Prescription safeguards failing children
Alarms are ringing over the lack of safety data for drugs prescribed for children. Health editor Adam Cresswell reports
MOST people assume that drugs used in children are studied more carefully for potentially dangerous side effects than those available for adults. But they are wrong. Far from being subject to more scrutiny, the use of prescription drugs in children remains a glaring blind spot in health systems across the world.
The uncomfortable truth is that, for the vast majority of drugs used in children, there is very little proper scientific data to reassure doctors about the drugs’ safety and side effects, how well they work — if at all — or what dosages are best.
Without this data, many drugs are not officially approved for use in children, and the manufacturers publish no guidelines for doctors in how they should be used in younger age groups. Doctors can still prescribe drugs for other groups not covered by the original licence, such as children, a practice known as ‘‘ off-label’’ prescribing.
Such use may be appropriate in some circumstances, but it leaves children exposed to potentially ineffective or unsafe medicines. Doctors prescribing off-label are effectively left to infer from adult trials and their own experience what dosages will work best.
Recent data shows that from 2002 to 2004 there were 820 suspected serious adverse drug reactions reported spontaneously to the European Agency for the Evaluation of Medicinal Products — 130 of which were fatal, and 361 of which caused prolonged hospitalisation.
A separate Swedish study of adverse drug reaction reports related to children found 158 cases, of which 42.4 per cent were linked to off-label prescribing.
Drugs for behavioural and psychiatric disorders, and newer antibiotics and analgesics are all examples of drugs that are both frequently prescribed for children, and for which there is poor evidence for their safety and efficacy.
Studies suggest that up to 92 per cent of hospitalised children are prescribed at least one drug off-label during their stay, and up to 97 per cent of newborn babies. And with the world’s top health body about to step in, paediatricians and ethical experts are now saying enough’s enough.
‘‘ A lot of paediatricians have become concerned in recent years that the data isn’t there to reassure them that these prescribing practices are safe,’’ says doctor Robert Loblay, chairman of the ethics review committee for Sydney South-West Area Health Service.
‘‘ There’s been a growing call . . . for pharmaceutical companies to do the necessary studies to assure them that these drugs are safe and effective (in children).
‘‘ The pharmaceutical companies don’t have a lot of incentive to do that, unless it’s a big slice of their market. It’s a very expensive thing to run clinical trials.’’
Loblay warned experts attending the na- tional ethics conference of the National Health and Medical Research Council, held in Melbourne in October, that doctors were ‘‘ treading on very thin ice’’ by continuing to prescribe drugs to children when the clinical trials conducted to test the safety of those drugs had not included children.
In answer to a question, Loblay told the conference that hospital ethics review committees should be more vigilant for the possibility that drugs might have a use in patients under 18.
In such cases, he said ethics committees ought to ask researchers seeking permission to conduct trials if children were included in the study population — and if not, why not.
‘‘ The answer may be ‘ we are (including children), but not at this hospital’,’’ Loblay told WeekendHealth . ‘‘ That’s fine — but we need to be asking the question.’’
In London next week the WHO is expected to launch a list of medicines approved for use in children, to help guide doctors about which medicines are safe and effective in children.
In the meantime, experts here are pushing for regulatory bodies such as the Therapeutic Goods Administration, NHMRC and drug manufacturers to address the problem.
Dr Madlen Gazarian, a paediatric clinical pharmacologist, has been warning of the dangers caused by inadequate data in paediatric prescribing for several years. The chairwoman of the paediatric portfolio of the therapeutics committee of the Royal Australasian College of Physicians, Gazarian in 2003 wrote an editorial for the professional journal Australian Prescriber (2003;26(6):122-3) reporting that adverse reactions were more common when drugs were prescribed off-label. While many children had undoubtedly benefited from drug treatment, data on benefits was poor and it was also true that in a few cases
‘ ‘‘ some children have died as a result’’ of offlabel prescribing.
‘‘ Widespread off-label prescribing really is a major issue — it’s been around for yonks, but seems now to have grabbed enough people’s attention for something to be done about it,’’ Gazarian told Weekend Health .
Loblay says although doctors currently have little option but to prescribe drugs for children off-label, the fact that they do so removes the incentive for drug companies to do further studies. The problem is compounded by the fact that adverse reactions are less likely to be reported when the drug was prescribed off- label, so there is not even good data to show which drugs are causing most adverse reactions in kids.
There is also a financial angle, in that drugs do not attract a subsidy under the Pharmaceutical Benefits Scheme when prescribed outside the terms of their licence, so parents also end up out of pocket.
Loblay likens the situation to a similar research gap that existed for women as late as the 1990s.
‘‘ Fifteen to 20 years ago . . . most clinical trials did not include women of childbearing age, because they were worried women might be pregnant (without realising it) and the drug might affect the developing baby,’’ Loblay says. ‘‘ So it was standard practice to exclude women from most clinical trials. But then people started to realise that we are prescribing these drugs for women, but there’s no data to say it’s safe. The (US) Food and Drug Administration was the first regulatory body to say, and the TGA followed, that to get a drug registered companies had to include women as well as men. So they all started doing it; now it’s standard to do pregnancy tests on women of childbearing age (when they are enrolled in trials).’’
Loblay, Gazarian and others agree that what’s needed to tackle the evidence gap for children is better research — either by giving bodies such as the TGA the power to order drug companies to include children in trials, or to allocate public funds to run trials directly — as in the US and European Union.
Loblay concedes that including children in trials is not as straightforward as including women, due to ethics and safety issues. But Gazarian says suggestions these are a major hurdle are overblown, and points to the alacrity with which drug giants in the US rushed to take up financial incentives offered by the FDA to run children-specific trials.
‘‘ Whenever you remove a financial barrier or create a financial incentive (for drug companies), lo and behold, the research seems able to be done,’’ she says.
‘‘ But it’s tended to happen with more profitable drugs with a larger market. It’s becoming clear that the (US) incentives are not going to ensure that all the needed research will be done.’’
Earlier this year Gazarian wrote a discussion paper for the World Health Organisation on the question of off-label prescribing in children. While her paper said the practice not illegal, ‘‘ and may sometimes be appropriate’’, it was ‘‘ associated with important clinical and ethical concerns’’.
The paper added that off-label prescribing ‘‘ does bypass the safeguards of the drug regulatory process and places a greater onus of responsibility on the individual prescriber to assess the benefits and risks of such use for an individual patient.
‘‘ While this may be acceptable
Warning signals: Doctor Robert Loblay says the medical profession is becoming increasingly concerned about off-label’ prescriptions for children