Last month members of the Nordic Cochrane posted a letter of complaint to the European Medicines Agency (EMA) on their website. Does this mean that members of the Nordic Cochrane have uncovered previously undiscovered evidence about the HPV vaccine?
No! The vaccine has an excellent safety profile and as of todays date the scientific community are unanimous about that fact.
But what is ironic is that anti-vaxxers, generally resolute in their ignorance of Cochrane-level evidence are, in contrast, zealous about a letter from a few members of the Cochrane’s Nordic faction, one complainant appears miffed that her case reports have not been interpreted as evidence for causality. This behaviour is called hypocrisy. The anti vaxxers have elected to ignore systematic reviews and meta-analysis under the name of the Cochrane but when a bellyaching letter of complaint by a few individuals gets sent to the EMA whinging about processes and perceived lack of attention to some published case reports then I am inclined to call them a bunch of hypocrites.
So what happened?
A complaint has been made by members of the Nordic Cochrane Collaboration against the EMA claiming that their review of the safety of HPV vaccine was not transparent and did not take in to account case reports that document onset of complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS) as evidence for causality.
If I have bitched about anything then I have bitched about the use of spontaneous reporting in the assessment of causality. DON’T DO IT, this practice is not science.
Who are the Nordic Cochrane?
The Cochrane Collaboration is an international independent non-profit NGO group of over 37,000 volunteers. They are committed to preparing, maintaining and disseminating systematic reviews and meta-analysis of the effects of health care.
The Nordic Cochrane is an independent centre and part of the Cochrane Collaboration.
Who are the EMA?
The EMA are a regulator. They monitor compliance with the law and regulations. Their job is to remind the companies of their responsibilities. The EMA can ask the company to respond to questions and then then they review the answers. This is the usual process for all safety concerns in every country. In New Zealand these functions are performed by MedSafe.
Who ensures that the company provides the correct information?
This is done through pharmacovigilance inspections.
The authors complain that the EMA has not been open and accountable to citizens, not lived up to professional and scientific standards, not treated Louise Brinth fairly for raising concerns, not treated fairly the Danish Health and Medicines Authority, not ensured proper safety evaluations and that they have conflicts of interest.
The Nordic Cochrane expectation that the EMA would do the work of the companies to review the safety of their products demonstrates a misunderstanding.
It would therefore appear that the authors of this complaint do not fully understand the regulatory process.
Anyway, the main gripe of this Complaint appears to be about a perceived lack of transparency and process at the EMA. The data at the centre of the complaint consist of spontaneous reports, not even observational studies, so in other words there is no scientific evidence at the centre of their report.
The more I look at the letter the more fluff I see, and by fluff I politely mean classical anti-vax rhetoric. In fact there is a gaffe so spectacular it deserves a round of applause.
Gripe about conflicts of interest
The Complaint highlights Julie Williams as having undeclared conflicts of interest. The CVs and conflicts of interest of the EMA Pharmacovigilance Risk Assessment Committee (PRAC) members are in the public domain on the EMA website. Dr Julie Williams’s details indicate she is from the United Kingdom, has degrees in biochemistry and training in pharmacovigilance and pharmacoepidemiology, is an Expert Assessor at Medicines and Healthcare Products Regulatory Agency and declares no conflicts including industry involvement. See for yourself here.
Now this bit is hilarious! The Complainants must have googled Julie Williams and found Julie Williams from Wales, who is a Professor of Psychological Medicine and Clinical Neurosciences. They must have thought “she will do nicely” and then gone on to document Julie from Wales’s activities and conflicts. But the bloody muppets have the wrong woman! I think this howler really draws in to question the validity of the other claims but let’s look at a few of them anyway.
In terms of transparency. There is a big moan about lack of transparency on the part of the EMA. Just what do these complainants expect? The regulator and experts must be able to communicate freely and confidentially. This is vital if the topic is to be thrashed out thoroughly. People must be able to speak their minds and be challenged in a safe environment without risk of having things taken out of context and manipulated. They made their rationale and conclusions public.
What are the responsibilities of PRAC? If you check out the rules and responsibilities you will find that the complaint has not specified that any of these have been broken.
So what are they complaining about exactly?
The complaint begins by outlining the case of Dr Louise Brinth’s article that describes some cases of chronic fatigue-related syndromes along with a hypothesis. This article presents a series of cases and the only case provided in detail had an alternative explanation of viral illness at the time of vaccination. Only a very high level overview is provided in the paper for the other cases and no comparison with unvaccinated cases is included, despite the author suggesting that they had a very long experience of diagnosing these cases which would presumably pre-date the start of the vaccination programme. Below is the EMA conclusion on the Brinth paper, which they reviewed:
Overall, the case series reported by Brinth and colleagues (2015) is considered to represent a highly selected sample of patients, apparently chosen to fit a pre-specified hypothesis of vaccine-induced injury. The methods used to ascertain the trigger and time to onset of specified symptoms of autonomic dysfunction may inherently bias patient recall. Whilst Brinth and colleagues (2015) acknowledge that their cases series cannot prove a causal association with HPV vaccine, they do not acknowledge or discuss the possibility that their case series simply reflects the expected characteristics and prevalence of POTS and autonomic dysfunction amongst a population cohort with 90% vaccine uptake. The authors speculate that high intensity physical exercise may be a risk factor for development of HPV vaccine-induced illness, but do not reflect upon the available medical literature suggesting that this is a commonly-reported characteristic in POTS patients, regardless of putative trigger. Finally, Brinth and colleagues (2015) now propose that their case series should be considered as having CFS induced by HPV vaccine and that this requires further, robust study, but dismiss an existing study that has already tested this hypothesis and found no association.
I think this whole thing boils down to one author disgruntled that their case series data (and that of others) has not being found to imply causality.
If the Cochrane Collaboration are all about evidence as a whole then why would they argue the value of a series of case reports when no other evidence supports them? They don’t tend to include case reports. A whingey letter in no way constitutes scientific evidence.
Just one final footnote
I have criticised Brinth as having sour grapes about her work, however Tom Jefferson is a bit of a surprise.
Tom Jefferson is one of the authors of the complaint and he has published loads of Cochrane Reviews of influenza vaccines – by no means our most effective vaccines to be sure, and Jefferson has enjoyed publishing on the limitations inherent in trying to study annual influenza vaccines. For years he has pointed out the lack of high quality studies evaluating influenza vaccine effectiveness (he does have a point), while avoiding the overall evidence from other study designs. Interesting how a purveyor of the randomised controlled trial, meta-analysis and systematic review can turn tail and add his name in support of the relevance of a series of case reports with no controls, no denominators and no baselines. But that is effectively what Tom Jefferson has done. Not the first time he has drawn criticism for double standards.
Featured image: Gardasil vaccine and box. CC Wikimedia