UK researchers who reviewed safety conditions in international drug trials with children have called on sponsors to make sure independent safety monitoring committees are included in these trials.

The team led by Dr Helen Sammons, clinical associate professor in child health at the University of Nottingham’s Medical School, carried out a detailed analysis of 739 paediatric trials published between 1996 and 2002 to assess what safety measures were in place to monitor for adverse drug reactions.

They found that, while 74% of the papers described how safety monitoring was conducted during the study, only 2% – 13 out of 739 trials – had independent safety monitoring committees.

“We need to test drugs on children as the only other options are to use unlicensed drugs or prescribe drugs that have been licensed for adults off-label – outside the terms of their licence,” Dr Sammons commented.
“But we feel that the small number of studies that reported having safety monitoring committees was unacceptable. It is invaluable to have an independent monitor who can swiftly question any adverse drug reactions or differences in illness and death rates between groups taking part in the clinical trials.”

The researchers published their findings in the journal Acta Paediatrica. In all, 71% or 523 of the trials reported adverse events and 20% (151) of them reported a serious adverse event. These were not necessarily related to the drug used. Adverse drug reactions (ADRs) occurred in 36.5% (270) of the trials, with a moderate or severe ADR reported in 11% (80).

Six of the paediatric trials reviewed were terminated early because of significant drug toxicity, and all of these trials had safety monitoring committees. Studies reporting severe drug toxicity problems came from a wide range of countries, including Argentina, Belgium, Canada, Chile, China, France, India, Israel, Italy, Japan, the Netherlands, South Africa, Sweden, Taiwan, Thailand, Turkey, the UK and the US.

Deaths in 11% of trials
Deaths were reported in 11% (83) of the trials. In the majority of these, mortality was thought to be unrelated to the investigational drug, although in two trials mortality was higher in the treatment group.

Death rates were highest in trials involving newborn babies. The researchers looked at 99 of these studies and 56% reported a death. Other major specialities in which mortality occurred included infectious diseases, neurology, respiratory diseases and kidney problems.

The Nottingham University team only reviewed papers published in English in the Medline database during the seven-year study period. They excluded trials covering HIV and cancer because of the high death rates from these diseases.

Another reason for including independent safety monitoring committees in paediatric trials is to ensure that parents are aware of the risks involved and the mechanisms that will be used during the trial to safeguard the children taking part.

As Dr Sammons pointed out, the issue has taken on greater urgency in the European Union with the incentives to conduct clinical trials in children provided by the regulation on medicinal products for paediatric use (No. 1901/2006).

“There is general agreement by paediatric health professionals, regulatory authorities and the pharmaceutical industry, as well as politicians and parents, that drug trials are essential in order to improve drug therapies,” she said.

“We are calling for all paediatric drug trials to include independent safety monitoring committees to ensure that this vital work is carried out in a way that minimises risks, and maximises benefits, for the children taking part.”