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Children's clinical drug trials now mandated in US

A new law in the US requiring new adult drugs to be tested for use in children could result in a three-fold increase in the number of pediatric clinical trials.

By | October 10, 2000

HOUSTON. "We have inadequate information regarding the safety and effectiveness of drugs for children. As a result, children have not been equal recipients of the great advances in medicine and drug research," observes Mark S. Schriener, MD, medical director of the Children's Clinical Research Institute, part of the Children's Hospital of Philadelphia "Currently, only about 20% of the drugs on the market are well studied in children," he said. "That will change in December 2000 when a new law goes into effect requiring that all new drugs and new formulations of existing drugs be tested for use in children." The US Food and Drug Administration rule will require any new adult drug that could be used in children with the same disease to undergo pediatric study.

On a national level, some 180 pediatric drug trials are typically running every year. On the basis of the number of drugs approved in the past five years with potential benefit for children, the FDA estimates that an additional 375 pediatric trials should be conducted annually. Thus, as of December 2000, the number of pediatric clinical trials required every year will increase three-fold.

At present, many drugs — from antibiotics to allergy relievers to painkillers — used by children have never been tested in kids to determine best dosage or how well they work. Thus pediatricians must often guess at the appropriate dosage for their young patients. However, children are not scaled-down versions of adults. Many of their physiological processes work differently and thus they respond to many drugs differently than adults according to Gregory Kearns, MD, chief of pediatric pharmacology at Children's Mercy Hospital in Kansas City, Missouri. This facility is one of the few specialising in children's medicines.

Kearns notes that the effect of age on drug response is complex. A tragic example from the 1960s illustrates this. Several newborn babies died because doctors didn't know their immature livers couldn't process the adult antibiotic chloramphenicol. In contrast, some of today's antibiotics require a 50% greater dose for a 1-year-old than for a teenager, because the baby's body eliminates antibiotics more rapidly.

Despite such problems, for many years drug manufacturers have had little incentive to study children because US doctors legally can prescribe adult products to youngsters. Since Congress passed the 1997 Better Pharmaceuticals for Children Act, more than 300 pediatric drug studies of 127 products have been initiated, compared with only 11 in the previous five years. This law granted drug makers an additional six months of patent protection if they voluntarily performed pediatric clinical trials to test existing drugs that could be prescribed to children.

This incentive could disappear for existing drugs if presidential candidate Al Gore is elected and fulfils his pledge that, as president, he would oppose extensions of drug company patents. The incentive could also lapse if Congress allows the Act to expire in 2002 as currently scheduled. The FDA rule going into effect in December 2000 requires pediatric trials only of any new adult drug that could be used in children with the same disease.

The anticipated three-fold increase in pediatric clinical drug trials means many more children will be participating in such trials. The FDA expects more than 18,000 youngsters to participate in the next few years. The FDA already has requested 129 new clinical trials. How will those managing pediatric clinical trials locate suitable juvenile subjects? Kathryn Edwards, MD, professor of pediatrics at Vanderbilt University Medical Center, Nashville, Tennessee has noted that the co-operation of pediatricians is critical in recruiting child drug trial participants. Newspaper articles about impending pediatric clinical trials often persuade parents to step forward to learn more and possibly have their child participate. Some researchers are offering enticements such as Toys 'R Us gift certificates to persuade parents to sign up their children for clinical trial.

These trials also raise some important ethical issues, according to FDA pediatrics chief Dianne Murphy, MD. For example, some studies subject children to possible drug side-effects in the hope of helping future patients. Consider a group of otherwise healthy children with allergies participating in a study to determine appropriate child dosage of an adult antihistamine. During the trial they would have blood samples taken periodically after swallowing the drug to determine appropriate dosage and could be subject to unpleasant drug side effects.

Parents must make decisions as trustees for their children because children are not legally or developmentally able to make those decisions themselves. "Pediatricians should become involved in this decision-making process," urges Dr. Schreiner. "They should scientifically review the study and in their own minds come to a decision about its value for their patients."

A difficult problem for many parents is that longer trials involving sick children sometimes have a group of patients taking only a placebo. The children receiving only a placebo could become sicker. Also, taking a drug while adjusting the quantity consumed to determine the appropriate dosage could be dangerous to the children particularly babies and pre-schoolers.

So how should parents decide whether to enrol their child in a clinical study? They should be sure they fully understand the study. Dr Kearns notes that he spends as much as an hour discussing a clinical trial with parents before showing them a consent form. He recommends that the consent form should explain risks in laymen's terms. Parents should understand who is running the study. University-based studies, particularly those at pediatric speciality centres, often receive more careful monitoring. At least one of the senior investigators should have pediatric expertise. Adult doctors can miss subtle signs of side-effects in children such as playing less or eating less.

Parents should be sure doctors and nurses will minimise factors that could cause fear and pain such as severe institutional surroundings, blood tests and other injections. For example, children with juvenile arthritis can experience severe pain during drug injections. Children may cry and come to fear and resist their periodic injections. Simply rubbing an anaesthetic cream onto the child's skin may deaden the pain.

These various difficulties can be overcome, however, and pediatric drug trials hold the promise of improving youngsters' health and happiness.

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