Prescribing medicines for childrenBMJ 1999; 319 doi: https://doi.org/10.1136/bmj.319.7202.70 (Published 10 July 1999) Cite this as: BMJ 1999;319:70
Major problems exist, but there are some promising developments
- Alastair G Sutcliffe, Lecturer in child health ()
- Royal Free and University College Hospital Medical School, University College London, Royal Free Campus, London NW3 2PF
All parents would like the drugs administered to their child to have been fully evaluated using studies based in children (but not their child). However, infants and older children present a challenge for drug monitoring and testing, and there are far fewer clinical studies designed to test drugs in children than to test them in adults. The factors that limit such studies include technical constraints such as blood sampling. There are also ethical difficulties in involving children in studies that may not directly benefit them, even if the studies involve minimal risk. Fortunately, with the development of new non-invasive methods to measure drug concentrations therapeutic drug monitoring will be less limited by the necessity for blood sampling.1 Moreover, drug regulatory authorities and professional bodies are beginning to address the need to test drugs for children in the same way as those for adults.
The disposition of drugs in children varies from that in adults because children differ from adults pharmacokinetically and pharmacodynamically. Factors such as growth, surface area, organogenesis, enzyme development, plasma and tissue binding, brain development, physiological and functional development, and psychosocial issues need to inform the development of new medicines in children. Unsurprisingly, adverse drug reactions are also different. The so called “grey baby syndrome” with chloramphenicol2 might have been avoided with adequate knowledge of routes of metabolism and immature physiology, but other such deaths associated with propofol3 remain poorly understood.
Many drugs given to children in the United Kingdom are unlicensed or prescribed “off label.” The so called off label prescribing of a licensed medication to a patient outside the specification of the product licence involves medicines being administered by an unlicensed route, in an unlicensed formulation or dosage, or to a child below the stated age range. Yet without such prescribing effective treatment would be denied to many children. A recent British study found that one third of all patients admitted to a general paediatric medical or surgical ward received one or more unlicensed or off label drug during their stay.4 In the United States nearly 80% of the new drugs approved in 1984-9 had no indication for use in children.5 Some medicines given to children are not licensed for human administration at all. These so called “orphan drugs”— such as sodium benzoate, caffeine, tolazoline— are not licensed by their manufacturers because the cost involved in obtaining a licence may never be recovered.
Drug errors are a further important problem. Recent concerns about the deaths of babies who were given miscalculated doses of common drugs (morphine, digoxin) is reflected by reports in the medical literature suggesting an increase in drug errors.6 Most paediatricians have at least second hand experience of incidents in which a child's care has been compromised by medication errors. The difficulties of using medicines formulated in adult dose volumes are often compounded by complex dilutions and rate calculations (such as μmol/kg/min) being performed by tired medical staff.7 Medication errors could be reduced by the use of software programmes such as those in use in general practice,8 but such systems are seldom evident on paediatric wards. Reports emphasise the need for a systematic approach to avoid such events, including close attention to prescription writing, pharmacy dispensing, and nursing processes.9
In an attempt to improve this situation the European Agency for the Evaluation of Medicinal Products has given guidance to pharmaceutical companies on the need to conduct clinical trials in children. This states that there is a shared responsibility to ensure that children are not denied timely access to safe and effective medicines which have accurate, scientifically justified prescribing information.
In a more robust directive the Food and Drug Administration in the United States has declared that new drugs likely to be used to treat children must be tested by pharmaceutical companies for their effects in children.10 Existing drugs used off label may also be required to have their licences amended if there is substantial use in childhood.10 The National Institutes of Health have established a paediatric pharmacology unit, based in seven centres, which provides a base for clinical trial coordination by paediatric pharmacologists. A similar centre should be developed in the European Union. To encourage the development of orphan drugs, the Australian Therapeutic Goods Administration has waived its evaluation fee for orphan drugs. Orphan drug legislation in Europe is awaited.
In the United Kingdom the Royal College of Paediatrics and Child Health has produced a formulary, Medicines for Children, published last week. This formulary is divided into three sections: a therapeutics section, a drug monograph section (with information on licensed, unlicensed, and off label use of drugs), and a dietary section on borderline substances. The secondary aims of this initiative are to establish a database on the efficacy and safety of medicines given to children that can be used by those who make, test, market, prescribe, dispense, and administer medicines for children. A nation's children are its investment in the future. There must be further progress in the development and prescribing of medicines for children to ensure that children do not remain therapeutic orphans.11