The EMA Review of HPV Vaccines and Complaints of Maladministration

A potential safety signal with the HPV vaccines in relation to two neurological conditions, Postural Orthostatic Tachycardia Syndrome (POTS) and Complex Regional Pain Syndrome (CRPS), was raised by the Danish Health and Medicines Authority in July 2015, when it asked the European Commission to evaluate the signal.  An Article-20 referral procedure was triggered and the European Medicines Agency (EMA) was asked to give an opinion on whether there was evidence of a causal association between HPV vaccines and CRPS and/or POTS.

At the conclusion of the referral procedure in November 2015, the EMA opinion was formalised in an Assessment Report, which found no evidence of a causal association between HPV vaccines and CRPS and/or POTS.

On the 26th May 2016, Professor Peter C. Gøtzsche, Director of the Nordic Cochrane Centre and Karsten Juhl Jørgensen, Deputy Director of the Nordic Cochrane Centre, along with others, filed an official complaint with the EMA about how the Agency had conducted the HPV safety referral procedure.

Dissatisfied with the EMA response to their complaint, Professor Gøtzsche and the signatories to the initial complaint to the EMA escalated their complaint to the European Ombudsman, supported by several eminent scientists.

The documents from the EMA review and subsquent complaints are listed below, with links to the documents and selected excerpts.

We await the European Ombusdman’s report

 European Medicines Agency (EMA) Article-20 referral procedure: Human papillomavirus (HPV) vaccines

” In its review the PRAC will consider the latest scientific knowledge, including any research that could help clarify the frequency of CRPS and POTS following vaccination or identify any causal link. Based on this review, the Committee will decide whether to recommend any changes to product information to better inform patients and healthcare professionals. While the review is ongoing there is no change in recommendations for the use of the vaccine.”

(EMA to further clarify safety profile of human papillomavirus (HPV) vaccines,  13 July 2015)

Report from the Danish Health and Medicines Authority for consideration by EMA and rapporteurs in relation to the assessment of the safety profile of HPV-vaccines

“In summary, this review of VigiBase data suggests that there is an increasing trend in the number of HPV reports of containing the PTs of POTS and related syndromes. Furthermore, there is the suggestion that a similar constellation of symptoms may have been labelled with different diagnostic labels depending on the country of origin. Also, the HPV case reports from Denmark are distinguished from those from other countries primarily by the fact that there is an increased amount of clinical information provided in the reports and that certain, specific diagnostic PTs are more commonly used; however, there is no difference between Danish HPV reports and all other HPV reports in the reporting of clinical relevant PTs describing symptomatology experienced by young women after HPV vaccination. Finally, the data suggest that there is an over-representation of serious case reports which describe a constellation of symptomatology and subsequent medical evaluation potentially consistent with a chronic fatigue – like syndrome which may be specific to HPV vaccines “

(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 , 4 September 2015 )

EMA (PRAC) Assessment report

“Taking into account the totality of the available information the PRAC concluded that the evidence does not support that HPV vaccines (Cervarix, Gardasil, Gardasil 9, Silgard) cause CRPS or POTS. The benefits of HPV vaccines continue to outweigh their risks. The safety of these vaccines should continue to be carefully monitored. This should include follow-up of CRPS or POTS reports to determine relevant clinical characteristics, to identify possible cases of POTS and CRPS based on broad search strategies including outcome details and to compare reporting rates against available information on the known epidemiology of POTS and CRPS. “

“The PRAC also noted that most of the reviewed reports of POTS would more appropriately have been labelled as having features of chronic fatigue syndrome (CFS). The PRAC therefore considered the results of a large published study which showed no link between HPV vaccine and CFS, as relevant for the current review.”

“The Committee, having considered all the information available, concluded that the evidence does not support a causal association between HPV vaccination and CRPS and/or POTS. The PRAC confirmed that the benefit-risk balance of the HPV vaccines (Cervarix, Gardasil, Gardasil 9 and Silgard) remains favourable and recommends the maintenance of the marketing authorisations.”

(Pharmacovigilance Risk Assessment Committee (PRAC) Assessment report, Review under Article 20 of Regulation (EC) No 726/2004, Human papillomavirus (HPV) vaccines, 11 November 2015, EMA/762033/2015

Complaint to the European Medicines Agency (EMA) over maladministration at the EMA

“The bottom line for the EMA seems to have been that the vaccine should be protected from criticism at all costs because it is believed to save lives by protecting against development of cervical cancer. One sign of this is that the text in the official report is nearly identical to the assessments of the rapporteur and the companies. However, this paternalistic attitude comes at a great cost. The EMA accepted uncritically substandard research performed by the MAHs and produced a superficial, substandard official report (2) that was clearly flawed and unrepresentative, considering the serious concerns raised in internal discussions, which were sealed by life-long confidentiality agreements.”

“Unfounded dismissal of signals from ADR reports as reported by the UMC also seriously undermines this central mechanism to monitor adverse drug reactions. These serious failures on behalf of the EMA could create a problem orders of magnitude greater than declining participation rates in HPV screening programmes. Should the concerns over possible harms of the HPV vaccine be confirmed, the trust in the EMA and in vaccines in general may be damaged beyond repair. In fact, we know that the EMA’s handling of the HPV controversy – pretending that we have sufficient knowledge when we haven’t – has already become a PR disaster. “

“As far as we can see, the actions of the EMA in this case indicates that the agency is more concerned about protecting its own previous decisions and the vaccine than about protecting the citizens and giving them the option of choosing for themselves whether or not they would like to get vaccinated against HPV.”

“The citizens need honest information about the vaccine and the uncertainties related to it; not a paternalistic statement that all is fine based on a flawed EMA report .”

(Complaint to the European Medicines Agency (EMA) over maladministration at the EMA, 26 May 2016 ,  Nordic Cochrane Centre, Copenhagen)

Complaint to the European ombudsman over maladministration at the European Medicines Agency (EMA) in relation to the safety of the HPV vaccines

“Contrary to the EMA’s statements, the evidence was not assessed in an objective and scientifically acceptable way and the evidence provided by experts was not given equal consideration. The evidence provided by the vaccine manufacturers was generally accepted at face value, unlike the more reliable and independent publications by the Danish researcher and her colleagues, the Danish Health and Medicines Agency and the WHO Uppsala Monitoring Centre. “

“The scientific approach to finding possible harms of the HPV vaccines was insufficient. The drug companies’ searches for possible harms in their own databases were grossly insufficient, and the search strategies for the companies’ and the EMA’s searches in the published literature were not revealed, and the EMA even redacted its search strategies. Such redactions make the EMA’s work 4 not replicable and ultimately unaccountable, and may engender suspicion that the searches were scientifically inadequate. “

“In all the vaccine trials apart from a small one, the so-called placebo was either not a placebo as it contained aluminium adjuvant, which is neurotoxic in high doses, or it was another vaccine. This makes it difficult to find a difference between harms of the vaccine and the “placebo,” but the EMA failed to address this fundamental problem in its official report and allowed the manufacturers to lump all the “placebo” data together. This is contrary to good scientific practice to such a degree that we consider it outright scientific misconduct committed by the EMA. “

(Complaint to the European ombudsman over maladministration at the European Medicines Agency (EMA) in relation to the safety of the HPV vaccines , 10 October 2016)

The complaint was submitted by: Peter C Gøtzsche, (DrMedSci, MSc, Director and Professor, the Nordic Cochrane Centre), Karsten Juhl Jørgensen, (MD, DrMedSci, Deputy Director, the Nordic Cochrane Centre), Tom Jefferson, (MD, Honorary Research Fellow, Centre for Evidence Based Medicine, Oxford, UK), Margrete Auken, MEP (The Greens/European Free Alliance), Louise Brinth, (MD, PhD, Danish Syncope Unit)

And supported by: Silvio Garattini (Director, Instituto di Ricerche Farmacologiche Mario Negri, Milano, Italy),  Ralph Edwards (Ex-director, WHO Uppsala Monitoring Centre, Sweden),  International Society of Drug Bulletins (ISDB),  Angela Spelsberg (Chair, Working Group on Health, Transparency International, Germany), No Gracias (Independent civil organization for transparency, integrity and equity, Spain),  Juan Gérvas (Visiting Professor, National School of Public Health, Madrid, Spain),  Ulrich Keil, (Prof. Emer., Institute of Epidemiology and Social Medicine, Univ. of Münster, Germany), HealthWatch (a UK charity which promotes evidence-based medicine)

The European Medicines Agency’s handling of the so-called referral procedure of a particular pharmaceutical product

“In October 2016, the Ombudsman received a complaint alleging that the European Medicines Agency had not dealt properly with a so-called referral procedure related to a pharmaceutical product and alleging a lack of transparency. The complaint does not concern the safety of the product.

After an initial examination of the allegations, the Ombudsman decided to ask EMA for a meeting. A meeting between EMA and Ombudsman staff took place on Wednesday, 7 December 2016.

The steps the Ombudsman has taken in response to the complaint solely concern administrative and procedural issues. To that end, the Ombudsman is looking into whether EMA has procedures in place that ensure that all the relevant evidence is available to its scientific committees and whether EMA has been sufficiently transparent about how its committees reach their scientific conclusions. The Ombudsman’s staff have not identified any deficiencies to date.

The Ombudsman is not in a position to question scientific conclusions made by the competent scientific bodies.”

(Strasbourg, 05/12/2016  –  Case: 1475/2016/JAS,  opened on 05 Dec 2016)

Decision in case 1475/2016/JAS on the European Medicines Agency’s handling of the referral procedure relating to human papillomavirus (HPV) vaccines

Abstract

This case concerned how the European Medicines Agency (EMA) carried out a “referral procedure”, which is a procedure to deal with questions relating to medicines already on the market in the EU. The specific referral procedure related to human papillomavirus (HPV) vaccines. HPV vaccines prevent infections with the most common types of HPV, which can cause cervical cancer.

The procedure was conducted by the Pharmacovigilance Risk Assessment Committee (PRAC), which is EMA’s committee responsible for monitoring the safety of medicines on the market. The aim of the procedure was to examine whether there is any evidence of a causal link between HPV vaccination and two syndromes, complex regional pain syndrome (CRPS), a chronic pain condition affecting the limbs, and postural orthostatic tachycardia syndrome (POTS), a condition where the heart rate increases after sitting or standing up, causing symptoms such as dizziness and fainting. PRAC concluded that the evidence did not support a finding that HPV vaccines cause CRPS or POTS. This finding was later confirmed by EMA’s Committee for Medicinal Products for Human Use. The finding is shared by other public health bodies around the world.

The complainants expressed concerns about the handling of the referral procedure, its transparency and openness, and its impartiality. They mainly disagreed with the nature of PRAC’s scientific work.

The European Ombudsman’s Office is not a scientific body. The Ombudsman’s role does not include taking a view on the merits of scientific evaluations carried out by specialised scientific agencies, such as EMA’s assessment of the safety of a medicine.

The Ombudsman may, however, seek to assess whether scientific bodies such as EMA have the necessary procedural safeguards in place to ensure that the examination of scientific evidence is complete and independent, and whether these safeguards have been properly applied in any given procedure.

Following her inquiry into the procedural aspects complained about, the Ombudsman concludes that her inquiry did not identify any procedural issues that could have negatively affected the work and conclusions of PRAC in the referral procedure. The examination of the scientific evidence was complete and it was independent.

Given the importance of ensuring citizens’ trust in the procedures of bodies such as EMA, the Ombudsman suggests that EMA proactively makes public as much information as possible on the scientific work of its committees.

In response to a suggestion made by the Ombudsman during her inquiry, EMA agreed to review the confidentiality requirements on experts so that experts may discuss in public details of the scientific debate once that debate has been completed.

The Ombudsman also suggests that EMA provides more information on the documents of relevance it has in its possession, so that it is easier for citizens to request access to such documents.

Finally, the Ombudsman considers that EMA’s conflict of interest policy was fully complied with during the referral procedure on HPV vaccines. There were no identified conflicts of interest. The procedure in question was therefore deemed to have been conducted in full independence by the relevant scientific experts.

The Ombudsman concludes that there was no maladministration by EMA in the handling of the referral procedure on HPV vaccines.

Nordic Cochrane scientists’ comment on the decision by the European Ombudsman about the complaint over maladministration at the European Medicines Agency related to safety of the HPV vaccines

“The Ombudsman made a decision in our case on 16 October 2017. We provide here a comment on this decision in the same order as in the Ombudsman’s letter to us. We started the case on the 26th May 2016 by submitting a complaint to the European Medicines Agency (EMA) over the EMA. The documents in the case are available at here.

Summary

“The Ombudsman concludes that there was no maladministration by the EMA in the handling of the referral procedure on HPV vaccines. We disagree. We found many examples of scientific maladministration. As long as the Ombudsman is not willing to comment on scientific maladministration, even when it is apparent for people without a scientific background, there is, in reality, no public safeguard against poor conduct by EMA. As far as we know, there is no disciplinary committee in the European Union that can take appropriate action against EMA. We find this deeply concerning.

The Ombudsman considers that EMA has abided by the rules about transparency and conflicts of interest in its handling of its investigation into possible serious neurological harms from the HPV vaccines. We believe that if the rules are so flexible, they need to be changed, as they do not allow the public to assess the basis for EMA’s conclusions. We question EMA’s independence from industry because chairs of important committees are allowed to have conflicts of interest in relation to the companies whose products are being evaluated.

We acknowledge and welcome the Ombudsman’s recommendation of greater openness and more user-friendliness for researchers and others who wish to get access to EMA’s documents.

The Ombudsman recommends that experts who participate in EMA’s assessments should be allowed to participate freely in the public debate. We hope that these recommendations will be the rule and not just friendly calls to EMA.

The main part of our complaint is about the substandard way that EMA evaluates science. This has huge consequences for public health. We acknowledge that it is not the Ombudsman’s task to take a view on the science. However, we note that the Ombudsman on many occasions has chosen to trust EMA’s scientific assessments, which are based on the data the drug companies gave them, even though EMA knew that the companies could not be trusted.

The Ombudsman does not challenge that the assessment of a possible relation between a drug or a vaccine and serious harms is provided by the marketing authorisation holders without independent re-analysis of the underlying raw data and scrutiny of the methods used to reach the conclusions.

The evidence is, however, that drug companies often underreport even lethal harms for the authorities, and it has been documented, both to EMA and to the Ombudsman, that Sanofi Pasteur MSD, one of the HPV vaccine manufacturers, on two occasions, both in Sweden and Denmark, had seriously underreported neurological harms associated with its HPV vaccine to the authorities.

The Ombudsman does not believe that pooling heterogenous active substances (misreported as “placebos”) is scientific misconduct. It also appears to be acceptable to dismiss the results of independent researchers and the Uppsala WHO Monitoring Centre, which found signals that suggested neurological harms. Furthermore, the EMA has not been reprimanded for the excruciating slowness with which it releases clinical study reports of the HPV vaccines, and with its unnecessary redactions that make any independent re-analysis very difficult.

We believe it is important for the public to know about the many problems there are with EMA’s substandard approach to science. We have demonstrated a large number of factual errors and inconsistencies in EMA’s work and arguments, some of which are pretty serious. This is why we repeat in this document some of the issues we have written about earlier, so that newcomers do not need to read the previous documents in the case.”

And in the concluding remarks…

“EMA has not respected the citizens’ rights to know about the scientific uncertainties related to the possible harms of the HPV vaccines, as envisaged in Article 6 of the EU Treaty and the Charter of Fundamental Rights of the European Union.

Furthermore, EMA has not lived up to the scientific standards that must be expected of the agency. Finally, EMA withheld important information from its expert committee, namely the results of EMA’s own literature searches and EMA’s interpretation of what it found.

EMA’s procedures for evaluating the harms of medical interventions – where the companies are by and large their own judges – need to be fundamentally reworked. And all procedures, information, scientific uncertainties and internal disagreements should be made available to the public. The citizens should decide for themselves whether they think any particular vaccine, drug or other intervention is a good idea. This is not a decision an authority can make for them.”

Public Responses to the EMA Assessment Report

Responsum to Assessment Report on HPV-vaccines released by EMA November 26th 2015
by Louise Brinth MD PhD, lead author of peer-reviewed, published research which was heavily criticised by the PRAC and in the EMA Assessment Report

In the Responsum, Brinth outlines her work at the Synope unit and defends her published papers. Her concluding remarks include the following:

“In the assessment report written and published by EMA, three of my publication regarding my clinical experience with patients with suspected side effects to the HPV vaccine are directly criticised. Furthermore, my clinical expertise and judgement 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. The 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.”

Read Louise Brinth’s ‘Responsum to Assessment Report on HPV-vaccines released by EMA November 26th 2015’ here

A Public Responsum
Prepared by Torben Palshof, 10th December 2015

Torben Palshof MDSci, is a specialist in clinical oncology and internal medicine and he participated in an advisory board recommending whether Denmark should choose Cervarix or Gardasil in the national vaccination programme.  His Responsum looked at whether the EMA was justified in it’s criticism of published research papers flagging up potential safety signals. His introductory remarks included:

“I have no doubt that the vaccine works in the way, that it stops/inhibits the development of the premalignant changes and that this, together with the national screening progams, may reduce morbidity and mortality in a vaccinated population.  The additional effects of reducing the frequency of genital warts in women and men is also acknowledged.

However, patient safety must be prioritised very high, because this is a very large group of healthy people, who are exposed to potentially serious side effects – with unknown prognosis – which may trump the benefits of the vaccines.”

And he commented in his concluding remarks:

“If, over time, it turns out that the suspicion of serious adverse reactions to the vaccines is confirmed in one degree or another, it may perhaps be the biggest scandal in the history of medicine”

Read Torben Palshof’s ‘A Public Responsum” here

 

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