SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

Sundheds- og Ældreudvalget 2015-16
SUU Alm.del Bilag 109
Offentligt

Responsum to Assessment Report on HPV-vaccines

released by EMA November 26

2015

By Louise Brinth, MD PhD

Syncope Unit

Bispebjerg and Frederiksberg Hospital

Copenhagen December 15

2015

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

Contents

1: Preface

2. Introduction

2.1. Vaccines

2.2. HPV-vaccines and their suspected side effects

2.3. A scientific approach

3. The work at the Syncope Unit

3.1. Why have we seen these patients at the Syncope Unit – and which

patients have we seen?

3.2. The three papers we have published describing our clinical

experience with patients suffering from suspected side effects to the

HPV-vaccine, and a response to the criticism set forth by EMA

4: The assessment of the Uppsala Monitoring Center (UMC) report

5: Comments on the EMA process

6: Is myalgic encephalomyelitis/chronic fatigue syndrome a relevant diagnosis?

7: What to do?

8: Concluding remarks

9: English Summary

10: Danish Summary

11: References

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

1: Preface

Over the past few years a growing concern has emerged in Denmark - as well as in other

countries around the world - with regard to the safety of the HPV-vaccines

The debate was boosted in Denmark as a consequence of the TV2-Denmark documentary

“De vaccinerede piger” (The Vaccinated Girls) released March 26

2015. The Danish

Health and Medicines Authorities (DHMA) therefore asked the European Commission to

initiate an in depth review. The European Commission requested the European Medicines

Agency (EMA) to give its opinion on whether there is a causal association between HPV-

vaccines and the two syndromes: Chronic Regional Pain Syndrome (CRPS) and/or

Postural Orthostatic Tachycardia Syndrome (POTS). November 27

the assessment

report was released.[1] The aim of this assessment was to use the available data to draw

a conclusion on causality between HPV vaccine and POTS/CRPS.

In the assessment report written and published by EMA, three of my publications regarding

my clinical experience with patients with suspected side effects to the quadrivalent HPV

vaccine are directly criticised. Furthermore, my clinical expertise and judgment are

indirectly criticised as a substantial part of our adverse event reports (AER) are overruled.

I want to defend my work but most of all I want to join in and encoruage to an open and

honest debate. In the following I will primarily adress the critique directed against my work

and only touch briefly on a few other aspects of the EMA report that I find is closely related

to my own work or the conclusion of my work. I can and will not comment on the report as

a whole.

My agenda is not to miscredit the vaccine, rather it is to maintain public confidence in the

vaccine itself and the entire childhood vaccine program. To reach this goal, I believe that it

is imperative to appreciate that vaccines can have side effects and it is the responsbility of

the health care community to monitor and investigate serious problems which are

suspected to be related to the vaccines. I will not go into the science behind the benefits. I

know that we have strong evidence that both HPV-vaccines prevent development of

precursor stades to cervical cancer if the vaccine is given before HPV-infection.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

This is a very long responsum. It is even longer than the EMA report that it relates to. You

may find that strange – maybe even ridiculous. But – I have been deeply involved in this

matter – suspected side effects to the HPV-vaccines – for years now. And I am so

frustrated by the trouble and grief I believe that we create for ourselves and each other by

not allowing room for the nuances, doubts and uncertainties in this very complex – and

highly important matter.

This is a scientific response addressing the critique of the EMA which has been echoed by

a number of stakeholders, including the DHMA who surprisingly seem to have partially

abandoned their conclusions from July 2015. But – it is also a personal responsum. I have

been in this highly explosive field in four years now. I want to voice my ever increasing

feeling of our considerable inabillity to be nuanced and balanced when discussing

vaccines – both their efficacy and side effects. We are in desperate need of a shift in

paradigm, a groundbreaking one, or the future of public confidence in vaccines will be lost.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

2: Introduction

My Chief of research at the Syncope Unit at Bispebjerg and Frederiksberg Hospital,

Jesper Mehlsen and I have had a constructive and fruitful collaboration with the DHMA. As

from October 8

2015, the former DHMA has been split into three new agencies, The

Danish Health Authority, The Danish Medicines Agency and The Danish Patient Safety

Authority. In order to avoid confusion I will use the abbreviation DHMA in this responsum

as our collaboration with the authorites has primarily taken place while they still existed as

DHMA.

We may not always have agreed on the degree of transparency in the process – but I have

felt that the DHMA has reacted when we have voiced our concern. They have been willing

to discuss and evaluate our concerns, have themselves initiated looking into both the

Danish cases, and requested the Uppsala Monitoring Centre (UMC) to participate in the

process with an evaluation of adverse event reports in an international context. We have

informed them continuously of our findings, our thoughts, our approach, our methods and

our publications. I think that both we – at the Syncope Unit – and the DHMA has dared to

disagree and dared to admit to ourselves and each other that we had a problem that

urgently needed our attention. A question that we needed to answer in collaboration

In July 2015 the “Report from the Danish Health and Medicines Authority for consideration

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

vaccines” was sent to EMA .[2]

I found that this report was the honest and sound consequence and conclusion of our

collaborative work trying to get to the bottom of this signal.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

2.1: Vaccines

Vaccines are, within medical science, considered a global and groundbreaking health

success. Through vaccination programs coordinated and implemented throughout the

globe, diseases such as smallpox have been eradicated. Moreover, other infectious

diseases have been reduced significantly with impressive impact on both mortality and

morbidity worldwide. I can and will not contradict from the obvious revolutionary

significance of the vaccination programs. But a considerable and increasing uneasiness

surrounding the vaccines and their suspected side effects demonstrates an urgent need

for us to discuss the way we handle vaccine safety issues. This includes how we

investigate, acknowledge and cope with the possible side effects and the consequences

for the individual.

Vaccinomics is the emerging scientific field that: “encompasses the fields of

immunogenetics and immunogenomics as applied to understanding the mechanisms of

heterogeneity in immune responses to vaccines.”[3] Adversomics is the closely related

study of genetically determined vaccine-associated adverse events.[3]

There have been two recent publications within these fields in which a genetic

predisposition to adverse events from a vaccine has been demonstrated. Pandemrix, one

of the pandemic influenza vaccines used in 2009-2010, has been associated with the

occurrence of narcolepsy in subjects of a specific HLA subtype. [4]Also, common variants

of certain genes have been found to be associated with an increased risk of febrile

seizures after measles mumps rubella vaccination. [5]

Both these relatively new “omics” are mirroring our emerging understanding of the need for

an individualized vaccines technology - and our leaving a “one size fits all” approach

towards vaccines.

Why do I introduce these two “omics”?. I do so, because I believe that both “omics” and

the science and knowledge they represent point the way forward towards “personalized

vaccines” based on an emerging understanding of the importance of immune response

phenotype regarding both effects and side effects of vaccines. However – this approach

focusing on the individual may clash with the whole mindset behind our childhood

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

vaccination programs and the “one-size-fits-all” approach that lies inherent in these

programs and our wish to obtain herd immunity.

So where does that leave us when science is beginning to contradict our “old ways”? I

have no answer to this question except that denial is unlikely to be the right way forward.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

2.2: HPV-vaccines and their suspected side effects

Infection with HPV has been identified as a carcinogen in an array of cancer types. Nearly

5% of cancers worldwide are thought to be associated with HPV-infection[6] and almost

100% of cervical cancers are associated to HPV infection.[7] The ability to counter that

threat by a vaccine is obviously extremely important.

The HPV vaccines in current use have been licensed on surrogate markers,

immunological and histological, and therefore have not been shown to have yet prevented

a single case of cervical cancer death - which is to be expected as the latency from the

time of infection with the cancerogenic HPV-subtypes that the HPV vaccine is directed

against to fully developed cervical cancer is very long. It is understandable, that we can

not wait for evidence of that robustness before we implement the vaccine. We have

evidence demonstrating that the vaccine prevents precursor states and that is as good an

indication as it gets. I believe that the HPV-vaccines have the potential to counter both

mortality and morbidity – both death and suffering – in the long run. However, we are

dealing with a preventive measure and this calls for a very high focus on safety.

The quadrivalent recombinant vaccine, protecting against human papilloma virus types 6,

11, 16, and 18 (qHPV vaccine, Gardasil®), was included in the Danish childhood

vaccination program in 2009. Both the clinical studies and post licensure register studies

have demonstrated a beneficial safety profile for both the bivalent, the quadrivalent and

the new nonavalent HPV-vaccines [8-13]. However, post licensure monitoring may be

superior in detecting rare adverse events compared to pre licensure reviews and during

the past years, case stories describing patients with suspected severe side effects to the

HPV-vaccines are emerging from several countries.[14] [15-20] [21-23]

All medicines have the potential of eliciting side effects, vaccines being no exception. It is

well accepted that highly immunogenic vaccines are often associated with both local and

systemic reactions. Furthermore, vaccines may carry an inherent risk of provoking

autoimmune phenomena in susceptible individuals [24]. We have evaluated more than 300

patients with suspected side effects to the Q-HPV-vaccine in the last four years. We have

found consistency in the reported symptoms as well as between our findings and those

described by others. A case definition of the patients we have seen would be longlasting

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

excessive fatigue and pronounced autonomic dysfunction coupled with severe non-

migraine-like headache, cognitive dysfunction, gastrointestinal discomfort, and widespread

pain of a neuropathic character.[15, 16, 25] The patients described may have been

labelled with different diagnoses – and many have not been diagnosed at all. But – the

symptoms described are apparently quite similar.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

2.3: A scientific approach

We all use the words “scientific”, “evidence”, “hypothesis” and “proof”. The core of all

science is and has been for centuries based on hypothesis testing which in turn is based

on questions arising from observations. Scientific method is defined by “The Oxford

English Dictionary” as:

"a method or procedure that has characterized natural science since the 17th century, consisting in

systematic observation, measurement, and experiment, and the formulation, testing, and modification of

hypotheses."[26]

So, basically the knowledge and ideas that we base our medical professionalism on are

obtained though the following steps on the scientific ladder:

This is very important to keep in mind when we evaluate and discuss the evidence already

available to us – and when we plan and discuss how to obtain more and better evidence.

This is the scientific toolbox. All the steps are equally important. They all depend on each

other. The way we obtain knowledge, the way we get to “know” things are through a never

ending ascending through these steps with all new findings leading to new questions, new

hypotheses that need testing…..

I have made very clear in my communication with colleagues, authorities and patients that

my work is a description of an observation and a formulation of a question – I am working

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

on the lowest steps of the ladder. Therefore my findings should not be seen as proof of

anything. However, they should remind us that we need to initiate research that can test

the hypothesis that these patients may be suffering from side effects to the qHPV-vaccine.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

3: The work at the Syncope Unit

3.1: Why have we seen these patients at the Syncope Unit – and what patients have

we seen?

I am a medical doctor working at a Syncope Unit specializing in orthostatic intolerance and

autonomic dysfunction. At the Syncope Unit at Bispebjerg and Frederiksberg Hospital in

Copenhagen, we have interest and expertise in and a diagnostic toolbox at hand directed

at the evaluation of function and dysfunction of the autonomic nervous system. I have

seen more than 200 patients with suspected side effects to the HPV-vaccines through the

last four years.

The autonomic nervous system consists of two subsystems: the parasympathetic and the

sympathetic nervous systems which in many cases have "opposite" actions: one activates

a physiological response - the other inhibits it. For example sympathetic stimulation will

increase heart rate, parasympathetic stimulation will decrease heart rate. These two

subsystems exert their influence on most of the cells, tissues and organs of the body in an

antagonistic but coordinated interplay. The coordination between the two subsystems

takes place both centrally in the central autonomic network and in the periphery. The

autonomic nervous system senses and responds to both intra and extra somatic stimuli

thereby maintaining bodily homeostasis and enabling a shift towards fight and flight mode

if so needed. Most of the actions of the autonomic nervous system run in reflexes with

sensory input through the afferents, central processing – and an output through the

efferents. The autonomic nervous system is intimately connected with the way we interact

with the world – both physically and emotionally.

Walking upright on two legs is a challenge and a trait that defines the human race. Rowell

writes in his book “Human Cardiovascular Control” that:

“The

circulatory adjustments to upright posture demand the full capabilities of the reflexes that govern

cardiovascular function.”[27]

These important reflexes controlling cardiovascular function is primarily taken care of by

the autonomic nervous system and the interaction between the autonomic nervous system

and the cardiovascular system.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

Therefore, any disease, condition or drug that effects the function of the autonomic

nervous system will as one of the first manifestations very often have orthostatic

intolerance. Orthostatic intolerance is symptoms related to the upright posture – with

symptom relief in recumbence.

Orthostatic intolerance comes in the acute form – syncope, as well as more chronic forms

with symptoms related to upright posture seen at a daily basis.

At the Syncope Unit we evaluate both syncopal patients but also specialize in evaluation

and treatment of chronic orthostatic intolerance. In our elderly patients referred with

chronic orthostatic intolerance the most common finding is orthostatic hypotension which

can be understood as an age related inability to maintain a sufficient blood pressure in the

upright position. In our younger patients the most common finding is chronic orthostatic

intolerance related to tachycardia in the upright position and marked symptoms compatible

with autonomic dysfunction and cerebral hypoperfusion and patients often fulfilling the

diagnostic criteria for postural orthostatic tachycardia syndrome - POTS.

POTS is a heterogeneous condition of dysautonomia and suspected autoimmunity

characterized by abnormal increments in heart rate upon assumption of the upright

posture accompanied by orthostatic intolerance and symptoms of cerebral hypoperfusion

and sympathoexcitation. An increase in heart rate equal to or greater than 30 min-1 or to

levels higher than 120 min-1 during a head-up tilt test is the main diagnostic criterion.

POTS can be diagnosed with a standing test or tilt table test, although tilt tests are not

always available. A routine physical examination will not diagnose POTS, nor, in most

instances, will orthostatic vital sign testing that lasts less than 1-2 minutes. Before

diagnosing a patient with POTS other medical conditions causing tachycardia should be

ruled out. POTS is more common in women with a 5:1 female-to-male ratio. The overall

prevalence is not known but it is estimated that POTS is found in 500.000 patients in the

USA which would translate to 10.000 in Denmark . The orthostatic symptoms consist of

lightheadedness, visual blurring or tunnel vision, palpitations, tremulousness, and

weakness (especially of the legs). Other symptoms include fatigue, exercise intolerance,

hyperventilation, nausea, concentration difficulties, and headaches. [28-31]

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

In 2011 we had the first patient referred to our Syncope Unit for evaluation of orthostatic

intolerance as suspected side effect to a qHPV-vaccine. She suffered from both syncopal

attacks and chronic orthostatic intolerance – as well as an array of other symptoms –

including muscular twitching and weakness, cognitive dysfunction, sleeping disorder,

nausea and extreme fatigue. The patient reported symptom onset in the first month after a

qHPV-vaccination.

During the next two years a few more patients were referred who described a somewhat

similar symptom complex and suspected a causal link to the HPV-vaccine due to a

temporal association between the vaccine and symptom onset. In 2013, after having

evaluated 6-7 patients who all described that they suspected that it was the qHPV-vaccine

which had made them ill – we started to compare the symptoms described and the

objective findings we had seen in these patients. We felt that we could not dismiss the

possibility that we actually saw a pattern of symptoms in these patients suspecting to

suffer from a post-qHPV-vaccine symptom complex. We therefore contacted the DHMA,

telling them about our suspicion, asking them how they wanted us to proceed and initiating

a collaboration.

Denmark is a small country. Many patients who suspect that they suffer from side effects

to a vaccine tell us that they have felt that their suspicion has been ridiculed or dismissed

when presented to medical professionals. We have not reported all the patients who

suspected to suffer from side effects as AER. However, if we had a suspicion that their

symptoms could be related to the vaccine – and we could not dismiss this suspicion by

finding other explanations for their symptoms etc – we reported it. We are obliged to do

this by Danish law.

At the Syncope Unit we do tilt table testing. We are good at treating orthostatic intolerance.

We were able to give some of these patients a diagnosis. We tell all our patients who

receive the POTS-diagnosis that POTS should probably be looked upon more as a

symptom than a disease entity.

People became aware that we did not dismiss the idea of the HPV-vaccine being capable

of producing side effects in a few susceptible individuals and had some treatment options

for the symptoms experienced by the patients – primarily directed against the orthostatic

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

intolerance. Due to these circumstances, during 2013, 2014 and 2015 we had an ever

increasing number of patients referred from all parts of Denmark with suspected side

effects to the qHPV-vaccine.

It is important to keep in mind that until June 1

2015 we were a “normal” Syncope Unit.

Danish Regions decided spring 2015 that as of June 1

each of the five Regions of

Denmark should offer what was called “One Entrance” for patients with suspected side

effects to the HPV-vaccine – who had serious symptoms and were not better helped in

another department. We were appointed “One Entrance” in The Capitol Region of

Denmark.

In the figure below are given the approximate numbers of patients referred through the last

years who themselves or the referring physician suspected that the symptoms they

experienced were caused by the qHPV-vaccine. Our three publications on the subject are

also given with indications on the period in which the patients presented in the papers

were evaluated at our clinic. All three papers were based on data from all patients referred

at the time of data analysis. However, with some exclusion criteria used in the two last

papers but these exclusion criteria are clearly stated and explained in the papers. All

patients described in the papers were evaluated before the big rush of patients seen in

2015 following the TV-documentary in late March 2015 and prior to the massive number of

patients referred to us after the start of “One Entrance” in June 2015.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

3.2: The three papers we have published describing our clinical experience with

patients suffering from suspected side effects to the HPV-vaccine and a response to

the criticism set forth by EMA

EMA writes:

“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.”(Page 24)

This is the most serious allegation I have ever been presented with. I can only understand

this statement and their use of the word “apparently” as if they actually reveal that they just

made an assumption. They made a guess. Contrary to this assumption made by the EMA,

we did not select patients to fit a pre-specified hypothesis of vaccine-induced injury. We

did not select patients based on symptoms in order to make sure that they would fit into a

preexisting hypothesis. EMA suggests that we did.

We did not.

We did not ask all patients

that we had referred with orthostatic intolerance whether they suspected that their

symptoms were causally linked to the qHPV-vaccine. Only when the patients themselves

mentioned that they had the suspicion we took it into consideration and discussed with the

patient whether other possible eliciting factors could be recognized and whether it was

relevant to report their symptoms as possible side effects to the qHPV-vaccine.

I do not mean to be patronizing but we urgently need to create common ground here.

Therefore let us start out by clarifying that what I have described in my three papers are

case series, that can be defined as:

A group or series of case reports involving patients who were given similar treatment. Reports of case series

usually contain detailed information about the individual patients. This includes demographic information (for

example, age, gender, ethnic origin) and information on diagnosis, treatment, response to treatment, and

follow-up after treatment.[32]

We published case series, which by nature do not do hypothesis-testing – and are prone

to selection-bias. To minimize selection bias, we included all consecutively referred

patients – with exception of the ones excluded due to exclusion criterias.

EMA writes:

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

“The

consistency in symptom profile across the case series is highlighted in the papers. However, it is

unclear whether or not the absence or 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 interviewed retrospectively in this way would yield these symptom

characteristics. Furthermore, many of these symptoms would require some sort of objective clinical

evaluation, yet there is no information on how this was done or what other clinical assessment may have

been undertaken to exclude other causes of the symptoms.”(Page 23)

Nausea, headache, abdominal pain, fatigue etc. are in essence subjective symptoms and

as such they escape “objective clinical evaluation”. Orthostatic intolerance was quantified

through tilt-testing, which in our book constitutes more than “some sort of objective clinical

evaluation”. The diagnosis of POTS rests upon this – only if combined with severe

orthostatic intolerance as defined in the international consensus reports. Assessment of

symptoms is fundamental in the dialog between medical doctors and their patients. If the

statement put forward by EMA: “the absence or presence of specific symptoms was

solicited by the interviewer” was correct, then we would be guilty of malpractice, which is

definitely not the case.

I think we did a good job with these case series. But in recognition of the many limitations

inherent in case series – and the extremely urgent need for clear answers – we stated very

clearly that we were not able to dismiss or confirm a causal link between the symptoms

experience in the patients and the HPV-vaccine – but further research was urgently

needed.

Through autumn 2013 we had a continuous and constructive dialogue with the DHMA. In

December 2013 I was asked by the DHMA to describe our clinical experience and findings

in a report with regard to the suspected side effects to the HPV-vaccine in a report. This

report was written in the beginning of 2014 and was based on all of the first 35 patients

consecutively

referred to our syncope unit for head-up tilt test under the diagnosis of

orthostatic intolerance as a suspected adverse event following vaccination with the qHPV-

vaccine and was finalized and submitted to the DHMA March 2014. In other words – the

report described the characteristics of the first 35 patients who had told us –

spontaneously - that they suspected their symptoms were side effects to the qHPV-

vaccine. We did not apply any exclusion criteria in this report. This was not asked for by

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

the DHMA – and it would not have made sense to us. This was just a “clear” description of

the first 35 patients referred to us with suspected side effects to the qHPV-vaccine.

Our paper: “Orthostatic intolerance and postural orthostatic tachycardia syndrome as

suspected adverse effects of vaccination against human papilloma virus” [16] published in

the journal “Vaccine “is based on this report – as agreed upon by the DHMA. It took some

time to get it published – that is the reality of publishing scientific papers. All scientists will

know this. The report as well as the paper was finished March 2014 and included all the

patients that we had evaluated so far with suspected side effects. As the cohort described

included ALL patients with suspected side effects consecutively referred at this time we did

not write in the methods section in which period we had had the patients referred.I realize

it would have been easier for the reader to understand how the cohort described had been

“selected”. But – I believe that the report I handed over to the DHMA March 2014 was

forwarded immediately to EMA – so it should be very clear from the data available to EMA

that it is the same 35 patients described in our paper and in the report.

I believe that communication is the cornerstone of pharmacovigilance and we are obliged

to communicate our findings and suspicions. We gave the diagnosis POTS to the patients

fulfilling the diagnostic criteria. And we had patients referred from all over Denmark. The

POTS-diagnosis received a lot of attention. We repeatedly stated at meetings and in

correspondence with health authorities, physicians and all interested that we found it very

important not to focus blindly on the POTS-diagnosis – but rather look at the symptoms

described by the patients. However – we felt that the focus was still too heavily on POTS.

We therefore sat out to demonstrate from the patients that we had seen so far (December

2014), suspecting side effects to the qHPV-vaccine – that they actually presented with the

same symptoms independent of the diagnosis given. We therefore wrote the paper: ”A

descriptive analysis of suspected side effects to the quadrivalent human papilloma

vaccine” that was published in Danish Medical Journal.[15]

EMA writes (and they call this our first paper – but as mentioned above, this was actually

our second paper):

“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).”(EMA report page 23)

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

This was a retrospective analysis based on 75 patients consecutively referred to our

Syncope Unit between May 2011 and December 2014 for head-up tilt test on the grounds

of orthostatic intolerance and symptoms compatible with autonomic dysfunction as

suspected side effect following vaccination with the Q-HPV-vaccine. We included ALL

patients referred until December 2014 with symptoms that the patients themselves or the

physicians referring them suspected were causally linked to the HPV-vaccine. We did not

select the patients – beside from the exclusion criteria given in the methods section:

“We have chosen to include only those patients with onset of symptom within the first two post-vaccination

months excluding 11 patients. Patients with known chronic diseases pre-vaccination as well as patients in

whom other possible eliciting factors could be recognised (7 patients) were excluded as well as patients who

were unable to account for the temporal association between vaccination and symptom onset (4 patients)

leaving 53 patient for further analysis.”

I find it very strange that EMA apparently criticizes that we excluded patients with pre-

existing illnesses etc. We made an observation. We wanted to describe only those patients

in whom we thought it plausible to suspect a causal link between symptoms described and

the HPV-vaccine. We therefore excluded patients with pre-existing illnesses. If we had not

– we would have had a hard time determining and describing which of the symptoms

experienced by the patients could be ascribed to a pre-existing medical condition.

We found it important and relevant to write this paper as it clearly showed that the POTS-

diagnosis would NOT be a relevant diagnosis or at least not the sole diagnosis relevant

when evaluating possible side effects to the qHPV-vaccine. We stated in the discussion

section that:

“We may have diagnosed more than half of these patients with POTS – but 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 ex-peri-enced the same degree and pattern of symptoms

regardless of the POTS diagnosis.”

We found it troubling that often when discussing our clinical experience with colleagues

and authorities we were told that this “POTS-thing” was a Danish phenomenon – which is

true to that extent that we included that diagnosis POTS in the AER that we filed as we

found it relevant information. But still – we kept on stating that this was not “just about

POTS”.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

Therefore, we wanted to establish whether another diagnosis would encompass more of

the symptoms described by the patients – and a greater proportion of the patients. We

therefore developed a questionnaire asking questions relevant for the diagnosis myalgic

encephalomyelitis/chronic fatigue syndrome (ME/CFS) and wrote the paper ”Is Chronic

Fatigue Syndrome/Myalgic Encephalomyelitis a Relevant Diagnosis in Patients with

Suspected Side Effects to Human Papilloma Virus Vaccine? ”published in International

Journal of Vaccines and Vaccination. [25]

This was done as a retrospective analysis based on 90 patients referred to the Syncope

Unit from May 2011 to April 2015 for clinical evaluation due to suspected side effect

following vaccination with the qHPV vaccine. The questionnaire was sent out to all 90

patients. Only those patients who had returned the relevant questionnaires (see below) (39

patients) where included in the analysis.

We demonstrated that most of the patients (87%) of the patients seemed to fulfill the

diagnostic criteria for M/CFSE and that this diagnosis encompassed a greater share of the

patients than the POTS diagnosis. Further, it gave a better reflection of their symptom

burden related to autonomic dysfunction.

Our study was not designed to establish whether or not a diagnosis of ME/CFS would

lead to a correct classification of patients with suspected side effects. However, we

suspected from our clinical experience that the ME/CFS diagnosis would encompass most

of the symptoms seen and this was confirmed by the analysis. It is important to get an

appropriate diagnosis and reach an agreement on this subject in order to provide a more

firm basis for pharmacovigilance and thus in the evaluation of the probability and

prevalence of suspected side effects to the qHPV vaccine.

We did of course recognize several limitations to our approach and transparently stated

those in the paper:

1: The results may be regarded as a mere confirmation by circular reasoning as our

clinical impression was tested systematically in the same group of patients.

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2. The ME/CFS diagnosis should be used only when possible somatic and psychiatric

differential diagnosis have been thoroughly evaluated, which was not done on a

systematic basis in our study.

3: Our suggestion of using the ME/CFS diagnosis for the possible side effect should be

considered a first methodical approach to reach consensus as to how these patients are

classified. I believe that reading the EMA report underscores how impaired our possibilities

for creating evidence for the existence or non-existence of a post-HPV-vaccine-syndrome

is due to our lack of this diagnostic consensus in patients with complex symptoms – such

as the patients at hand.

Regarding the time span between symptom onset and vaccination:

EMA writes:

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

recall of exact symptom onset (as well as the date/trigger for the symptoms) will be difficult to achieve. This

is particularly so given that the mean time between onset of symptoms and examination was stated as 1.9

years (range: 0–5). The reliability and objectivity of such recall is questionable, and inherent recall bias in the

methods is likely”(EMA-report page 23)

I agree with EMA that it would have been optimal if this time span between vaccination

and symptom onset and evaluation at our clinic had been much shorter bordering on non-

existent. But again: This is not a clinical study. Our experience with the patients were not

based on a protocol. It was not designed. We report an observation we have done in our

clinical work. This was how it was. This is what our patients told us. I do not have the

imaginative abilities or academic skills to figure out how we could have done this

differently.

I have performed the descriptive case series and put forth a question – a hypothesis. I

have added my observations to the growing medical literature reporting observations

reported as adverse events after HPV vaccination. This is my role, contribution and

obligation as a medical doctor seeing patients. This is my place and role in the whole

pharmacovigilance chain. Then it is up to others to do the epidemiological studies. And as

we have some serious and fundamental problems with regard to applying the

epidemiological approach to this issue – primarily due to the lack of unambiguous

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diagnostic practice – we may need to collaborate. I believe that this is what we have been

doing on our dialogue and collaboration with the DHMA. We have contributed from each

our viewpoint in shared recognition of the need to bridge the gap between the clinical

experience with the patients and the epidemiological approach.

EMA criticize that I do not do observed versus expected analysis – and that I do not

include a control group. I am a clinician telling you what I have seen. I am not an

epidemiologist. These are case series – and one of the main conclusions of my three

papers is that we have a huge problems with regard to diagnostic practice in these

patients which I believe hampers meaningful O/E observations.

I believe that I address this problem in the discussion of my last paper. We suspected from

our clinical experience that the CFS/ME diagnosis would encompass most of the

symptoms seen, and this was confirmed by the systematic analysis. It is important to get

an appropriate diagnosis and reach an agreement on this subject in order to provide a

more firm basis for pharmacovigilance and thus in the evaluation of the probability and

prevalence of suspected side effects to the qHPV vaccine. We need to discuss how we

approach the pharmacovigilance process when dealing with patients with unclear and

diffuse symptoms as suspected side effects. How do we handle a situation where we may

suspect that patients with the same complex of symptoms get different - or no - diagnoses

dependent on country and/or medical specialty? We suggest that future research should

aim at elucidating which diagnosis we should be looking for when assessing the suspected

side effects to the qHPV-vaccine on a global scale

It is also important to agree on the diagnostic criteria if a systematic approach to the study

of these patients should be attained. We need futures studies aimed at elucidating the

disease processes disabling these patients and hopefully thereby enable better and

targeted treatment options.

Although we recognize that our studies do not establish whether or not the qHPV vaccine

is a cause of the symptoms seen in our patients we are also aware that vaccines have the

potential of eliciting side effects and that the rare side effects are only seen when the

vaccines are used in a much larger cohort than that used in the registration studies.

Genetic susceptibility perhaps coupled with environmental triggers could likely cause new

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onset symptoms or a flare in a pre existing condition. Because of the concerns expressed

worldwide with regard to the HPV-vaccines, we find that there is an urgent need for a

systematic approach to the patients and for solid, scientific studies of the possible relations

between the vaccine and their symptoms.

As I understand it, the observed versus expected analyses is a measure of the "observed"

rate of the event versus the "expected" background rate. I believe that the "observed" rate

is calculated with both an uncertain numerator and an uncertain denominator: the

numerator being the total number of AER (which we believe may be a very large

underestimation?) and the denominator is the total number of doses of the vaccine sold or

distributed (which we know is a very large overestimation – I believe that health clinics buy

in bulk and leave on the shelf and use until the expiration date comes). Therefore, of

course, if you underestimate the numerator and you overestimate the denominator, you

get a smaller-than-true "observed" rate. As I read it, the "expected" rate is taken primarily

from literature sources? Given the overwhelming problem with the use of different

diagnostic terms – or no diagnosis at all in this group of patients – how does this make any

sense?

Back to the way EMA overrules the reported cases of POTS and CRPS as suspected side

effects: I can only have an opinion on the POTS-cases. But as I read it, EMA reduce the

observed even further (in the Gardasil-analysis by including only those cases that met

either the full or partially the case definition. On page 16 in the EMA report it is shown that

there were 83 cases where the term POTS was reported and 30 additional cases with

suspected POTS. But after evaluation the cases, only 46 of these 113 cases were

included in the observed versus expected analysis. I will get back to this later – but I

believe that it was the MAH doing this assessment as to what degree the reported cases

met the diagnostic criteria? And I cannot read anywhere if they based their evaluation on

the text written in the AER only – or gained access to medical records.

The EMA acknowledge the many known weaknesses and limitations of spontaneous

reporting systems and that the sensitivity for some types of pain remains uncertain.

Despite this statement they make support calculations on observed versus expected. I

would suspect that such calculations are premature at this stage due to the limitations just

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mentioned by EMA themselves – and the whole issue of the “diagnostic mess”

surrounding these patients.

So – altogether I find the criticism put forth with regard to my work and my scientific

approach unjust. I find that the evaluation of my work presented by EMA is based on many

assumptions. Most of these assumptions are to my best knowledge wrong. I find this

approach strange and unscientific. I find it very worrying that EMA apparently base their

judgement of my work – and thereby indirectly also part of their judgement of the safety of

the HPV-vaccines - on guesses. This is too important for guess-work. We need to know

and we need to reach consensus on what we know, what we need to know and what

should be done.I do not think EMA’s methods, approach and rhetoric encourages this.

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4: The assessment of the Uppsala Monitoring Center (UMC) report

Our observations and hypotheses were supported by an independent review of global data

made by the Uppsala Monitoring Center (UMC) which was included in a report sent from

the Danish Health and Medicines Authorities to EMA July 2015

Overall, the UMC report was written on the request of the Danish Health and Medicines

Agency in an attempt to describe the adverse event profile for HPV vaccine using data

from VigiBase®, the WHO international database for suspected adverse drug reactions,

specifically as it related to the safety concern of postural orthostatic tachycardia syndrome

(POTS) and related symptomatology which have been reported from the unexpectedly

high proportion of serious adverse event reports from Denmark.

As I understand it, the analysis of the data was intended to be exploratory and hypothesis-

generating, as it was based entirely upon spontaneously reported individual case safety

reports (ICSRs) which have two very important limitations:

1. The reports are passively collected, meaning that they are received from health care

providers and patients who make an individual decision to report a suspicion of causal

relationship between an adverse event and a drug. Studies have estimated that

spontaneous reporting represents only a small fraction of the true number of adverse

events.[33]The reports are limited in the information that they provide; in order words, they

are limited to the amount of information that the reporter decides to provide when writing

the AER. Reports display a variety of levels of completeness, sometimes limited only to

reporter, patient, drug and event, other times with very complete information including

exact dates of administration of drug, case narratives, and laboratory and imaging data.

As a result of these limitations, it is not possible to draw firm conclusions upon the data.

However, as written in the conclusion of the UMC report, the review of the worldwide data

suggested a number of potential findings: that there is an increasing trend in the number

of HPV reports of containing the “Preferred terms” (PTs) of POTS and related syndromes;

that reports from Denmark were similar to other reports from other parts of the world in the

reporting of symptoms but were distinguished by increased amounts of information and

certain, specific diagnostic terms; and that a similar constellation of symptoms may have

been labelled with different diagnostic labels depending on the country of origin. Finally, it

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was hypothesized that the constellation of symptomatology may be consistent with a

chronic fatigue – like syndrome which appeared specific to HPV vaccines upon

comparison to other vaccines used in this population. These suggestions were put

forward as hypotheses, intended to further investigation, prior to either their acceptance or

rejection.

In the EMA report, it is concerning that the complete data set was not included. Only

specific parts of the report have been reproduced, and it is not defined how these parts

were chosen. As a result, there are a number of examples of inconsistency between the

representation of UMC data in the original DHMA report and the EMA report.

Provided below are texts taken from the EMA report and the corresponding paragraphs

from the original UMC report which was contained within the “Report from the Danish

Health and Medicines Authority for consideration by EMA and rapporteurs in relation to the

assessment of the safety profile of HPV-vaccines”. [2]

Example 1.

EMA report page 27

“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.”

UMC report (page 22, DHMA Report)

“As can been seen, the total number of reports of POTS, CRPS, CFS and fibromyalgia have been increasing

since 2012 with a marked increase between 2012 and 2013.”

In other words, I believe that the EMA report misinterprets the data, as the total number of

reports of CFS (chronic fatigue syndrome) have increased as well (i.e. not “have been

reported relatively constantly”). This is clearly seen on the bar graph included on page 22

in the DHMA report.

Example 2.

EMA report page 27:

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

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

events, rather than only serious events. However, given that Denmark had received 1,228 reports (322

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

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 countries. Eczema,

sensory disturbance, disturbance in attention, memory impairment, palpitations, cognitive disorder, fatigue,

infection, visual impairment, influenza-like illness, muscle spasms, and arthralgia also show

disproportionality.”

UMC report (page 27, DHMA report):

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

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

age.

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

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

(determined the amount of clinically relevant information in an ICSR of the report 2), were classified as

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

Danish reports were “Skin and subcutaneous disorders” and “Cardiac disorders”. PTs significantly reported

more commonly in Danish reports were the following: autonomic nervous system imbalance, orthostatic

intolerance, eczema, sensory disturbance, disturbance in attention, POTS, memory impairment, palpitations,

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

…The PTs significantly reported more commonly in HPV reports from the rest of the world were exposure

during pregnancy, vaccination site pain, and injection site pain.

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

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

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

abdominal pain, tremor, hypersomnia, quality of life decreased and activities of daily living impaired. Nor was

there a significant difference between Danish reports and reports from the rest of the world for the following

diagnosis PTs: chronic fatigue syndrome, post viral fatigue syndrome, fibromyalgia, or CRPS.”

Here, the EMA has failed to mention that the Danish reports were more often classified as

“serious” and were more often to include a large amount of clinical relevant information.

Perhaps more importantly, the EMA has failed to mention all those clinically relevant terms

for which there was NO difference between the Danish and “rest of world reports”. There

were a greater number of such terms for which there was NO observed difference

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between Danish and “rest of world reports” – I think that this indicates that we are not

dealing with a Danish phenomenon – and it is therefore important information-

Example 3.

EMA report page 28:

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

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

postural dizziness, muscular weakness, mobility decreased, exercise tolerance decreased, various pain

terms, and skin discolouration. Although the numbers are small for the non HPV vaccine group, this

comparison argues against such reporting patterns pointing to a specific undiagnosed ‘syndrome’ reported

with HPV vaccine.”

UMC report (DHMA report, page 31):

“The MedDRA High Level Terms (HLT) most over-represented in HPV reports were imaging procedures,

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

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

conditions NEC.

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

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

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

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

In the table that was provided after this text (page 32 in the DHMA report), one could see

that there were a number of HLT which were statistically significantly over-reported with

HPV vaccine which were not mentioned in the EMA report: disturbances in

consciousness, muscular weakness, disability issues, and neurological signs and

symptoms.

Furthermore, the EMA fails to mention at all the large number of HLT describing diagnostic

testing which are over-represented in the HPV reports: imaging procedures, neurologic

diagnostic procedures, central nervous system imaging procedures, ECG investigations,

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autoimmune analyses, gastrointestinal and abdominal imaging procedures, and vascular

tests.

I find this highly important – and very problematic that this information as far as I can see

was left out in the EMA assessment report. As the symptoms that we describe in Denmark

as well as in the rest of the world very clearly make us suspect that we could be dealing

with a condition involving the nervous system both the symptoms and the procedures that

was over-represented in the HPV-reports seems a highly relevant finding.

Example 4

EMA report page 28:

“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).”

UMC report (DHMA report page 34):

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

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

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

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

In the table provided below this text (DHMA report page 34, it was displayed that there

were many other relevant HLTs which were significantly more reported (it was not just

asthenic conditions): Gastrointestinal and abdominal pains (excl oral and throat),

Migraine headaches, Gait disturbances, Visual disorders, Muscle related signs and

symptoms, Sensory abnormalities, memory loss, musculoskeletal and connective tissue

pain and discomfort, mental impairment and musculoskeletal and connective tissue signs

and symptoms

These are among the symptoms that we describe in our papers. These are the symptoms

that our patients describe. I find it frustrating that the UMC found the same symptoms

when looking through their data – but this finding is not communicated in the EMA report.

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In spite of the numerous examples of what I find is problematic representation of the data,

there are a number of statements of the EMA within the assessment report that can be

agreed, or at least partially agreed, such as the following:

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

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

be excluded that this is the case, many factors influence the levels of reporting… and the nature of

reports submitted. Overall, the observations included the Uppsala Monitoring Centre report does not

allow any conclusions to be made on clinical or diagnostic practice between countries.”(EMA report

page 28 )

I agree that the data presented in the UMC report do not allow firm conclusions on clinical

on diagnostic practice. However, the hypothesis which was generated by the UMC based

upon this data “that the same clinical syndrome may be occurring following HPV

vaccination but is being diagnosed/coded differently across countries” appears to have

been acknowledged by the EMA “…it cannot be excluded that this is the case”. I find it

strange that the EMA is not interested in further investigating this possibility given the

gravity of the situation at hand.

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

multiple analysis and data-mining of suspected ADR data (at MedDRA SOC, high level and

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

as well as non-HPV reports, as shown in the Uppsala Monitoring Centre report. However, the

approach taken to selection of SOCs, high level and preferred terms, amendment of a pre-specified

‘signal threshold’ and selective discussion of disproportionate reporting for HPV vaccines does raise

questions about the conclusions.”(EMA report page 29 )

It is agreed that multiple analyses of large databases will, by chance, yield some results of

disproportionality. This would be the greatest argument against drawing firm conclusions

from the review. It has been clearly acknowledged in the UMC report that there is only the

suggestion of a pattern in the results; a hypothesis has been generated which should be

subject to further study prior to either accepting or discarding the results.

3. “Overall, it is considered that the Uppsala monitoring centre report serves to highlight what is already

known, i.e. that some countries are observing an increasing number of reports of different types of

adverse events associated with HPV vaccine and that such reporting has increased over time.”(EMA

report page 29 )

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It is agreed that this is perhaps the most firm conclusion that can be drawn from the data

provided. However, the exploration of spontaneous data that was provided here was

intended to be hypothesis generating. The assessment by the UMC suggests that more

extensive analyses of spontaneous reports (such as the use of vigiPoint) may be able to

better inform decisions in pharmacovigilance. Shouldn’t we do this?

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5: The EMA process

The EMA states in their report that

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. (EMA report page 32)

It should be noted, that we are not told the names, numbers, affiliations etc of these

experts. As I understand it, all participants at the SAG meeting held October 21

are

bound to secrecy with regard to the details of the meeting. As far as I can see, the minutes

of the meetings are not released. What data did they get to review? Did they write a report

for the PRAC to use? And if they did where is the report – can we see it? To my best

knowledge the conclusion of the meetings and the report put forth by EMA is presented as

if it is the result of an unanimous discussion and opinion of the SAG and these experts.

This makes us unable to judge if all the experts agreed on the conclusion of the final

report. I find this a very strange, unscientific and undemocratic approach. In a matter as

complex as this I believe that not two single scientists will share exactly the same

viewpoints. There are so many facets and nuances and so many unknowns and

uncertainties – so we will all disagree to some extent, Creating a sort of false consensus

based on the participants being bound to secrecy will inevitably lead to the impression that

“all these many experts agreed on the conclusion set forth by EMA”. This makes it difficult

for solitary scientists and medical professionals as myself to disagree. Who am I to

disagree with all these many experts who voice this conclusion unanimously? I am not

questioning whether the people selected for the SAG-meeting were qualified. I am not

saying that they did not do a good job. But I find it hard to believe that they all agreed on

all aspects of this highly complicated and controversial matter. I believe that all the

different viewpoints presented at a meeting like this would enable us to grasp a little more

of the nuances of this issue.

I can understand why EMA feel the need to come out strong with a simple and strong

conclusion. But – what if data does not support a simple and strong conclusion?

The questions that EMA asked the companies as part of this process are freely

available[34] – which is good as it enables us to gain some insight into the process:

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The questions were the following and they were also quoted in the EMA report:

Question 1

The MAHs should provide a cumulative review of available data from clinical trials, post-

marketing surveillance, and literature in order to evaluate the cases of CRPS and POTS

with their product.

Review and case detection methods should be clearly described and MAHs were asked to

provide in depths reviews of all identified reports, and discuss whether they fulfil published

or recognized diagnostic criteria.(EMA page 12)

Reading EMA’s report it seems to me that the review of the safety data which includes

available data from the clinical trials and post-marketing surveillance and the literature

review was all collected by the marketing authorization holders (MAHs)? This must have

been in the form of a report written by the MAHs to the EMA?. Is this report freely

available?

1: Data from clinical trials

I will comment on that under “Question 2”.

2: Data from post-marketing surveillance:

I cannot figure out whether the safety data reviewed came from the MAHs only or if safety

data was also drawn from the EudraVigilance – I believe this is where we in Europe gather

safety data – and therefore this will be the “safety data of EMA?” Did EMA go looking in

the EudraVigilance safety data or did they rely on the data presented by the MAH from the

MAHs database and reviewed data from the MAH only? Were there any opportunities for

PRAC- members, SAG-members or other assessors to ask additional questions or for

clarifications?

I find it highly problematic that we as readers of the EMA reports – and I as medical

professional having diagnosed and evaluated a substantial part of the Danish Cases – my

diagnoses and work altogether downed and overruled by MAH/ EMA – have not access to

their case detection methods.

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Regarding the evaluation of the AERs: I know that a substantial proportion of the POTS-

cases reported as suspected side effects from Denmark have been done by me. I

therefore find it troubling and strange to see that POTS-cases have been overruled and

judged as not meeting or only partially meeting the diagnostic criteria in 50 out of 83 cases

given the diagnosis POTS in the AER. As I read the EMA assessment I think that I

interpreted the report as if it is the MAH who has evaluated the AER – and have found that

most of the POTS cases do not meet the proper diagnostic criteria? The EMA report

mentions the diagnostic criteria put forth by Raj and Sheldon [30, 31]. I have the highest

regard for these two authors and regard them as some of the worlds leading experts on tilt

table testing and POTS. Thus, I agree on the reference to their work with regard to the

diagnostic criteria applied. We use the exact same criteria and have experience in

diagnosing and treating POTS – and are to some extent quite restrictive in our diagnostic

practice. It can be discussed- as we do in our papers – whether POTS is a relevant

diagnosis or not. However, that is a whole other issue. Therefore, we need to know: Has

the MAH based their evaluation on the AER alone – or have they been through the whole

medical record of these patients? It is well known that an AER will not include all the

details of the clinical history and therefore it is rare that any spontaneous report will meet

diagnostic criteria. Evaluating the diagnosis given in AER will be very difficult bordering on

impossible if based only on the AER. But – if they did obtain full medical record – then the

discrepancy between the diagnoses given by the clinicians seeing the patient and filing the

report and the MAH is a more relevant discussion. But then this discussion should be out

in the open. We need to close the gap between the reality as it looks like from the

clinicians (and the patients) point of view and the MAH and EMA. Either I have

misunderstood the whole diagnostic approach to POTS – and then I need to know. Or –

the reports have been judged on a too lose background. Both scenarios represent - as I

see it - a quite serious problem. We have a common interest in reaching consensus on

how to use this POTS- diagnosis as it is now very much on the agenda.

We have been as thorough as possible when assessing the relevance of reporting and

doing the AE reports - given our time schedule and clinical setting. Our thoroughness

underlined by the fact that WHO has stated that the Danish AER did not in the essense

differ from reports from the rest of world – but were of a higher quality. [2] We have heard

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from DHMA through our collaboration and many meetings and close dialogue through the

last 3 years that they have appreciated the high quality of our reports.

In the assessment report it is noted on page 12 that the MAH searched their own database

for reports including the terms of POTS and CRPS. They explain that PRAC requested

that they searched for undiagnosed cases using “"common search strategies". I think it

would have been relevant for us to have these search strategies clearly defined and given.

To my best knowledge there are no common search strategies which have been

previously defined for either POTS or CRPS. In contrast, I believe there are for some

common events such as myocardial infarction, anaphylaxis, etc.

3: Litterature review

I will comment on that under “Question 4”

Question 2

Please provide an in depth review of cases of CRPS and POTS observed within all clinical

studies; with comparison of HPV vaccine groups and control groups. If differences are

observed, please discuss potential explanations including risk factors for the development

of CRPS and POTS.

Both CRPS and POTS are difficult syndrome diagnosis with huge overlap to other

syndrome diagnosis. For both diagnoses goes that they often will only be diagnosed at

specialized clinics. They are applied very differently by different countries. It is difficult to

count things that may not necessarily have a label or a labeled differently around the

world.

To my best knowledge, in the clinical trials of the HPV-vaccines in currently use, potentially

harmful adjuvants or adjuvanted products were used as the control: alum adjuvant for

Gardasil and alum adjuvanted hepatitis-A vaccine for Cervarix?. Therefore, even if there

was no clear difference in serious adverse events between vaccine groups and controls –

it may be too early to conclude that the vaccine is safe?

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If data is available evaluating suspected side effects in a vaccine group compared to a

“pure” placebo group given pure saline with nothing in it – except saline – then I hope the

MAH or EMA will share this very important and relevant knowledge with us. A lot of the

mistrust in the vaccines are arising from people failing to understand how this can be a

good way to estimate the safety profile of a vaccine - including the adjuvant in both

“vaccine” and “placebo”. If there is a good explanation – or data to look at – I hope we can

see it.

Actually –“Question 2” does not make any sense to me: If both the “vaccine group” and the

“control group” received aluminium adjuvanted “placebo” or another aluminium adjuvanted

vaccine as “placebo” – how does it make sense to ask the company to only discuss

potential explanations including risk factors for the development if a

difference

observed? By asking this question – I find that EMA actually states and take for granted

that we know with a very high degree of certainty that we will not see side effects due to

the adjuvant? Have we scientific evidence available that convincingly demonstrates that

aluminium adjuvant are not able to elicit serious side effects in few but susceptible

individuals? It may be present this evidence – but then we urgently need to communicate

this knowledge to the many worried people being afraid that it is the aluminium that causes

the suspected serious side effects.

As I understand it, clinical trials have two primary goals:

1: First of all – we need to determine if the drug we are testing actually works. We need to

establish “efficacy”. How does it work and how well does it work?

2: Secondly – we need to determine if the drug we are testing is safe to use. Does it have

side effects? Does it cause cancer? Does it affect our ability to reproduce or the health of

the offspring to the recipients?

Clinical trials may not “catch” rare side effects as most of these events are too rare to be

observed in the clinical trials. This is OK. That is why we do post licensure safety

evaluation. Determining safety from the clinical trials is simple math. We count the cases

participating in the clinical trials. Total number of people in the trial who got the vaccine is

the denominator. Subjects who reported a specific symptom as suspected side effects are

the numerator. Am I right?

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In the EMA report it is stated that:

“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 symptoms

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

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

person-years in each of the Gardasil 9, Gardasil/Silgard and placebo cohorts.” ).(EMA report page 15)

However – in order to make the conclusion that we want to make from this – that POTS is

not seen post-HPV-vaccines – we need to know how the scientific question was asked: So

I would have liked to know: The one case in the Gardasil-9-study that did not fulfill the

criteria – who decided this on what evidence? Was it EMA or the MAH? Were the experts

in the SAG-group involved in these assessments? And – with regard to the second case –

the diagnosis was made 1389 days after the administration - but did the EMA and/or the

MAH not have any information with regard to the time span between vaccination and

symptom onset? The question we want to answer is: “Do people fall ill from the HPV-

vaccines?” – not “when do people that believe they fall ill from the HPV-vaccine get a

proper diagnosis?” I think it would be very valuable if EMA would provide us with details on

the process.

In the clinical trial data for Gardasil 9 which can be accesses at EMAs homepage [35]it is

stated that:

“Within the clinical safety database for 9vHPV, there are 3 cases of POTS (Postural Tachycardia Syndrome)

and 1 case of CRPS (Complex Regional Pain Syndrome), which are both on-going signals identified in the

post-marketing period for quadrivalent Gardasil. Both signals have been the subject of extensive assessment

in the most recent and previous PSURs for quadrivalent Gardasil. It has been concluded in the recent PSUR

procedure (EMEA/H/C/000703/PSUV/0052) that there is currently insufficient evidence to support a possible

a possible causal association between qHPV vaccine and CRPS and POTS. In light of this and given the

uncertainty surrounding the background incidence of these syndromes, especially for POTS, these

conditions were not included into the RMP. It is instead suggested that these safety concerns are closely

monitored within PSURs during the post-marketing period..”(page 113-114)

I would like to know in detail how these three cases were evaluated. And I would like to

understand how three cases in the clinical trial data transforms to two in the EMA report.

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Question 3

The MAHs should provide an analysis of the observed number of post-marketing cases of

CRPS and POTS in association with their HPV vaccine in comparison to those expected in

the target population, stratified by region, if available. The analysis should discuss the

assumptions made with respect to the background incidence in the target population and

also the influence of potential under-reporting of cases in association with HPV vaccines.

I think the whole assumption underlying this question – that it is even possible to establish

a reasonable estimate of the background incidence in the target population is a key issue.

It is not possible for the time being to give a reasonable estimate of the incidence of these

very underrecognized, underdiagnosed and poorly understood disease entities with very

different diagnostic practices applied depending on nationality, medical specialty etc.

Question 4

The MAHs should provide a critical appraisal of the strength of evidence for a causal

association with HPV vaccine for CRPS and POTS. This should consider the available

published literature, including epidemiological studies, and also the possible causes and

pathophysiology of CRPS and POTS and discuss whether there is biological basis for a

possible causal association.

In my point of view

we are dealing with a causal link between the vaccines and the

symptoms described as suspected side effects we could be dealing with

pathophysiological changes in the nervous system with an (auto)immune genesis in

(genetically) susceptible individuals.

The literature review that lies behind the EMA assessment report – I think it would be

relevant to know if it was performed by the MAH only or supplemented by the EMA? I

think it would be highly relevant to gain insight into the search strategies applied in the

literature research. I have an interest in POTS, and have had for many years. I know that

POTS is probably associated to autoimmunity, because this is the current perception in the

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scientific field of POTS. Publications are starting to emerge describing the findings of

autoantibodies in patients diagnosed with POTS. The same autoantibodies are also found

in CRPS and ME/CFS. I know that these studies are small studies, – but I think that they

represent some very important information and a hypothesis generating body of evidence.

I will get back to this and include references to this in section 6 (“Is myalgic

encephalomyelitis/chronic fatigue syndrome a relevant diagnosis?”).

Again – back to the scientific ladder – we now very little about what is going on. At this

stage I believe that we have to include all available data in our analysis – and then we

have to design case control studies, epidemiological studies etc in order to test the

hypothesis generated based on the available literature.

I am not stating that EMA would have reached another conclusion if they had included this

specific knowledge in their assessment; however, I find it problematic that we cannot

determine from the report if they are aware of these pathophysiological similarities

between the diseases that we discuss as possible side effects. Pathophysiological

changes that seems relevant in this context as they have previously been described to be

seen as side effects to vaccinations.

The study by Klein et al. was sponsored (entirely?) by MERCK, looked only at events with

diagnosis codes, did only look at the first 60 days after vaccination, emergency room visits

and hospitalizations only. They did not include other relevant medical care visits such as

outpatient visits. They state that this is "not a long-term safety study".[36]

The study by Donegan et al. was a one-country study and the vaccine investigated was

Cervarix only. This is problematic since the most used vaccine in many countries,

including Denmark is Gardasil, which contains another adjuvant. On this basis, the study

cannot be used as scientific evidence underlying possible side-effects of Gardasil. Another

relevant comment is that limited information about the control group is present in the study.

The control group is estimated; however, in the study they specifically pointed that the

control group may be biased, since vaccination took place in schools and other institutions

with inadequate registration. Further, in the study they It looked at data from the first 2

years of the vaccination campaign and looked specifically at diagnoses related to fatigue,

where some of the diagnoses included decreases during the previous 15 years. Those

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diagnoses are included in the statistical analyses, which may have confounded the results.

[37]

EMA states on their homepage:

“The review noted that some symptoms of CRPS and POTS may overlap with chronic fatigue syndrome

(CFS, also known as myalgic encephalomyelitis or ME). Many of the reports considered in the review have

features of CFS and some patients had diagnoses of both POTS and CFS. Results of a large published

study that showed no link between HPV vaccine and CFS were therefore particularly relevant.”[38]

If EMA thinks that the Donegan study is this important, my advice would be that we should

be looking at fatigue-related conditions as core issues in this matter. If EMA partially base

their conclusion of the report on the Donegan study is it then a way of shifting focus from

CRPS/POTS to ME/CFS? I on one hand totally agree with this notion – that we should

forget about POTS and CRPS and merely look at them as diagnostic markers for another

underlying disease. I find it difficult to understand that EMA have not yet looked into the

fatigue-related conditions – or asked the MAH to do it. Why have a new process not been

initiated focusing on a case-definition with long-lasting fatigue as core symptom?

I know very well how difficult it will be to use registers for this evaluation – due to all the

caveats mentioned. However, being difficult does not mean that it should be ignored or is

out of importance.

I believe that I read somewhere but I have not been able to locate it – that LAREB from the

Netherlands signaled chronic fatigue as suspected side effect to the HPV-vaccine already

in 2013? I am sure that if this is so EMA has access to the underlying data. If there was

already a signal raised in 2013 on chronic fatigue I find this highly relevant for the

evaluation at hand? And please correct me if I am wrong. This is a question – not an

assumption.

Question 5

The MAHs should discuss the need for possible risk minimisation tools and provide

proposals as appropriate.

No comments

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6: Is myalgic encephalomyelitis/chronic fatigue syndrome a relevant

diagnosis?

An array of diagnostic entities that have been described as suspected side effects to the

HPV-vaccines share many characteristics – both with regard to symptoms and clinical

findings : ME/CFS, POTS, CRPS, Fibromyalgia, Macrophagic myofasciitis and others.

The term "ASIA-Autoimmune/inflammatory Syndrome Induced by Adjuvants" (ASIA-

syndrome) encompasses an array of clinical conditions and has many similarities to the

above mentioned conditions – and has been reported as suspected side effect to the HPV-

vaccine[39]

Furthermore, Nishioka et al. presented in 2014 an abstract as well as a paper (in

Japanese) introducing: “Clinical features and preliminary diagnostic criteria of human

Papillomavirus vaccination associated with neuroimmunopathic syndrome (HANS)”. They

propose a new disease entity – a new HPV-vaccine associated syndrome with widespread

pain, memory loss as well as general fatigue as the key symptoms. [20]

Most of the above mentioned conditions have been linked more or less convincingly to

autoimmunity.[40-45] Recent publications have demonstrated the findings of

autoantibodies directed against and in many instances activating receptors of the

autonomic nervous system.[43, 44, 46] This is interesting as many of the symptoms

described in these conditions can be explained by autonomic disorder. These are in most

cases preliminary studies in small groups of patients – but they are very interesting and

should be tested in larger cohorts with well-selected and characterized patients and

compared to well-matched subjects.

EMA writes:

“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.”(EMA report page 33)

I agree that we do not have clear evidence. But – doing a literature review should

demonstrate very clearly that even the evidence is scarce when looked at from each of the

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mentioned disease entities – the emerging evidence is strikingly similar in the different

conditions – involving autoimmunity, autoinflammation and autonomic dysfunction. I think it

would have strengthened the EMA report if this was taken into consideration and if this

had been included in the literature review and discussed in the report.

The EMA report refers to a publication by Sheldon et al.:

In this paper the proposed pathophysiological mechanisms behind POTS are mentioned –

including peripheral autonomic denervation:

“ Reports from tertiary care centers have indicated that up to 50% of patients with POTS have a restricted

autonomic neuropathy of small and distal postganglionic sudomotor fibers, predominantly of the feet and

toes. It is believed that impaired sympathetic tone (as measured by norepinephrine spillover) reduces

venoconstriction, leading to venous pooling in the lower limbs and splanchnic beds. This neuropathic

manifestation of POTS requires a high cardiac output to compensate for reduced splanchnic and peripheral

resistance and venous pooling. ………The autonomic denervation might be due to an autoimmune disease

in some patients.[30]”

I will not go further into the shared patophysiological findings in the mentioned diagnostic

entities - I find it will be too comprehensive and out of scope to elaborate on that in this

responsum. I will only mention small fiber neuropathy the importance of which is explained

in a recent paper by Manuel Martínez-Lavín.[19] Both CRPS and POTS have been

associated with small fiber neuropathy [49-51]

I think it is a shame that these new insights were apparently not included in the literature

review.

We have in our three papers tried to narrow down a case definition describing patients with

suspected side effects to the Q-HPV-vaccine. We have a suspicion that we see a complex

of symptoms with long-lasting fatigue and pronounced autonomic dysfunction coupled with

severe non-migraine-like headache, excessive fatigue, cognitive dysfunction,

gastrointestinal discomfort, and widespread pain of a neuropathic character. We therefore

ask the question: do we see this symptom complex more often in vaccinated girls than

unvaccinated girls? Further studies are warranted. We find that no existing diagnostic

entity fits perfectly well, but suggests that the diagnosis G 93.3 ME/CFS could be worth

considering.

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This conclusion is in accordance with the UMC, the DHMA and the Lareb (Netherland).

We know nothing with certainty, but we need to find out. If we do end up finding a

significant association between HPV-vaccine-status and an ME/CFS like syndrome – this

will not tell us how the vaccine and symptoms are causally linked. Most of the vaccinated

tolerate the vaccine very well. So if we have an association – we are probably looking at

individuals with a genotypic and phenotypic susceptibility and maybe an existing sensitivity

that renders them susceptible for vaccine-triggered disease.

The “Lareb” of Netherland which as I understand it is the Dutch pharmacovigilance center

that work together with but are separate from their medicines board states in their report ”

Long-lasting adverse events following immunization with Cervarix® “ published December

2015:

“A causal relation between Cervarix® vaccination and long-lasting symptoms can not be

concluded nor excluded based on the analysis of these reports. In order to study whether

long-lasting fatigue occurs more often in vaccinated girls than in unvaccinated girls,

epidemiological research is recommended. The National Institute for Public Health and the

Environment (RIVM) already started a study.”[52]

The DHMA writes [2]:



In the section discussing the evaluation of reported serious ADR cases for HPV-

vaccination in Denmark:

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

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

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

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

condition.

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

number of different diagnoses.”(DHMA-report page 7)

……. ….”Based on the review we recommend not only to focus any review of reported adverse reactions for

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

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

pattern.” (DHMA-report page 8)

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

In the section describing information obtained through dialogue with the Japanese

Ministry of Health, Labour and Welfare:

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

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

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

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

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

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

reported in the Danish cases.”(DHMA-report page 10)

Reading the EMA-report and available literature, I find that the only possible conclusion at

this stage is that we do not have convincing or enough evidence that support an

association between the HPV-vaccines and the two syndromes POTS and CRPS – if we

regard these syndromes as well-defined and separate disease-entities.

However, I believe that evidence – or at least observations – are piling up suggesting a

signal which warrants further investigation, the question being:

“Is there an association between the HPV-vaccines and a ME/CFS-like syndrome?”

In Denmark – and I guess the same problem will apply to other countries – if you are sick –

it is easier to get help if you have a diagnosis. Just “being sick” is not enough. We use

diagnoses as a language. When we can match a certain patient with a certain diagnosis -

we have a sense of how sick is this patient, what treatment is relevant, is it contagious,

can she drive a car etc. Around the world, Denmark is known as one of the leading

countries regarding register-based research, because we during decades have developed

hospital registers of high validity. However, the vaccinated girls suffering from possible

side-effects will not be listed in the registers, if they are not given a diagnosis.

As medical professionals, diagnoses help us to prorate patients. We know which medical

specialty we should refer the patient to, and the patients know where to turn for help. We

have a shared reality, a common language between patients, medical professionals and

health care system.

Patients with more or less unexplained and multiple symptoms may not always have this

luxury of a shared reality and a common language. They may not get a diagnosis. Or they

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get many different diagnoses. Some of them will have a diagnosis that belongs to a

language that people may all understand – but they understand it very differently

depending on who you talk to. If a patient is diagnosed with G93.3 Myalgic

Encephalomyelitis, some medical professional will understand this as a functional disorder.

They may recognize the patient as actually misdiagnosed as the diagnosis is a

neurological code (all the diagnosis beginning with a “G”), but they may find that this

patient is actually suffering from a disorder in the psychiatric spectrum. Other physicians

will look at ME as an immune disorder associated with autoimmunity and disrupted

function of the white blood cells. Other physicians again will recognize these patients with

the G93.3 diagnosis as suffering from a cellular depletion syndrome – a mitochondrial

dysfunction – and so on.

All these physicians may tell you that they can evaluate these patients and that the

findings in the actual patient confirm their notion. But the problem arises when we are to

treat these patients – to help and support them. What treatment should we give them? And

what do we do if the treatment that makes sense in one of the explanatory models may

seem harmful when you look at the patient though other glasses? The patient and different

medical professionals do not live in a shared reality when it comes to these patients. It is

my experience from working with this kind of patients that many of them end up having no

trust in the established health care system and simply stay away – receiving no diagnosis,

no medical evaluation and no treatment. They are on their own. They are invisible.

Why am I writing all this? Because I want to advocate that these patients – including many

of the patients with suspected side effects to the HPV-vaccines – they are impossible to

count in register studies. They are difficult to handle and evaluate by an epidemiological

approach. They may not pop up having a diagnosis, they may not pop up as visits to the

hospital or GP. Many of them almost live in a parallel society seeking help from

complementary medicine, or just trying to get on on their own.

This leaves us with many problems as society. We cannot count them when doing the

belonging self-evidently to one medical specialty will contribute to their being invisible.

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It is like the story of the six blind men who all touched different parts of the elephant and

began to argue about the true nature of the elephant. Every one of them insisted that he

was right. They kept on arguing until a wise man passed by and calmed them and

explained to them that they were all right. The reason for their understanding the elephant

so differently was because each of them touched different parts of the elephant. The

elephant had all the features they saw and described. There was some truth to what

everybody said. I think that most of you may agree – that we are acting like these blind

men when we discuss a condition like ME – or the patients with suspected side effects to

the HPV-vaccines. And rather than fighting and arguing like the blind men – we should

value each others view points and get together and appreciate and use our disagreement.

Listen to each others description of the corner of the condition that we believe that we

understand – in order to get the bigger picture…… I think that one of the core reasons for

this debate surrounding the suspected side effects to the HPV-vaccines are the heated

debate that has been going on in decades concerning these complex conditions….

Am I saying that all these conditions are one and the same? No, I am not – but I think that

some of them to a variable extent share some features – and we understand all of them

very poorly. They may to some extent represent different phenotypic representations of

similar underlying pathophysiological changes.

I find that all physicians, researchers, patients that I meet who has really invested some

time and effort in the deeper understanding of these issues recognizes the shortcomings

and drawbacks of our existing diagnostic system with regard to these patients. I believe

that the failure to recognize this underlying challenge when evaluating the possibility and

the extent of possible side effects to the HPV-vaccines is one of the main reasons that the

whole debate is off track.

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As I see it – the “truth” concerning each and every one of the patients suspecting to suffer

from side effects to the HPV-vaccines will lie somewhere along this continuum .

At one end of the continuum is the possibility that there is no direct biological causal link

between the vaccine administered and the symptoms experienced. But the patient blame

the vaccine – attribute the suffering to the vaccine. It is very human and common - the

craving for an explanation – a cause for our suffering. Via social media, media attention

etc this attribution, this notion that the HPV-vaccines have the potential for eliciting serious

side effects spread and is therefore “contagious” – we are dealing with an outbreak of

mass psychogenic illness.

At the other end of the continuum we have the possibility that there is a direct biological

causal link between the vaccine and the symptoms experienced. We are dealing with

actual side effects. The biology of the vaccine and the interaction between the vaccine and

the (genetic and otherwise vulnerable and susceptible) individual elicits a biological

process in the body of the vaccinee that directly leads to the symptoms experienced.

I think that it is impossible to say with certainty – both with regard to every single patient

and with regard to the patients seen as a group – where along this continuum the “truth”

lies. We may be able to make more or less qualified guesses – but we all share and face

the same frustrating reality: We do not know with 100% certainty. This uncertainty is a

huge problem. We want to be certain. But our need for being certain does not

automatically equal that we have evidence to qualify a certain quess. We want the vaccine

to be safe – but just because it would be so much easier and better for all of us if we knew

with 100% certainty that the vaccine is safe – this does not make the vaccine more or less

safe.

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7: What to do?

This is so very complicated in so very many ways. I strongly advocate that we stop

accelerating the aggression and confusion and instead seek common ground. Seek

consensus – create the shared reality that I keep talking about.

The more we argue and the more unscientific and heated the debate gets – the further we

get away from the fact central in this – we need to optimize health and minimize suffering.

Why don’t we try to establish this shared reality – because reality is based on facts. It

should be doable to look at facts together. What if we listened to each other – and to data

- and then tried to answer the following questions together:

Efficacy of the HPV-vaccines

What do we now about efficacy?

What do we believe we have strong indications for with regard to efficacy?

What do we need to find out about efficacy?

How do we get wiser?

Safety of the HPV-vaccines

What do we now about side effect?:

What do we believe we have strong indications for with regard to safety?

What do we need to find out with regard to safety?

How do we get wiser?

I believe that we can all agree on one thing: The mistrust in the HPV-vaccine is a World

wide problem. It is not a Danish problem and it is not a European problem. From many

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wide spread countries around the world we hear case stories of young women who have

fallen seriously ill as a suspected side effect to the HPV-vaccines. At the same time

women die from cervical cancer each day and many suffers from sequela to treatment

directed against cervical cancer

I believe that none of us know with certainty to what degree a smaller or bigger proportion

of these patients suffer from a condition that is causally linked to the vaccine. We can

guess, we can discuss, we can argue. But – as long as we do not know for sure we have

to endure not knowing – and at the same time acknowledge the importance of getting

answers – fast. Issues are not being clarified or solved just because we find uncertainty

unpleasant and inconvenient. A vaccine is not safe just because we want it to be.

I have felt the need to write this responsum in order to oppose the criticism directed very

openly and harshly at my person and my publications and scientific method directed

against me from EMA and mirrored by the DHMA and other stakeholders in Denmark. But

– most important of all – I have written this responsum hoping that it can be of some use in

the task I believe we have at hand: We need to recognize that patients, politicians, health

authorities, patient organization, parents of patients, health professional….all these

stakeholders wants to optimize health, prevent disease and suffering – at a cost that we

can afford as society. We want the same.

We want to safeguard our vaccination program. We want to obtain herd immunity. We

cannot avoid side effects. However, by doing whatever possible to recognize and

understand the mechanisms behind suspected side effects and thereby qualifying and

strengthening both prevention and treatment of suspected side effects – we can truly say

that we do all in our power to keep the benefit/risk ratio as beneficial as possible. It is not

good enough just to keep repeating that “the benefits outweigh the risks” – if we by daring

to recognize an eventual problem with side effects and having an honest, impartial and

scientific look at it can minimize the suffering suspected to be caused by the vaccines –

thereby optimizing the trust in the vaccines – and thereby eventually increase vaccination

rates again.

I am afraid that we do not take this seriously enough. No matter to what degree we are

dealing with side effects or not I think we need to act much more progressive than we do

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now. If the symptoms experienced in these many girls and women around the world are

NOT related to the HPV-vaccines we owe it to all of us to find good evidence for this – and

then we need to elucidate what else could be the trigger – the common denominator in

these patients. We need to know what is going on.

And if the symptoms in these patients are at all related to the HPV-vaccines – I do not

think that we are acting proactively and innovative enough in order to establish what

actions could be taken to prevent more vaccinees from getting side effects – and how we

should treat the patients already afflicted.

There are so many new vaccines in the pipeline. I believe that we will see new vaccines

that we will want to include in our childhood vaccination program. We need to be ready for

the next challenge. When we next time have a signal – a suspicion regarding vaccine

safety – we need to be able to look back at this HPV-vaccine-issue and say – we handled

that one right – we know how to handle suspicions with regard to vaccine safety. We need

to grow a new kind of responsibility that leaves room for a much more nuanced and

targeted approach to vaccines. We owe that to the vaccines – and ourselves.

I really hope that EMA will reconsider their report and their conclusion. I hope that my local

health authorities will reconsider their harsh critique of me as well as their conclusion. I will

remind EMA, our local health authorities and all of us that a Dutch study demonstrated that

the number one reason for people to decline HPV-vaccines were mistrust in the health

authorities. [53]

I have been contacted by quite a few fellow- doctors, researchers from Denmark as well as

from other countries. Many of them tell me that they have the same suspicion, they see the

same pattern – but most of them tell me that they are afraid to speak up. I find that we

have established a culture where it is not acceptable to have a critical approach towards

vaccines. We may all state that ”of course all medicine, vaccines included, have the

potential of eliciting side effects….” But when it gets tangible and concrete – when an

actual doctor suspects that an actual patient has contracted an actual disease as a side

effect to an actual vaccine – then many of us find it difficult to handle. We want him or her

to shut up. We want the suspicion to go away. We want vaccines to be 100% safe. There

are many good and also many terrible reasons for this. But we need to discuss how we

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

handle suspected side effects most reasonably. I think we should learn from the two

emerging “omics” that I presented in the beginning of this responsum – vaccinomics and

adversomics. They tell us that we have to accept and embrace that the way a vaccine

interacts with each and one of us is very variable – both when it comes to efficacy and

safety. This may be laboriously – but that is how it is. And this knowledge – that vaccines

are complex to a degree that makes me dizzy – it won’t go away. So – we might as well

take the discussion about vaccines into a version 2.0.

Back to basics: The aim of the EMA report was to use the available data to draw a

conclusion on causality between HPV vaccine and POTS/CRPS. I find it hard to

understand how the type of data that is reviewed in the EMA report – and the way the data

is reviewed – is enough on which to draw a firm conclusion on causality. Secondly – the

review are primarily limited to CRPS and POTS. That is as it should be as that was what

was asked of them – but I believe that the question asked was too narrow – which I guess

is the conclusion also reached by the EMA report. But they do not conclude that the

question should be rephrased – or another report made focusing on conditions with

excessive and long-lasting fatigue. I think that we are left with an answer that is not very

usable – actually I find it counterproductive for the whole process of getting to the bottom

of this.

I have been in a hurry writing this in the weeks before Christmas – after working hours

between Christmas preparations. I just wanted to get it out. Therefore I hope that you will

acknowledge this as a statement in progress. I will correct it and expand it. I hope that

some of you will enter a dialog with this responsum and me. Write me. Also the EMA and

the MAH. Tell me where and why I am wrong. Let us all contribute to an open, translucent,

democratic and constructive dialog. It may not seem the easiest way out – but I think it is

the only way out

Write me:

[email protected]

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

8: Concluding remarks

I think that the only possible conclusion at this stage is that we do not have convincing or

enough evidence to support an association between the HPV-vaccines and the two

syndromes POTS and CRPS – if these syndromes are looked upon as well-defined and

separate disease-entities.

However, I believe that evidence – or at least observations – are piling up suggesting a

signal which warrants further investigation, the question being:

“Is there an association between the HPV-vaccines and an ME/CFS-like syndrome?”

And – we would do ourselves a favor if we made sure to create consensus on how to “ask”

this question using the epidemiological toolbox. I have chosen the diagnostic term

ME/CFS – but the important thing is for us to create a “case definition” of the symptoms..

In that way we have the best starting point for estimating whether we see these symptoms

involved in the case definition more often in HPV-vaccinated versus non-vaccinated. And

we need to gather expertise from all relevant fields of medicine in order to determine if and

how it is possible to create a case definition and to formulate that case definition.

If we can agree on a case definition before we do the register studies – then we will end up

with a conclusion that will be “our” conclusion. A conclusion that as many as possible will

consider trustworthy and useful.

And one last word about elephants and a shared reality: I think much of the aggressive

rhetoric, disagreement, mistrust, worry and confusion that we all face in this matter would

dissolve instantly if we would do ourselves and each other the favor of having the

underlying and fundamental discussion about “functional disorders”, ME/CFS etc. And if

we would admit that this whole group of very complex disorders – as well as the whole

matter of efficacy and safety of vaccines raises many simple, central and important

questions – but mostly we only have inconclusive answers.

But – this is what we are facing together. This is our shared reality. If we actually help each

other – and aim at establishing the bigger picture – establishing the nature of the whole

elephant by creating a milieu where it is allowed to doubt and allowed to disagree. And

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

where we encourage humble and qualified scientific curiosity – then I think we would have

all the best possible opportunities to solve this issue.

Let us all collaborate to make the best possible estimate of the efficacy of the HPV-

vaccines

Let us all collaborate to make the best possible estimate of the safety of the HPV-vaccines

Then we can ask our health authorities to do what is their job and expertise: Evaluate and

decide to what degree the benefits of the vaccine outweigh the risks.

Then we can as vaccinees and parents be confident that we have sufficient information

available to us in order to give an informed consent when offered the HPV-vaccine.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

9: English Summary

During the past years a growing concern with regard to the safety of the human papilloma

virus (HPV) vaccines has emerged in Denmark – as well as in other countries around the

world.

Denmark therefore asked the European Commission to initiate an in depth review. The

European Commission requested the European Medicines Agency (EMA) to use the

available data to draw a conclusion on causality between HPV-vaccines and the two

syndromes: Chronic Regional Pain Syndrome (CRPS) and/or Postural Orthostatic

Tachycardia Syndrome (POTS).

In the assessment report written and published by EMA, three of my publications regarding

my clinical experience with patients with suspected side effects to the HPV vaccine are

directly criticised. Furthermore, my clinical expertise and judgment are indirectly criticised

as a substantial part of our adverse effect reports (AER) are overruled. I want to defend

my work but most of all I want to join in and encourage to an open and honest debate.

My agenda is not to miscredit the vaccine, rather it is to maintain public confidence in the

vaccine itself and the entire childhood vaccine program. To reach this goal, I believe that it

is imperative to appreciate that vaccines can have side effects and it is the responsibility of

the health care community to monitor and investigate serious problems which are

suspected to be related to the vaccines.

We are in desperate need of a shift in paradigm, a groundbreaking one, or the future of

public confidence in vaccines could be lost.

Regarding the critique directed against me I find that EMA suggesting that we selected

patients based on symptoms in order to make sure that they would fit into a preexisting

hypothesis is one of the most serious allegations I have ever been presented with. We did

not. I address this in the responsum.

I think that the only possible conclusion at this stage is that we do not have convincing or

enough evidence to support an association between the HPV-vaccines and the two

syndromes POTS and CRPS – if these syndromes are looked upon as well-defined and

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

separate disease-entities. However, I believe that evidence – or at least observations – are

piling up suggesting a signal which warrants further investigation, the question being:

“Is there an association between the HPV-vaccines and an ME/CFS-like syndrome?

I think much of the aggressive rhetoric, disagreement, mistrust, worry and confusion that

we all face in this matter would dissolve instantly if we would do ourselves and each other

the favour of having the underlying and fundamental discussion about “functional

disorders”, ME/CFS etc. And if we would admit that this whole group of very complex

disorders – as well as the whole matter of efficacy and safety of vaccines raises many

simple, central and important questions – but mostly we only have inconclusive answers.

Let us all collaborate to create common ground – a shared reality with regard to these

complex disorders – so that we can offer these patients the best possible evaluation and

treatment. This will not happen before we have reached consensus at another level than

we have for the time being. The Danish Health and Medicines Authority has just initiated

this work by establishing a task force on the subject. Let us support and follow this

initiative – and let us all join in the discussion and contribute. And let us use are

disagreements to create a multifaceted but still targeted approach to these patients. – Both

medical professionals, patients, patient organisations.

Let os all collaborate to make the best possible estimate of the efficacy of the HPV-

vaccines

Let us all collaborate to make the best possible estimate of the safety of the HPV-vaccines

Then we can ask our health authorities to do what is their job and expertise: Evaluate and

decide to what degree the benefits of the vaccine outweigh the risks.

Then we can as vaccinees and parents be confident that we have sufficient information

available to us in order to give an informed consent when offered the HPV-vaccines

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

10: Danish Summary

I de senere år har der i Danmark og andre lande rundt om i verden været en stigende

bekymring for sikkerheden ved vacciner mod human papillomavirus (HPV).

Danmark bad på den baggrund Europakommissionen om at sætte en dybdegående

undersøgelse i gang. Europakommissionen bad derfor det europæiske medicinagentur

(EMA) anvende tilgængelige data til at konkludere på kausaliteten mellem HPV-vaccinerne

og de to syndromer: chronic regional pain syndrome (CRPS) og/eller postural ortostatisk

takykardisyndrom (POTS).

I rapporten skrevet og udgivet af EMA bliver tre af mine publikationer om mine kliniske

erfaringer med patienter med mistænkte bivirkninger til HPV-vaccinen kritiseret direkte.

Derudover bliver min kliniske ekspertise og dømmekraft indirekte kritiseret, idet en

substantiel del af mine bivirkningsindberetninger bliver underkendt. Med dette responsum

ønsker jeg at forsvare mit arbejde, men mest af alt ønsker jeg at deltage i og tilskynde til

en åben og ærlig debat.

Det er ikke min dagsorden at miskreditere vaccinen. Tværtimod er det mit primære

anliggende overordnet set at bevare tilliden til HPV-vaccinen og til hele

børnevaccinationsprogrammet. For at opnå dette mener jeg, at det er afgørende at

anerkende, at vacciner, herunder også HPV-vaccinen, kan have bivirkninger, og at det er

sundhedsvæsenets og syndhedsmyndighedernes ansvar at overvåge og undersøge de

alvorlige problemer, som er mistænkt at hænge sammen med vaccinen.

Der er et akut behov for et helt grundlæggende paradigmeskifte – ellers risikerer vi at den

fremtidige tiltro til vacciner går tabt.

EMA kritiserer mig direkte for, at vi i vores artikler skulle have udvalgt patienter efter

symptomer – for at være sikre på, at de ville passe ind i en på forhånd eksisterende

hypotese. Det er en af de alvorligste anklager, jeg nogensinde er blevet præsenteret for.

Det har vi ikke. Jeg adresserer dette i mit responsum.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

Jeg mener, at den eneste mulige konklusion på nuværende tidspunkt er, at vi ikke har

overbevisende eller nok evidens til at konkludere at der er en sammenhæng mellem HPV-

vaccinerne og de to syndromer POTS og CRPS – hvis man ser på disse syndromer som

veldefinerede og isolerede sygdoms-enheder. Til gengæld mener jeg, at der hober sig

evidens – eller i det mindste observationer – op, der kalder på yderligere undersøgelser,

hvor spørgsmålet er:



Er der en sammenhæng mellem HPV-vaccinerne og et ME/CFS-lignende syndrom?

Jeg mener, at meget af den aggressive retorik, uenighed, mistillid, bekymring og forvirring,

som vi alle er vidne til i denne sag, ville forsvinde, hvis vi gjorde os selv og hinanden den

tjeneste at tage den underliggende og fundamentale diskussion om ”funktionelle lidelser”,

ME/CFS osv. Og hvis vi ville indrømme, at hele denne gruppe af komplekse og

mangelfuldt forståede tilstande - og hele spørgsmålet om vacciners effekt og bivirkninger –

rejser mange enkle, men centrale spørgsmål, som vi indtil videre i de fleste tilfælde kun

har utilstrækkelige svar på.

Lad os alle samarbejde for at skabe fælles grund – en fælles og delt virkelighed, hvad

angår disse komplekse tilstande - så vi kan tilbyde patienterne den bedst mulige

evaluering og behandling. Dette vil ikke ske, før vi har nået konsensus på et andet niveau,

end vi har nu. Sundhedsstyrelsen har netop sat sådan et arbejde i gang ved at etablere

en arbejdsgruppe om emnet. Lad os støtte og følge dette initiativ, og lad os alle bidrage og

være med i diskussionen – både læger, patienter og patientorganisationer. Og lad os

bruge alle de uenigheder, der måtte være, til at skabe en multifacetteret, men stadig

målrettet tilgang til disse patienter.

Og sidst men ikke mindst:

Lad os alle samarbejde om at lave den bedst mulige vurdering af HPV-vaccinernes effekt.

Lad os alle samarbejde om at lave den bedst mulige vurdering af HPV-vaccinernes

sikkerhed.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

Så kan vi bede vores sundhedsmyndigheder om at gøre, hvad der er deres job og

ekspertise: evaluere og beslutte, i hvilken grad HPV-vaccinernes fordele opvejer deres

ulemper.

Så kan vi både som dem, der skal vaccineres og som deres forældre være sikre på at vi

har tilstrækkelig med information til at afgive et informeret samtykke når vi tilbydes en

HPV-vaccine.

SUU, Alm.del - 2015-16 - Bilag 109: Henvendelse af 15/12-15 fra Louise Brinth vedr. bivirkninger ved HPV-vaccine

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