluation of the Uppsala Monitoring Centre report

It is likely that the apparent increase in reports since 2013 across countries has been stimulated by the

concerns in Japan, particularly for CRPS, and Denmark, particularly for POTS. This overall trend in

reporting over time is therefore not unexpected given the known influences of media attention on

spontaneous reporting. However, as the Uppsala Monitoring Centre report includes no information on

the number of doses of vaccine used over this time period, conclusions cannot be drawn on this.

The Uppsala Monitoring Centre report suggests that the same clinical ‘syndrome’ may be occurring

excluded that this is the case, many factors influence the levels of reporting (e.g. the US accounts for

originate in the US) and the nature of reports submitted (e.g. public awareness of a specific event such

as POTS and CRPS will influence this). Overall, the observations included the Uppsala Monitoring

Centre report does not allow any conclusions to be made on clinical or diagnostic practice between

In relation to the comparison of the top 20 reported symptoms worldwide from serious reports for HPV

difference between the HPV vaccine and all other vaccines. However, the comparison actually shows

very few differences and a lot of consistency, in terms of the type of event reported at the various age

bands. This consistency is perhaps not surprising given that the majority of these top 20 serious

events include the signs and symptoms (or related terms) of the most common, expected events of

most vaccines given to adults and adolescents, which are usually transient. Many of these top 20

these are also already included in the product information for HPV vaccines.

reports may also include the signs and symptoms of immediate faints following vaccination. Many of

it show a very wide range of more relevant and more specific higher level terms that may potentially

include symptoms of undiagnosed CFS (as well as POTS, CRPS, PVFS and fibromyalgia). This includes,

cognitive disorders, postural dizziness, muscular weakness, mobility decreased, exercise tolerance

HPV vaccine group, this comparison argues against such reporting patterns pointing to a specific

Of these more relevant and specific higher level terms, only asthenic conditions shows any apparent

disproportionality and this only occurred when the decision was taken to lower the ‘signal threshold’,

but this was only marginal (12.3% of HPV vaccine reports vs 9.3% of other vaccine reports). It should

be noted that this higher level term includes fatigue, which is one of the most common adverse effects

of any adult or adolescent vaccine. Possibly the most relevant terms that showed some

disproportionality were syncope, presyncope, muscular weakness and activities of daily living impaired.

However, this is a very small number of PTs, and there are many more relevant and more specific PTs

that did not show any disproportionality for HPV vaccines. Overall, the data show no specific reporting

Assessment report

EMA/762033/2015

undiagnosed ‘syndrome’ reported with HPV.

decreased, various pain terms, and skin discolouration. Although the numbers are small for the non-

autonomic nervous system disorders, asthenic conditions, GI motility disorders, tachyarrhythmia,

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CFS and PVFS/ME showed no statistically significant disproportionate reporting for HPV vaccine, nor did

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vaccines against all other vaccines, the Uppsala Monitoring Centre report concludes that this showed a

countries.

about half of the worldwide use of Gardasil, which is a likely reason most reports of each syndrome

following HPV vaccination but is being diagnosed/coded differently across countries. Whilst it cannot be

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profile for HPV vaccine compared to other vaccines that may indicate a particular undiagnosed

syndrome.

The analysis of Danish HPV events vs worldwide HPV events showed that the terms POTS, orthostatic

intolerance and autonomic nervous system imbalance are reported disproportionately more vs HPV

reports in other countries. However, the report states that other PTs that are also clinically-relevant (to

undiagnosed POTS and related syndromes) did not show disproportionality. It is acknowledged in the

Uppsala Monitoring Centre report that, aside from Nervous system disorders, arguably the most

relevant MedDRA SOCs to consider in order to detect any relevant symptom clusters did not show any

apparent disproportionality in reporting for HPV vaccines (General disorders, Gastrointestinal disorders,

Musculoskeletal disorders and Cardiac disorders).

The PRAC noted that although the analysis appears to incorporate statistical adjustment, this sort of

terms level) will inevitably yield some results of disproportionality for HPV vaccines reports as well as

selection of SOCs, high level and preferred terms, amendment of a pre-specified ‘signal threshold’ and

conclusions.

The Danish Health and Medicines Authority report included a brief description of the situation in Japan.

It is stated that although the initial concerns in Japan focused on pain and the diagnosis of CRPS, the

adverse event reports in the Japanese database have been characterised by a wider variation of

symptoms, often difficult to standardise. It states that often reported symptoms were pain, movement

The Danish Health and Medicines Authority report considers that due to differential clinical practice

across countries, similar suspected ADRs to HPV vaccine are receiving different diagnoses (or indeed

suspected ADRs, including the worldwide data obtained from Uppsala monitoring centre, in order to

identify any potential ‘non-specific’ safety signals.

As many of the serious suspected ADRs reported following HPV vaccine have no confirmed diagnosis

but a wide range of overlapping symptoms, and based on hypotheses that POTS, CRPS, fibromyalgia

and CFS may have a common pathophysiology (i.e. autonomic dysfunction, possibly due to small fibre

neuropathy), the Danish Health and Medicines Authority report proposes that the constellation of

symptoms and reports should be considered as ‘chronic fatigue-like’ illness, which accords with the

current opinion of Brinth and colleagues (2015c). It is difficult to formally diagnose CFS from the

available reports but the collection of features in many of them may be seen as suggestive of CFS.

Assessment report

EMA/762033/2015

no clear diagnosis). This theory appears to have prompted the comparative overview of all serious

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Overall conclusions on the Danish Health and Medicines Authority report

the Danish cases.

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Authority report states that the pattern reflects much of the same symptoms as are also reported in

reported to fluctuate and in some patients lasting for a long time. The Danish Health and Medicines

disorders, orthostatic intolerance, dizziness, menstrual abnormalities and fatigue. Symptoms were

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Overview of data from Japan

adverse events associated with HPV vaccine and that such reporting has increased over time.

known, i.e. that some countries are observing an increasing number of reports of different types of

Overall, it is considered that the Uppsala monitoring centre report serves to highlight what is already

selective discussion of disproportionate reporting for HPV vaccines does raise questions about the

non-HPV reports, as shown in the Uppsala monitoring centre report. However, the approach taken to

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multiple analysis and data-mining of suspected ADR data (at MedDRA SOC, high level and preferred

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Several studies relevant to POTS and CRPS are referred to in the Danish Health and Medicines

Authority report. The report also refers to studies looking at a range of autoimmune disorders, other

serious events and CFS. These were generally large studies that used electronic health record data and

used a variety of study designs, from cohort, case control and risk interval or self-controlled case

series analysis. None of the studies found conclusive evidence of increased risks for the included

outcomes.

The Danish Health and Medicines Authority report then comments on the limitations of studies which

use ‘registers’ (which is presumed to mean electronic health record data) as they consider data capture

in this case is highly dependent on diagnosis. The report argues that because the adverse events being

reported following HPV vaccine are difficult to diagnose and have overlapping symptoms, the currently-

available studies could not identify cases relevant to the current issue.

when relevant to the objectives, observational studies are based on medically-diagnosed illness using

likelihood/practice between the groups under comparison). It is acknowledged that not all of these

and Medicines Authority report under-estimates the value of two of these studies to the current issue,

which are considered further in section 2.2.4.2 below.

The following two studies from literature publications were also considered relevant to the review:

Klein et al, (2012) Safety of Quadrivalent Human Papillomavirus Vaccine Administered Routinely to

Females. Arch Pediatr Adolesc Med. 2012;166(12):1140-1148.

The study by Klein and colleagues (2012)

was not reliant on diagnosed illness, and evaluated hospital

visits amongst 189,629 females aged 9 to 26 years for a very wide variety of clinical reasons (256 ICD

categories were included, based on discharge coding) within 14 and 60 days of vaccination (the study

vaccination. Other categories included that could be relevant to the current issue were “Hereditary and

system disorders), ear disorders (which included the subcategory of dizziness), “ill-defined conditions

There were very few cases in the category that would have included a discharge summary for

autonomic nervous system disorders, and discharges for malaise and fatigue were not significantly

used risk interval analysis). An increased risk for syncope was identified only on the day of

associated with vaccination (it is not stated if or how many cases of dizziness contributed to this

category).

Although this study did not evaluate CRPS and POTS and was largely a data-mining exercise, it does

give some insight into the general behaviour in a large cohort following vaccination for a wide variety

of clinical reasons, and revealed no obvious clusters of concern.

Klein et al, (2012) Safety of Quadrivalent Human Papillomavirus Vaccine Administered Routinely to Females. Arch

Pediatr Adolesc Med.;166(12):1140-1148.

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vaccination, were opportunistic evaluation/coding at the vaccine visit, or had obvious aetiologies not

a slightly elevated risk, but individual case review revealed most events were either present before

raised in the post vaccine risk period following adjustment for multiple analyses. Ear conditions showed

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and factors influencing health status” (which also included the subcategory of malaise and fatigue).

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degenerative nervous system conditions” (which included the subcategory of autonomic nervous

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2.2.4.2. Additional studies

studies included outcomes that are directly relevant to the current review. However, the Danish Health

valid case definitions, and the study should minimise information bias (such as differential diagnostic

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Of course, any such observational study will have limitations, as well as strengths. It is important that,

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Donegan et al (2013) Bivalent human papillomavirus vaccine and the risk of fatigue syndromes in girls

in the UK. Vaccine; 31(43): 4961-7

In this study, O/E analyses were conducted comparing the number of reports of fatigue syndromes

submitted with what would be expected in the target population. Subsequently, an ecological analysis

and a self-controlled case series compared the incidence rate of fatigue syndromes in girls before and

after the start of the vaccination campaign and the risk in the year post-vaccination compared to other

periods.

The O/E analysis showed that the number of spontaneous reports of chronic fatigue following Cervarix

vaccination was consistent with estimated background rates even assuming low reporting. Ecological

analyses suggested that there had been no change in the incidence of fatigue syndromes in girls aged

12-20 years after the introduction of the vaccination despite high uptake (IRR: 0.94, 95% CI: 0.78-

of fatigue syndromes in the year post first vaccination (IRR: 1.07, 95% CI: 0.57-2.00, p=0.84).

CFS such as fibromyalgia, CRPS and POTS were not specifically studied. However, given the current

suggestion in the DHMA report that the constellation of undiagnosed symptoms should be considered a

chronic fatigue-like syndrome, as CFS and POTS are known to have a high level of overlap, and as

Brinth and colleagues (2015c) now consider that CFS may be a more relevant diagnosis in the Danish

cases, the study by Donegan and colleagues (2013) is a relevant epidemiological study for the this

2.2.4.3. Data from Eudravigilance

Up to 07 August 2015, 22 cases of CRPS have been reported in the European Medicines Agency’s

Gardasil/Silgard in the same age range who belong to the target population for HPV vaccination. Most

of the cases have occurred in Japan. These two observations may be explained by the initial concerns

Eleven (11) cases of POTS have been reported in the Eudravigilance database in girls between 12 and

cases have occurred in Denmark, USA and UK.

No reports on Gardasil 9 were identified in Eudravigilance database.

The PRAC also received a report from the Dutch Pharmacovigilance centre LAREB, which was intended

to share the experience from the Netherlands with the PRAC. This report contained information on the

suspected ADR reports received since the introduction of the HPV vaccination in the Dutch population.

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17 years old with Cervarix and 60 cases in the same age group with Gardasil/Silgard. Most of these

2.2.4.4. Data from Netherlands Pharmacovigilance centre LAREB

regarding HPV vaccines and CRPS having originated in Japan.

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safety database, Eudravigilance, in girls between 12 and 17 years old with Cervarix and 35 cases with

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review.

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allowed Cervarix-exposed subjects to be included. Although the study included conditions related to

The study by Donegan and colleagues does not address all of the current issues. The study period only

conditions studied and was powered to detect a relative risk of 3 or more.

syndrome and neurasthenia. The study found no association between HPV vaccine and any of the

symptoms of chronic fatigue and exhaustion, as well as diagnoses for fibromyalgia, post viral

evaluated not only diagnosed CFS, but also referrals from General Practice for as yet undiagnosed

(and therefore avoiding the issue of differential diagnostic practice in vaccinated and unvaccinated),

The study by Donegan and colleagues (2013), as well as using the self-controlled case series design

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1.14). The self-controlled case series, including 187 girls, also showed no evidence of an increased risk

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From the start of the national immunisation program in the Netherlands in January 2009 up to 25

August 2015, in total 1239 reports have been received. The report from LAREB focussed on the

increased retrospective reporting of suspected ADRs following media interest during the summer of

2015. Neither CRPS nor POTS were reported in the Netherlands as suspected ADRs in association with

HPV vaccines.

The LAREB report concludes that the results presented in their report are based on spontaneous

reporting, which is a signal generating methodology, sensitive to media attention. It is also commented

that these data cannot be used to determine if there is any causal relationship between the reported

event and the HPV vaccine. The PRAC agreed with the conclusion by LAREB.

2.2.4.5. Data submitted by the public

Sweden and the United Kingdom. This current assessment is focused on CRPS and POTS, and the

submitted data are summarised here and were given full consideration by PRAC.

had undertaken and summarised. In addition, these submissions commented on problems encountered

groups proposed to be undertaken.

The PRAC noted that within the submitted information, there were a number of detailed descriptions of

young girls suffering from debilitating and long-lasting conditions. There was a wide range of

symptoms, many of which were similar to those considered elsewhere in this referral assessment in

the context of POTS and CRPS, but also including seizures, other neurological and psychiatric

symptoms and pain, but with no apparent diagnosis. The clinical characteristics were highly variable.

pathophysiological mechanism finding adequate healthcare was a common problem in these reports.

described long before introduction of the HPV vaccines. In general, the cases described appear to have

time-to-onset or association with a particular dose was seen. Co-morbidities and complex symptom

combinations further complicate causality assessment. The CFS described in many of these cases has

possible side effects to HPV vaccine. When taking the totality of data in the referral into account, it is

the opinion of the PRAC that these reports do not suggest a causal link to the HPV vaccines.

3. Expert consultation

The PRAC consulted the Scientific advisory group (SAG) on vaccines on 21 October 2015 which

provided advice on a number of issues. The expertise of the SAG was enriched by experts on the

syndromes, on neurology, cardiology and pharmacoepidemiology. The questions that PRAC asked the

SAG and their answers are presented below.

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It is acknowledged that the patients/ parents refer to a range of other disorders which they describe as

2.2.3).

some symptom overlap with POTS. This is further discussed elsewhere in this report (see Section

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similar characteristics to cases ascertained from other sources in this review. No pattern in terms of

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These conditions also occur in individuals who have not been exposed to HPV vaccines and were

As symptoms are highly varied and unspecific without a clear definition of the underlying

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of the data provided. Finally, these submissions also provided a list of actions which the patient/parent

adverse reactions recorded by National competent authorities and concerns about accuracy and quality

with trying to report and record suspected side effects accurately, official statistics on number of

This information consisted of descriptions of individual experiences, of surveys the patients/parents

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submissions included a very wide range of other information and variable symptoms. The relevant

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A large amount of information was received from the public in Denmark, France, Ireland, Italy, Spain,

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What is the current understanding about the pathophysiology of Complex Regional Pain

Syndrome (CRPS) and Postural Orthostatic Tachycardia Syndrome (POTS)?

CRPS is defined as continuing pain that is disproportionate to the inciting event, may be associated

with dysautonomic signs and symptoms and is usually confined to a single limb. Other symptoms,

including psychological symptoms are recognised, particularly amongst those with more persistent

pain. CRPS typically follows an episode of trauma including fracture of the wrist or carpal tunnel

syndrome surgery, or immobilisation of the limb. The experts were not familiar with cases in which

needle trauma from an immunisation had triggered an episode of CRPS. Consequently, the onset of

symptoms of CRPS are difficult to define because the syndrome is usually only diagnosed from the

point when normal recovery from the initiating trauma should have occurred (may be as much as 5-7

afterwards. The majority of CRPS cases (>70%) improve over time and show no recurrence; recovery

investigating genetic, inflammatory, auto-immune and psychological contributors to the condition.

symptoms (after one or two years) reduces the plausibility of an association.

POTS is a systemic syndrome which has been known for a long time under different names and is still

poorly understood. POTS patients typically show persistent tachycardia for more than 10 minutes upon

standing, as well as an increase in heart rate to above 120 bpm or by ≥ 30bpm, and in children and

juveniles below 19 years of age by ≥ 40bpm, without arterial hypotension. A diagnosis of POTS cannot

solely rely on these symptoms; other symptoms (e.g. syncope, fatigue, headaches, light-headedness,

may be prolonged following a period of bed rest or inactivity as a result of “deconditioning”. It was

noted that many of the POTS cases that are part of the referral do not fit well into the typical

or chair rest (e.g. following an acute illness or CFS), may lead to POTS-like syndrome but can be

managed by rehabilitation, and should be differentiated by other cases of POTS which are persistent

and particularly debilitating for individuals.

POTS pathophysiology is still poorly understood, and the lack of strict application of diagnostic criteria

hampers study of the syndrome. Researchers are currently investigating autonomic dysfunction,

autoimmunity and genetic predisposition to POTS, but there is no clear evidence regarding the

underlying cause.

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patients and features of chronic fatigue syndrome (CFS) may dominate. The deconditioning from bed

psychological and genetic predisposition may be involved. Fatigue is a common symptom in POTS

often athletic, may have had recent illness, although stress, surgery, hypermobility in joints,

Those with the diagnosis of POTS are typically pubertal high achieving girls who are very active and

syndrome definition, or are poorly documented or inadequately diagnosed.

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overlaps with orthostatic tachycardia which occurs as a normal physiological response on standing and

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this label (i.e. a subjective syndrome), but it is otherwise not particularly well characterised. POTS

across patients and are otherwise non-specific. Consequently, POTS seems to be defined only if given

diaphoresis, tremor, palpitations, exercise intolerance, near syncope upon standing upright) vary

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diagnosis. In some cases discussed in the referral the long interval from vaccination to onset of

available diagnostic criteria. In some of the cases the available information is insufficient to make a

from Japan, do not clearly fall into the definition of CRPS as it is currently understood using the

cases, the SAG concluded that most of the reported cases ascribed to HPV vaccines, including those

Based on the overall considerations made by the CRPS and pain experts who studied the reports of the

is higher in children. The pathogenesis of CRPS is incompletely understood but researchers are

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weeks post-trauma), and is usually only recognised some time later among those with continuing pain

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The SAG were of the view that the vast majority of the cases after vaccination reported in the

literature and database review conducted for the referral do not fit with the accepted definitions of

POTS or CRPS and would more appropriately be labelled as having features of CFS. It is currently not

clear how many of the remaining reported cases are truly POTS and CRPS, but it seems to be a small

proportion of those which have been documented so far. The SAG noted that CFS is difficult to formally

diagnose from the available reports but the collection of features fit better than with CRPS or POTS in

many of them. It was also noted that some of the patients reported from Denmark had features

consistent with CFS and had become deconditioned as a result of fatigue symptoms, such that they

also now had features in common with POTS. The cause of CFS is a topic of intense research activity

but the pathophysiology of the condition remains unclear in many cases.

The SAG were not aware of any pathophysiological evidence that vaccines in general, or HPV vaccine in

that the condition might be triggered by a needle, the pain experts did not consider this to be a likely

trigger given the lack of cases presenting to the clinics of the assembled experts, despite the large

majority of the cases labelled as POTS either didn’t fit the accepted definition or seemed to be more

numbers of adolescents receiving immunisations in their countries. The SAG were of the view that the

What is the strength of the available information with respect to the cases of CRPS and POTS

It was not made explicit by the question whether it should have been interpreted as the strength of the

existing information or the strength of the association between the cases of CRPS and POTS and HPV

vaccines. The SAG opined to address both elements.

Regarding the strength of the information, the SAG noted the known weakness and limitations of

a sensitive tool to pick up unexpected rare signals, which are not predicted at the time of introduction

reporting of the case definitions in the databases, which may continue to affect future investigations.

The SAG noticed that most of the cases presented in the referral could possibly better fit the definition

undertaken for CFS. The Clinical Practice Research Datalink (CPRD) study on CFS was found to provide

robust data demonstrating a lack of an association between HPV vaccines and CFS.

The O/E analysis conducted by the MAHs in the frame of the referral, and thoroughly assessed by the

Rapporteurs, seems to be as robust as it could be, given the difficulties with the type of data gathered

and the assumptions made. One of the difficulties mentioned was the background rates estimation;

background rates seem to vary across ages and over time possibly due to changes in diagnostic

criteria. Some experts considered that expected rates based on the Netherland GP data could be about

30% lower if applying Budapest criteria vs. IASP criteria, which in turn may change some of the signal

calculations. However it was noted that the O/E analyses covered a range of scenarios taking into

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This observation is important, since a careful study, with better methodology has already been

definitions of CRPS or POTS.

of CFS or at least include some features of chronic fatigue syndrome and less clearly fit the formal

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as sensitive as active surveillance. A major limitation of the evidence provided is the inadequate

identifying signals which warrant investigation but, because cases might not always be reported, is not

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of a vaccine, but its sensitivity for some types of pain, is uncertain. The system was effective in

spontaneous passive reporting systems. However, the SAG agreed that spontaneous reporting remains

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which have been reported in girls previously exposed to HPV vaccination?

distressing for the affected individual and their families but usually resolves through adolescence.

rare but reported amongst adolescent girls in developed countries and that the condition is very

likely CFS cases with deconditioning (as a result of fatigue and inactivity). The SAG noted that CFS is

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particular, leads to CRPS or POTS. Although the association of trauma with CRPS suggests plausibility

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account uncertainties in both numerator and denominator, and the most plausible scenarios showed no

excess of POTS or CRPS cases above the background rate considering the situation in individual

countries (e.g. completeness and quality of reporting).

As far as the strength of association between HPV vaccines and POTS and CRPS is concerned, the SAG

concluded that an association is not currently supported by the data, although limitations of the data,

as mentioned above, must be recognised. Concerning the data that are available from the literature

case series, these do not support an association both because of the lack of fit with formal definitions

and because of the high risk of bias (e.g. due to lack of the necessary information to assign a diagnosis

and interval to onset, or selection of cases with specific time to onset range).

In conclusion, despite the limitations of case series and passive reporting, the SAG agreed that the

reports to date do no constitute a signal which would warrant further investigation by the MAH.

the view that the available evidence does not support a causal association, they were aware that

the data available thus far, but would be challenging for the reasons described above.

There was a clear view from the SAG that enhanced surveillance should continue to be performed. It

What are these characteristics:

CRPS is coded in international used systems, e.g. MedDRA or ICD10 code, and reference could be

made to these. The SAG agreed that ‘continuous limb pain’ should be used as a non-specific, but

possibly sensitive term that could be used to retrieve potential cases of CRPS in safety databases that

definition of the syndrome might affect the sensitivity of the searches. Flagging search terms

had not been appropriately labelled as CRPS; although these terms are not specific, using the tight

sensitivity. POTS is coded in MedDRA, however due to the lack of awareness, or even consistent clinical

this term might be seldom used. Due to all the uncertainties mentioned, the SAG could not come to a

clear conclusion on specific characteristics that could improve case identification in large databases.

However, the SAG noted that many POTS cases include features of CFS and that many of the cases

labelled as POTS in the review fitted better with a CFS definition such that identification of CFS cases

may be valuable in extracting data on POTS.

Considering the possible overlap of CRPS/POTS cases with CFS, which has an established code and a

clear set of symptoms, the SAG considered that CFS codes and symptoms could be useful

characteristics to be monitored.

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/diagnostic views, around this syndrome in many countries, and due to the difficulties with diagnosis

and upon standing, which may allow identification of data from safety databases, albeit with limited

diagnosis of POTS such as the table-tilt test or heart rate and blood pressure recordings at supine rest

Concerning POTS, it is possible to search for symptoms of the syndrome or specific features of the

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searches cannot provide a robust answer because of lack of defined diagnostic codes.

characteristics would change the reporting rates seen, as it should be acknowledged that database

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prospectively could help in seeking adequate follow-up of potential cases. It is not clear whether these

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b) If yes, then:

and vaccines and the public and the health care professionals in Europe are able to report directly.

was noted that there are various mechanisms to obtain information about possible reactions to drugs

monitored in post-marketing surveillance?

a) Based on the available information, are there specific characteristics that should be

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additional work to provide further evidence would be helpful from a public health perspective to add to

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Ongoing surveillance activities are supported in order to monitor future trends. While the SAG were of

SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

ii.

Discuss the feasibility of performing further studies with the potential to provide robust

and meaningful results within existing data sources in Europe.

The SAG opinion was that enhanced surveillance should continue as the main pharmacovigilance

measure.

In addition, the SAG considered other measures, e.g. population-based registries; the main issue

identified with this approach was the risk of bias (i.e. due to enhanced consultation for the outcomes in

individuals who know they are vaccinated) and the lack of consistently used diagnostic codes, which

may lead to inconclusive results (though it was acknowledged that there is now a Read code for CRPS

in CPRD).

Concerning the feasibility of performing studies, overall they might be feasible, despite the challenges

risk that studies may lead to results difficult to interpret due to bias, e.g. enhanced ascertainment of

vaccinated cases due to media reporting. It was stressed that in any study the method of case

ascertainment should be independent of vaccination status as preferential inclusion of vaccinated cases

Finally, the SAG recommended for PRAC consideration that for example the CPRD study, or similar,

could be built upon and updated to cover the more recent period previous to the media reporting, and

overlap in syndromes; however there may be some benefit in looking again at the definitions based on

the current reporting, as it may shed some further light on CRPS and POTS in association with HPV

vaccines.

If retrospective register-based studies are taken, MAHs or public health authorities should carefully

consider whether the coding of conditions would adequately capture the diagnosis of POTS, CRPS and

CFS, or other relevant search terms and whether there are potential sources of ascertainment bias.

the risk of bias; however, in light of the lack of a signal so far from case reports, the question remains

whether these are warranted at this stage.

The PRAC considered that the pharmacovigilance activities that are currently in place for the HPV

vaccines should persist. Targeted questionnaires are already in place for CRPS and POTS and these are

sent to reporters by the MAHs to obtain more complete information in relation to these reports. In light

of the recommendations of the SAG, consideration should be given to how these questionnaires need

to be updated.

More specifically, ‘continuous limb pain’ should be used as a non-specific, but possibly sensitive, term

to retrieve potential cases of CRPS that had not been appropriately labelled as CRPS. Specific features

of the diagnosis of POTS, such as the tilt table test or heart rate and blood pressure recordings at rest

and upon standing, should be monitored. Furthermore, CFS has a clear set of symptoms, which should

be monitored due to the possible overlap of POTS cases with CFS.

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vaccines should continue. This includes that close monitoring of these syndromes in relation to HPV

4. Pharmacovigilance activities

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perhaps the PRAC could consider (e.g. CPRD study or similar retrospective designs), being aware of

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In conclusion, as far as feasibility of further studies is concerned, there are some designs which

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Such an update may or may not identify more cases than those already identified so far, due to the

characteristics of CFS to ensure cases which less closely met the case definition could be identified.

to specifically include the characteristics for CRPS and to increase the sensitivity of some

retrospective cohort studies to be potentially of use, and that these should predate media interest.

(selection bias) could not be dealt with by statistical methods. Several experts considered only

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due to the large sample size and confounders. However, concern was expressed by the SAG about the

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The PRAC also considered whether any additional pharmacoepidemiological studies should be

requested from the MAHs. Taking into account the O/E analyses, which do not suggest an increased

occurrence of CRPS or POTS in relation to the HPV vaccines, alongside the advice of the SAG regarding

difficultly of reliable capture and identification of these outcomes in healthcare databases and the risk

of bias, it was concluded that requesting such studies from the MAHs was not warranted.

Nevertheless, the PRAC acknowledged that further research in the area of both CRPS and POTS, may

be beneficial in improving the general understanding of these syndromes, and thereby possibly

improve the care of these patients, irrespective of any HPV vaccine exposure.

5. Overall discussion and conclusions

prevention of cervical and various other cancers caused by HPV infection. Routine surveillance of

suspected adverse reaction reports has raised questions on the potential association between the use

syndromes have been subject to previous repeated review by PRAC.

of the vaccines and two syndromes in particular, which are known as CRPS and POTS. These

Regulation (EC) No 726/2004 resulting from pharmacovigilance data, and requested the EMA to assess

these concerns.

and post-marketing safety data, and took into account literature review, data from Eudravigilance,

information submitted voluntarily by the public. The advice of the Scientific advisory group (SAG) on

vaccines was sought; the expertise of this group was supplemented with additional European experts

on these syndromes and on neurology, cardiology and pharmacoepidemiology.

CRPS is defined as continuing pain that is disproportionate to the inciting event and may be associated

is usually only diagnosed from the point when normal recovery from the initiating trauma should have

Gardasil 9 and 42,047 subjects for Cervarix. No cases were identified in the Cervarix and comparator

cohorts. The incidence of CRPS in the Gardasil/Silgard and Gardasil 9 clinical trials was less than 1 case

per 10,000 person-years and comparable in the Gardasil/Silgard and Gardasil 9 and corresponding

placebo cohorts.

Analyses of observed versus expected number of spontaneous reports were undertaken, covering a

wide range of scenarios regarding underreporting (from 1 – 100 % reporting) and including reports

that did not fully meet the diagnostic criteria for the syndrome.

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In the review of clinical trial data a total of 60,594 subjects were included for Gardasil/Silgard and

million aged 10 to 19 years may develop CRPS each year.

Available estimates suggest that in the general population around 150 girls and young women per

occurred, and is usually only recognised sometime later among those with continuing pain afterwards.

lis

immobilisation of the limb. The onset of symptoms of CRPS is difficult to define because the syndrome

an episode of trauma including fracture of the wrist or carpal tunnel syndrome surgery, or

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with dysautonomic signs and symptoms and is usually confined to a single limb. CRPS typically follows

CRPS

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reports submitted by Member States, including Denmark, as well as information from Japan and

The PRAC requested data and analyses from the MAHs regarding CRPS and POTS from clinical trials

On 09 July 2015 the European Commission therefore triggered a procedure under Article 20 of

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Human papillomavirus (HPV) vaccines have been authorised in the European Union since 2006 for the

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Overall, the comparisons of observed versus expected number of spontaneous reports do not suggest

an increased occurrence of CRPS in relation to the HPV vaccines.

Furthermore, the detailed review of the reports of CRPS did not show a consistent pattern regarding

time-to-onset following vaccination or clinical characteristics.

The SAG also concluded that most of the reports of CRPS under review did not appear to fulfil the

established diagnostic criteria for CRPS.

Overall, available data do not provide support for a causal association between HPV vaccines and

CRPS.

POTS

POTS is a systemic syndrome which has been known for a long time under different names and is still

poorly understood. Available estimates suggest that at least 150 girls and young women per million

minutes upon standing, as well as an increase in heart rate to above 120 bpm or by ≥ 30bpm, and in

may develop POTS each year. POTS patients typically show persistent tachycardia for more than 10

cohorts. The incidence of POTS in the Gardasil/Silgard and Gardasil 9 clinical trials was less than 1 case

per 10,000 person-years and comparable in the Gardasil/Silgard/Gardasil 9 and corresponding placebo

cohorts.

Overall, comparisons of observed versus expected number of spontaneous reports, with the same

scenarios as described above for CRPS, do not suggest an increased occurrence of POTS in relation to

the HPV vaccines.

recently published more information on these reports, suggesting that some of these individuals were

likely to have had CFS. This is in accordance with the SAG conclusions that most of the reviewed

avoiding the issue of differential diagnostic practice in vaccinated and unvaccinated), evaluated

diagnoses of CFS, as well as referrals from general practice for as yet undiagnosed symptoms of

chronic fatigue and exhaustion, as well as diagnoses for fibromyalgia, post viral syndrome and

neurasthenia. The study found no association between HPV vaccine and any of the conditions studied.

Overall, available data do not provide support for a causal relation between HPV vaccines and POTS.

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A study by Donegan and colleagues (2013), using self-controlled case series design (and therefore

CFS.

reports of POTS could better correspond to the definition of CFS or at least include some features of

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The vast majority of POTS reports came from a centre in Denmark (Brinth et al, 2015). This centre has

onset following vaccination or clinical characteristics.

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Furthermore, the detailed review of the reports did not show a consistent pattern regarding time-to-

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Gardasil 9 and 42,047 subjects for Cervarix. No cases were identified in the Cervarix and comparator

In the review of clinical trial data a total of 60,594 subjects were included for Gardasil/Silgard and

upright) vary across patients and are otherwise non-specific.

headedness, diaphoresis, tremor, palpitations, exercise intolerance, near syncope upon standing

POTS cannot solely rely on these criteria; other symptoms (e.g. syncope, fatigue, headaches, light-

children and juveniles below 19 years of age by ≥ 40bpm, without arterial hypotension. A diagnosis of

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SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

Overall conclusions

More than 80 million girls and women worldwide have now received these vaccines, and in some

European countries they have been given to 90% of the age group recommended for vaccination. Use

of these vaccines is expected to prevent many cases of cervical cancer and various other cancers and

conditions caused by HPV.

Symptoms of CRPS and POTS may overlap with other conditions, making diagnosis difficult in both the

general population and vaccinated individuals. However, available estimates suggest that in the

general population around 150 girls and young women per million aged 10 to 19 years may develop

CRPS each year, and at least 150 girls and young women per million may develop POTS each year. The

review found no evidence that the overall rates of these syndromes in vaccinated girls were different

from expected rates in these age groups, even taking into account possible underreporting. The PRAC

known as myalgic encephalomyelitis or ME). The results of a large published study

showed no link

and some patients had diagnoses of both POTS and CFS, these results were considered relevant for the

and CRPS based on broad search strategies including outcome details and to compare reporting rates

against available information on the known epidemiology of POTS and CRPS.

6. Grounds for the PRAC recommendation

The Pharmacovigilance Risk Assessment Committee (PRAC) considered the procedure under

•

The PRAC considered the totality of the data submitted with regard to a potential association

between HPV vaccination and the occurrence of Complex regional pain syndrome (CRPS) and

the marketing authorisation holders, published literature, Eudravigilance data, and the

Member States and information submitted by the public.

Postural orthostatic tachycardia syndrome (POTS). This included the responses submitted by

outcome of the Scientific advisory group (SAG) on vaccines as well as data submitted by

population and have been described in the medical literature before HPV vaccines were

introduced.

•

The PRAC considered that the observed versus expected analyses took into account a wide

range of scenarios regarding underreporting and included reports that did not fully meet the

diagnostic criteria for the syndromes. Overall, in these analyses the rates of these syndromes

in vaccinated girls were consistent with expected rates in these age groups.

Donegan et al, (2013) Bivalent human papillomavirus vaccine and the risk of fatigue syndromes in girls in the UK.

Vaccine; 31(43): 4961-7

Assessment report

EMA/762033/2015

•

The PRAC took note of the fact that CRPS and POTS occur in the general unvaccinated

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Article 20 of Regulation (EC) No 726/2004 for HPV vaccines.

Whereas,

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CRPS or POTS reports to determine relevant clinical characteristics, to identify possible cases of POTS

The safety of these vaccines should continue to be carefully monitored. This should include follow-up of

benefits of HPV vaccines continue to outweigh their risks.

not support that HPV vaccines (Cervarix, Gardasil, Gardasil 9, Silgard) cause CRPS or POTS. The

Taking into account the totality of the available information the PRAC concluded that the evidence does

current evaluation.

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between HPV vaccine and CFS. As many of the reports considered in the review have features of CFS

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noted that some symptoms of these syndromes may overlap with chronic fatigue syndrome (CFS, also

SUU, Alm.del - 2015-16 - Bilag 68: Orientering om statusopgørelse fra regionerne om HPV og EMA's endelige rapport, fra sundheds- og ældreministeren

•

The PRAC also noted that most of the reviewed reports of POTS would more appropriately have

been labelled as having features of chronic fatigue syndrome (CFS). The PRAC therefore

considered the results of a large published study which showed no link between HPV vaccine

and CFS, as relevant for the current review.

The Committee, having considered all the information available, concluded that the evidence does not

support a causal association between HPV vaccination and CRPS and/or POTS. The PRAC confirmed

that the benefit-risk balance of the HPV vaccines (Cervarix, Gardasil, Gardasil 9 and Silgard) remains

favourable and recommends the maintenance of the marketing authorisations.

Assessment report

EMA/762033/2015

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