Children are given drugs that have never been tested on their age group and doctors guess at dosages, as Wendy Wallace reports
Nine-year-old Lexie McConnell had recently moved from Wales to Oxfordshire when she was accidentally hit in the eye by a ball. The bright little girl, who was enjoying making new friends at her new school, was prescribed a powerful steroid as a treatment for the blurred vision she began to develop in her left eye.
After only two days, Lexie developed adverse reactions to the drug, which she had been prescribed at a high dose. The side effects ranged from facial swelling to psychotic episodes, but despite her parents' concern, doctors thought she should remain on the combination of steroids and antibiotics for three weeks. A fortnight later, Lexie went down with chickenpox; shortly afterwards, her parents watched helplessly as she died 'an excruciatingly painful death'. An inquest later gave the cause of death as misadventure, naming steroids as a contributory factor.
Lexie's father, Art McConnell, has campaigned ever since for more attention to be paid to the drugs prescribed for children. 'How many children are being injured,' asks Art McConnell, 'as a result of the drugs they are inappropriately being prescribed?'
It's a good question - although nobody is quite sure of the answer. What the McConnells, like many parents and carers, did not know before the tragedy that befell them is that currently 40 per cent of drugs used in treating children are not licensed for that purpose. An astonishing 60 per cent of drugs used on newborn babies in hospital have not been formally tested for that use.
Tried but not tested
The importance of testing drugs before putting them on the market was highlighted by the thalidomide tragedy, in which hundreds of babies were born with defects after their mothers took the drug as an antidote to morning sickness. Now, all medicines must be passed by the Medicines Control Agency.
When a new drug is developed, the extensive set of trials the licensing process demands are carried out on adults. But the market is adult-led; pharmaceutical companies do not routinely test drugs specifically for use with children.
This means that many of the medicines currently prescribed for children do not have a dosage for children approved by the Medicines Control Agency, so doctors are forced to rely on their own experience or anecdotal evidence when prescribing. 'Drug companies do very extensive testing in adults, to determine safety and dosage,' says Dr Mike Shields, a paediatrician at the Queen's University children's hospital in Belfast. 'But it's always been regarded as unethical to do that in children. Yet for doctors, it would be unethical not to treat children. So what people have ended up doing is giving them smaller doses - and seeing what happens.'
Particularly with medicines which have been on the market a long time, a substantial body of knowledge is likely to have built up among medical prac- titioners about how they work. Still, the method is hit-and-miss. 'You can get some surprises,' says Dr Shields. 'Children may handle a drug very differently to an adult. People are coming round to the view that it's unethical not to do tests.'
For example, an antibiotic called chloramphenicol was widely used in the 1980s. Although there were some concerns about its effect on adult bone marrow, it wasn't until several babies had died that it was realised that chloramphenicol was responsible for so-called 'grey baby syndrome', or heart failure in under-ones. More recently, there have been sporadic cases of adverse reactions in children to various drugs.
Recent research in Sheffield found that babies of up to one month old have significantly fewer enzymes in their gut than older children and adults. Paediatric pharmacist Trevor Johnson, who led the research, says 'this may mean they have an increased absorption of certain drugs and toxins ingested by mouth, placing them at greater risk of adverse effects'. The team looked at babies' ability to break down midasolam, a commonly used oral sedative given before operations.
Campaign for change
Action Research, a medical research charity which funded the Sheffield study, is campaigning for better regulation of the drugs used on children. The fact that children may react quite differently to drugs is highlighted by the name of their campaign for improved testing - 'Children Are Not Little Adults.' Action Research's director John Grounds says, 'The situation is an unacceptable and potentially fatal one which needs to be remedied, for the benefit of all children, parents and doctors.' The Consumers' Association is backing the campaign.
But when the Consumers' Association wrote to 80 members of the Association of the British Pharmaceutical Industry (ABPI), asking them to outline their views on carrying out clinical trials on drugs used to treat children, only eight companies replied. One of them was Merck Sharp and Dohme, a company that has recently developed a new asthma drug for children; unusually, it is fully tested for children aged two to five years.
Richard Ley, spokesman for the ABPI, denies that the industry as a whole is putting profits before safety. 'We're largely in favour of trying to do more clinical trials,' he says, 'but there are practical problems. For instance, what is a child?' He says that the drug companies have recently reached international agreement on five different stages of childhood, because what is appropriate for a pre-term baby is unlikely to meet the needs of, say, a hefty 15-year-old.
However, even if the pharmaceutical industry adopts a more rigorous approach to testing drugs for childhood use, finding families willing to enrol their children for drug trials is unlikely to be easy. 'There's no easy answer,' says Mr Ley. 'How ethical is it to carry out clinical trials on pre-term babies?' The Association funds two research posts in clinical pharmacology, one at London's Great Ormond Street Hospital for children.
Calming the fears
But some people believe ethical testing is possible. Dr Shields and colleagues in Belfast have been undertaking a study, funded by Action Research, into how babies and children break down a range of half a dozen commonly used drugs, including a pain relief medicine used after surgery. Their technique has been to secure parents' consent for using part of the blood samples that were being taken from the children for other purposes.
Dr Shields believes that while no concerned parent would want a drug tested on a healthy child - as happens in the adult research - many would agree to their child's blood samples being used for research if the child was ill and needed the drug anyway.
Campaigners for changes in the way children's drugs are tested are aware of the danger of scare mongering. 'We don't want people to get scared and suddenly withdraw drugs from their children,' says Emma Harrison of the Consumers' Association.
Politically, the tide may be turning in favour of drug testing. New legislation brought in during Bill Clinton's presidency in the United States requires American pharmaceutical companies to tests drugs for use with children, if there is any chance of them being used on them. Companies there have a financial incentive, in the form of patents, to carry out rigorous trials and make public the results.
In this country, the Consumers' Association and Action Research are lobbying the Government to introduce legislation obliging drug companies to fully test the effects on children of new drugs coming on to the market. The Government acknowledges the issue but says that guidelines need to be drawn up at a European level. The European Commission is currently drawing up advice for manufacturers, a lengthy procedure with uncertain outcomes.
'The marketing of drugs is a global industry and standards need to be agreed at international level,' says Dr Ike Iheanacho, deputy editor of the Consumer Association's Drug and Therapeutics Bulletin. 'We're very keen to promote the appropriate testing of drugs in children, but systems and attitudes are entrenched and the situation is not going to change overnight.'
Further information n For more information on the Action Research campaign, visit http://www.actionresearch.co.uk
