Not to judge by a recent inquiry by the Commons health select committee into the influence of the pharmaceutical industry, which describes a "lack of effective discipline and regulation", a "pervasive and persistent" industry, a "failing system of pharmacovigilance" and an "extremely passive" process of drug surveillance. The MHRA is, says the inquiry report, "oblivious to the critical views of outsiders and unable to accept that it has any obvious shortcomings... [its] attitude to its public health responsibilities suggested some complacency and a lack of requisite competency".
Charles Medawar, the founder-director of Social Audit, an offshoot of Ralph Nader's Public Citizen network in the US, with the pharmacologist Dr Andrew Herxheimer, carried out "probably the only independent analysis of what yellow cards say", to see if, in the case of the antidepressant Seroxat (paroxetine), the scheme was set up adequately to respond to reports of side effects. They found that forms that might raise suspicions of "suicidality" were often classified under different headings, thus reducing their impact, leading Herxheimer to conclude the system was "chaotic and misconceived".
"Most yellow cards lacked important information," Medawar writes in his book Medicines out of Control. "Three in four said nothing about past medical history, one in four recorded the 'outcome' of the reported reaction as 'unknown'. There was no evidence of regulatory follow-up of any reports of suicidal behaviour and injury/poisoning. Descriptions and comments were often nonexistent and typically brief." For example: "Suicide by cutting his throat" (hospital). "Pt shot himself a few days after starting medication" (GP).
Medawar was way ahead of the MHRA in declaring that antidepressants such as Seroxat, known as selective serotonin reuptake inhibitors (SSRIs), were addictive. "In a paper published by the regulator in 1996," he told me, "they concluded that the risk of withdrawal symptoms was 'rare'. Then, overnight, on June 25, 2003, a small-print change was made to the data sheet for Seroxat, saying the incidence is actually 25%. For about 15 years, the regulator failed to spot a side effect affecting one in four users."
The Augean stables are now being mucked out. Under reforms outlined in November, CSM members will be barred from having any links with pharmaceutical companies. The MHRA is to set up a Commission on Safety and Efficacy of Medicines, to include more lay and patient members as well as medical experts. But the best efforts of the CSM/MHRA will be undermined if doctors fail to file yellow cards. It is estimated that reports are submitted in as few as 10% of suspected ADRs. So 20,000-odd cards filed each year suggests as many as 200,000 cases.
In his oral evidence to the Commons inquiry in December, Richard Horton, editor of The Lancet, said five-yearly reviews of every drug on the market, "looking at what the evidence is for and against, would clear out all the dross and give up-to-date evidence for prescribers".
In January the Association of the British Pharmaceutical Industry (ABPI) weighed in, with executives from GlaxoSmithKline (GSK) and AstraZeneca, calling on the government to do more to ensure that doctors report side effects from new drugs. Stuart Dallow, for GSK, told the committee the scheme ought to be re-examined. This was rich from a company that, last August, paid £1.4m to settle a lawsuit brought by New York state's attorney-general, Eliot Spitzer, who accused GSK of withholding negative clinical-trial data on Seroxat. But the industry had to try to restore confidence in its blockbuster medications, amid continuing drug catastrophes.
In November, following the withdrawal of Merck's painkiller Vioxx, suspected of causing heart disease and strokes in tens of thousands, Dr David Graham, associate director of the US Food and Drug Administration (FDA), accused his agency of laxity in monitoring drug safety. The American public was "virtually defenceless", he asserted, if another medication proved to be unsafe after it was approved for sale.
The roll call of drugs withdrawn over four decades may be evidence of a system working — or a litany of failure. "Dross" medications represent a cost not only to the individual but to an ailing NHS. How high a cost? That's anybody's guess. While the Liverpool study was impeccable as far as it went, no under-16s were included, as one of the two hospitals surveyed had no paediatric unit. "We're planning to do a study at Alder Hey children's hospital," the research team leader, Professor Munir Pirmohamed, said. "Owing to lower drug usage in children, the overall scale of the problem is going to be smaller."
Yet minors are among the most vulnerable in society, and we are medicating them more and more. Prescriptions for mind-altering drugs rose from around 400,000 in 2000 to more than 700,000 in 2002. In the 12 months to June 2003, when the regulator warned that the benefits of the SSRI Seroxat in under-18s did not outweigh the attendant risk of suicide and self-harm, an estimated 8,000 young people had been prescribed the drug. Are so many children truly clinically depressed, or is this evidence of a reckless prescribing culture? Then children are, of course, targeted for vaccinations, and the 1979 Vaccine Damage Payments Act acknowledges that these can cause damage.
An estimated 25% of drugs given on general paediatric wards, and 65% of those given on neonatal intensive-care units, are licensed only for adults. Few clinical trials are conducted with children, not only because of ethical concerns, but because the market is too small to bear the expense. Thus, many medicines are given to children with limited guidance on dosage — although a new European regulation, expected to come into force in 2007, will provide both incentives and requirements for the industry to develop medicines for children where there is therapeutic need.
Reports of ADRs have not, traditionally, been accepted directly from patients, lest, presumably, they taint the rich scientific distillate. However, the MHRA is piloting reporting from patients and their carers. We have access to the agency via their website — and, perhaps more constructively, to communities of ADR sufferers via the internet.
