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
” 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)
“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 )
“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
“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)
“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)
“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.”
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.”
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”