UPDATE - MAY 2004

The future of direct patient reporting of ADRs
Professor Sir Alasdair Breckenridge is still there, but his position looks increasingly uncomfortable (Medicines out of Control? page 212). On 4th May, he hosted a press briefing at the MHRA/CSM to launch a report on the Yellow Card system, and to announce a major commitment to direct user reporting of adverse drug reactions. Several days later, the MHRA/CSM had still not deleted from their website evidence of their long-standing, emphatic and no doubt persisting opposition to the core idea.

Direct user reporting of ADRs was in fact outside the terms of reference of this review, and its minutes show that the subject was barely discussed: the initiative came from the Department of Health, no doubt with headlines in mind. The real purpose of the review was to recommend who should, or should not, get access to Yellow Card data (Medicines out of Control? page 208-209). Its proposals on this are unwelcome; see below.

However, the launch barely touched on questions of access to information. These were the headlines in the press reports published the following day: "Patients get the right to report drug side effects" (Guardian); "Patients to report drug side effects" (Daily Telegraph); "Patients to report drug problems" (BBC News); "Patients to Tell Watchdog of Drug Side-Effects" (The Scotsman); "Patients to play central role in drug safety UK" (Medical News Today).

On the face of it, the story is a triumph for Panorama and friends. Public pressure finally forced the MHRA to say that they would take patients’ views seriously – having refused to do so for years. The regulators failed to contain the antidepressant crisis because of it, and because they relied on evidence from Yellow Cards, which they misinterpreted time and again. (Medicines out of Control? pages 61-62, 187-194). Fallout from the antidepressant crisis, so far, has even led to the current plan to disband the CSM.

Is the MHRA to be taken seriously when it now announces that it "intends to begin pilots" for patient reporting, even as it launches a further consultation? Fifteen months ago, the National Audit Office announced that the MHRA was just about to "roll out" patient ADR reporting (Medicines out of Control? pages 151-153). All that happened was a dismal and unimaginative pilot study – patients reporting by telephone through nurses in NHS Direct - that attracted fewer user reports in a year (39) than reach this website in a week.

Perhaps the most important key to the future of user ADR reporting was to be found inside the press packs. Along with the paperwork was a mouse mat and two coasters, advertising the Yellow Card scheme and the dedication of its sponsors, along with telephone numbers and a website address. This is a new website: www.yellowcard.gov.uk. Follow the link to Patient Information and this is what you find:

"Can I report the reactions I experience using the Yellow Card Scheme? We do not accept reports directly from patients, as we believe it is vital to have your doctors or pharmacists interpretation of the suspected reaction in order for us to be able to evaluate the report fully. If you think you have suffered an adverse reaction associated with the medicine you are taking, you should speak to your doctor or pharmacist, who can report the reaction on your behalf, if appropriate."

Under its present leadership, and in its present shape, the MHRA capacity to make a success of user ADR reporting brings to mind the words ‘piss-up’ and ‘brewery’. Surely Breckenridge must go.

Restricted access to Yellow Card data
The decision to highlight user ADR reporting at the launch of the Yellow Card review may well have been influenced by the desire not to discuss new proposals for restricting access to Yellow Card data. Speakers at the launch said little about access, beyond a pointed but unspecified reference to "some well publicised occasions when misleading findings and/or ineffective communication of the results of research have caused public alarm and avoidable harm to patients who stopped taking medicines, when the research findings did not justify this."

No questions allowed, following speeches from – in ascending order of conviction – Prof. Breckenridge, Prof. Gordon Duff, Chairman of the now expiring Committee on Safety of Medicines, Dr Jeremy Metters, chairman of the Yellow Card review (Medicines out of Control? page 208-209); and Lord Warner, the Health Minister. He replaced Lord Hunt (Pages 122-126). Speeches gave way to kitsch.

This was no press briefing. The whole thing was packaged as a celebration of the 40th anniversary of the Yellow Card scheme; MHRA staff and friends outnumbered journalists by many to one. Speeches ended with very slow wheeling in - as if over road bumps - of a birthday cake as big as your desk. Long wait while they tried to find a knife, so the Minister could cut it. Stranded, he bantered solo. Relieved laughter when seriously blunt and inelegant table knife is eventually found.

The combination of tight press deadlines and all the distractions ensured that journalists missed the point. Only a close reading of the Metters review would reveal how the authorities now plan to bring the shutters down. The review made recommendations as if to protect the public from misleading interpretations of Yellow Card data; the hidden agenda was clearly to stop criticism of the regulators' own performance.

To this end, the review proposed the setting up of a scientific committee, to vet and approve not only all requests for access to data, but also all drafts intended for publication. The review team charitably proposed that "the independence of the scientific committee from the CSM/MHRA will be crucial to the credibility of the system" – but then pulled the mat from under its feet by formally recommending "that the Licensing Authority should appoint the committee." (3.10.1). As the MHRA website explains: the MHRA is the Licensing Authority for pharmaceuticals.

Hence these key recommendations:

"that requests for data … should be assessed by an independent scientific committee set up by the licensing authority to ensure that proposals for research using Yellow Cards are scientifically robust" (3.5)

"The scientific committee will also need to consider whether … the principal applicant understands the constraints on the use of the data and has the experience necessary to interpret the data appropriately" (3.7)

"The Steering Committee recommends that all researchers should be contractually required, within a defined period of time prior to publication, to notify the scientific committee, main Research Ethics Committee and MHRA of their intention and plans to put their findings in the public domain, and provide copies of their draft publication. The Steering Committee recommends the defined period should be 28 days." (3.7.2)

Later on the launch day (4 May), the MHRA posted all the paperwork on its website, along with another document in Question and Answer format. Under cover of the 40th anniversary celebrations, the MHRA had decided also to respond to criticism of its failures in regulating antidepressants. It did this by posing a number of tough questions about its own performance – before effortlessly concluding that it had performed along world-class lines.

1. So why has the Yellow Card Scheme failed to detect withdrawal reactions on SSRIs?  Read on

2. So why has the Yellow Card Scheme failed to detect suicide reactions on SSRIs?  Read on

3. Haven’t there been recent criticisms of the Yellow Card Scheme in the media, particularly with regard to the issue of SSRIs and suicidal thoughts and self-harm?

For answers to the first two questions, see also Medicines out of Control? pages 152-154 and 187-193. But what did the MHRA/CSM have to say about our criticisms of the Yellow Card scheme (Medawar & Herxheimer, 2003)?

An article recently published by Mr Charles Medawar and Dr Andrew Herxheimer - ‘A comparison of drug reaction reports from professionals and users, relating to the risk of dependence and suicidal behaviour’, expressed concerns about the miscoding of reactions reported through the Yellow Card Scheme and about proper follow up of reports. The criticisms of the coding and follow up of reports are unfounded. MHRA has robust procedures in place to ensure that reports of adverse reactions are accurately coded and where necessary, further information is obtained from the reporter.

Andrew Herxheimer and I wrote immediately to Breckenridge, asking him to produce the evidence for this sweeping dismissal of unassailable evidence of regulatory inadequacy (Medicines out of Control? pages 185-194). Two days later, the MHRA’s Roy Alder (pages 69-70) got another letter - pointing out that these questions about the evidence were a mere formality, and that a prompt apology was due. No response. Watch this space.

The MHRA consultation closes on 28 July 2004. For lack of confidence in the MHRA, Social Audit intends to comment on the consultation via this website. If you want the MHRA to take account of ideas, comments or spontaneous thoughts that you might have, you can pass them on - informally, indirectly, even anonymously (but please use a distinctive pseudonym) - through us. If you would like to respond to the MHRA consultation, "all responses are welcome and should be addressed to Amanda Lawrence, Room 14-162, MHRA etc ..." . The Metters et al report on access to Yellow Card data costs 20 and can be ordered online

Is antidepressant suicidality really an age-related effect?
The European Medicines Evaluation Agency, through the CPMP, has just published an opinion based on its own ten-month investigation of paroxetine withdrawal reactions and induced suicidal behaviour.

They have not published the evidence they relied on, nor indicated whether it’s old or new. Their opinion comes down to just a few paragraphs recommending some small-print changes in the drug warning label. The CPMP does not comment on the small print change in the paroxetine warning made in June 2003, announcing that withdrawal reactions affected 25% of paroxetine users, rather than 0.2% - as the regulators had previously believed, for a decade or more. (Medicines out of Control? pages 205-206).

Though painfully thin, the CPMP statement does include one bit of new information: "there is a possibility of an increased suicide-related behaviour in young adults". This is an advance on what the UK regulators said in December 2003: "the CSM Expert Working Group is looking carefully at the balance of risks and benefits of SSRIs in young adults."

Both the European and UK regulators seem to be taking for granted that the risk of induced suicidality is age-related – but they have yet to produce good evidence of this. They have speculated instead:

Q9. Why would SSRIs have a negative balance of risks and benefits in children and not in adults? Childhood depression is different from adult depression, partly because the brain is still developing, partly because children think differently to adults and partly because children report their experiences in a different way to adults. It has only been since the 1970 and early 1980’s that depression in childhood and adolescence has been recognised. A number of antidepressants that have been shown to be beneficial in adult depression have not been shown to work in childhood depression. Children react very differently to some medicines and some side effects are seen in children which are not seen in adults on the same medicine.

Do not trust the regulators when they suggest "not in adults" – not at least until more evidence comes though. It may not. It seems that the regulators have inferred some greater risk in younger people – not because of a greater risk, per se, but because of "a negative balance of risks and benefits" that has mainly to do with lack of efficacy. Until the authorities produce evidence of no increased risk in other age groups, their assumptions should be regarded with caution. Moreover, in the light of what is known about the increased susceptibility of older patients to adverse drug effects, it would seem scientifically and ethically improper not to investigate the SSRI benefit-harm relationship for them.

A breathtaking perspective on drug "effectiveness"
Medicines out of Control? explains how and why drug regulation, in its present shape, distorts understanding of drug benefits and harms. This happens in many ways, but the antidepressant crisis nicely illustrates the point made in the Lancet editorial on Depressing Research (24 April 2004) - that drug use "based on the selective reporting of favourable research should be unimaginable". But it appears to be the norm.

The pivotal requirement for drug approval by the US Food and Drug Administration (FDA) is evidence of superiority of active drug over placebo, from two studies of sufficient size to establish statistical (if not clinical) significance. This FDA efficacy requirement is probably the toughest in the developed world. However, so long as companies provide evidence from two such studies, the FDA discounts the results of studies which do not show evidence of drug efficacy. Only meta-analysis would reveal how weak the evidence was, but regulators rarely attempt it and secrecy prevents others from doing so.

A leading academic psychiatrist and industry consultant (Thase M, 2003) recently remarked that the manufacturers of SSRI antidepressants have now established that they need to plan for eight placebo-controlled efficacy studies in order to get positive results from two. Thase should know what he’s talking about: a professor of psychiatry at the University of Pittsburgh School of Medicine, he has grant support from Pharmacia and Wyeth; is a consultant to Bristol-Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Novartis, Organon, Pfizer, Pharmacia, and Wyeth; and on the speakers’ bureau for Bristol-Myers Squibb, Eli Lilly, Forest Pharmaceuticals, GlaxoSmithKline, Organon., Pfizer, Pharmacia, Solvay Pharmaceuticals, and Wyeth.

Imagine buying a car on this basis. It would be as if the vendor was fully within his legal rights when recommending the car you might buy as a nice little runner – because it ran at least twice out of every eight attempts to make it go.

If drugs get approved as "effective" on this basis, it does make one wonder about the benefit–harm balance of SSRIs in all age groups, and how it differs according to severity of depression. What a triumph it would be for "drug safety" and rational prescribing, if only people knew how little the regulators actually know, and how brazenly they exceed their limitations.

Charles Medawar
10 May 2004

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