Far Few Drugs Are Tested On Children

February 17, 1999

Forty years ago, dozens of children in the US died of a condition known as grey baby syndrome after taking a new antibiotic. The drug, chloramphenicol, had been used to treat blood infections in adults, but had never been tested on children. Doctors did not realise until too late that children's immature livers were incapable of clearing it from their bodies, and toxic levels quickly built up in their bloodstream.

Astonishingly, children still face similar risks today. The vast majority of drugs have never been tested on children, forcing doctors to prescribe them "off label"-outside the conditions for which they were licensed. They have to gamble on a child being able to cope with the dosage they prescribe. This also means that liability for the outcome rests with them or their health authority, rather than the drugs company.

"Every paediatrician and GP caring for children faces this problem on a daily basis," says Vas Novelli, a consultant in paediatric infectious diseases at Great Ormond Street Hospital in London. "Each is expected to weigh up the pros and cons of using an unlicensed medication, knowing full well that they are taking on the responsibility themselves for any major problems that may occur."

"Recent advances in biomedical research have not been translated into advances in child health," says Tim Westmoreland, a Washington lobbyist working with the Elizabeth Glaser Pediatric Aids Foundation in Santa Monica. "For years, doctors and parents have been put in the untenable position of [either] ignoring drugs that are effective in adults or exposing children to drugs of unknown safety."

In 1997 in Britain, a House of Commons health committee on the needs of young people expressed astonishment at this situation. Since then, however, nothing has been done to remedy it. "The present lack of resources and capacity of the workforce to improve knowledge and practice of paediatric drugs is nothing short of a national disgrace," says Al Aynsley-Green, the director of clinical research and development at Great Ormond Street.

In the US, an estimated 80 per cent of prescription drugs are not licensed for use in children, according to a 1996 report in Pediatrics (vol 98, p 18). And the National Institute of Child Health and Human Development in Bethesda, Maryland, estimates that only 5 of the 80 drugs most frequently used in infants are licensed for paediatric use. However, the situation is set to change with the Food and Drug Administration's 1997 Modernisation Act, which comes into force on 1 April this year. The act will force drugs companies to provide the FDA with information on the paediatric use of any medicine that may offer children better treatment than existing therapies, or will be widely used by children.

Life-threatening

The legislation is long overdue, and doctors in Europe are hoping it will encourage similar action there. On both sides of the Atlantic, there has been a string of tragedies resulting from giving children pharmaceuticals that have not been tested on them. In the 1980s, a drug called verapamil was widely used for the treatment of certain heart conditions in children. The drug was approved by the FDA after safety and efficacy tests in adults only. Between 1983 and 1987, reports emerged of life-threatening adverse reactions, including heart attacks, that required resuscitation. The drug is no longer recommended for use in children.

More recently, adverse effects have been reported in children taking cisapride, which helps gut contractions and is given every year to thousands of young children who regurgitate their food. Some children who were given unsuitably high doses suffered dangerous heart problems. The manufacturer now plans to test the drug in children.

"In many cases, we have no real idea of the side effects different drugs produce in children," says Richard Cooke, director of the research unit at the Royal College of Paediatrics and Child Health in London. "If randomised control trials have not been performed, it is impossible to tell whether symptoms are part of the patient's condition or an effect of the drug."

If a drug is not licensed for children, a doctor will often estimate a suitable dose by extrapolating according to body weight from the recommended adult dose. But children are not simply miniature adults-they react to chemicals quite differently. For a start, the way the kidney excretes substances changes in the first few years after birth, with different mechanisms maturing at different times. Because of this, the proportion of a drug that stays in the bloodstream depends on the age of a child.

The same applies to the liver, where enzyme systems that detoxify drugs mature at different times. Thus the ability of the body to break down drugs also varies with age. In addition, the proportion of water in the body changes dramatically during the first two years of life, which affects the concentration of a drug. Finally, children's ability to respond to a drug may be different. "The organ upon which it is supposed to work may be immature," says Robert Ward, a paediatric pharmacologist at the University of Utah in Salt Lake City.

Market forces

There are two main reasons why pharmaceuticals companies are reluctant to test their drugs on children. First, there is not much money to be made. Children consume small quantities of drugs and are a small proportion of the market. Secondly, parents are generally reluctant to allow their children to take part in clinical trials. For example, this month the Public Health Laboratory Service in Britain announced that trials of a new children's meningitis vaccine had been delayed for up to a year because only half the 2000 volunteers needed had been recruited. In particular, they lacked recruits aged three to four.

But in the US, drugs companies will soon have an incentive to overcome these difficulties. As part of the new Act, for 493 drugs that the FDA considers a priority, companies will be granted a six-month extension of their patents, in exchange for comprehensive paediatric data. This could be lucrative: a 1993 report estimated that for an average drugs company, each year of exclusivity is worth $100 million.

However, this deal will not help with drugs whose patents have expired and that can now be produced by any company. Without market exclusivity, there would be no financial incentive for the original patent holders to do trials in children.

Despite the lack of legislation in Britain, there is momentum for change. The Royal College of Paediatrics and Child Health is producing Medicines for Children, the first formulary with data on drugs prescribed for children. The dossier, due to be published in the spring, will provide information on how drugs should be used and their common complications.

And last August, Aynsley-Green and four colleagues set up the British Forum for Use of Medicine in Childhood. Their aim is to improve research, development and training in paediatric pharmacology, and to make sure doctors get the information they need. Such action is desperately needed to prevent children being treated as what Harry Shirkey, former chairman of paediatrics at the Children's Hospital in Birmingham, Alabama, described 30 years ago as "pharmaceutical orphans".
-end-
Author: Janet Fricker
New Scientist magazine issue 20th Feb 99

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