An FOI communiqué from Special Agent Fawbert
of the IPHG of the VRMM of the MHRA

Here is another sad little picture of the UK and European medicines’ control system at work – and an opportunity to reflect on the quality of drug policies and standards here and elsewhere.

When the potential dangers of prescribing paroxetine+pimozide were finally (and belatedly [1]) recognised, GlaxoSmithKline (GSK) alerted Canadian prescribers with a targeted ‘Dear Doctor’ letter, in July 2005. Meanwhile, British doctors have still not been notified of the risks. The difference is explained, overwhelmingly, by regulatory requirements (and the lack of them) here and there.

Nothing happened here (UK) until September 2006, when there appeared a surreptitious and this small print change in the paroxetine drug label – the so-called Summary of Product Characteristics (SPC) for Seroxat®, which only a minuscule number of doctors would ever read.

Doctors need such information, because a ‘contraindication’ is an almost absolute prohibition on use. Any doctor who did (in this case) prescribe paroxetine+pimozide, would need to be well aware of the possible harm (including litigation) that might result, also to appreciate that they would take pretty much full responsibility for any harm done to their patients. 

In short, what happened left UK doctors none the wiser – while the manufacturers, with full regulatory approval, excused themselves from legal liability. The label change amounts to an official blessing for GSK: the small print amendment firmly shifted the burden of responsibility for harm to doctors and patients.

So there were two separate strands in the Freedom of Information (FOI) requests we filed in September: why so little, and why so late? Now Special Agent Fawbert has replied. You may recall that he is not currently in our good books but, if you don’t, this missileive about the paroxetine (Seroxat) 'placebo suicides' explains why.

Agent F signs off as the FOI Co-ordinator for the IPHG of the VRMM of the MHRA – i.e. the "Information for Public Health Group" in the "Vigilance and Risk Management of Medicines Division" of the Medicines and Healthcare products Regulatory Agency. His reply to our FOI request is linked here.

Why did it take over a year for the paroxetine + pimozide contraindication to appear? Predictably, the MHRA (in the Agency’s view) did nothing wrong. However, you risk bursting at the seams with Agent Fawbert’s treacle pudding of words to see the reason: the European process is terribly slow, and the MHRA is so shackled by Europe that it cannot (or will not?) act on its own. The secondary excuse is spurious; Health Canada also had to negotiate with GlaxoSmithKline (and got a lot more out of it too):

"Following the European referral for paroxetine, Seroxat is authorised through one of the European licensing procedures, the Mutual Recognition procedure with the Netherlands acting as lead European Member State.  The agreed European timetables for review of applications to vary the marketing authorisation coupled with the need to seek further information from the company in relation to some of the proposed changes will have dictated the timescale for completion of this variation to add a contraindication against concomitant use of pimozide to the product information for Seroxat." 

Thereafter, the Agency goes into omnipotent mode: "it was not considered that a Dear Doctor letter was warranted on this particular occasion". Agent F gave several reasons for this and suggests they are compelling. Far from it – see below – but they certainly invite one to believe that some thought went into the matter.

And that brings us to the point of this new round of FOI requests. We need to establish how the MHRA actually did arrive at this decision. Did the Agency really consider the matter at all, and were these reasons the ones that mattered at the relevant time? Or was this a de facto decision, achieved mainly by sitting on bums? It would be reassuring – could even be impressive – if the paper trail showed that the MHRA actually did recognise the risks, and took the inaction they decided upon only after carefully weighing up the pros and cons. But wait and see.

We now turn to the reasons themselves. Collectively, the most striking thing about them is the lack of any evidence that the MHRA took into account the benefits that might have resulted from communicating more effectively. The stated reasons make no attempt to suggest the need to balance benefit and harm: they’re all reasons for doing virtually nothing, without reference to possible gains. This seems most unbecoming, not to say baldly hypocritical, in an Agency whose stated mission is to point the great unwashed in exactly the opposite direction. [2] These are the reasons the Agency gives: 

"We did not consider that it was necessary for any specific urgent communications to be issued in the UK with regard to the addition of this new contraindication. In making this decision we took into account i) the fact that the pimozide product information contains extensive warnings about its potential to cause prolongation of the QT interval, ii) the contraindication that already existed in the pimozide SPC against its use in combination with drugs which inhibit cytochrome P450 2D6 such as Seroxat, ii) the low usage of pimozide in the UK and iv) that the contraindication against the use of pimozide in combination with some other SSRIs was already recognised."

I have already purchased from Amazon a copy of Sir Ernest Gowers’ classic text [3], Complete Plain Words, and sent it on to Agent Fawbert, FOIC, IPHG, VRMM, MHRA. At under a tenner (including postage), it would surely not count as a bribe, and could prove vastly more useful than Mr Alder’s rubber stamp …. But now let us take the arguments apart:

Re (i) and (ii): Yes, there is an extensive warning in the pimozide SPC, but it is so worded as if to exempt paroxetine - and therefore seems potentially dangerous [4]. The same is true of the pimozide (Orap®) Patient Information Leaflet. Imagine reading the text below on behalf of someone else: surely you would think they were in the clear with paroxetine - but you would be wrong. In short, the regulators needed to act promptly, if only to defuse this ticking bomb. 

Do not use Orap 4 mg Tablets … in combination with the following ... certain antidepressants such as nefazodone, amitriptyline, maprotiline, sertraline, citalopram and escitalopram."

Re (iii): True, the usage of pimozide in the UK is low – around 10,000 prescriptions/year – yet last July the MHRA sent out a warning to doctors for a product for which there are only about 300 prescriptions per year [5]. Every month or two, the MHRA sends letters to healthcare professionals, "to inform of new safety information and advice on medicines" – and it would have been cheap and easy to warn about the dangers of paroxetine + pimozide, in this way. Was it really worth making no effort because only a few patients might survive? A ‘contraindication’ represents the highest level of warning – and here was a readily avoidable and potentially lethal drug interaction. Why not act?

Re (iv): Agent Fawbert’s last point also seems negligible: "the contraindication against the use of pimozide in combination with some other SSRIs was already recognised." The danger of naming some SSRIs (e.g. sertraline, citalopram) but excluding paroxetine has been discussed above. And any reference to, "significance … already recognised", is meaningless, if not misleading, without specifying how well recognised and by whom.

The issues here are important for reasons that go well beyond this particular drug problem. Paroxetine + pimozide is a hazard – perhaps only for a few people – but is the MHRA really on top of the issues? Why are they so lacking in imagination and empathy, and why so slow? What does it say about the quality of leadership that the Agency is so weak? Can SPCs be relied on and do they mean much to prescribers, and couldn’t the warnings be so much better than they are? Can’t anything be done about the pompousness and verbosity? Is the Agency really capable of honest communication, even when its reputation is on the line? Does the MHRA ever make mistakes? And should it be permitted to take such whopping liberties in covering them up?

Such questions will remain largely rhetorical until there is some adequate response to the findings of the UK Parliamentary Health Committee (2005) [6]. The Committee was scathing about the MHRA, and called for an independent review. [7]

That review must happen. It is long overdue (Which? October 2006), and public health depends upon it. The issues here go far beyond the prospect of drug injury of the paroxetine+pimozide variety; ultimately, they extend to 'social iatrogenesis' - ill-health in the community on the scale envisioned by Illich [8]. Arguably, the MHRA is playing a critical part in creating/sustaining a rapidly emerging public and global health disaster.

I increasing visualise the Agency as a well-motivated, well-organised and pretty effective road safety organisation – but one that is also largely oblivious to (and in no way responsible for) the need to soften the automotive carbon footprint. Maybe one day, we’ll face up to the reality: drug regulators are doing the wrong job, really quite effectively. The benefits of an MHRA seem obvious and considerable, yet its limited remit and perspectives seem scary, and the health consequences may well be grave.

Drug regulators (surely including Special Agent Fawbert) are no doubt honest, agreeable and usually competent people, trying their level best to make at least modest progress, and clearly succeeding in much of the work they do. And yet, collectively, they seem misaligned, straight-jacketed, stuck, pressured and confused. Thus the Agency (the collective) becomes more and more intoxicated by its sense of self-righteousness, and so the flows of self-justification must increase, unless and until they are curbed.

The greater the denial, the more it seems that the MHRA has lost the health plot. We need a really thorough review - and watch this space until it happens.


[1]  See below an outline chronology of labelling changes for SSRIs (+ pimozide) required by the US Food and Drug Administration. Far from applying The Precautionary Principle  - assuming some risk of a class effect, involving all SSRIs+pimozide, until proved otherwise – the regulatory tendency is to wait for the body count and then add new warnings to drug labels on a piecemeal basis, one by one. The process seems haphazard too: note that, several years on, the UK and European SPCs for Fluvoxamine, citalopram and escitalopram still don’t contraindicate concurrent use with pimozide. November 1996: Label change – Prozac (fluoxetine): “A single case report has suggested possible additive effects of pimozide and fluoxetine leading to bradycardia” June 2000: Label change – Luvox (Fluvoxamine): "Co-administration of … pimozide with Luvox tablets is contraindicated …" April 2003: Label change – Paxil (paroxetine)  “Voluntary reports of adverse events in patients taking paroxetine that have been received since market introduction and not listed above that may have no causal relationship with the drug include …. oculogyric crisis which has been associated with concomitant use of pimozide” July 2004: Label change – Zoloft (sertraline) “Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS)”. January 2005 – Label change – Celexa (citalopram) and Lexapro (escitalopram):    “Concomitant use in patients taking pimozide is contraindicated (see Drug Interactions – Pimozide and Celexa).” December 2005 – Label change – Paxil (paroxetine) - “Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS)”.   BACK

[2] Q 777  Professor Sir Alasdair Breckenridge: I think that the other area that I would pick up is that of the education of the public in terms of risk and benefit. A lot of the discussions which have taken place in the Select Committee have been about the safety of medicines and relatively little about this concept of risk and benefit. When we change a licence, we do not do this purely based on a safety profile of a drug. If we did this, there would be no anti-cancer drugs available and there would be no anti-HIV drugs because the adverse reactions to them are huge. They have got to be balanced against the benefits which these drugs have and the one thing which I would like to see you concentrating on, with all respect, is this concept of risk and benefit. We are going to be communicating that very strongly with our new communications set-up, but I would like to see that as one important aspect coming through from this Committee.”  House of Commons Health Committee: The Influence of the Pharmaceutical Industry, Fourth Report of Session 2004–05, Volume II, Formal minutes, oral and written evidence. London: House of Commons, April 2005. BACK

[3]Sir Ernest Arthur Gowers GCB GBE (1880–1966) was a British civil servant, now best known for work on style guides for writing the English language. At the invitation of HM Treasury he wrote Plain Words, a guide to the use of English in 1948. It was designed to woo officials away from pompous and over-elaborate writing, and was so successful that the Treasury asked for a sequel, The ABC of Plain Words, which was published in 1951. Both these works were slim paperbacks. Their success encouraged Her Majesty's Stationery Office to commission a hardback book combining the best of both earlier publications. This was The Complete Plain Words, published in 1954, and never (in various revisions) out of print since. Its success was wide — far beyond the original audience of civil servants — and Gowers was invited by the Oxford University Press to prepare a new edition of Fowler's Modern English Usage, which was in need of updating, having been in print since 1926 with only very minor changes. The second edition was published in 1965 and remained in print for three decades, being succeeded by a third edition in 1996.” (See: Wikipedia) BACK

[4] Pimozide SPC: “Orap is contraindicated with concomitant use of sertraline, citalopram and escitalopram (see Section 4.5).” BACK

[5] The drug was deferiprone (Ferriprox). See MHRA publication, “Safety information on medicines for healthcare professionals sent July and August 2006”. BACK

[6] Declaration of interest: CM was engaged as one of four specialist advisers to the House of Commons Health Committee, on its recent enquiry into "The Influence of the Pharmaceutical Industry". BACK

[7] "During this long inquiry we became aware of serious weaknesses in the MHRA. Worryingly, in both its written and oral evidence the Agency seemed oblivious to the critical views of outsiders and unable to accept that it had any obvious shortcomings, except those that could be remedied by more transparency. The Agency’s attitude to its public health responsibilities suggested some complacency and a lack of requisite competency, reducing our confidence in its ability to undertake the reforms needed to earn and deserve public trust. Nor did we conclude that the MHRA provides the discipline and leadership that this powerful industry needs. We recommend that there be an independent review of the MHRA …" House of Commons Health Committee: The Influence of the Pharmaceutical Industry, Fourth Report of Session 2004–05, Volume I, Report, together with formal minutes. London: House of Commons, April 2005. BACK

[8] “Medicine undermines health not only through direct aggression against individuals but also through the impact of its social organization on the total milieu. When medical damage to individual health is produced by a sociopolitical mode of transmission, I will speak of `social iatrogenesis', a term designating all impairments to health that are due precisely to those socio-economic transformations which have been made attractive, possible, or necessary by the institutional shape health care has taken. Social iatrogenesis designates a category of aetiology that encompasses many forms. It obtains when medical bureaucracy creates ill-health by increasing stress, by multiplying disabling dependence, by generating new painful needs, by lowering the levels of tolerance for discomfort or pain, by reducing the leeway that people are wont to concede to an individual when he suffers, and by abolishing even the right to self-care. Social iatrogenesis is at work when health care is turned into a standardized item, a staple; when all suffering is `hospitalized' and homes become inhospitable to birth, sickness, and death; when the language in which people could experience their bodies is turned into bureaucratic gobbledegook; or when suffering, mourning, and healing outside the patient role are labelled a form of deviance.”    Illich I., Limits to Medicine - Medical Nemesis: the Expropriation of Health, (London: Marion Boyars, 1976 (originally published in Ideas in Progress, January 1975). BACK

Charles Medawar
4 November 2006