A tale of two vaccines
BMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4152 (Published 04 October 2018) Cite this as: BMJ 2018;363:k4152
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Many matters arise from the letters here of Clifford Miller [1,2,3] not only about the MHRA's failure to pick up the signals relating to Pandemrix vaccine he has identified, but about their general methodology pertaining to all products. I wonder if the three officers of the MHRA - Philip Bryan, June Raine and Ian Hudson - who posted here before [4] can return and elucidate.
[1] Mr Clifford G Miller, 'Re: A tale of two vaccines - MHRA Published Incomplete ADR Data', 14 October 2018, https://www.bmj.com/content/363/bmj.k4152/rr-18
[2] Clifford G Miller, 'Re: A tale of two vaccines - MHRA - 6 Reports of "rare" suspected ADR in 60 days ignored', 18 October 2018, https://www.bmj.com/content/363/bmj.k4152/rr-21
[3] Clifford G Miller, 'Re: A tale of two vaccines - MHRA Had 178 Pandemrix Altered Consciousness Adverse Event Reports in 67 Days', 23 October, https://www.bmj.com/content/363/bmj.k4152/rr-23
[4] Philip Bryan, June Raine, Ian Hudson, 'MHRA response to BMJ Editor’s Choice – ‘A tale of two vaccines’', 10 October 2018, https://www.bmj.com/content/363/bmj.k4152/rr-11
Competing interests: No competing interests
It is now obvious that there are ADVERSE EFFECTS WHICH IMPAIR ABLITY TO DRIVE in some cases.
Question. Will the manufacturers of this vaccine now urgently advise doctors and pharmacists to warn the adults (especially the elderly) of the risk of loss of alertness, making driving hazardous?
Competing interests: No competing interests
Dear Editor,
It seems the position regarding the MHRA's practices is considerably worse than I reported in prior Rapid Responses [1], [2]. What is troubling is how is it a lawyer notices but the MHRA - whose job it is to do so and with all the medical and scientific expertise and resources at its disposal - did not and still does not?
In addition to the six reports of hypersomnia I noted previously [1], the MHRA had [and still has] another 172 reports of Pandemrix Adverse Events which relate in some form to what I will call here "abnormalities in the regulation of consciousness". And this total of 178 Pandemrix Adverse Event reports were received by the MHRA within the 67 day period to 21st December 2009.
What is related here is in addition to my identifying that the MHRA splits up Yellow Card reported symptoms in its analyses of Adverse Events. [2] This somewhat odd practice for a supposed drug safety regulator has the effect of preventing the identification of a condition or syndrome characterised by a group of symptoms presenting in each individual the subject of a Yellow Card report.
So what of this total of 178 reports relating to abnormalities in the regulation of consciousness? Should a competent medical professional have considered these reports together as potentially in some way linked?
Professor David Healy has expressed the view in a recent blog “Khashoggi and Pandemrix” that most if not all should have been and that view is expressed with little or no doubt. In addition, it appears the MHRA's practices determine its approach to reports of Adverse Events for all pharmaceuticals.
These are the examples of the MHRA's 31 December 2009 published Pandemrix Adverse Events [3] grouped together and cited by Professor Healy relating to abnormalities in the regulation of consciousness:
- under the heading of Narcolepsy and Hypersomnia:
6 reports of hypersomnia.
- under Disturbances in Initiating and Maintaining Sleep:
30 reports of Insomnia,
- under Parasomnias
3 reports of Abnormal Dreams (a classic feature of narcolepsy),
7 reports of Nightmares (ditto),
1 report of Sleep Terror (ditto).
- under Sleep disorders Not Elsewhere Classified:
9 reports
- under Disturbances in Consciousness Not Elsewhere Classified:
73 reports of lethargy,
5 reports of loss of consciousness,
1 of sedation,
27 of Somnolence
22 of syncope.
Professor Healy comments on these signals received by the MHRA well "before any reports of narcolepsy from Finland":
"Ordinarily, when patients present with what is later diagnosed as narcolepsy, on average there is a wait of 15 years before the diagnosis is made. This is well known. Initially doctors diagnose fatigue syndromes or somnolence disorders and all sorts of other things. The average doctor will have seen very few cases of narcolepsy if any.
"Given how few events are ever reported to MHRA or FDA or any regulator ... there was as good a case that Pandemrix Caused narcolepsy ...."
The MHRA appears to avoid identifying a condition from symptoms and signals from Yellow Cards and did not identify narcolepsy in particular because "no British doctors used the word narcolepsy".
Professor Healy goes on to identify the problem is more widespread stating "This not just a narcolepsy issue. There is a vanishingly small number of doctors who will send a report of PSSD (post SSRI sexual dysfunction), or PRSD (post retinoid sexual dysfunction) or PFS (post finasteride syndrome) to the regulator in their country. They’ve never heard of these conditions. They will send reports of sexual dysfunction of one sort or the other on antidepressants and other drugs."
"They don’t send reports of any old sexual dysfunction because everyone knows that happens on antidepressants and regulators don’t want reports of things already in the label. If doctors report at all it will be because there is something striking about what their patients are saying to them. So how many reports do the regulators have of significant sexual dysfunction on antidepressants? Over a thousand in the UK alone. There are reports of permanent sexual dysfunction going back to 1987 – before Prozac."
So in addition to Sweden and Finland identifying narcolepsy as a Pandemrix Adverse Drug Reaction when the MHRA did not, the decades long deficiencies in the MHRA's approach to monitoring drug safety are and remain manifold and uncorrected.
Other Pandemrix Adverse Events relating to abnormalities in the regulation of consciousness [mainly epilepsy, seizures and convulsions] as published by the MHRA on 31 December 2009 [3] include:
Generalised tonic-clonic seizures
Grand mal convulsion 3
Convulsion in childhood 1
Partial simple seizures NEC
Simple partial seizures 1
Seizures and seizure disorders NEC
Convulsion 9
Epilepsy 3 [1 fatal]
Febrile convulsion 2
Tonic convulsion 1
[1] Re: A tale of two vaccines - MHRA - 6 Reports of "rare" suspected ADR in 60 days ignored Clifford G Miller 18th October 2018
https://www.bmj.com/content/363/bmj.k4152/rr-21
[2] Re: A tale of two vaccines - MHRA Published Incomplete ADR Data Clifford G Miller 14th October 2018
https://www.bmj.com/content/363/bmj.k4152/rr-18
[3] MHRA'S UK Suspected Adverse Reaction Analysis Swine Flu (H1N1) Vaccines – Celvapan and Pandemrix 31 December 2009
http://webarchive.nationalarchives.gov.uk/20141205150130/http://www.mhra...
Competing interests: No competing interests
The "spectre of Andrew Wakefield" certainly should not be allowed to deflect from this important issue [1,2].
I wrote to this journal in February 2010 explaining why the GMC findings against Royal Free doctors were defective [3], and no one challenged me. The Wakefield Lancet paper had nothing to do with the Legal Aid Board commissioned protocol; investigations were carried out according to clinical need; the order of referral was a red-herring - all of which anticipated the views of the High Court judge, Sir John Mitting, when exonerating the senior clinician and senior author of the paper, Prof John Walker-Smith, two years later [4]. Mitting dismissed the central contention the of the GMC prosecution that the authors of the paper were executing the Legal Aid Board sponsored protocol (172/96):
“Its conclusion that Professor Walker-Smith was guilty of serious professional misconduct in relation to the Lancet children was in part founded upon its conclusion that the investigations into them were carried out pursuant to Project 172-96. The only explanation given for that conclusion is that it was reached ‘in the light of all the available evidence’. On any view, that was an inadequate explanation of the finding. As it may also have been reached upon the basis of two fundamental errors – that Professor Walker-Smith's intention was irrelevant and that it was not necessary to determine whether he had lied to the Ethics Committee, it is a determination which cannot stand ….” [para 20]
The case that Walker-Smith was undertaking research was dismissed:
“..their case was that he was in fact undertaking research, which required Ethics Committee approval, without realising that he was doing so. This is an untenable proposition, as the analysis of the letter of 11th November 1996 above demonstrates. In consequence, not only was the panel invited by the GMC not to determine Professor Walker-Smith’s intention, it was also invited not to determine his truthfulness in his dealings with the Ethics Committee.” [Par. 18]
“It is in its findings on the clinical issues in the individual cases of the Lancet children that the most numerous and significant inadequacies and errors in the determination of the panel occur. In no individual case in which the panel made a finding adverse to Professor Walker-Smith did it address the expert evidence led for him, except to misstate it. The issues to which this evidence went were of fundamental importance to the case against him. Universal inadequacies and some errors in the panel's determination accordingly go to the heart of the case. They are not curable. Unless the remainder of the panel's findings justify its conclusion that Professor Walker-Smith was guilty of serious professional misconduct, its determination cannot stand.”
Mitting rejects the idea that there was any misrepresentation over referrals:
“This paper does not bear the meaning put upon it by the panel. The phrase “consecutively referred” means no more than that the children were referred successively, rather than as a single batch, to the Department of Paediatric Gastroenterology. The words did not imply routine referral.”[par. 157]
Finally, Mitting states:
“For the reasons given above, both on general issues and the Lancet paper and in relation to individual children, the panel's overall conclusion that Professor Walker-Smith was guilty of serious professional misconduct was flawed, in two respects: inadequate and superficial reasoning and, in a number of instances, a wrong conclusion….The panel's determination cannot stand. I therefore quash it. Miss Glynn, on the basis of sensible instructions, does not invite me to remit it to a fresh Fitness to Practice panel for redetermination. The end result is that the finding of serious professional misconduct and the sanction of erasure are both quashed.” [para.186-7]
It remains concerning that the chairman (Surendra Kumar) of the fitness to practice panel in the case against the three Royal Free doctors sat on two MHRA committees and owned shares in GSK [5].
All this time Cochrane has been far from clear about MMR, finding safety studies in successive reviews (2003, 2005, 2012) to be "largely inadequate" [6]. Nor do we seem to be able to rely on the MHRA and the EMA to guard the public's safety - either with sufficient rigour or with sufficient distance from the industry.
[1] Fiona Godlee, "A tale of two vaccines", BMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4152 (Published 04 October 2018)
[2] Philip Bryan, June Raine, Ian Hudson, 'MHRA response to BMJ Editor’s Choice – ‘A tale of two vaccines’', r 2018, 18, https://www.bmj.com/content/363/bmj.k4152/rr-11
[3] John Stone, "The unexplained puzzle of the GMC verdict (and responses to Peter Flegg) 10 February 2010, https://www.bmj.com/rapid-response/2011/11/02/unexplained-puzzle-gmc-ver...
[4] In the High Court between Prof Walker-Smith and and the General Medical Council, http://www.bailii.org/cgi-bin/markup.cgi?doc=/ew/cases/EWHC/Admin/2012/5...
[5] John Stone, 'Re: Financial conflicts -shock horror', 22 October 2008, https://www.bmj.com/rapid-response/2011/11/02/re-financial-conflicts-sho...
[6] John Stone, 'Response to David Oliver II (Risks of Vaccines)', 28 August 2018, https://www.bmj.com/content/362/bmj.k3596/rr-11
Competing interests: No competing interests
Dear Editor,
As early as December 2009 the MHRA had already received six reports of suspected hypersomnia within a mere 67 days. These were reports associated with the administration of Pandemrix [1]. "Narcolepsy is a rare, natural illness, with around 10 new cases per million people every year" [2]. Although not as rare as narcolepsy, hypersomnia is rare. Six possible cases in 67 days [of a closely related condition and one potentially easily confused with the rarer narcolepsy] might be thought a large enough signal to warrant investigation, especially when under-reporting is taken into account. Irrespective of whether the cases were predominantly children, if many were children that suggests the signal should have been taken more seriously.
Narcolepsy and hypersomnias refer to a group of disorders for which excessive daytime sleepiness (ESD) is the core symptom, but when it is not due to insufficient sleep (sleep deprivation), disturbed nocturnal sleep, insomnia, circadian rhythm disorders, sleep-related breathing (sleep apnea) disorders or medical issues. In narcolepsy, other symptoms beside excessive daytime sleepiness are present as well and there is a tendency to falling asleep directly or extremely rapidly into Rapid Eye Movement (REM) Sleep (dreaming sleep). [3]
Should the MHRA have acted sooner to protect the public and especially their very small children?
The MHRA's 2011 explanation [2] was:
"Most reports of narcolepsy after exposure to Pandemrix vaccine came from Finland and Sweden. In September 2010, the European review concluded that the available evidence was insufficient to confirm a link between Pandemrix and narcolepsy, and that further studies were necessary to fully understand this issue. No restrictions on use of the vaccine were recommended.
After use of more than 6 million doses of Pandemrix vaccine in the UK, we have received 4 unconfirmed reports of narcolepsy following vaccination. These were received after the reports from Finland came to light. The reports so far in the UK are no more than we would expect to see by coincidence after vaccination.
After review of all of the available information, the case remains that a link between Pandemrix vaccine and narcolepsy has not been confirmed. Epidemiological studies are ongoing to further evaluate this."
No explicit mention is made of the six reports of hypersomnia received within 67 days by 21 December 2009 and whether any may have been narcolepsy confused with hypersomnia. And of course as explained in a prior response [4], the MHRA recorded the Yellow Card reported symptoms as if each one was a suspected Adverse Drug Reaction instead of investigating and recording the condition or syndrome indicated by the reported group of symptoms reported on the Yellow Card concerned.
Further, what was particular to Finland and Sweden's reporting systems which caught so many reports which the MHRA's Yellow Card systems appears to have missed?
Professor Bill Inman's criticisms of his adverse event reporting system, now the Yellow Card system, as inadequate could have been addressed in some good measure by the MHRA over the decades since its introduction.
Despite numerous drug scandals over that time one is tempted to think the MHRA appears less interested in keeping pharmaceuticals of questionable safety off the market than on. In my view it is time the MHRA was swept away with all the drug industry associations its personnel may have and for safety to be given priority over drug company profits.
However, it appears a complex web is woven. The longstanding problems of what appears to me to be drug industry bias amongst personnel in the Department of Health, including agencies like the MHRA, appears by inference to be in some way associated with anonymous senior civil servants. If it were otherwise one might argue that the problems could not continue and should be less likely to exist. That is coupled with the influence the pharmaceutical industry has invested heavily in acquiring throughout Government, the civil service, medical schools, the medical professions, medical societies, health charities and medical publishing. Generous donations and grants are known commonly and to be made on a routine basis. Throw in for good measure manipulation of the media, and daylight is less than likely to be shone to illuminate the darkness. [5]
[1] MHRA'S UK Suspected Adverse Reaction Analysis Swine Flu (H1N1) Vaccines – Celvapan and Pandemrix 31 December 2009
webarchive.nationalarchives.gov.uk/20141205150130/http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON06580...
[2] MHRA PUBLIC ASSESSMENT REPORT Swine flu vaccines and antiviral medicines: UK post-pandemic safety review February 2011
http://www.mhra.gov.uk/home/groups/s-par/documents/websiteresources/con1...
Accessed 18 Oct 2018
[3] Narcolepsy, Hypersomnia and Excessive Daytime Sleepiness
Stanford Healthcare
https://stanfordhealthcare.org/about-us.html
[4] Re: A tale of two vaccines - MHRA Published Incomplete ADR Data 14th October 2018 Clifford G Miller
https://www.bmj.com/content/363/bmj.k4152/rr-18
[5] The Influence of the Pharmaceutical Industry Fourth Report of Session 2004–05 Volume I Report, together with formal minutes Ordered by The House of Commons to be printed 22 March 2005
https://publications.parliament.uk/pa/cm200405/cmselect/cmhealth/42/42.pdf
Competing interests: No competing interests
I am all for immunisation - with informed consent with prior complete known information about side-effects known and recorded.
Therefore
1. Mr Clifford Miller’s rapid response calls for a quick reply from the MHRA.
2. Dr Rajagopal of the World Heath Organisation cannot stay silent about my question which simply needs a YES or NO answer.
3. Mr John Stone’s responses deserve an answer quickly if PUBLIC HEALTH ENGLAND wishes to regain the confidence of the public.
The present practice of our governmental agencies (playing deaf and dumb to questions raised by members of the public) only serves to destroy the confidence of the public.
Competing interests: No competing interests
Everyone should be grateful to Clifford Miller for illuminating the MHRA's methodology in breaking down adverse report data into statistical noise [1], and it would interesting know how widespread is this practice. Is it just for Pandemrix and HPV vaccines or for all products? Either way the agency urgently need to explain themselves.
Miller is however incorrect in suggesting I was claiming validity for the MHRA reporting - I thought I was pointing out its inadequacy while noting that only 6 million or so vaccinations had taken place according to their data despite contracts for 132m rounds, and this may have saved citizens a lot of harm {2].
[1] Mr Clifford Miller, 'Re: A tale of two vaccines - MHRA Published Incomplete ADR Data', 14 October 2018, https://www.bmj.com/content/363/bmj.k4152/rr-18
[2] John Stone, 'Re: A tale of two vaccines - how the British people averted disaster?' 13 October 2018,
https://www.bmj.com/content/363/bmj.k4152/rr-17
Competing interests: No competing interests
Dear Editor,
Mr John Stone is in error in taking MHRA claims as having validity.
The MHRA did the same with the safety analysis of Pandemrix as it did with the HPV vaccines. References are provided.
For HPV the symptoms reported in each Yellow Card report were reported as if each was a suspected adverse drug reaction rather than being a symptom of an underlying condition [1]. This meant of course that any underlying condition which gave rise to each combination of symptoms could never be identified.
If we suspect someone has contracted an illness we need obviously to consider all the symptoms together and not split them up. Also needed is an history and an examination of the individual.
There are a number of ways in which what the MHRA did for both these vaccines can be verified. The simplest is that the MHRA reports vastly more suspected ADR's than there were Yellow Card reports for the HPV vaccine [1] and for Pandemrix [2]. It can also be verified by more detailed data obtainable from the MHRA under FOI which lists the reported symptoms as if each symptom reported in a Yellow card were an individual suspected ADR rather than one of a number of symptoms of a suspected underlying condition.
For Pandemrix the MHRA claimed [2]:
"Up to and including Jan 19, 2010, we have received a total of 2817 UK reports of suspected ADRs to the H1N1 vaccines. The 2817 reports include a total of 7487 suspected reactions."
None of the schoolgirl or other subjects of any HPV Yellow Card had follow-up to investigate the cause of the reported symptoms nor what the underlying condition might be.
There were substantially in excess of 1000 reports of headache. That is one of the symptoms of an encephalopathy. As all the symptoms were split up we have no idea how many of these were cases of encephalopathy.
So we, the public, have no idea what conditions British schoolgirls developed following the HPV vaccine because of the manner in which the "analysis" was carried out.
For the HPV vaccine the MHRA claimed [1]:
" Results
Over 6 million doses of Cervarix have been given in the UK since the immunisation programme started in 2008. During the immunisation programme the MHRA has received 6213 case reports describing 14,300 suspected ADRs for Cervarix (including those where the HPV vaccine brand name was not specified). The overall reporting rate for all suspected ADRs is estimated to be about 1 report per 1,000 doses administered; this is not an unexpected reporting rate for a newly marketed vaccine used within a new national immunisation programme, with such high exposure over a four-year period.
Over 55% of the reported 14,300 reactions were recognised side effects listed in the product information such as dizziness (1385 cases), headache (1128 cases), injection-site reactions (652 cases), fatigue (378 cases), malaise (499 cases), pyrexia (319 cases) / feeling hot (147 cases), nausea (1078 cases), vomiting (487 cases), abdominal pain (240 cases) pain (128 cases) and allergic reactions (63 cases). This also included ‘psychogenic’ reactions, which are due to fear of the injection process rather than a side effect of the vaccine itself (mainly fainting and ‘panic attacks’)."
[1] MHRA PUBLIC ASSESSMENT REPORT Cervarix HPV vaccine: update on UK safety experience at end of 4 years use in the HPV routine immunisation programme December 2012. www.mhra.gov.uk/home/groups/s-par/documents/websiteresources/con213228.pdf
[2] Drug Safety Update Volume 3, Issue 7 February 2010
Competing interests: No competing interests
I have been looking at the MHRA's own report of the Swine Flu episode from February 2011 [1]. Even at that late stage its monitoring system had failed to pick up any significant adverse events and discovered only 4 cases of narcolepsy after European reports (p22). On p.16 it reports:
"As with most vaccines, the most common ADRs we expected to be reported were
headaches, dizziness, lethargy, and ‘psychogenic’ events (eg, fainting). It is therefore
not unexpected that nervous system disorders constitute almost 17% of all ADR
reports. The ADRs reported in this category raise no new safety concerns.
There is no indication that Pandemrix vaccine may be a cause of any serious
neurological adverse events. "
While the apparent failure of the MHRA detection system may raise eyebrows, and even the question what else they might miss, I also note the statement on p.3:
"Up to 18 June 2010, more than 6 million doses of Pandemrix, and more than 36 000
doses of Celvapan, were given across the UK. Out of these, there were 3400 reports
of suspected ADRs with Pandemrix, and 43 reports of suspected ADRs with
Celvapan. "
But on 25 September 2009 Fergus Walsh reported for the BBC [2]:
"The UK has contracts for up to 132 million doses of pandemic vaccine - enough for everyone in Britain to receive two shots."
In the end it was decided by the JCVI that one dose was sufficient for most people ([1] p.6), but it also looks like most people decided to give the vaccines a pass, reckoning perhaps that the risk from the vaccines was greater than the disease in spite of what they were being told by government officials. And who could say now that they were wrong?
[1] MHRA PUBLIC ASSESSMENT REPORT 'Swine flu vaccines and antiviral medicines: UK postpandemic
safety review', February 2011, http://www.mhra.gov.uk/home/groups/s-par/documents/websiteresources/con1...
[2] Fergus Walsh, ' Vaccines for swine flu', 25 September 2009, http://www.bbc.co.uk/blogs/thereporters/ferguswalsh/2009/09/vaccines_for...
Competing interests: No competing interests
Re: A tale of two vaccines
Dear Editor
Two years ago officers of the MHRA were defensive of their inability to detect the narcolepsy risk with the Pandemrix vaccine in the swine flu scare of 2009 nine years before [1], despite heavy criticism [2-5]. In 2020 they face a much more daunting task of assessing for licensure and monitoring a plethora COVID-19 vaccines, each of apparently novel design. I hope they are now able to give the public assurances that important lessons have been learned, and not just that they always get it right.
[1] Philip Bryan, June Raine, Ian Hudson, 'MHRA response to BMJ Editor’s Choice – ‘A tale of two vaccines’', 10 October 2018, https://www.bmj.com/content/363/bmj.k4152/rr-11
[2] Peter Doshi, 'Pandemrix vaccine: why was the public not told of early warning signs?',
BMJ 2018; 362 doi: https://doi.org/10.1136/bmj.k3948 (Published 20 September 2018)
[3] Responses to Peter Doshi, 'Pandemrix vaccine: why was the public not told of early warning signs?', https://www.bmj.com/content/362/bmj.k3948/rapid-responses
[4] Fiona Godlee, 'A tale of two vaccines', BMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k4152 (Published 04 October 2018)
[5] Responses to Fiona Godlee, 'A Tale of Two Vaccines, https://www.bmj.com/content/363/bmj.k4152/rapid-responses
Competing interests: AgeofAutism.com, an on-line daily journal, concerns itself with the potential environmental sources for the proliferation of autism, neurological impairment, immune dysfunction and chronic disease. I receive no payment as UK Editor